5 Physiology

Neurochemical Synaptic LAST UPDATED: 25TH
FEBRUARY 2019
Transmission  Bookmark
PHYSIOLOGY / BASIC CELLULAR / ACTION POTENTIAL
Action potentials in incoming neurons are transmitted by the release of

neurotransmitters that bind to receptors on the postganglionic neuron or e!ector
tissue. Between neurons (e.g. in ganglia), this occurs within the synapse, where the
axon terminates in a bouton separated from the target by a synaptic cleft.
The neurotransmitter is synthesised and stored in vesicles in the terminal bouton of

the preganglionic neuron. The arrival of an action potential at the nerve ending
causes opening of voltage-gated Ca2+ channels in the presynaptic membrane, and a
subsequent influx of Ca2+, which causes the neurotransmitter-containing vesicle to

fuse with the presynaptic membrane and release its contents into the synaptic cleft.
The neurotransmitter then di!uses across the synaptic cleft to bind with receptors
on the postsynaptic membrane of the dendrite and activate the response.
Neurotransmitter release can be suppressed by feedback onto presynaptic inhibitory
receptors.
After activation at the postsynaptic membrane, neurotransmitters must be removed

from the synaptic cleft. In cholinergic synapses, cholinesterase rapidly breaks down
acetylcholine into choline and acetate which are then recycled. In adrenergic
synapses, most noradrenaline is taken up by the nerve ending and recycled. Excess
noradrenaline and sympathomimetic amines such as tyramine are metabolised in the
neuron by mitochondrial monoamine oxidase (MAO).
Noradrenaline and other catecholamines in the circulation are metabolised

sequentially by catechol-O-methyltransferase (COMT) and MAO.
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Propagation of Action LAST UPDATED: 25TH
FEBRUARY 2019
Potentials  Bookmark
PHYSIOLOGY / BASIC CELLULAR / ACTION POTENTIAL
An action potential is a self-propagating response, successive depolarisation moving

along each segment of an unmyelinated nerve until it reaches the end. It is all-or-
nothing and does not decrease in size.
Conduction in myelinated fibres is much faster, up to 50 times that of the fastest

unmyelinated nerve. Myelinated fibres are insulated except at areas devoid of myelin
called nodes of Ranvier. The depolarisation jumps from one node of Ranvier to
another by a process called saltatory conduction.
Saltatory conduction not only increases the velocity of impulse transmission but also
conserves energy for the axon because depolarisation only occurs at the nodes and
not along the whole length of the nerve fibre.
Larger diameter myelinated nerve fibres conduct nerve impulses faster than small
unmyelinated nerve fibres.
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Resting Membrane LAST UPDATED:
30TH AUGUST
Potential 2019
PHYSIOLOGY / BASIC CELLULAR /  Bookmark

ACTION POTENTIAL
Electrical events in biological tissues are caused by the

movement of ions across the membrane.
A membrane potential is a property of all cell membranes, but

the ability to generate an action potential is only a property of
excitable tissues.
The value of the membrane potential depends on the relative

membrane permeability to the ions in the extracellular fluid
(mainly Na+ and Cl-) and the intracellular fluid (mainly K+). In
most neurons the resting potential has a value of approximately
-70 mV. A cardiac myocyte has a resting potential of about -90
mV.
The resting membrane is more permeable to K+ and Cl- than to

other ions. The cell contains negatively charged molecules (e.g.
proteins) which cannot cross the membrane. This fixed negative
charge attracts K+, leading to accumulation of K+ within the
cell. However, the consequent increase in the K+ concentration
gradient drives K+ back out of the cell. This means fewer K+ ions
move into the cell than are required to achieve electrical
neutrality with the fixed negative charges and the inside of the
cell therefore remains negatively charged compared to the
outside, causing a potential di!erence across the membrane.
These fixed anions also attract Na+ and the electrochemical
gradient for Na+ is strongly inwards, however the
resting membrane is relatively impermeable to Na+ and only a
small amount of Na+ can leak in. A consequence of this setup is
that if Na+ permeability were suddenly increased to more than

that of K+, the membrane potential will depolarise; this is the
basis of the action potential.
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Autonomic Nervous System LAST UPDATED: 30TH
AUGUST 2019
PHYSIOLOGY / BASIC CELLULAR /
AUTONOMIC NERVOUS SYSTEM  Bookmark
The autonomic nervous system mediates homeostatic reflexes, allows the integration
and modulation of function by central mechanisms in the brain in response to
external and internal stimuli, and provides the e!erent arm for the involuntary control
of most organs. It is divided into the sympathetic and the parasympathetic nervous
systems which work in concert, but often antagonistically. Both contain preganglionic
neurons originating in the central nervous system that synapse with non-myelinated
postganglionic neurons in peripheral ganglia; postganglionic neurons innervate the
target organ or tissue.
Preganglionic Neurons
Sympathetic preganglionic neurons originate in the lateral horn of segments

T1 - L2 of the spinal cord and exit the cord via the ventral horn on their way to the
paravertebral or prevertebral ganglia.
Parasympathetic preganglionic neurons originate in the brainstem from which

they run in cranial nerves III, VII, IX and X and also from the second and third
sacral segments of the spinal cord.
Both sympathetic and parasympathetic preganglionic neurons release acetylcholine

into the synapse, which acts on cholinergic nicotinic receptors on the
postganglionic fibre. The postganglionic neurotransmitters and receptors depend on
the system and organ.
Postganglionic Neurons
Parasympathetic peripheral ganglia are generally found close to or within their target,
whereas sympathetic peripheral ganglia are located largely in two sympathetic chains
on either side of the vertebral column (paravertebral ganglia), or in di!use
prevertebral ganglia of the visceral plexuses of the abdomen and pelvis. An exception
is the sympathetic innervation of the adrenal gland, where sympathetic preganglionic
fibres directly innervate the adrenal medulla.
Sympathetic postganglionic neurons terminate in the e!ector organs where they

release the catecholamine noradrenaline (norepinephrine)
(norepinephrine), which acts on alpha
and beta adrenergic receptors which are linked via G-proteins to cellular e!ector
mechanisms. A few sympathetic neurons release acetylcholine at the e!ector (e.g.
sweat glands) and are thus known as sympathetic cholinergic neurons.
Parasympathetic postganglionic neurons release acetylcholine

acetylcholine, which acts on
cholinergic muscarinic receptors
receptors.
Principle E!ects
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Generation of Action LAST UPDATED: 11TH
APRIL 2019
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AUTONOMIC NERVOUS SYSTEM
Once triggered an action potential will travel over the entire surface of an excitable
cell and will always have the same amplitude. An action potential is an all or nothing
response; because the size of the action potential is constant, the intensity of the
stimulus is coded by the frequency of firing of a neuron.
Threshold Potential
Action potentials are initiated in nerves by activation of ligand-gated Na+ channels by
neurotransmitters. Opening of these Na+ channels results in a small influx of sodium

and depolarisation of the negative resting membrane potential (-70 mV).
If the stimulus is su!ciently strong, the resting membrane depolarises enough to

reach threshold potential (generally around -55 mV), at which point an action
potential can occur.
Depolarisation
Voltage-gated Na+ channels open, causing further depolarisation and activating more
voltage-gated Na+ channels and there is a sudden and massive sodium influx, driving
the cell membrane potential to about +40 mV.
Repolarisation
The spike of the action potential is transient because as the membrane potential
becomes positive, the voltage-gated Na+ channels inactivate preventing further

sodium influx.
Voltage-gated K+ channels are also activated, causing the K+ permeability to again be
much greater than that for Na+, and the potassium e#ux leads to repolarisation.
Delayed closure of these rectifier K+ channels causes a transient hyperpolarisation.

Refractory Period
Following the action potential, Na+ channels remain inactive for a time in a period
known as the absolute refractory period where they cannot be opened by any amount
of depolarisation.
Following this there is a relative refractory period where the temporary

hyperpolarisation makes the cell more di!cult to depolarise and an action potential
can be generated only in response to a larger than normal stimulus.
The refractory period limits the frequency at which action potentials can be
generated, and ensures that, once initiated, an action potential can travel only in one
direction.
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Coagulation Cascade - MRCEM Success 28/03/2023, 12:35 PM
Coagulation Cascade LAST UPDATED: 11TH

APRIL 2022
BLOOD AND BLOOD FLOW  Bookmark
Blood coagulation involves a biological amplification system in which a few initiation

substances sequentially activate by proteolysis a cascade of circulating precursor
proteins (the coagulation factor enzymes) which culminates in the generation of
thrombin; this, in turn, coverts soluble plasma fibrinogen into fibrin. Fibrin enmeshes
the platelet aggregates at the sites of vascular injury and converts the unstable
primary platelet plug into a firm, definitive and stable haemostatic plug.
The generation of thrombin is a complex network of amplification and negative

feedback loops to ensure a localised and limited production. Generation of thrombin is
dependent on three enzyme complexes, each consisting of protease, cofactor,
phospholipids and calcium. The operation of this enzyme cascade requires local
concentration of circulating coagulation factors at the site of injury. Surface-
mediated reactions occur on exposed collagen, platelet phospholipid and tissue
factor.
Initiation
Coagulation is initiated after vascular injury by the interaction of the membrane

bound tissue factor (TF, factor III), exposed and activated by vascular injury, with
plasma factor VII. The factor VIIa-tissue factor (extrinsic factor Xase) complex
activates both factor IX and factor X. The factor Xa, in the absence of its cofactor,
forms small amounts of thrombin from prothrombin. This is insu!cient to initiate
significant fibrin polymerisation; amplification is needed. The initiation pathway is
rapidly inactivated by tissue factor pathway inhibitor (TFPI).
Amplification
The amplification phase takes place on the surface of platelets. The small amount of
thrombin generated during the initiation phase activates nearby platelets and also
cofactor V on their surface. Cofactor VIII is normally bound to plasma von Willlebrand
factor (VWF), which protects it from degradation. Thrombin cleaves factor VIII from
VWF and activates it, when it also binds to the platelet surface. The end product is a
large number of activated platelets covered with active cofactors.
https://mrcemsuccess.com/explanation/coagulation-cascade/?_sft_qc=physiology&sf_paged=4 Page 2 of 4
Coagulation Cascade - MRCEM Success 28/03/2023, 12:35 PM
Propagation
Thrombin activates a short cascade that leads to activation of factor IX (also

activated by the extrinsic factor Xase). The intrinsic Xase, formed by IXa and VIIIa on
phospholipid surface in the presence of Ca2+, activates su!cient Xa. Factor Xa, in
combination with Va, phospholipid and Ca2+, forms the prothrombinase complex and
results in the explosive generation of thrombin. Thrombin hydrolyses fibrinogen to
form fibrin monomers which link spontaneously to form a loose insoluble fibrin
polymer. Factor XIII is also activated by thrombin and stabilises the fibrin monomers
with the formation of covalent bond cross-links.
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Haemoglobin LAST UPDATED: 24TH
APRIL 2019

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BLOOD AND BLOOD FLOW
Red blood cells contain the specialised protein haemoglobin which is responsible for
carrying oxygen and carbon dioxide in the blood. Haemoglobin is composed of four
polypeptide globin chains each with its own iron containing haem molecule.
Haemoglobin Synthesis
Haemoglobin synthesis occurs in immature red blood cells. Haem synthesis occurs
largely in the mitochondria by a series of biochemical reactions commencing with the
condensation of glycine and succinyl coenzyme A under the action of the key rate-
limiting enzyme delta-aminolevulinic acid (ALA) synthase; ultimately protoporphyrin
combines with iron in the ferrous (Fe2+) state to form haem. The globin chains are
synthesised by ribosomes in the cytosol.
Haemoglobin Degradation
Red cells are destroyed by macrophages in the liver and spleen after ~ 120 days. The
haem group is split from the haemoglobin and converted to biliverdin and then
bilirubin. The iron is conserved and recycled to plasma via transferrin or stored in
macrophages as ferritin and haemosiderin. An increased rate of haemoglobin
breakdown results in excess bilirubin and jaundice.
Types of Haemoglobin
There are three types of haemoglobin in normal adult blood: haemoglobin A, A2 and F.
Normal adult haemoglobin (HbA) makes up about 96 - 98 % of total adult

haemoglobin, and consists of two alpha (α) and two beta (β) globin chains.
Haemoglobin A2 (HbA2), a normal variant of adult haemoglobin, makes up
about 1.5 - 3.5 % of total adult haemoglobin and consists of two α and two delta
(δ) globin chains.
Foetal haemoglobin (HbF) makes up about 0.5 - 0.8 % of total adult
haemoglobin and consists of two α and two gamma (γ) globin chains.
Hb Structure Normal adult %
HbA α2β2 96 - 98%
HbA2 α2δ2 1.5 - 3.5%
HbF α2γ2 0.5-0.8%
Foetal haemoglobin is the main Hb in the later two-thirds of foetal life and in the
newborn until approximately 12 weeks of age. Foetal haemoglobin has a higher a"nity
for oxygen than adult haemoglobin.
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Haemopoiesis LAST UPDATED: 15TH
JULY 2019

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Haemopoiesis Sites
Haemopoiesis in the foetus occurs firstly in the yolk sac, and later in the liver and
spleen, which are the major haemopoietic organs from about 6 weeks until 6 - 7
months gestation, at which point the bone marrow becomes the most important
site. In normal childhood and adult life, haemopoiesis is restricted to the bone
marrow.
Haemopoietic Stem Cells
All blood cells develop from haemopoietic stem cells (HSCs). Haemopoiesis occurs
when HSCs bind, via cell surface receptors, to adhesion molecules and to fixed or
secreted cytokines and growth factors. This binding triggers a cascade of
phosphorylation reactions which transmits a signal to the nucleus to upregulate gene
transcription. This signal promotes haemopoiesis by activating pathways that lead to
cell proliferation, di"erentiation, maturation, inhibition of apoptosis (programmed cell
death) or activation of mature cells.
HSCs give rise to two major lineages, the lymphoid lineage in which a common
lymphoid progenitor gives rise to B-cells, T-cells and natural killer (NK) cells, and a
myeloid lineage in which a common myeloid progenitor gives rise to erythrocytes,
platelets, granulocytes and monocytes.
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Haemostasis LAST UPDATED: 25TH
JUNE 2019

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Vasoconstriction
Immediate vasoconstriction of the injured vessel and reflex constriction of adjacent

small arteries and arterioles is responsible for an initial slowing of blood flow to the
area of injury. Where there is widespread damage, this vascular reaction prevents
exsanguination. The reduced blood flow allows contact activation of platelets and
coagulation factors.
Platelet Reactions and Primary Haemostatic Plug Formation
Following a break in the endothelial lining, there is an initial adherence of platelets (via
GPIa and GPIb receptors) to exposed connective tissue, mediated by von Willebrand
factor (VWF). Under conditions of high shear stress (e.g. arterioles), the exposed
subendothelial matrix is initially coated with VWF. Collagen exposure and thrombin
generated through activation of tissue factor produced at the site of injury cause the
adherent platelets to release their granule contents and also activate platelet
prostaglandin synthesis, leading to the formation of thromboxane A2 (TXA2).
Released ADP causes platelets to swell and aggregate; TXA2 and serotonin (5-HT)
also enhance the vasoconstriction.
Platelet rolling in the direction of blood flow over exposed VWF with activation of
GPIIb/IIIa receptors results in firmer binding. Additional platelets from the circulating
blood are drawn to the area of injury. This continuing platelet aggregation promotes
the growth of the haemostatic plug which soon covers the exposed connective
tissue. The unstable primary haemostatic plug produced by these platelet reactions in
the first minute or so following injury is usually su!cient to provide temporary control
of bleeding. The highly localised enhancement of platelet activation by ADP and TXA2
results in a platelet mass large enough to plug the area of endothelial injury.
Stabilisation of the Platelet Plug by Fibrin
Definitive haemostasis is achieved when fibrin, formed by blood coagulation, is added

to the platelet mass and by platelet-induced clot retraction. Vascular injury results in
to the platelet mass and by platelet-induced clot retraction. Vascular injury results in
the initiation and amplification of the coagulation cascade. Platelet aggregation and
release reactions accelerate the coagulation cascade by providing abundant
membrane phospholipid. The thrombin generated by the coagulation cascade
converts soluble plasma fibrinogen into fibrin monomers, potentiates platelet

aggregation and secretion and also activates factor XI and XIII and cofactors V and
VIII. The fibrin monomers spontaneously polymerise to a fibrous mesh of fibrin,
entrapping the platelets and other blood cells. The fibrin polymer is finally cross-linked
by factor XIIIa to create a tough network of fibrin fibres, and a stable clot. Clot
retraction occurs, mediated by GPIIb/IIIa receptors which link the cytoplasmic actin
filaments to surface-bound fibrin polymers, making it tougher and assisting repair by
drawing the edges of the wound together.
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Physiological Limitation of Blood Coagulation

Physiological Limitation of Blood Coagulation
Unchecked, blood coagulation would lead to thrombosis, of the protective

mechanisms of coagulation inhibitors, blood flow and fibrinolysis were not in
operation.
Coagulation Factor Inhibitors:
It is important that the e#ect of thrombin is limited to the site of the injury. The first
inhibitor to act is tissue factor pathway inhibitor (TFPI), which is synthesised in
endothelial cells and is present in plasma and platelets, and accumulates at the site of
injury caused by local platelet activation. TFPI inhibits Xa and VIIa and tissue factor.
There is also direct inactivation of thrombin and other protease factors by other
circulating inhibitors, of which antithrombin is the most potent. Heparin potentiates
its action markedly.
Protein C and Protein S:
Protein C and protein S are inhibitors of coagulation cofactors V and VIII.

Thrombomodulin on endothelial cells binds thrombin and converts it so it no longer
cleaves fibrinogen but instead activates protein C, which is able to destroy activated
factors V and VIII, thus preventing further thrombin formation. The action of protein C
is enhanced by protein S, which binds protein C to the platelet surface. Activated
protein C also enhances fibrinolysis by destroying plasma inhibitors of tissue
plasminogen activator (tPA).
Blood Flow:
At the periphery of a damaged area of tissue, blood flow rapidly achieves dilution and
dispersal of activated factors before fibrin formation has occurred. Undamaged
endothelium produces prostacyclin and nitric oxide which impede platelet adhesion
and activation.
Fibrinolysis:
Fibrinolysis is a normal haemostatic response to vascular injury. Plasminogen, a

proenzyme in blood and tissue fluid, is converted to plasmin by activators either from
the vessel wall (intrinsic activation) or from the tissues (extrinsic activation). The most
important route follows the release of tissue plasminogen activator (TPA) from
endothelial cells.
TPA binds to fibrin which enhances its capacity to convert thrombus-bound

plasminogen into plasmin. This fibrin dependence of TPA action strongly localises
plasminogen into plasmin. This fibrin dependence of TPA action strongly localises
plasmin generation by TPA to the fibrin clot. Release of TPA occurs after such stimuli
as trauma, exercise or emotional stress. Plasmin generation at the site of injury limits
the extent of the evolving thrombus. The split products of fibrinolysis are also
competitive inhibitors of thrombin and fibrin polymerisation.
Plasmin is capable of digesting fibrinogen, fibrin, factors V and VIII and many other
proteins. Plasmin itself is inactivated by alpha2-antiplasmin. Cleavage of peptide
bonds in fibrin and fibrinogen produces a variety of fibrin degradation products
(FDPs). The D-dimer is a measurement of FDPs and is thus an indication of sequential
thrombin and then plasmin activity. D-dimer may be raised in infection, malignancy
and pregnancy, as well as venous thromboembolism. Levels are very high in patients
with DIC.
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Platelets LAST UPDATED: 11TH
APRIL 2022

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The normal haemostatic response to vascular damage depends on a closely linked

interaction between the blood vessel wall, circulating platelets and blood coagulation
factors.
Platelet Production
Platelets are produced in the bone marrow by fragmentation of the cytoplasm of

megakaryocytes, derived from the common myeloid progenitor cell. The time interval
from di!erentiation of the human stem cell to the production of platelets averages 10
days.
Thrombopoietin is the major regulator of platelet formation and 95% of this is

produced by the liver.
The normal platelet count is approximately 150 - 450 x 109/L and the normal platelet
lifespan is 10 days. Under normal circumstances, about one-third of the marrow
output of platelets may be trapped at any one time in the normal spleen.
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Platelet Structure
Platelets are extremely small and discoid. The platelet surface coat has glycoproteins
that are particularly important in platelet adhesion and aggregation. Adhesion to
collagen is facilitated by glycoprotein Ia. Glycoproteins Ib and IIb/IIIa are important in
the attachment of platelets to von Willebrand factor (VWF) and hence to vascular
subendothelium. The binding site for IIb/IIIa is also the receptor for fibrinogen, which,
like VWF, is important in platelet-platelet aggregation.
The platelet plasma membrane invaginates into the platelet interior to form a
canalicular system which provides a large reactive surface area to which the plasma
coagulation proteins may be selectively absorbed. Plasma membrane phospholipids
are particularly important in the conversion of factor X to Xa and prothrombin (factor
II) to thrombin (IIa).
Platelets contain three types of storage granule;
1. dense granules containing ADP, ATP, serotonin and calcium
2. alpha granules containing clotting factors, von Willebrand factor (VWF),

platelet-derived growth factor (PDGF) and other proteins
3. lysosomes containing hydrolytic enzymes
Platelets are also rich in signalling and cytoskeletal proteins, which support the rapid
switch from quiescence to activation that follows vessel damage. During the release
reaction, the contents of the granules are discharged into the open canalicular
system.
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Platelet Function
The primary function of platelets is the formation of a platelet plug during the primary
haemostatic response to vascular injury via adhesion, aggregation and activation. The
immobilisation of platelets at the sites of vascular injury requires specific platelet-
vessel wall (adhesion) and platelet-platelet (aggregation) reactions, both partly
mediated through VWF. Platelet aggregation is characterised by cross-linking of

platelets through active GPIIb/IIIa receptors with fibrinogen bridges.
Primary activation by various agonists (e.g. thrombin) induces intracellular signalling,

leading to the release of alpha granule contents. These have an important role in
platelet aggregate formation and stabilisation and, in addition, the ADP released from
dense granules has a major positive feedback role in promoting platelet activation.
Thromboxane A2 (TXA2), produced by platelets, is important in secondary

amplification of platelet activation to form a stable platelet aggregate. TXA2 lowers
platelet cAMP levels and initiates the platelet release reaction; it also has powerful
vasoconstrictive activity.
After platelet aggregation and release, the exposed membrane phospholipid is

available for two reactions in the coagulation cascade. The first involves factors IXa,
VIIIa and X in the formation of factor Xa. The second results in the formation of
thrombin from the interactions of factors Xa, Va and prothrombin.
PDGF found in the alpha granules of platelets stimulates vascular smooth muscle
cells to multiply and thus may hasten vascular healing following injury.
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Natural Inhibitors of Platelet Function

Natural Inhibitors of Platelet Function
The release reaction is inhibited by substances that increase the level of platelet
cAMP. Prostacyclin (PGI2), synthesised by endothelial cells, is one such substance.
PGI2 has the opposing e!ects of TXA2; it is a potent inhibitor of platelet adhesion and
aggregation on normal vascular endothelium (and a potent vasodilator). Nitric oxide is
constitutively released from endothelial cells and also from macrophages and
platelets; it inhibits platelet activation and promotes vasodilation.
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Red Blood Cells LAST UPDATED: 4TH
AUGUST 2019

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Erythropoietin
The glycoprotein hormone erythropoietin (EPO) promotes the production of red cells.
About 90% of erythropoietin is produced in the peritubular complex of the kidney and
10% in the liver and other organs. Erythropoietin secretion is stimulated by reduced
O2 supply to the kidney receptor. Thus the principal stimuli to red cell production are
tissue hypoxia and reduced haemoglobin concentration (anaemia). Increased
pathological secretion may occur in polycystic kidney disease and renal cell
carcinoma. Decreased secretion may occur in advanced chronic kidney disease or in
polycythaemia vera. Recombinant erythropoietin is available for treating anaemia in
end-stage chronic kidney disease.
Red Cell Production
Red blood cells are formed from committed stem cells in a process called
erythropoiesis which occurs in the bone marrow in adults, and the liver and spleen in
the foetus. Erythropoietin increases the number of committed stem cells and
promotes production of red cells. Stem cells di"erentiate into erythroblasts (early
normoblasts) which are relatively large and nucleated. As di"erentiation proceeds,
the cells shrink and haemoglobin is synthesised, which requires iron, folate and
vitamin B12. In the late normoblast the nucleus breaks up and disappears and the
reticulocyte is formed.
About 2 x 1011 red cells are produced from the marrow each day. The spleen also holds
a reserve of red cells that can be released following blood loss.
Reticulocytes
Reticulocytes do not have a cell nucleus, but they have a network of ribosomal RNA
which allows continued synthesis of haemoglobin. Normally about 1 - 2% of
circulating red cells are reticulocytes, which are characterised by their slightly larger
size compared to mature erythrocytes and cresyl blue staining (due to residual RNA).
size compared to mature erythrocytes and cresyl blue staining (due to residual RNA).
The reticulocyte count is a measure of new red cell production by the bone marrow. It
is raised after haemorrhage or haemolysis when extra red cell production is needed. It
is low if the marrow is incapable of normal red cell production, for example in:
General bone marrow failure (e.g. malignant infiltration, aplastic anaemia)

Impaired red blood cell production (e.g. deficiency of iron, vitamin B12 or folate)
Lack of erythropoietin stimulus (e.g. chronic kidney disease)
Chronic systemic disease
An isolated reticulocytosis without anaemia is relatively common as a direct toxic

e"ect of alcohol.
Erythrocytes
The reticulocytes are released from the marrow into the peripheral blood, where after
about 1 - 2 days, they lose their remaining ribosomes and become mature
erythrocytes, at which point haemoglobin synthesis can no longer take place.
Mature erythrocytes are biconcave discs with no nucleus, ribosomes or mitochondria

but with the ability to generate energy as ATP by the anaerobic glycolytic pathway.
The red cell membrane consists of a bipolar lipid layer with a membrane skeleton of
penetrating and integral proteins anchoring carbohydrate surface antigens. The
shape and flexibility of red cells allows them to deform easily and pass through
capillaries.
Erythrocytes have a normal lifespan of about 120 days.
Red Cell Degradation
Senescent red cells are destroyed extravascularly by macrophages in the

reticuloendothelial system (in the bone marrow, liver and spleen).
Approximately 10 - 15% of developing erythroblasts die within the marrow without

producing mature cells; this is termed ine"ective erythropoiesis and may be more
marked in certain disease.
L I F E C Y C L E O F A R E D B LL O O D C E LL L .. ( IM AGE BY O P E N STAX C O LLEGE [C C BY 3.0

Cell Membrane Structure LAST UPDATED: 11TH
APRIL 2019
CELL STRUCTURE AND FUNCTION  Bookmark
Human cells are enclosed by a plasma membrane composed of a phospholipid bilayer

with embedded proteins which provide signalling, transport and structural functions.
such as ion channels, receptors and enzymes.
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C O M M O N S)
Bilayer Structure
Membrane lipids comprise a hydrophilic head and two hydrophobic fatty acid tails and
are arranged in a bilayer such that the hydrophobic tails face inwards, with the
hydrophilic heads facing externally. This means that lipid-soluble substances such as
cholesterol incorporate into the membrane, whilst molecules with both hydrophobic
and hydrophilic domains such as proteins can be tethered part in and part out of the
membrane.
The membrane is selectively permeable; lipid-soluble molecules such as O2 and CO2,

and small molecules such as water and urea can readily pass through the lipid bilayer,
but larger molecules such as glucose, and polar molecules such as ions cannot, and
their transport is mediated by transporter and ion channel membrane proteins.

their transport is mediated by transporter and ion channel membrane proteins.
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Glycocalyx
Most cells are also covered by a thin gel-like layer called the glycocalyx, containing
glycoproteins and carbohydrate chains extending from the lipid membrane, which
protects the membrane and plays a role in cell-cell interaction.
Membrane Proteins
Peripheral membrane proteins associated with cell signalling include enzymes bound
to the inner surface such as phospholipases, which produce arachidonic acid, and
adenylyl cyclase which generates the second messenger cyclic adenosine
monophosphate (cAMP). cAMP activates protein kinase enzymes to initiate numerous
changes in cell function by phosphorylating membrane and intracellular proteins.
Transmembrane proteins penetrate the entire thickness of the bilayer, and include ion
channel proteins and receptors such as G-protein-coupled receptors (GPCRs). On
binding the appropriate molecule, GPCRs activate specific membrane-associated
GTP-binding proteins, which cleave guanosine triphosphate (GTP) to guanosine
diphosphate (GDP), and depending on the type, activate or inhibit other membrane
bound signalling enzymes such as adenylyl cyclase.
Cell Membrane LAST UPDATED:
3RD OCTOBER
Transport 2021
PHYSIOLOGY / BASIC CELLULAR /  Bookmark

CELL STRUCTURE AND FUNCTION
Proteins provide several routes for the movement of materials

across membranes:
Large pores, constructed of several protein subunits that

allow the bulk flow of water, ions and sometimes larger
molecules
Transporter (carrier) proteins, some of which use direct or
indirect metabolic energy to move molecules against
electrochemical gradients
Ion channels, specialised to allow the passage of
particular ion species across the membrane under
defined conditions
Di!usion
Di!usion is the passive movement of ions across a cell

membrane down their electrochemical or concentration
gradient through ion channels.
Ion channels are transmembrane proteins which provide a

charged, hydrophilic pore through which ions can move across
the lipid bilayer. Ion channels are selective for particular ions
and their pores may be opened or closed; in this way ion
channels confer upon the cell the ability to closely control the
movement of ions across the membrane.
The transition between an open and closed ion channel state is

called gating, and is brought about by a change in the
conformation of the protein subunits that opens or closes the
ion-permeable pore. Ion channels can be voltage-gated
(regulated according to the potential di!erence across the cell
(regulated according to the potential di!erence across the cell
membrane) or ligand-gated (regulated by the presence of a
specific signal molecule).
Facilitated Di!usion
Facilitated di!usion is the process of spontaneous passive

transport of molecules or ions down their concentration
gradient across a cell membrane via specific transmembrane
transporter (carrier) proteins. The energy required for
conformational changes in the transporter protein is provided
by the concentration gradient rather than by metabolic activity.
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C O M M O N S)
Active Transport
Primary active transport uses chemical energy in the form

of ATP to pump ions against their electrochemical gradient. The
Na+/K+ -ATPase antiporter pump uses metabolic energy to
move 3 Na+ ions out of the cell for every 2 K+ ions in, against
their respective electrochemical gradients. This allows the cell
to maintain a high concentration of K+ ions and a low
concentration of Na+ ions intracellularly.

concentration of Na+ ions intracellularly.
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Secondary active transport relies on an electrochemical
gradient (usually the Na+ electrochemical gradient) created by

primary active transport to pump another ion (or molecule)
against its electrochemical or concentration gradient. There is
no direct coupling of ATP but the initial Na+ electrochemical
gradient that drives the secondary active transport is set up by
a process that requires metabolic energy. Examples include the
sodium/calcium exchanger, or the sodium/glucose symporter.

Cell Structure LAST UPDATED: 11TH
APRIL 2019
About half of each cell is filled with cytosol, a viscous, protein-rich fluid between the
internal structures which consist of organelles, which are themselves enclosed by
lipid membranes, and components of the cytoskeleton which provide structural
stability.
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Nucleus
The nucleus contains most of the cell's genetic material organised as chromosomes.
It also contains the nucleolus, a membrane-less structure which is responsible for the
production of ribosomes.
Mitochondria
Mitochondria are responsible for the production of chemical energy in the form of ATP
by oxidative phosphorylation, which is then used by all energy-requiring reactions.
Mitochondria are also involved in other cellular processes, including Ca2+ homeostasis
and signalling. Mitochondria contain a small amount of maternal DNA.
Endoplasmic reticulum
The smooth endoplasmic reticulum serves as a store for intracellular Ca2+ and is the
major site of lipid production (including triglyceride, steroid and phospholipid
synthesis).
The rough endoplasmic reticulum has ribosomes bound to its outer surface, which
are responsible for protein assembly and post-translational processing of proteins.
This includes trimming amino acid chains to the right length, protein folding, addition
of polysaccharide chains and identification of improperly folded proteins, which are
tagged for subsequent destruction by lysosomes.
Golgi apparatus
The Golgi apparatus packages proteins for delivery to specific intracellular

destinations or into vesicles which can then be secreted from the cell for extracellular
action.
Lysosomes
Lysosomes, containing digestive enzymes, are responsible for the digestion and
breakdown of unwanted and defective proteins, the recycling of raw materials and
the prevention of accumulation of waste.

Cellular Respiration LAST UPDATED: 30TH
AUGUST 2019
Cellular respiration is the process by which cells obtain energy in the form of
adenosine triphosphate (ATP). ATP transfers chemical energy from the energy rich
substances in the cell to the cell's energy requiring reactions e.g. active transport,
DNA replication and muscle contraction.
Cellular respiration is essentially a three step process:
1. Glycolysis
2. The Krebs cycle
3. The electron transfer system
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Respiratory Substrates
Respiratory Substrates
The main respiratory substrate used by cells is 6-carbon glucose. Respiration is a

series of reactions in which 6-carbon glucose is oxidised to form carbon dioxide. The
energy released due to the oxidation of glucose is used to synthesise ATP from
adenosine diphosphate (ADP) and inorganic phosphate (Pi).
Fats and proteins can also be used as respiratory substrates. When fats are being
used as the primary energy source, in the absence of glucose, an excess amount of
acetyl-CoA is produced, and is converted into acetone and ketone bodies. This can
occur in starvation, fasting or in diabetic ketoacidosis. Proteins are used as an energy
source only if protein intake is very high, or if glucose and fat sources are depleted.
Glycolysis
Glycolysis takes place in the cytoplasm of the cell and does not require oxygen.
Glycolysis is the breakdown of 6-carbon glucose into two 3-carbon pyruvic acid
(pyruvate) units. The hydrogens removed join with the hydrogen carrier NAD to form
NADH2. Although some energy is needed to start glycolysis there is an overall net
gain of 2 ATP. The pyruvic acid (3C) then enters the matrix of the mitochondrion
where it is oxidised (i.e. 2H removed) and a carbon dioxide is lost, forming acetyl CoA
(2C).
Krebs Cycle
The Krebs cycle takes place in the matrix of the mitochondrion and requires oxygen.
The Krebs cycle begins when the 2-carbon acetyl CoA joins with a 4-carbon
compound to form a 6- carbon compound called citric acid. Citric acid (6C) is
gradually converted back to the 4-carbon compound ready to start the cycle once
more. The carbons removed are released as CO2. The hydrogens which are removed
join with NAD to form NADH2.
Electron Transfer System
Most of the energy produced during respiration is made by the electron transfer
system. The electron transfer system is a system of hydrogen carriers located in the
inner mitochondrial membrane. The NADH2 molecules produced during glycolysis
and the Krebs cycle transfer the hydrogens to the electron transfer system. In doing
so, a H+ ion gradient is generated across the inner membrane which drives ATP
synthase. Oxygen is the final hydrogen acceptor and the H+ ions and O2 combine to
form water.
Anaerobic Respiration
When anaerobic respiration occurs there is no oxygen to act as the final hydrogen
acceptor and so the hydrogen cannot pass through the electron transfer system. As a
result, both the Krebs cycle and the electron transfer system stages cannot take
place. The only ATP produced is formed during glycolysis, that is, 2 ATP per glucose
molecule (compared to the 38 molecules of ATP produced during aerobic respiration).
The pyruvic acid produced following glycolysis is converted to lactic acid in a process
called lactic acid fermentation. No energy is generated in this process but it allows
ongoing glycolysis and ATP synthesis (which would otherwise stop) via the
regeneration of NAD+ from NADH. The anaerobic pathway is reversible with lactic acid
being converted back to pyruvic acid when oxygen is present.
Anaerobic respiration produces an oxygen debt. This is the amount of oxygen needed
to oxidise lactic acid to carbon dioxide and water. The existence of an oxygen debt
explains why we continue to breathe deeply and quickly for a while after exercise.

Osmolarity and Osmolality LAST UPDATED: 4TH
APRIL 2019
PHYSIOLOGY / BASIC CELLULAR / FLUID SPACES
 Bookmark
The osmotic potential of a solution depends on the concentration of osmotically

active particles in the solution. It can be expressed as osmolarity or osmolality.
Osmolality
The osmolality is the concentration of a solution expressed as the total number

of solute particles per kilogram weight of solvent. The normal serum osmolality
is between 275 - 295 mosmol/kg.
Serum osmolality can be measured directly or it can be calculated

(approximately) if the concentrations of the major solutes are already known.
The equation for calculating serum osmolality is = 2[Na+] + 2[K+] + [Glucose] +

[Urea].
Osmolal gap
The osmolal gap is the apparent di!erence between the measured and the
calculated osmolality. The normal osmolal gap is < 10.
Osmolal gaps of > 10 are considered abnormal and represent the presence of an
osmotically active substance in the blood. A raised osmolal gap can be caused
by toxic alcohols (e.g. ethanol, methanol or ethylene glycol ingestion); sugars
(e.g. mannitol, sorbitol); and lorazepam infusions (which contain propylene
glycol).
There may also be a discrepancy where there is a gross increase in plasma

protein or triglyceride concentration, both of which decrease the plasma water
per unit volume and give a pseudohyponatraemia which in turn will lead to an
erroneously low calculated osmolality.
Osmolarity
The osmolarity is the concentration of a solution expressed as the total number

of solute particles per litre of solution. Its measurement or calculation has been
largely replaced by osmolality.
For a given solution, osmolarity is always slightly less than osmolality because
the total solvent weight (the divisor used for osmolality) excludes the weight of
any solutes, whereas the total solution volume (used for osmolarity) includes
solute content. Changes in volume, and thus osmolarity, are a!ected by
changes in water content, as well as temperature and pressure. In contrast, the
weight of a solvent and thus osmolality, is independent of temperature and
pressure and is therefore relatively easier to determine. In practice, there is
negligible di!erence between the absolute values of the di!erent
measurements.

Osmosis and Tonicity LAST UPDATED: 11TH
APRIL 2019

 Bookmark
Definition
Osmosis is the passive movement of water across a semipermeable membrane from

regions of low solute concentration to those of higher solute concentration. Biological
membranes are semipermeable in that they usually allow the free movement of water
but restrict the movement of solutes.
The creation of osmotic gradients in this way is the primary method of movement of
water within the body, and thus the osmotic potential of body fluids is tightly
regulated by homeostatic control mechanisms.
Tonicity
Tonicity is a measure of the relative e!ective osmotic potentials of two solutions

separated by a semipermeable membrane. Tonicity is usually used to describe the
e!ective osmotic potential of a solution relative to plasma.
A fluid at the same osmotic potential as plasma is said to be isotonic; one at higher
potential is hypertonic and one at lower potential is hypotonic.
Taking on board fluids of di!ering osmotic potentials has distinct e!ects on the
distribution of water between cells and extracellular fluids.
Fluid Water Movement
Hypertonic Extracellular fluid becomes more concentrated relative to

fluid intracellular fluid, osmotic potential draws water out of cells,
cells lose water and shrink (crenation)
Isotonic Extracellular and intracellular fluid are isotonic, no osmotic

fluid potential generated, no net movement of water
Hypotonic Extracellular fluid diluted relative to intracellular fluid, osmotic

fluid potential draws water into cells, cells swell and may burst

Relative Fluid Distribution in LAST UPDATED: 15TH
OCTOBER 2022
Fluid Spaces  Bookmark

An 'average' 70 kg male contains about 40 litres of water in total, separated into

di!erent fluid compartments by biological semipermeable membranes; plasma cell
membranes between extracellular and intracellular fluid, and capillary walls between
interstitial and intravascular fluid.
Distribution of Fluid
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C O M M O N S)
Around two-thirds of the total fluid (27 L) is intracellular fluid (ICF) and one-third of
this (13 L) is extracellular fluid (ECF). The ECF can be further divided into intravascular
fluid (3.5 L) and interstitial fluid (9.5 L). Transcellular fluid refers to any fluid that does
not contribute to any of the main compartments but which are derived from them e.g.
gastrointestinal secretions and cerebrospinal fluid, and has a collective volume of
approximately 2 L.
Fluid Space Volume
Intravascular fluid 3.5 L
Interstitial fluid 9.5 L
Intracellular fluid 27 L
Total 40 L
Plasma Oncotic Pressure
The main di!erence between interstitial and intravascular fluid is that intravascular
fluid contains more protein than interstitial fluid which under normal circumstances
does not penetrate the capillary wall. The presence of protein in plasma exerts an
osmotic force (plasma oncotic pressure) which counteracts the hydrostatic pressure
imposed on plasma by the action of the heart, allowing only a small net movement of
water out of plasma into the interstitial space, which is absorbed by the lymphatic
system.

Relative Ionic Distribution in LAST UPDATED: 11TH
APRIL 2019
Fluid Spaces  Bookmark

The extracellular and the intracellular fluid compartments di!er markedly in terms of
the concentrations of the ions that are dissolved in them. It should be noted that,
within any one compartment, there must be electrical neutrality, i.e. the total number
of positive charges must equal the total number of negative charges.
Intracellular vs Extracellular Fluid
The most important di!erence is the relative concentrations of the cations:
Sodium (Na+) is the principal extracellular cation; approximately 140 mmol/L

(93%) is extracellular and 10 mmol/L (7%) intracellular.
Potassium (K+) is the principal intracellular cation; approximately 4 mmol/L is

extracellular (3%) and 140 mmol/L intracellular (97%).
Of the other cations, most Ca2+ in the cell is transported actively either out of the cell
or into the endoplasmic reticulum and mitochondria, leaving very low levels of
free Ca2+ in the intracellular fluid. Mg2+ is a predominantly intracellular ion.
Intracellularly the main anions are protein and phosphate, whereas extracellularly the
main anions are chloride (Cl-) and bicarbonate (HCO3-).

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Na/K+ ATPase Pump
Ion channel proteins allow the cell to determine the flow of ions across its own
membrane. In most circumstances, relatively few channels are open so that the
leakage of ions is low. There is, however, always a steady movement of ions across the
membrane, with Na+ and K+ following their concentration gradients into and out of
the cell, respectively. Uncorrected, the leak would lead to the equalisation of the
compositions of the two compartments, e!ectively eliminating all bioelectrical
signalling. This is prevented by the action of the Na+/K+ ATPase pump which is
e!ectively responsible for maintaining the ionic gradient between the intracellular
and extracellular fluid.
Gibbs-Donnan Equilibrium
Negatively charged intracellular proteins (and other large fixed anions e.g. phosphate
ions) that cannot cross the plasma membrane of cells, e!ectively repel Cl- ions, which
can di!use freely across the plasma membrane, forcing them out of the cell. The
electrical force driving the Cl- ions out is balanced by the chemical gradient driving
them back in, a situation known as the Gibbs-Donnan equilibrium.

Homeostasis LAST UPDATED: 30TH
AUGUST 2019
PHYSIOLOGY / BASIC CELLULAR / HOMEOSTASIS
 Bookmark
Normal functioning of proteins is essential for life. Seemingly small changes in the
external environment (particularly in temperature and pH) can irreversibly
denature proteins that are essential for normal physiological function. As long as
conditions are maintained within the normal physiological range within the internal
environment, the cells of the body continue to live and function properly.
Definition
Homeostasis is defined as 'the property of a system in which variables are regulated

so that internal conditions remain stable and relatively constant'. Homeostasis
preserves protein functionality and maintains most physiological systems in the body.
Set Point
The 'set point' is a narrow range of values within which normal physiological function
occurs. The set point can under certain circumstances be reset to meet physiological
requirements e.g. acclimatisation at high altitude.
Negative Feedback
The most common type of regulation is by negative feedback e.g. control of body
temperature, acid-base balance and blood pressure.
A negative feedback system comprises three components:
A detector (often neural receptor cells) to measure the variable in question and
to provide input to the comparator
A comparator (usually a neural assembly in the central nervous system) to
receive input from the detector, to compare the variable against the set point
and to determine the need for a response
An e"ector (usually muscular or glandular tissue) that is activated by the
comparator to enact the appropriate response to restore the variable to its set
point
The term 'negative feedback' refers to the fact that e"ectors always act to move the
variable in the opposite direction to the change that was originally detected.
Due to the inherent time delay between detecting a change in a variable and e"ecting
a response, negative feedback mechanisms cause oscillations in the variable they
control. This delay means that feedback control always causes the variable to
overshoot the set point slightly activating the opposite restorative mechanism to
induce a smaller overshoot in that direction, until the oscillations fall within the range
of values that are optimal for physiological function.
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C O M M O N S)
Positive Feedback
Some physiological systems use positive feedback mechanisms e.g. hormonal control
of childbirth (where pressure on the cervix causes increased release of oxytocin
increasing uterine contraction) or initiation of an action potential (where a sodium
influx causes depolarisation which causes further sodium channel opening).
Positive feedback systems are less common in the body due to their inherent
instability and risk of uncontrolled amplification. Positive feedback mechanisms
require a mechanism to break the feedback loop ( such as by birth of the child in the
first example above and by inactivation of sodium channels in the second).
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
Isometric vs Isotonic LAST UPDATED: 11TH
APRIL 2019
Contraction  Bookmark
SKELETAL MUSCLE PHYSIOLOGY
Isometric Contraction
Isometric contraction occurs when the two ends of the muscle are held at a fixed
distance apart, and stimulation of the muscle causes the development of tension
within the muscle due to the tension being transferred to elastic filaments within the
muscle without a change in muscle length e.g. holding a weight with an outstretched
hand.
Isotonic Contraction
In isotonic contraction one end of the muscle is free to move and the muscle length
changes. There are two types of isotonic contraction - concentric and eccentric.
In concentric movements the muscle shortens as the muscle fibres contract,

thereby generating force e.g. repeatedly lifting a weight.
In eccentric movements the muscle lengthens in a controlled manner, due to the

resistance being greater than the force the muscle is producing e.g. lowering a weight
gently.
In practice, most contractions are made up of both isometric and isotonic

contractions.
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
Motor Unit LAST UPDATED:
15TH MAY 2019
SKELETAL MUSCLE PHYSIOLOGY  Bookmark
Definition
In normal skeletal muscle, muscle fibres never contract as isolated

individuals. Several contract at almost the same time as they are all
supplied by the same alpha-motor neuron. The single motor neuron and all
the fibres it innervates is called the motor unit. This is the smallest part of a
muscle that can be made to contract independently from other parts of
the muscle.
Motor Unit Recruitment
The number of muscle fibres supplied by a single motor neurone is

correlated with the precision required of that muscle, for example the total
number of muscle fibres is small in muscles such as the extraocular
muscles that provide fine smooth movements, but large in muscles such
as the gluteus maximus that needs to generate powerful but coarse
movements.
Each motor unit contracts in an all or nothing fashion, i.e. if a motor unit is
excited, it will stimulate all of its muscle fibres to contract. The force of
contraction of a muscle is controlled by varying the motor unit recruitment
(spatial summation), and by varying the firing rate of the motor units
(temporal summation).
Spatial Summation
Spatial summation is the recruitment of additional motor units to generate

more force; there is a recruitment order of the motor units in that the
smallest cells discharge first and the largest last (size principle). During a
gradual increase in contraction of a muscle, the first units start to

discharge and increase their firing rate, and, as the force needs to
increase, new units are recruited and, in turn, also increase their firing rate.
increase, new units are recruited and, in turn, also increase their firing rate.
Temporal Summation
Increasing the firing rate of motor units is temporal summation where the
tension developed by the first action potential has not completely decayed
when the second action potential and twitch is grafted onto the first and
so on. If the muscle fibres are stimulated repeatedly at a faster frequency,
a sustained contraction results where it is not possible to detect individual
twitches. This is called tetany. The tension of tetany is much greater than
the maximum tension of a single, double or triple twitch.
For most motor units, the firing rate for a steady contraction is between 5
and 8 Hz. Because the unitary firing rates for each motor unit are di!erent
and not synchronised, the overall e!ect is a smooth force profile from the
muscle.

Neuromuscular Junction LAST UPDATED: 30TH
AUGUST 2019

 Bookmark
For skeletal muscle to contract, there must be neuronal activation to the muscle
fibres themselves from either higher centres in the brain or via reflex pathways
involving either the spinal cord or brainstem.
The neurons that innervate skeletal muscles are called alpha-motor neurons. Each
motor axon splits into a number of branches that make contact with the motor end
plate of individual muscle fibres at the neuromuscular junction (NMJ). The role of the
NMJ is the one-to-one transmission of excitatory impulses from the alpha-motor
neuron to the muscle fibres it innervates.
The motor neuron axon terminal has a large number of vesicles containing the
neurotransmitter acetylcholine (ACh). When an action potential reaches the
prejunctional membrane, the opening of voltage-gated Ca2+ channels increases the
permeability to Ca2+ ions and the sudden Ca2+ influx causes the release of
acetylcholine by exocytosis.
Acetylcholine di"uses across the synaptic cleft between the nerve and the muscle
cells, and stimulates a large number of cholinergic nicotinic receptors on the post-
junctional membrane. These receptors contain an integral ion channel, which opens
and allows the influx of small cations, mainly Na+. This movement of positively
charged ions generates an end plate potential (EPP) that is above threshold for
triggering a self-propagating action potential in the muscle fibre.
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
Sarcomere LAST UPDATED: 18TH
JULY 2021
The sarcomere is the functional unit of the muscle.
Each muscle fibre is divided at regular intervals along its length into sarcomeres
separated by Z-lines.
The I-band extends from either side of the Z-line to the start of the thick myosin
filament (i.e. it is the zone of thin actin filaments that is not superimposed by thick
myosin filaments).
The A-band extends along the whole length of the myosin filament. The A-band
therefore does not shorten in muscle contraction, as the myosin filament does not
shorten itself (rather the sarcomere shortens as the myosin and actin filaments slide
over one another).
The H-zone is at the centre of the sarcomere ending at the start of the actin filaments
(i.e. it is the zone of thick myosin filaments that is not superimposed by thin actin
filaments).
The M-line is a disc of filaments in the middle of the H-zone that holds the myosin
filament in position so that each one is surrounded by six actin filaments.
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
Skeletal Excitation- LAST UPDATED: 28TH
FEBRUARY 2019
Contraction Coupling  Bookmark

Muscle contraction occurs when the concentration of intracellular Ca2+ rises.
An action potential travels down tube-shaped invaginations of the sarcolemma called

T-tubules which penetrate throughout the muscle fibre and lie adjacent to the
terminal cisternae of the sarcoplasmic reticulum.
Voltage changes in the T-tubules results in the opening of sarcoplasmic reticulum
Ca2+ channels and the release of stored Ca2+ into the sarcoplasm.
Thus muscle contraction occurs via excitation-contraction coupling.
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Skeletal Muscle Structure LAST UPDATED: 11TH

APRIL 2019
The skeletal muscles and skeleton function together as the musculoskeletal system.
Gross Structure
The connective tissue surrounding the whole muscle is called the epimysium. The
connective tissue that extends beyond the body of the muscle eventually blends into
a tendon, which is attached to bone or cartilage. Skeletal muscle is composed of
numerous parallel, elongated, multinucleated cells called muscle fibres (or myofibres)
each enclosed by endomysium, which are grouped together to form fascicles. Each
fascicle is surrounded by perimysium.
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Muscle Fibres
Beneath the endomysium is the sarcolemma, an elastic sheath that projects into the
cell as invaginations called T-tubules which wrap around the sarcomeres, particularly
where the thin and thick filaments overlap. Each muscle fibre is composed of
myofibrils separated by sarcoplasm and arranged in a parallel fashion along the long
axis of the cell. Each myofibril is further subdivided into thick myosin and thin actin
myofilaments which are responsible for the cross-striations.
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O F B L AU SEN MEDI CAL 20 14". WI K I JO URN AL OF MEDIC IN E 1 (2) . DOI:10.15347/ WJM/2 014.010.
ISSN 2002-4436. (OWN WOR K) [C C BY 3.0
( H TTP://CREATIV ECOMMON S.ORG/ LICEN SES/ BY/ 3.0)], V IA WIKIMEDIA COMMON S)

Sliding Filament Theory LAST UPDATED: 21ST
MARCH 2023
Myofilaments
The thin filament consists of two intertwining strands of actin with smaller strands of
tropomyosin and troponin between the intertwining strands. The thick filament is
composed predominantly of myosin. Each molecule is club shaped, with a thin tail,
comprising two coiled peptide chains and a head made up of two heavy peptide
chains and four light peptide chains. The ATPase activity of the myosin molecule is
concentrated in the head. The thin tails of the myosin form the bulk of the thick
filaments, whereas the heads project outwards to form cross bridges between the
thick filaments and their neighbouring thin filaments.
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Muscle Contraction
The contraction of muscle is triggered by the release of Ca2+ from the sarcoplasmic
reticulum where it is stored bound to calsequestrin. This raises the concentration of
calcium which saturates the binding sites on troponin. This results in a shift of
tropomyosin, exposing actin binding sites thus allowing myosin cross-bridges to form
with actin.
The myosin head then pivots and bends as it pulls on the actin filament sliding it
towards the M line. Release of ADP and Pi from the myosin head frees the head for
another molecule of ATP. As new ATP attaches to the myosin head, the cross bridge
detaches and frees the myosin head for further binding. ATP is hydrolysed to ADP and
Pi, returning the myosin head to the 'cocked' position. Like fingers of the hands sliding
over one another, actin and myosin molecules slide past each other.
This mechanism is called the sliding filament theory. The muscle fibre itself does not
shorten in contraction, but the sarcomere shortens as the thick and thin filaments
slide over one another. This constant interaction of the thin and thick filaments,
binding, tilting, releasing and rebinding and sliding over one another using cross-
bridges will continue as long as Ca2+ remains high. The duration of the contraction is
dependent on the rate at which the sarcoplasmic reticulum pumps back the Ca2+ into
the terminal cisternae.
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Di!usion and Permeability LAST UPDATED: 11TH
APRIL 2019
VESSEL FLUID DYNAMICS  Bookmark
Passive di!usion refers to movement down a concentration gradient and

accounts for movement across small distances e.g. within the cytosol or across
membranes.
Di!usion Within a Solution
The rate of di!usion in a solution is described by Fick's law which states:
Js = -DA (ΔC/Δx)
where,
Js = Amount of substance transferred per unit time
ΔC = Di!erence in concentration
Δx = Di!usion distance
A = Surface area over which di!usion occurs
D = Di!usion coe#cient
The di!usion coe#cient is a measure of how easy it is for the substance to

di!use - it is related to temperature, solvent viscosity and the size of the
molecule.
Di!usion Across a Membrane
Di!usion across a membrane is also a!ected by the permeability (p) of the

membrane. The permeability is related to the membrane thickness and
composition, and the di!usion coe#cient of the substance.
Therefore Fick's equation for di!usion across a membrane can be rewritten as:
Js = -pAΔC
where,
Js = Amount of substance transferred per unit time
ΔC = Di!erence in concentration across the membrane

A = Membrane area over which di!usion occurs
p = Membrane permeability

Tube Flow LAST UPDATED: 11TH
APRIL 2019
Flow through a tube is dependent on the pressure di!erences across the ends of the
tube (P1 - P2) and the resistance to flow provided by the tube (R).
Darcy's law states that: Flow = (P1 - P2)/R.
Resistance is due to frictional forces and is determined by the length of the tube (L),
the radius of the tube (r) and the viscosity of the fluid flowing down that tube (V).
Poiseuille's law states: R = (8VL)/(πr4).
Combining these equations shows us that flow ∝ (radius)4. Therefore the radius of the
tube has the largest e!ect on resistance and therefore flow; the constriction of an
artery by 20% will decrease the blood flow by ~ 60%. This explains why smaller gauge
cannulas (with larger diameters) have a faster rate of flow.
Fluids with higher viscosity also have a slower rate of flow. Plasma has a similar
viscosity to water, but blood contains cells which e!ectively increase the viscosity by
three- to four-fold. Changes in cell number e.g. polycythemia, therefore a!ect blood
flow.
Turbulent vs Laminar Flow
Frictional forces at the sides of a vessel cause a drag force on the fluid touching
them, creating a velocity gradient where the flow is greatest at the centre. This is
termed laminar flow which for the most part is the normal physiological flow. A
consequence of the velocity gradient is that blood cells tend to move away from the
sides of the vessel and accumulate towards the centre, aligning themselves to the
flow, which e!ectively reduces blood viscosity and minimises resistance.
At high velocities, especially in large arteries or where the velocity increases sharply
at points of sudden narrowing in the vessels, or across valves, laminar blood flow may
become disrupted and flow may become turbulent.
Turbulent blood flow is multidirectional and travels at di!erent velocities leading to

increased resistance and additional shear stress on the vessel wall. This may result in
damage to endothelium or existing plaques resulting in an increased tendency to
thrombus formation. Clinically turbulence may be heard as a murmur or a bruit.
Turbulent blood flow may sometimes occur due to elevated cardiac output, even
across anatomically normal cardiac valves, resulting in physiological murmurs e.g. in
pregnancy.
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Wall Tension LAST UPDATED: 21ST
FEBRUARY 2019
Pressure across the wall of a flexible tube (transmural pressure) tends to

extend it, and increases wall tension.
This can be described by Laplace's Law:
Pt = (Tw)/r
where,
Pt = Transmural Pressure
T = Wall Tension
w = Wall Thickness
r = Radius
Thus, a small bubble with the same wall tension as a larger bubble will
contain a greater pressure, and will collapse into the larger bubble if they
are joined. In the lung, small alveoli would collapse into larger ones were it
not for surfactant, which reduces the surface tension more strongly as the
size of the alveolus decreases.
Laplace's Law also means that a large dilated heart (e.g. heart failure) has
to develop more wall tension (contractile force) in order to obtain the same
ventricular pressure, making it less e!cient.

Cardiac Excitation- LAST UPDATED: 21ST
APRIL 2019
Contraction Coupling  Bookmark

PHYSIOLOGY / CARDIOVASCULAR / CARDIAC CYCLE
Cardiac muscle contracts when intracellular Ca2+ rises (> 100 nmol/L).
Contraction
Although Ca2+ entry during the action potential (AP) is essential for contraction, it
only accounts for about 25% of the rise in intracellular Ca2+. The rest is released from
Ca2+ stores in the sarcoplasmic reticulum (SR).
APs travel down invaginations of the sarcolemma called T-tubules, which are close to,
but do not touch, the terminal cisternae of the SR. During the AP plateau, Ca2+ enters
the cell and activates Ca2+ sensitive Ca2+ release channels in the sarcoplasmic
reticulum allowing stored Ca2+ to flood into the cytosol; this is called Ca2+-induced
Ca2+ release. The amount of Ca2+ released is dependent on how much is stored, and
on the size of the initial Ca2+ influx during the AP.

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Relaxation
In relaxation, about 80% of Ca2+ is rapidly pumped back into the SR (sequestered) by
Ca2+ ATPase pumps. The Ca2+ that entered the cell during the AP is transported out
of the cell primarily by the Na+/Ca2+ exchanger in the membrane which pumps one
Ca2+ ion out in exchange for three Na+ ions in, using the Na+ electrochemical gradient
as an energy source. This is relatively slow and continues during diastole.
Treppe E!ect
When more action potentials occur per unit time, more Ca2+ enters the cell during the
AP plateau, more Ca2+ is stored in the SR, more Ca2+ is released from the SR and thus
more Ca2+ is left inside the cell and greater tension is produced during contraction.
Increased heart rate increases the force of contraction in a stepwise fashion as
intracellular [Ca2+] increases cumulatively over several beats.

Cardiac Myocyte LAST UPDATED: 28TH
FEBRUARY 2019
Microstructure  Bookmark
The myocardium is composed of cardiac muscle cells called myocytes. The cells are
striated due to the arrangement of the thick and thin filaments which make up the
bulk of the muscle, although they are less organised than in skeletal muscle. The
myocytes are small and branched, with a single nucleus and are rich in mitochondria.
The normal pumping action of the heart is dependent on the synchronised
contraction of all cardiac cells.
Cardiac myocyte contraction is not dependent on an external nerve supply but

instead the heart generates its own rhythm (inherent rhythmicity). The nerves
innervating the heart only speed up or slow down the rhythm and can modify the
force of contraction.
The synchronicity between myocytes occurs because all the adjacent cells are linked
to one another at their ends by specialised gap junctions (formed of connexons),
within the intercalated discs, which essentially provide a low-resistance pathway
between cells. Gap junctions allow action potentials to spread rapidly from one cell to
another and allows the myocardium to act as a functional syncytium. The intercalated
discs also provide structural attachments (desmosomes) between myocytes to
distribute force.
Although a rise in intracellular [Ca2+] initiates contraction in the same way as in

skeletal muscle, the mechanisms leading to the rise in intracellular [Ca2+] are
fundamentally di"erent.
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
Conducting System of Heart LAST UPDATED: 7TH
JUNE 2022
 Bookmark
The cardiac conduction system initiates and coordinates contraction of the heart.
Sinoatrial Node
The heartbeat is initiated by spontaneous depolarisation of the sinoatrial node (SAN),

a region of specialised myocytes in the right atrium. The rate is modulated by the
autonomic nervous system. Action potentials in the SAN activate adjacent atrial
myocytes and a wave of depolarisation and contraction therefore spreads through
atrial muscle. This is prevented from reaching the ventricles directly by the annulus
fibrosus.
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Atrioventricular Node
The impulse generated by the SAN is then channelled through the atrioventricular
node (AVN), located between the right atrium and ventricle near the atrial septum.
The AVN contains small cells and thus conducts slowly and delays the impulse for
about 120 ms allowing time for atrial contraction to complete ventricular filling.
Conduction of the Impulse
Once ventricular filling is complete, the impulse is then transmitted by specialised,

wide, fast conducting myocytes in the bundle of His, the left and right bundles, and
the Purkinje fibres, by which it is distributed over the inner surface of both ventricles.
From here a wave of depolarisation and contraction moves from myocyte to myocyte
across the endocardium until the whole ventricular mass is activated.
Pathophysiology
Because the SAN is responsible for the rest of the heart's electrical activity, it is called
the primary pacemaker. The SAN will normally discharge at a rate of 60-100 bpm. If
the SAN does not function properly or the impulse generated in the SAN is blocked
before it travels down the electrical conduction system, a group of cells further down
the heart will become its pacemaker.
The AVN is the secondary pacemaker and will normally discharge at about 40-60
beats per minute. The left and right branches of the bundle of His, and the Purkinje
fibers, will also produce a spontaneous action potential at a rate of 20-40 beats per
minute, so if the SAN and AVN both fail to function, these cells can become
pacemakers. It is important to realise that these cells will be initiating action
potentials and contraction at a much lower rate.
The SAN controls the rate of contraction for the entire heart muscle because its cells
have the quickest rate of spontaneous depolarisation, thus they initiate action
potentials the quickest. The action potential generated by the SAN passes down the
electrical conduction system of the heart, and depolarises the other potential
pacemaker cells to initiate action potentials before these other cells have had a
chance to generate their own spontaneous action potential, thus they contract and
propagate electrical impulses to the pace set by the cells of the SAN. This is the
normal conduction of electrical activity in the heart.

Electrocardiogram (ECG) LAST UPDATED: 28TH
FEBRUARY 2019
 Bookmark
The wave of depolarisation through the heart causes local currents in surrounding
fluid which are detected at the body surface as small changes in voltage. This forms
the basis of the ECG.
The classical ECG records voltage between the left and right arm (lead I), the right
arm and left leg (lead II) and the left arm and left leg (lead III). This is represented by
Einthoven's triangle.
The size of the voltage at any time depends on the quantity of muscle depolarisation
and the direction in which the wave of depolarisation is travelling. Thus lead II
normally shows the largest deflection during ventricular depolarisation, as the muscle
mass is greatest and depolarisation travels from apex to base, more or less parallel to
a line from the left hip to the right shoulder.
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Inotropic E!ects on Heart LAST UPDATED:
28TH FEBRUARY
PHYSIOLOGY / CARDIOVASCULAR / 2019
CARDIAC CYCLE
 Bookmark
Factors that a!ect intracellular [Ca2+] and hence cardiac contractility are
called inotropes.
Sympathetic stimulation increases cardiac muscle contractility because it

causes release of noradrenaline. Noradrenaline is a positive inotrope; it
binds to β1-adrenoceptors on the membrane and causes increased Ca2+
entry via L-type channels during the AP and thus increases Ca2+ release
from the SR. Noradrenaline also increases Ca2+ sequestration into the SR
and thus more Ca2+ is available for the next contraction.
Cardiac glycosides (e.g. digoxin) slow the removal of Ca2+ from the cell by
inhibiting the membrane Na+ pump which generates the Na+ gradient
required for driving the export of Ca2+; consequently the removal of Ca2+
from the myocyte is slowed and more Ca2+ is available inside the myocyte
for the next contraction.
Acidosis is negatively inotropic, largely because H+ competes for Ca2+

binding sites.

Pressures, Volumes and Key LAST UPDATED: 31ST
JANUARY 2022
Events in Cardiac Cycle  Bookmark

The cardiac cycle describes the events that occur during one beat of the heart.
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( H TTPS://CREATIV ECOMMON S.ORG/ LICEN SES/ BY-SA/2.5)], V IA WIKIMEDIA COMMON S)
At the start of the cardiac cycle, towards the end of diastole, the whole of the heart is
relaxed. The atrioventricular (AV) valves are open because the atrial pressure is still
slightly greater than the ventricular pressure. The semilunar valves are closed, as the
pressure in the pulmonary artery and aorta is greater than the ventricular pressures.
The cycle starts when the sinoatrial node (SAN) initiates atrial systole.
Diastole: Atrial Systole (AV valves open, Semilunar valves closed)
Atrial depolarisation causes the P wave on the ECG and initiates atrial contraction
(atrial repolarisation is too di!use to be seen on the ECG).
As the atria contract, the atrial pressure increases which forces more blood flow
across the open AV valves, leading to rapid flow of blood into the ventricles. There are
no valves between the veins and atria and atrial systole causes a small pressure rise
in the great veins (the a wave on the JVP waveform).
At rest, atrial contraction only contributes the last 15 - 20% of the final ventricular
volume, as most of the ventricular filling has occurred passively in diastole due to
venous pressure. The proportion of atrial contribution increases with heart rate as
diastole shortens and there is less time for passive ventricular filling.
The end-diastolic volume (EDV) is usually about 120 - 140 mL, and the end-diastolic
pressure is less than 10 mmHg (and higher in the left ventricle than the right due to
the thicker and therefore sti!er left ventricle).
In ventricular hypertrophy, filling of the 'sti!' ventricle by atrial systole causes

a fourth heart sound
sound, which is not audible in normal adults.
Systole: Isovolumetric Contraction (All valves closed)
Ventricular depolarisation causes the QRS complex on the ECG, and triggers
excitation-contraction coupling and myocyte contraction.
The ventricular pressure rises sharply during contraction and the AV valves close
as soon as this is greater than the atrial pressure (causing the first heart
sound
sound). Because the mitral valve closes before the tricuspid valve, the first heart
sound may be split.
For a short period, as the forces are developing, both the AV and the semilunar valves
are closed as the ventricular pressure is still less than that in the pulmonary artery
and aorta, and no ejection occurs. This is isovolumetric contraction.
The increasing pressure makes the AV valves bulge into the atria, causing a small
atrial pressure wave (the c wave of the JVP waveform).
Systole: Ventricular Ejection (Semilunar valves open, AV valves

closed)
When the ventricular pressure exceeds that in the pulmonary artery and the aorta,
the semilunar valves open and blood is ejected, initially rapidly (rapid ejection
phase) and then more slowly (reduced ejection phase).
Atrial pressure initially decreases as the atrial base is pulled downward during
ejection, expanding the atrial chamber (the x descent of the JVP waveform). Atrial
filling begins in the rapid ejection phase and continues during the reduced ejection
phase and atrial pressure begins to rise (the v wave of the JVP waveform).
During the second half of ejection, the ventricles stop actively contracting, the
ventricular pressure starts to decrease and the muscle starts to repolarise; this
causes the T wave on the ECG
ECG, which marks the end of both ventricular
contraction and rapid ventricular ejection.
The ventricular pressure during the reduced ejection phase begins to decrease.
Aortic pressure also decreases because of the runo! of blood from large arteries into
smaller arteries. The ventricular pressure falls slightly below that in the aorta, but
initially blood continues to flow out of the ventricle because of momentum; eventually
the ventricular pressure falls su#ciently and the semilunar valves close.
The amount of blood ejected is the stroke volume (SV), and is usually about 70 mL
(therefore about 50 mL is left; this is the end-systolic volume). The proportion of
EDV that is ejected (i.e. the SV/EDV) is the ejection fraction and this is normally about
0.6.
Diastole: Isovolumetric Relaxation (All valves closed)
Closure of the semilunar valves causes a small increase in aortic pressure (the
dicrotic notch on the arterial waveform), and the second heart sound. Inspiration
delays closure of the pulmonary valve and thus causes splitting of the second heart
sound.
Immediately after the closure of the semilunar valves, the ventricles rapidly relax and
ventricular pressure decreases rapidly but the AV valves remain closed as initially the
ventricular pressure is still greater than atrial pressure. This is isovolumetric
relaxation.
Atrial pressure continues to rise because of venous return, with the v wave of the JVP
waveform peaking during this phase. As the ventricles continue to relax, the
ventricular pressure falls below that of the atrial pressure and the AV valves open.
Diastole: Ventricular Filling (AV valves open, Semilunar valves

closed)
When the AV valves open

open, the atrial pressure falls (the y descent of the JVP
waveform) and the ventricles refill, initially rapidly (the rapid filling phase) and then
more slowly as the ventricles expand, become less compliant, and ventricular
pressures rise (the reduced filling phase). Rapid flow of blood from the atria into the
ventricles causes the third heart sound
sound, which is normal in children but, in adults,
is associated with disease such as ventricular dilation.
Diastole is usually twice the length of systole at rest, but decreases with increased
heart rate. During systole, contraction of the ventricles compresses the coronary
arteries and suppresses blood flow. This is particularly evident in the left ventricle,
where during systole the ventricular pressure is the same as or greater than that in
the arteries and as a result more than 85% of left ventricular perfusion occurs during
diastole. This becomes a problem if the heart rate is increased as the diastolic interval
is shorter and can result in ischaemia.
Valve Opening/Closure during Cardiac Cycle
Cardiac Cycle Atrioventricular Valves Semilunar Valves

Phase
Atrial systole Open (atrial pressure > Closed (arterial pressure >
ventricular pressure) ventricular pressure)
Isovolumetric Closed (ventricular Closed (arterial pressure >

contraction pressure > atrial pressure) ventricular pressure)
Ventricular Closed (ventricular Open (ventricular pressure >

ejection pressure > atrial pressure) arterial pressure)
Isovolumetric Closed (ventricular Closed (arterial pressure >

relaxation pressure > atrial pressure) ventricular pressure)
Ventricular Open (atrial pressure > Closed (arterial pressure >

filling ventricular pressure) ventricular pressure)
JVP Waveform during Cardiac Cycle
JVP Phase of Physiology

waveform Cardiac
Cycle
a wave Atrial systole Occurs due to right atrial contraction

(end diastole)
c wave Isovolumetric Occurs due to the bulging of the tricuspid

contraction valve into the right atrium during right
(early isovolumetric ventricular contraction
systole)
x descent Rapid Occurs due to a combination of right atrial

ventricular relaxation, the downward displacement of the
ejection (mid tricuspid valve during right ventricular
systole) contraction, and the ejection of blood from
both the ventricles
v wave Ventricular Occurs due to right atrial filling from venous
ejection and return
isovolumetric
relaxation
(late systole)
y descent Ventricular Occurs due to opening of the tricuspid valve

filling (early and the subsequent rapid inflow of blood from
diastole) the right atrium to the right ventricle
Heart Sounds during Cardiac Cycle
Heart Phase of Mechanical Event

Sound Cardiac
Cycle
First Start of Caused by closure of the atrioventricular (mitral

heart systole and tricuspid) valves
sound
Second End of Caused by closure of the semilunar (aortic and

heart systole pulmonary) valves
sound
Third Early Caused by rapid flow of blood from the atria into
heart diastole the ventricles during the ventricular filling phase
sound
Fourth Late Caused by filling of an abnormally sti! ventricle in

heart diastole atrial systole
sound
ECG Deflections during Cardiac Cycle
ECG Event
P wave Atrial depolarisation
QRS complex Ventricular depolarisation
T wave Ventricular repolarisation

Sinoatrial Node Action LAST UPDATED: 21ST
APRIL 2019
Potential  Bookmark
Pacemaker Potential
The action potential (AP) of the sinoatrial node (SAN) di!ers from that in ventricular
muscle.
The resting potential of the SAN is about - 60 mV, and it decays steadily with time
until it reaches a threshold potential of about - 40 mV, when an action potential is
initiated.
The upstroke of the AP is slow, as it is not due to activation of fast Na+ channels like
cardiac myocytes, but instead slow L-type Ca2+ channels; the SA node contains no
functional fast Na+ channels. The slow upstroke means that conduction between
nodal myocytes is slow, which is particularly important at the atrioventricular node
(which has a similar AP to the SAN).
The rate of decay of the SAN resting potential determines the rate of AP and therefore
of heart rate; it is therefore called the pacemaker potential. The pacemaker potential
decays because of a slowly reducing outward K+ current set against a slow inward
Na+ leak through slow Na+ channels (and to a lesser extent, a slow inward Ca2+ leak
through T-type Ca2+ channels). Factors that a!ect these currents alter the rate of
decay and the time to reach threshold and thus heart rate and are called chronotropic
agents.
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Chronotropic Agents
Noradrenaline (the sympathetic neurotransmitter) is a positive chronotrope and

causes a faster rate of decay and thus heart rate whereas acetylcholine (the
parasympathetic neurotransmitter) is a negative chronotrope and lengthens the time
to reach threshold and decreases heart rate.
Other Cardiac Action Potentials
Other atrial cells, the AV node, the bundle of His and Purkinje system may also exhibit
decaying resting potentials that can act as pacemakers. However the SAN is normally
fastest and predominates - this is called overdrive suppression.

Ventricular Myocyte Action LAST UPDATED: 21ST
APRIL 2019
Potential  Bookmark
The resting potential of ventricular myocytes is about -90 mV. An action potential (AP)
is initiated when the myocyte is depolarised to a threshold potential of about -65 mV,
as a result of transmission from an adjacent myocyte via gap junctions.
Depolarisation
Fast voltage-gated Na+ channels are activated and a Na+ influx depolarises the
membrane rapidly to about +30 mV. This initial depolarisation is similar to that in
nerve and skeletal muscle, and assists the transmission to the next myocyte.
Na+ channels and currents rapidly inactivate, but in cardiac myocytes, the initial
depolarisation activates voltage-gated Ca2+ channels (slow L-type channels,
threshold approximately - 45 mV) through which Ca2+ floods into the cell. The
resulting influx of Ca2+ prevents the cell from repolarising and causes a plateau
phase, that is maintained for about 250 ms until the L-type channels inactivate. The
cardiac AP is thus much longer than that in nerve or skeletal muscle.
Repolarisation
Repolarisation occurs due to activation of voltage-gated K+ rectifier channels and a
K+ e"ux. As the AP lasts almost as long as contraction, its refractory period prevents
another AP being initiated until the muscle relaxes, thus cardiac muscle cannot
exhibit tetanus.
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Other Cardiac Action Potentials
Atrial myocytes have a similar but more triangular AP compared to the ventricles (less
plateau). Purkinje fibres in the conduction system are also similar to ventricular
myocytes, but have a spike at the peak of the upstroke reflecting a larger Na+ current
that contributes to their fast conduction velocity.

ANS E!ects on Heart LAST UPDATED: 2ND
MAY 2019
PHYSIOLOGY / CARDIOVASCULAR /
CARDIAC OUTPUT  Bookmark
Both the heart rate and contractility can be modulated by the autonomic
nervous system.
Sympathetic Stimulation
Sympathetic stimulation increases heart rate and cardiac

contractility. Activation of sympathetic nerves also causes arterial and venous
vasoconstriction. Arterial vasoconstriction increases total peripheral resistance
(TPR) and thus reduces flow, so downstream pressure and venous return will
fall. Venoconstriction does not significantly impede flow because venous
resistance is low compared to arteries, but it reduces their compliance and
hence capacity. Thus vasoconstriction has the same e"ect as increasing blood
volume, and increases CVP. Sympathetic stimulation thus increases cardiac
output by increasing heart rate, contractility and CVP, and increases blood
pressure by increasing TPR and cardiac output.
Parasympathetic Stimulation
Parasympathetic stimulation causes a marked decrease in heart rate (negative

chronotropic e"ect) but only a slight decrease in heart muscle contractility
(negative inotropic e"ect) as parasympathetic ventricular innervation is sparse.

Baroreceptor Reflex LAST UPDATED: 21ST
APRIL 2019
PHYSIOLOGY / CARDIOVASCULAR / CARDIAC OUTPUT
 Bookmark
Mean arterial pressure (MAP) = Cardiac output (CO) x Total peripheral resistance (TPR).
Cardiac output is itself dependent on the central venous pressure (CVP), which in turn
is highly dependent on the blood volume. Alterations of any of these variables may
change MAP.
Postural Hypotension
On standing from a prone position, gravity causes blood to pool in veins in the legs.
Central venous pressure (CVP) falls, causing a fall in stroke volume and cardiac output
(due to Starling's law) and thus a fall in blood pressure. Normally this fall in BP is
rapidly corrected by the baroreceptor reflex which causes venoconstriction (partially
restoring CVP), and an increase in heart rate and contractility, so restoring cardiac
output and blood pressure. Impaired autonomic nervous activity in the elderly
accounts for the greater likelihood of postural hypotension. Any symptoms of
dizziness, blurred vision or syncope is due to a transient fall in cerebral perfusion that
occurs before cardiac output and MAP can be corrected.
Baroreceptor Reflex
Arterial baroreceptors are located in the carotid sinus and aortic arch, and detect the
mean arterial pressure (MAP).
A decrease in MAP (such as in postural hypotension, or haemorrhage) reduces arterial

stretch and decreases baroreceptor activity, resulting in decreased firing in a"erent
nerves travelling via the glossopharyngeal nerve (carotid sinus) and vagus nerve
(aortic arch) to the medulla where the activity of the autonomic nervous system is
coordinated.
Sympathetic nerve activity consequently increases, causing an increase in heart rate

and cardiac contractility, peripheral vasoconstriction with an increase in TPR, and
venoconstriction with an increase in CVP and thus an increase in cardiac output and
blood pressure. Parasympathetic activity (vagal tone) decreases, contributing to the
rise in heart rate. MAP therefore returns to normal. An increase in MAP has the
opposite e"ect.
The baroreceptors are most sensitive between 80 and 150 mmHg and their sensitivity
is increased by a large pulse pressure. They also show adaptation; if a new pressure is
maintained for a few hours, activity slowly moves towards normal. The baroreceptor
reflex is important for bu"ering short-term changes in MAP e.g. with postural
changes, or when muscle blood flow increases rapidly in exercise.
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
CVS Systemic Overview LAST UPDATED: 2ND
MAY 2019
CARDIAC OUTPUT  Bookmark
Definitions
The total blood volume in the circulatory system of a healthy adult is

about 5 L.
The stroke volume is the volume of blood ejected per beat. It is usually
about 70 mL/beat at rest.
The heart rate is the number of beats per minute. It is usually about 70
beats/minute at rest.
The cardiac output is the volume of blood pumped out of heart via the
aorta per minute.
Cardiac output (CO) = Stroke volume x Heart rate = 70 mL/beat x 70

beats/min = 4900 mL/min
Therefore cardiac output is usually about 5 L/minute at rest in humans.
Mean Arterial Pressure (MAP)
During systole, the pressure in the left ventricle increases and blood is
ejected into the aorta. The rise in pressure stretches the elastic walls of
the aorta and large arteries and drives blood flow. Systolic pressure is the
maximum arterial pressure during systole. During diastole, arterial blood
flow is partly maintained by elastic recoil of the walls of large arteries. The
minimum pressure reached before the next systole is the diastolic
pressure. The di"erence between the systolic and diastolic pressure is the
pulse pressure.
The mean arterial pressure (MAP) cannot be calculated by averaging these

pressures, because for about 60% of the time, the heart is in diastole. It is
instead estimated as the diastolic + one-third of the pulse pressure, e.g. =
80 + 1/3(110 - 80) = 90 mmHg where BP 110/80 mmHg.

Normal Pressures in the Circulation
The mean arterial pressure (MAP) at the start of the arterioles is about 65
mmHg. The pressure on the arterial side of capillaries is about 25 mmHg,
and on the venous side is about 15 mmHg. Venules converge into veins and
finally the vena cava. The pressure in the vena cava at the level of the
heart (the central venous pressure) is usually close to 0 mmHg.

Frank-Starling Relationship LAST UPDATED: 18TH
APRIL 2020
 Bookmark
Cardiac output is determined by the heart rate and stroke volume. Stroke volume is
dependent on the filling pressure (the preload), the cardiac muscle force (the
contractility) and the pressure against which the heart has to pump (the afterload).
Frank-Starling Relationship
The volume of blood in the ventricle at the start of systole, the end-diastolic volume
(EDV), depends on the end-diastolic pressure (EDP) and the compliance of the
ventricular wall. Right ventricular EDP is dependent on right atrial and hence central
venous pressure (CVP). If EDP (and thus EDV) is increased, the force of the following
contraction, and thus stroke volume increases; this is known as the Frank-Starling
relationship.
Starling's law of the heart states that 'the energy released during contraction
depends on the initial fibre length'. An increase in EDV causes an increase in
ventricular fibre length, which produces an increase in developed tension and results
in an increased force of systolic contraction. As muscle is stretched, more myosin
cross-bridges can form, increasing force. However, cardiac muscle has a much
steeper relationship between stretch and force than skeletal muscle, because in the
heart stretch also increases the Ca2+ sensitivity of troponin, so more force is
generated for the same intracellular Ca2+.
The most important consequence of Starling's law is that output is matched between
the right and left ventricles. It thus explains how CVP, although only perceived by the
right ventricle, also influences left ventricular function and cardiac output, and why
postural hypotension and haemorrhage reduce cardiac output. It also allows the heart
to sustain output when afterload is increased, or contractility is reduced, as both lead
to accumulation of venous blood and a raised EDP, which increases ventricular force
and restores stroke volume.
Factors a!ecting the Frank-Starling Curve
The Frank-Starling curve is a!ected by:
Preload
Increases in preload cause a rightward shift along the curve
Decreases in preload cause a leftward shift along the curve
Contractility
Increases in contractility shift the curve upwards and to the left

Decreases in contractility shift the curve downwards and to the right
Afterload
Increases in afterload shift the curve downwards and to the right

Decreases in afterload shift the curve upwards and to the left
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Preload
Preload can be defined as the initial stretching of the cardiac myocytes prior to
contraction. Preload, therefore, is related to muscle sarcomere length. Because
sarcomere length cannot be determined in the intact heart, other indices of preload
are used such as ventricular end-diastolic volume or pressure. When venous return to
the heart is increased, the end-diastolic pressure and volume of the ventricles are
increased, which stretches the sarcomeres, thereby increasing their preload.
Ventricular filling and therefore preload is increased by:
Increased central venous pressure which can result from:
Decreased venous compliance caused by venoconstriction

Increased thoracic blood volume caused by either an increase in total
blood volume or an increase in venous return (augmented by increased
respiratory activity, increased skeletal muscle pump activity or by gravity
in head-down tilt).
Increased ventricular compliance

Increased atrial activity caused by sympathetic stimulation or from increased
filling of the atria
Reduced heart rate (which increases ventricular filling time)
Ventricular filling and therefore preload is decreased by:
Decreased central venous pressure caused by:
Reduced blood volume e.g. haemorrhage

Gravity causing blood to pool in lower limbs when standing
Impaired atrial activity e.g. in atrial fibrillation

Tachycardia which reduces ventricular filling time
Decreased ventricular compliance e.g. ventricular hypertrophy
Inflow (mitral and tricuspid) valve stenosis which reduces ventricular filling
Contractility
Contractility (inotropy) is the intrinsic ability of cardiac muscle to develop force at a
given muscle length. It is determined by the intracellular [Ca2+] and can be estimated
by the ejection fraction. Increases in contractility cause an increase in stroke
volume/cardiac output for any level of right atrial pressure or end-diastolic volume,
and hence shift the Starling curve upwards. Decreases in contractility cause a
decrease in stroke volume/cardiac output for any level of right atrial pressure or end-
diastolic volume and hence shift the Starling curve downwards.
Afterload
Afterload is determined by the resistance to outflow from the ventricle, which for the
left ventricle is mainly determined by the aortic pressure, and for the right, the
pulmonary artery pressure.
An increase in afterload (e.g. hypertension, valve stenosis) means that the ventricles
must eject blood against a higher pressure, resulting in a decrease in stroke volume
and a downward shift of the Starling curve.
This decrease in stroke volume however results in an increase in end-systolic volume.

As a result, blood accumulates on the venous side and filling pressure rises. This will
result in a secondary increase in preload and a rightward shift along the Starling
curve; cardiac output is restored at the expense of an increased EDP.

Something wrong?
Functional Anatomy of Heart LAST UPDATED: 21ST

APRIL 2019
 Bookmark
Heart Chambers
The heart consists of four chambers - two thin-walled atria and two muscular
ventricles. The atria are separated from the ventricles by a band of fibrous connective
tissue called the annulus fibrosus, which provides a skeleton for the attachment of
muscle and cardiac valves, and prevents electrical conduction between the atria and
ventricles (except at the atrioventricular node).
Heart Valves
Blood flows from the right atrium into the right ventricle via the tricuspid
atrioventricular valve and from the left atrium into the left ventricle via the mitral
atrioventricular valve.
Blood is ejected from the right ventricle through the pulmonary semilunar valve into
the pulmonary artery and from the left ventricle via the aortic semilunar valve into
the aorta.
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C O M M O N S)
Heart Wall
The walls of the heart are formed from myocardium, and the left side has more
muscle than the right (as the systemic circulation has greater resistance to flow, the
left ventricle requires more force).
The inner surface of the heart is covered by the endocardium which provides an anti-
thrombogenic surface. The outer surface is covered by epicardium, a layer of
mesothelial cells. The whole heart is enclosed in a thin fibrous sheath, the
pericardium.
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
Capillary Filtration LAST UPDATED: 22ND
NOVEMBER 2022
PERIPHERAL VASCULAR SYSTEM  Bookmark
The capillary wall is very permeable to water. Water tends to flow from a low to a high
osmotic pressure, but from a high to a low hydrostatic pressure. The net flow of water
across the capillary wall is therefore determined by the balance between the
hydrostatic pressure which tends to drive water out of the capillaries and the oncotic
pressure which tends to draw water into the capillaries from the interstitial space.
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Starling's Equation
Starling's equation tells us that the net flow of water across the capillary wall is
proportional to (Pc - Pi) - (πp - πi), where (Pc - Pi) is the di!erence in hydrostatic
pressure between the capillary and interstitial space and (πp - πi) is the di!erence in
osmotic pressure between plasma and interstitial fluid. A positive value means there
is a net fluid movement out of the capillary (filtration), a negative value means there is
a net fluid movement into the capillary (absorption).
Oncotic Pressure
Across capillary walls, unlike proteins, most ions and small molecules di!use easily
and thus the crystalloid osmotic pressure they exert is roughly the same on either
side of the capillary wall; for this reason, the osmotic force across the capillary wall is
largely determined by protein concentration in the blood. Plasma protein
concentration is normally much higher than interstitial protein concentration because
very little protein is filtered; plasma colloid osmotic pressure is therefore higher than
interstitial colloid osmotic pressure and tends to draw fluid intravascularly.
Hydrostatic Pressure
Capillary hydrostatic pressure normally varies from about 35 mmHg at the arteriolar
end to about 15 mmHg at the venous end, whereas the interstitial hydrostatic
pressure is normally close to 0 mmHg (or is slightly negative). The greater hydrostatic
pressure inside the capillary tends to drive filtration of water out of the capillary
into the tissues.
Net Filtration
Normally overall the hydrostatic pressure along the length of the capillary is greater
than plasma oncotic pressure and thus there is a small net filtration of fluid from the
capillary into the interstitial space; of about 4000 L of plasma entering the capillaries
daily as the blood recirculates, a net filtration of 8 L occurs. Although arteriolar
constriction will reduce capillary hydrostatic pressure and therefore lead to the
reabsorption of fluid, this will normally be transient due to the concentration of
interstitial fluid, i.e. the increased interstitial oncotic pressure.
A reduction in plasma protein (e.g. starvation), or a loss of endothelium integrity with

di!usion of protein into the interstitial space (e.g. inflammation, ischaemia), will
reduce (πp - πi), leading to enhanced filtration and loss of fluid into the tissues.
Increased filtration is also caused by high venous pressures.
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
Characteristics of Special LAST UPDATED: 21ST
APRIL 2019
Circulations  Bookmark
PERIPHERAL VASCULAR SYSTEM
Skeletal Muscle Circulation
The skeletal muscle circulation normally receives about 15 - 20% of the cardiac
output, but this may rise to > 80% during exercise. Skeletal muscle provides a major
contribution to the total peripheral resistance and sympathetic regulation of muscle
blood flow is important in the baroreceptor reflex. At rest most capillaries are not
perfused as their arterioles are constricted. Capillaries are recruited during exercise
by metabolic hyperaemia, caused by release of K+ and CO2 from the muscle and
adenosine. This overrides sympathetic vasoconstriction in working muscle; the latter

reduces flow in non-working muscle conserving cardiac output.
Pulmonary Circulation
The pulmonary circulation is not controlled by either autonomic nerves or metabolic

products, and the most important mechanism regulating flow is hypoxic pulmonary
vasoconstriction, in which small arteries constrict in response to hypoxia (in contrast
to elsewhere in the body).
If an area of lung is poorly ventilated and the alveolar partial pressure of oxygen is low,
pulmonary blood vessels are constricted and blood is diverted to areas of the lung
that are better ventilated, thus maintaining optimal ventilation-perfusion matching.
This e"ect is accentuated by high alveolar PCO2.
The response is unhelpful in the presence of global lung hypoxia, at altitude or in

respiratory failure, where it may contribute to the development of pulmonary
hypertension and right-sided heart failure (cor pulmonale).
Cutaneous Circulation
The main function of the cutaneous circulation is thermoregulation. Arteriovenous
anastomoses (AVAs) directly linked arterioles and venules, allowing a high blood flow
into the venous plexus and thus radiation of heat. AVAs are mostly found in the
hands, feet and areas of the face.
Temperature is sensed by peripheral thermoreceptors and the hypothalamus

Temperature is sensed by peripheral thermoreceptors and the hypothalamus
coordinates the response.
When temperature is low, sympathetic stimulation of alpha-adrenergic receptors

causes vasoconstriction of cutaneous vessels minimising loss of body heat (a similar
response occurs in the baroreceptor reflex). Piloerection traps insulating air.
Increased temperatures reduce sympathetic adrenergic stimulation, causing

vasodilation and allowing more blood to flow to the skin and radiate its heat to the
environment, whereas activation of sympathetic cholinergic fibres promotes sweating
and the release of bradykinin, which also causes vasodilation.
Cerebral Circulation
The brain receives around 15% of the total cardiac output and has a high capillary
density.
The endothelial cells of the capillaries of the blood-brain barrier have very tight
junctions, and contain membrane transporters that control the movement of
substances, such as ions, glucose and amino acids, and tightly regulate the
composition of cerebrospinal fluid. This is continuous except where substances need
to be absorbed or released e.g. pituitary gland, choroid plexus.
The autoregulation of cerebral blood flow can maintain a constant flow for blood
pressures (MAP) between 50 and 170 mmHg. CO2 and K+ are particularly important
metabolic regulators in the brain, with increasing concentration causing vasodilation

and a functional hyperaemia.
Hyperventilation reduces blood PCO2 and can cause fainting due to cerebral
vasoconstriction.
Coronary Circulation
The heart has a high metabolic demand and its high capillary density allow it to
extract an unusually large fraction (about 70%) of oxygen from the blood.
In exercise, the reduced diastolic interval and increased oxygen consumption demand
a greatly increased blood flow which is achieved by metabolic hyperaemia mediated
by adenosine, K+ and hypoxia. This overrides the vasoconstriction mediated by
sympathetic nerves acting at alpha-adrenergic receptors and is assisted by

circulating adrenaline which causes vasodilation by acting on beta-adrenergic
receptors.

Something wrong?
Local Control of Blood Flow LAST UPDATED: 21ST

APRIL 2019
In addition to central control of blood pressure, tissues can regulate their own
blood flow to match their requirements via autoregulation, metabolic
factors and local hormones (autocoids).
Autoregulation
Autoregulation is the ability to maintain a constant blood flow despite variations

in blood pressure (between 50 - 170 mmHg). It is particularly important in the
brain, kidney and heart. There are two main methods contributing to
autoregulation.
The myogenic mechanism involves arterial constriction in response to

stretching of the vessel wall, probably due to activation of smooth muscle
stretch-activated Ca2+ channels and Ca2+ entry. A reduction in pressure

and stretch closes these channels, causing vasodilatation.
The second mechanism of autoregulation is due to locally produced
vasodilating factors; an increase in blood flow dilutes these factors
causing vasoconstriction, whereas decreased blood flow has the opposite
e"ect.
Metabolic Factors
Many factors may contribute to metabolic hyperaemia (increased blood flow),
with the most important being K+, CO2 and adenosine, and in some cases
hypoxia itself.
K+, released from active tissues and in ischaemia, causes vasodilation
partly by stimulating the Na+ pump, thus increasing Ca2+ removal from
smooth muscle cells and hyperpolarising the cell.
smooth muscle cells and hyperpolarising the cell.
CO2 and acidosis cause vasodilation largely through increased nitric oxide
production and inhibition of smooth muscle Ca2+ entry.

Adenosine, released from the heart, skeletal muscle and brain during
increased metabolism and hypoxia, causes vasodilation by stimulating the
production of cAMP in smooth muscle.
Hypoxia may reduce ATP su#ciently for K+ channels to activate causing

hyperpolarisation.
Autocoids
Autocoids are mostly important under certain circumstances, for example:
In inflammation, local inflammatory mediators such as histamine and

bradykinin cause vasodilation and increased permeability of exchange
vessels, leading to swelling but allowing access by immune cells to
damaged tissues.
In clotting, serotonin and thromboxane A2 released from activated
platelets cause vasoconstriction to help reduce bleeding.

Something wrong?
Lymphatic Capillaries LAST UPDATED: 28TH

FEBRUARY 2019
Normally, filtration of fluid out of the capillaries is slightly greater than absorption
of fluid into the capillaries. Fluid filtered by the microcirculation (about 8 L per day)
is returned to the circulation by the lymphatic system.
Lymphatic capillaries are blind-ended tubes walled with endothelial cells which
allow the entry of fluid, protein and bacteria, but prevent their exit. Lymphatic
capillaries drain into collecting lymphatics and then into larger lymphatic vessels,
both containing smooth muscle and unidirectional valves.
From here, lymph is propelled by smooth muscle constriction and compression of

the vessels by body movements into a!erent lymphatics and then the lymph
nodes, where bacteria and other foreign materials are removed by phagocytes.
Most fluid is reabsorbed here by capillaries, with the remainder returning via
e!erent lymphatics and the thoracic duct into the subclavian veins.
The lymphatic system plays a major role in the body's immune defence and is also
important for absorption and transport of fats.
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
Oedema LAST UPDATED: 28TH
FEBRUARY 2019
Oedema is swelling of the tissues due to excess fluid in the interstitial space.
This may be caused by increased filtration, resulting in fluid overwhelming the

lymphatic system, or due to obstruction or dysfunction of the lymphatic system itself.
A reduction in plasma protein (e.g. starvation), or a loss of endothelium integrity with

di!usion of protein into the interstitial space (e.g. inflammation, ischaemia), will
reduce the oncotic pressure gradient, leading to enhanced filtration and loss of fluid
into the tissues.
Reduced venous drainage (increased venous pressure) will increase capillary

hydrostatic pressure with a similar e!ect. Standing without moving the legs prevents
the operation of the muscle pump leading to local venous pressure rises and leg
oedema. In congestive heart failure, reduced cardiac function results in increased
pulmonary and central venous pressures, leading to pulmonary oedema and
peripheral oedema respectively.
Mechanism of Causes
Oedema
Increased capillary Caused by increased venous pressures e.g. by

hydrostatic pressure gravitational forces, volume expanded states, in heart
failure or with venous obstruction
Decreased Caused by decreased protein concentration in blood

plasma oncotic e.g. nephrotic syndrome, protein malnutrition, liver
pressure failure
Increased capillary Caused by proinflammatory mediators or by damage

permeability (leading to the structural integrity of capillaries so that they
to reduced oncotic become more 'leaky' e.g. in tissue trauma, burns and
pressure gradient) severe inflammation
Lymphatic Caused by, for example, filariasis or following lymph

obstruction node dissection, surgery or radiation therapy

Transcapillary Exchange LAST UPDATED: 21ST
APRIL 2019
Capillaries and the smallest venules are formed from a single layer of endothelial cells
supported on the outside by a basal lamina containing collagen. The luminal surface is
covered by the glycoprotein network called the glycocalyx.
Capillary Permeability
Capillaries throughout the body vary in their permeability based on the size of their
pores. There are three basic types:
Continuous capillaries
capillaries, found in the skin, lungs, muscles and CNS, are the
most selective with low permeability, as junctions between the endothelial cells
are very tight, restricting the flow of molecules with MW > 10,000.
Fenestrated capillaries
capillaries, found in renal glomeruli, endocrine glands and
intestinal villi, are more permeable with less tight junctions, and the endothelial
cells are also punctured by pores which allow large amounts of fluids or
metabolites to pass.
Discontinuous capillaries
capillaries, found in the reticuloendothelial system (bone
marrow, liver and spleen), have large gaps between endothelial cells and are
permeable to red blood cells.
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Transcapillary Exchange
Water, gases and other substances cross the capillary wall mainly by di"usion down
their concentration gradients.
Non-polar lipophilic substances e.g. CO2 and O2 can cross the endothelial lipid bilayer
membrane easily. The membrane is however more impermeable to hydrophilic

molecules such as glucose and polar molecules and ions. Such substances mainly
cross the wall of continuous capillaries through the gaps between endothelial cells,
slowed down by tight junctions between cells and by the glycocalyx so that di"usion
is much slower than for lipophilic substances.
This small pore system also prevents the di"usion of substances greater than 10,000
Da such as plasma proteins. Plasma proteins can cross the capillary wall, but
extremely slowly; this may involve large pores through endothelial cells, such as in
fenestrated capillaries or large spaces between endothelial cells, such as in
discontinuous capillaries.

Vascular System Structure LAST UPDATED: 21ST
APRIL 2019
The vascular system consists of arteries and arterioles that take blood from the heart
to the tissues, thin-walled capillaries and postcapillary venules that allow the
di!usion of gases and metabolites, and venules and veins that return blood to the
heart. The blood pressure, vessel diameter and wall thickness vary throughout the
circulation. Varying amounts of smooth muscle are contained within the vessel walls,
allowing them to constrict and alter their resistance to flow.
Arteries and Arterioles
Large arteries are elastic and partially damp out oscillations in pressure produced by
pumping of the heart; sti! arteries (e.g. age, atherosclerosis) result in larger
oscillations. The major arteries are conductance vessels and divide repeatedly into
smaller muscular arterioles.
Smaller arteries and arterioles contain relatively more muscle and are resistance
vessels, responsible for controlling tissue blood flow through constriction. Each small
arteriole feeds many capillaries via several terminal arterioles.
Microcirculation
The microcirculation consists of the terminal arterioles and the exchange vessels, the
capillaries and small postcapillary venules, which have no smooth muscle or valves
and which provide the exchange surface between blood and tissues.
Venules and Veins
Small venules rejoin into larger venules which ultimately drain into veins. Veins have a
larger diameter than equivalent arteries and provide less resistance. They have thin
distensible walls and contain about 70% of the total blood volume at any one time.
Large veins are capacitance vessels and act as a blood volume reservoir; when
required they can constrict and increase the e!ective blood volume. Large veins in
the limbs contain one-way valves, and when muscle activity intermittently
compresses these veins, they act as a pump and assist venous return to the heart.
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
Vascular Tone Regulation LAST UPDATED: 21ST
APRIL 2019
Basis of Vasoconstriction
Most vasoconstrictors bind to G-protein coupled receptors which mediate elevation
in intracellular [Ca2+], leading to vascular smooth muscle contraction. Important

vasoconstrictors include endothelin-1, angiotensin II and noradrenaline.
The increase in intracellular [Ca2+] is brought about by release of Ca2+ from the
sarcoplasmic reticulum and by depolarisation and entry of Ca2+ via L-type voltage-
gated Ca2+ channels. Most types of vascular smooth muscle do not generate action
potentials, but instead depolarisation is graded, allowing graded entry of Ca2+.
Basis of Vasodilation
Vasodilation occurs by decreasing intracellular [Ca2+] through sequestration by the
sarcoplasmic reticulum Ca2+ ATPase and by removal from the cell by a plasma
membrane Ca2+ ATPase and Na+/Ca2+ exchange.
Most endogenous vasodilators cause relaxation by increasing cyclic guanosine

monophosphate (cGMP) (e.g. nitric oxide) or cyclic adenosine monophosphate (cAMP)
(e.g. prostacyclin, beta-adrenergic receptor agonists), which activate protein kinases
causing substrate level phosphorylation. L-type Ca2+ channel blocker drugs are
clinically e!ective vasodilators.
Endothelial Function
The endothelium plays a vital role in regulation of vascular tone (as well as regulation
of haemostasis, angiogenesis and inflammatory response).
In response to substances in the blood, endothelial damage or changes in blood flow,

it can synthesise several important substances; nitric oxide and prostacyclin are
important vasodilators and endothelin-1 and thromboxane A2 are potent
vasoconstrictors.
Nitric oxide (NO) production by the endothelium is increased by factors that elevate
intracellular Ca2+, including local mediators such as bradykinin, histamine and
serotonin, and some neurotransmitters (e.g. substance P). Increased flow (shear
stress) also stimulates NO production and additionally activates prostacyclin
synthesis. The basal production of NO continuously modulates vascular resistance.
Nitric oxide also inhibits platelet activation and thrombosis.
Endothelin-1 (ET-1) is an extremely potent vasoconstrictor peptide which is released

from the endothelium in the presence of many other vasoconstrictors, including
angiotensin II, antidiuretic hormone (ADH) and noradrenaline, and may be increased in
disease and hypoxia.
The eicosanoids prostacyclin (PGI2) and thromboxane A2 (TXA2) are synthesised by

the cyclooxygenase pathway from arachidonic acid, which is made from membrane
phospholipids by phospholipase A2.
Vasoconstricting Agents Vasodilating Agents
Endothelin-1 Nitric oxide
Thromboxane A2 Prostacyclin
Angiotensin II Beta-agonists
Noradrenaline (alpha 1-receptors) Calcium-channel blockers

Adrenal Function LAST UPDATED: 2ND
MAY 2019
PHYSIOLOGY / ENDOCRINE / ADRENAL FUNCTION
 Bookmark
The adrenal glands are located on the superior pole of each kidney. The glands are
retroperitoneal, covered in perinephric fat and enclosed in renal fascia. The adrenal
gland is divided into two functionally distinct regions; the larger outer region
(comprising about 90% of the gland) called the adrenal cortex and the inner, much
smaller region called the adrenal medulla.
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Adrenal Cortex
The adrenal cortex is functionally and anatomically divided into three zones of tissue
which each secrete di"erent steroid hormones:
The outer zona glomerulosa secretes mineralocorticoid (aldosterone) which

regulates salt and water homeostasis.
The zona fasciculata secretes glucocorticoid (cortisol and its analogues) which
regulates carbohydrate metabolism and the response to stress.
The inner zona reticularis secretes the androgen dehydroepiandrosterone
(DHEA) which has e"ects on the maintenance of secondary sexual
characteristics.
The release of cortisol and DHEA is stimulated by adrenocorticotropic (ACTH)

hormone from the anterior pituitary, which in turn is released in response to
corticotropin-releasing hormone (CRH) from the hypothalamus.
The secretion of aldosterone, in contrast, is mainly regulated by the renin-angiotensin
system, in response to low circulating blood volume, hyponatraemia or hyperkalemia.
Adrenal Medulla
The adrenal medulla produces catecholamines, and is controlled by and functions in

concert with the sympathetic nervous system.

Adrenal Insu!ciency LAST UPDATED: 21ST
APRIL 2019
 Bookmark
Primary Adrenal Insu!ciency
Primary insu!ciency of the adrenal cortex, called Addison's disease, arises as a result
of a destructive process in the adrenal gland or genetic defects in steroid synthesis.
All three zones of the adrenal cortex are typically a"ected.
Causes
Causes of primary adrenal insu!ciency include:
Autoimmune adrenalitis (over 70% of cases in the developed world)

Genetic e.g. congenital adrenal hyperplasia/hypoplasia
Iatrogenic e.g. bilateral adrenalectomy, drugs
Infarction/haemorrhage e.g. antiphospholipid syndrome, anticoagulants
Infection e.g. TB, fungal, AIDS
Infiltration e.g. amyloidosis, haemochromatosis
Malignancy e.g. lung, breast or kidney (symptomatic adrenal insu!ciency
uncommon)
Clinical Features
Symptoms/Signs:
Onset is usually gradual and symptoms may be non-specific

Fatigue, weakness, anorexia, weight loss, nausea and abdominal pain
Dizziness and postural hypotension (due to mineralocorticoid deficiency)
Increased pigmentation (due to ACTH excess from reduced cortisol negative
feedback leading to melanocyte stimulation)
Reduced libido and loss of axillary/pubic hair in women (due to androgen
deficiency)
Typical Biochemistry:
Hyponatraemia (due to mineralocorticoid deficiency)

Hyperkalaemia (due to mineralocorticoid deficiency)
Hypoglycaemia (due to glucocorticoid deficiency)
Low morning cortisol
Elevated ACTH
Elevated plasma renin
Synacthen test (cortisol post Synacthen < 500 nmol/L)
Positive adrenal autoantibodies
Management
Patients with primary adrenal failure need lifelong glucocorticoid and

mineralocorticoid replacement therapy, typically given as hydrocortisone and
fludrocortisone. Patients should be advised to increase the dose of their
glucocorticoid at times of illness and glucocorticoids need to be administered IV/IM
during surgery or in cases of prolonged vomiting/diarrhoea. Patients should be
provided with a steroid emergency card, encouraged to wear medical alert jewellery,
and be provided with emergency contact details for their endocrine team.
An acute exacerbation of Addison's disease is called an adrenal crisis. It is a life-

threatening emergency characterised by hypotensive hypovolaemic shock and
hypoglycaemia. The mainstay of treatment is rehydration and urgent systemic
glucocorticoid therapy.
Acute adrenal failure may also occur if long-term high-dose steroid treatment is
stopped abruptly (as the prolonged steroid treatment has suppressed the HPA axis
and natural ACTH release). Patients taking long-term steroids should thus be
instructed not to stop their steroids abruptly, at least until an adequate adrenal
reserve has been demonstrated.
Secondary Adrenal Insu!ciency
Secondary adrenal insu!ciency can arise as the result of any cause of

hypopituitarism. Patients display similar features as above with the exception that
pigmentation is absent as ACTH is not raised, and mineralocorticoid deficiency is not
a feature, because aldosterone secretion is not significantly influenced by ACTH.

Something wrong?
Aldosterone LAST UPDATED: 2ND

MAY 2021
PHYSIOLOGY / ENDOCRINE / ADRENAL FUNCTION /
RENAL / MECHANISM OF FILTRATION  Bookmark
Aldosterone is secreted by the zona glomerulosa of the adrenal cortex.
Stimulating Factors
Aldosterone release is stimulated by:
Angiotensin II (secondary to a fall in blood volume, blood
pressure or plasma [Na+])
High plasma [K+]

ACTH
N.B. ACTH is less important as a regulator, so pituitary failure does not severely
impair aldosterone secretion.
Function
Aldosterone acts mainly at the renal distal convoluted tubule (DCT) to

cause sodium retention and potassium loss. It increases the synthesis of
transport mechanisms in the distal nephron including the Na+ pump, Na+/H+
antiporter, and Na+ and K+ channels in principal cells, and H+ ATPase in
intercalated cells. Na+ (and thus water) reabsorption and K+ and H+ secretion
are thereby enhanced.
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
Catecholamines LAST UPDATED: 21ST
APRIL 2019
 Bookmark
The chroma!n cells of the medulla secrete noradrenaline (20%) and adrenaline (80%),
stimulated by sympathetic preganglionic neurones located in the spinal cord.
Derivation and Degradation
These catecholamine hormones are derived from tyrosine by a series of steps

catalysed by specific enzymes. The production of the rate-limited enzyme,
phenylethanolamine-N-methyltransferase, is stimulated by cortisol, providing a direct
link between the functioning of the adrenal medulla and cortex.
Catecholamines are broken down extracellularly and in the liver by catechol-O-

methyltransferase (COMT) and intracellularly by monoamine oxidase (MAO).
E"ects of Adrenaline
These catecholamines act on alpha- and beta- G-protein coupled receptors , having
the same e"ect in tissues as the stimulation of sympathetic nerves. Noradrenaline
has equal potency at all adrenoceptors, but adrenaline at normal plasma
concentrations will only activate beta-receptors (higher levels do stimulate alpha-
receptors).
Actions of adrenaline:
Cardiovascular system
Increased rate and force of cardiac contraction

Vasoconstriction of vessels in skin, mucous membranes and splanchnic
bed
Vasodilation of skeletal muscle vessels
Increased cardiac output and blood pressure
Respiratory system
Bronchodilation
Increased ventilation rate
Gastrointestinal system
Smooth muscle relaxation

Contraction of sphincters
Metabolism
Decreased insulin release

Increased glucagon release
Increased thermogenesis
Increased glycolysis
Increased lipolysis
Eye
Pupillary dilation

Cortisol LAST UPDATED: 22ND
NOVEMBER 2022
 Bookmark
Cortisol and its analogues have powerful e!ects on glucose metabolism and all
collectively classified as glucocorticoids (although they do have some
mineralocorticoid action). Cortisol is secreted from the zona fasciculata of the adrenal
cortex.
Regulation of Cortisol Secretion in Health
Cortisol release is stimulated by adrenocorticotropic hormone (ACTH) from the

anterior pituitary, which in turn is released in response to corticotropin-releasing
hormone (CRH) from the hypothalamus. Cortisol has a negative feedback e!ect on
the hypothalamus and the anterior pituitary gland, inhibiting release of CRH and
ACTH respectively.
The e!ects of cortisol are mediated by intracellular receptors that translocate to the
cell nucleus after binding the hormone.
Cortisol is released during the course of normal physiological activity in a pulsatile

pattern. Cortisol release displays a circadian rhythm, with the highest levels in the
early morning.
Regulation of Cortisol Secretion in Stress
The primary stimulus for the increased release of glucocorticoids is stress, which is
the result of exposure to adverse situations.
Stress response:
The stress response is driven by the amygdala, part of the forebrain that stimulates:
activity in the hypothalamic CRH neurons

activity in the sympathetic nervous system
activity in the parasympathetic nerves that cause acid secretion in the
stomach
the feeling of fear
The actions of the two parts of the adrenal gland are complementary in response to
stress. Catecholamines are released from the adrenal medulla to produce a rapid
increase in cardiac output and the mobilisation of metabolic fuels. Corticosteroids
produce a slower, more sustained response.

produce a slower, more sustained response.
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YÉ P E Z J, R E YN A-GAR F IAS H, BAR B OSA-CAB R E R A R E , DR AGO-S E R R AN O M E [C C BY 3.0
E!ects of Cortisol
Cortisol acts to:
raise plasma glucose by stimulating gluconeogenesis in the liver and inhibiting

peripheral glucose uptake into storage tissues
increase protein breakdown in skeletal muscle, skin and bone to release amino
acids
increase lipolysis from adipose tissues to release fatty acids
and at higher levels...
mimic the actions of aldosterone on the kidney to retain Na+ and water
and lose K+ ions
suppress the action of immune cells

Something wrong?
Cushing’s Syndrome LAST UPDATED: 21ST

APRIL 2019
 Bookmark
Cushing's syndrome is the name given to the clinical symptoms and signs
induced by chronic glucocorticoid excess.
Cushing's disease refers to the specific condition of excess corticosteroids as a

result of an ACTH-secreting pituitary adenoma, leading to bilateral adrenal
hyperplasia and excess cortisol secretion. Cushing's disease is also associated
with hyperpigmentation due to the melanocyte-stimulating action of ACTH.
Causes
This may occur due to:
1. Excess secretion of ACTH
ACTH secreting pituitary adenoma (Cushing's disease)
Ectopic ACTH e.g. lung cancer
2. Excess secretion of cortisol
Adrenal adenoma or carcinoma
3. Exogenous steroids
Clinical Features
Plethoric moon face

Central obesity
Impaired glucose tolerance or diabetes
Hypertension
Menstrual irregularity, erectile dysfunction
Osteoporosis and kyphosis
Purple striae and tendency to bruise easily
Proximal myopathy
Hirsutism and frontal alopecia
Ankle oedema
Interscapular fat pad
Acne
Musculoskeletal aches and pains
Depression
Poor wound healing
Polycythaemia
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Management
If an adrenal tumour is found, adrenalectomy is the treatment of choice. In

ectopic ACTH, appropriate treatment of the underlying malignancy and medical
control of cortisol levels are needed. In Cushing's disease, trans-sphenoidal
removal of the pituitary adenoma is indicated. Medical treatment (e.g.
metyrapone which blocks cortisol production) can be used pre-operatively if
symptoms are severe, or there is uncontrolled hypokalaemia, diabetes and
hypertension.

Hyperaldosteronism LAST UPDATED: 24TH
APRIL 2020

 Bookmark
Hyperaldosteronism can be defined as excessive levels of aldosterone which may be

independent of the renin-angiotensin axis (primary hyperaldosteronism) or due to
high renin levels (secondary hyperaldosteronism).
Pathophysiology
Excessive aldosterone levels act at the distal renal tubule, promoting sodium
retention, which results in water retention and volume expansion with hypertension.
There is also excretion of potassium, resulting in hypokalaemia.
Causes of Primary Hyperaldosteronism
Adrenal adenoma (Conn's syndrome, accounts for >80% of cases of

hyperaldosteronism)
Adrenal hyperplasia
Familial hyperaldosteronism
Adrenal carcinoma
Features of Primary Hyperaldosteronism
Hypertension
Hypokalaemia
Metabolic alkalosis
Hypernatraemia (may be high end of normal or only mildly raised)
Aldosterone levels high
Renin levels low
Management of Primary Hyperaldosteronism
Medical management is used in the period prior to surgery - which is the definitive
treatment. Medical management involves the use of aldosterone antagonists e.g.
spironolactone. Surgical treatment involves adrenalectomy.
Phaeochromocytoma LAST UPDATED: 21ST
APRIL 2019
 Bookmark
Phaeochromocytomas are catecholamine-secreting tumours which occur in about

0.1% of patients with hypertension. In about 90% of cases they arise from the adrenal
medulla. The remaining 10%, which arise from extra-adrenal chroma!n tissue, are
termed paragangliomas.
Clinical Features
Common presenting symptoms include one or more of headache, sweating, pallor and
palpitations. Less commonly, patients describe anxiety, panic attacks and pyrexia.
Hypertension, whether sustained or episodic, is present in at least 90% of patients.
Left untreated phaeochromocytoma can occasionally lead to hypertensive crisis,
encephalopathy, hyperglycaemia, pulmonary oedema, cardiac arrhythmias, or even
death. Patients with undiagnosed phaeochromocytoma having routine surgery can
develop severe hypertension or sudden death.
Diagnosis
Diagnosis relies on the biochemical confirmation of elevated catecholamines or their

metabolites (metanephrines), followed by radiological localisation of the tumour.
Management
The definitive treatment is surgical excision. In advance of the surgery, it is mandatory

that all patients are protected from the e"ects of catecholamine excess by alpha-
blockade with or without beta-blockade. Alpha-blockade, conventionally
administered as oral phenoxybenzamine, should be commenced before beta-
blockade in order to avoid unopposed alpha-adrenergic stimulation and the risk of
hypertensive crisis. Beta-blockers can be introduced subsequently to control reflex
tachycardia.

Calcitonin - MRCEM Success 28/03/2023, 12:14 PM
Calcitonin LAST UPDATED: 13TH

MARCH 2019
PHYSIOLOGY / ENDOCRINE / CALCIUM AND BONE
 Bookmark
Calcitonin is secreted by the parafollicular cells (C-cells) of the thyroid gland.
Calcitonin is secreted in response to rising or high levels of plasma Ca2+ ions and acts
to lower circulating levels of calcium.
Calcitonin acts on the kidneys to inhibit renal reabsorption of calcium and phosphate
and on the bones to inhibit bone resorption by osteocytes.
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Calcium Handling LAST UPDATED: 24TH
NOVEMBER 2020
PHYSIOLOGY / ENDOCRINE / CALCIUM AND BONE /
RENAL / CALCIUM BALANCE  Bookmark
Normal Values of Calcium and Rationale for Corrected Calcium

Values
RCEM defines the normal value for total serum calcium as 2.1 - 2.5 mmol/L. This is the
sum of free ionised calcium and calcium bound to albumin.
This total serum calcium measurement must be adjusted for albumin levels (as
patients with a low albumin have total serum calcium lower than the reference range
yet have normal free ionised calcium and vice versa). 0.02 mmol/L should be added to
the calcium concentration for every g/L that albumin is below 40 and 0.02 mmol/L
should be subtracted for every g/L that albumin is above 40.
Corrected calcium = Measured calcium + [(40 g/l - albumin) x 0.02]
Calcium Absorption
Calcium rich foods include: cheese, milk, yoghurt, fish and some vegetables and nuts.
Of dietary calcium, about 25 - 30% is absorbed by the gut. Ca2+ is absorbed

throughout the small intestine but mainly in the duodenum and proximal jejunum.
Absorption occurs by a transcellular process involving intracellular calcium-binding
proteins called calbindins. Gut absorption is increased by activated vitamin D.
Physiological Actions of Calcium
Calcium is essential for:
enzymatic reactions
intracellular signalling
nerve conduction
skeletal, cardiac and smooth muscle contraction
the release of neurotransmitters
the release of hormones
secretion from exocrine glands
blood clotting
bone mineralisation
Transport of Calcium in the Blood
Only unbound ionised calcium is physiologically active.
Free intracellular Ca2+ must be maintained at a very low level; most is bound to
proteins or stored in the endoplasmic reticulum and mitochondria.
Blood calcium levels in the extracellular fluid are kept within a very narrow range to
maintain normal physiological processes:
about 45% of serum calcium is bound to albumin

about 5% is complexed to other ions and
about 50% is free ionised Ca2+.
Ionised calcium binds to negatively charged sites on protein molecules, competing

with hydrogen ions for the same binding sites on albumin and other calcium-binding
proteins. This binding is pH dependent and alters the level of ionised calcium in the
blood. An increase in pH, alkalosis, promotes increased protein binding, which
decreases free calcium levels. Acidosis, on the other hand, decreases protein binding,
resulting in increased free calcium levels.
Renal Calcium Handling
Calcium that is not protein bound is freely filtered in the glomerulus, and there is
reabsorption along the nephron.
About 70% is reabsorbed in the proximal tubule.

About 20% is reabsorbed in the thick ascending limb of the loop of Henle.
This reabsorption is mainly passive and paracellular and driven by sodium
reabsorption. Sodium reabsorption causes water reabsorption, which raises
tubular calcium concentration, causing calcium to di"use out of the tubules.
The positive lumen potential also encourages calcium to leave the tubule.
About 5 - 10% is reabsorbed in the distal convoluted tubule.
Less than 0.5% is reabsorbed in the collecting ducts.
Calcium reabsorption in the distal nephron is active and transcellular and is the
major target for hormonal control.
Regulation of Renal Calcium Handling
Calcium homeostasis is primarily controlled by three hormones: parathyroid hormone,

activated vitamin D and calcitonin.
Parathyroid hormone acts on the kidneys to increase calcium reabsorption in
the distal tubule by activating Ca2+ entry channels in the apical membrane and
the Ca2+ ATPase pump in the basolateral membrane (and to decrease

phosphate reabsorption in the proximal tubule).
Activated vitamin D acts to increase calcium reabsorption in the distal tubule
via activation of a basolateral Ca2+ ATPase pump (and to increase phosphate

reabsorption).
Calcitonin acts to inhibit renal reabsorption of calcium (and phosphate).
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
Osteomalacia LAST UPDATED: 21ST
APRIL 2019

 Bookmark
Osteomalacia is a disorder of mineralisation of bone matrix leading to soft malleable

bone. Rickets is a disorder of defective mineralisation of cartilage in the epiphyseal
growth plates of children.
Osteomalacia is caused by impaired bone metabolism primarily due to inadequate

levels of available phosphate, calcium, and vitamin D, or because of resorption of
calcium. The most common cause of osteomalacia is a deficiency of vitamin D.
Clinical Features
Features of osteomalacia include:
Bone pain (particularly bone, pelvis, ribs)

Neuromuscular dysfunction (particularly in the gluteal muscles, leading to
waddling gait)
Pseudofractures on x-ray (looser zones)
Elevated alkaline phosphatase, hypocalcaemia and low phosphate due to
secondary hyperparathyroidism
Features of rickets include:
Bowing of tibia
Poor growth
Pain in spine, pelvis, legs
Projection of sternum and chest wall deformities
Back deformities e.g. kyphosis
Management
Management includes reversal of risk factors, increased dietary intake, correction of

hypocalcaemia and vitamin D replacement.

Osteoporosis LAST UPDATED: 21ST
APRIL 2019

 Bookmark
Osteoporosis is a disease characterised by reduced bone mass and increased bone

fragility resulting in an increased risk of fracture after minimal trauma (particularly of
the hip, spine and distal radius). It is very common in postmenopausal women.
Bone densitometry, measured by dual energy X-ray absorptiometry (DXA) scan, is the
mainstay of diagnosis. Osteoporosis, defined according the the T score, occurs when
bone density is >2.5 standard deviations below normal peak bone mass.
Risk Factors for Primary Osteoporosis
This is multifactorial, usually resulting from a combination of oestrogen deficiency

and aging. Risk factors include:
Oestrogen deficiency
Ageing
Family history
Smoking
Alcohol
Vitamin D deficiency
Causes of Secondary Osteoporosis
(Consider when osteoporosis occurs in non-'at risk' groups including men and
premenopausal women)
Hypogonadism
Hyperthyroidism
Hyperparathyroidism
Cushing's syndrome
Exogenous steroids
Hyperprolactinaemia
Management
Clinical risk prediction of fracture is a better guide to treatment than DXA scanning
alone. Algorithms exist to calculate the 10 -year fracture risk e.g. the FRAX score.
Non-pharmacological
Balanced diet
Exercise
Smoking cessation
Falls prevention
Avoidance of excessive alcohol intake
Avoidance of drugs that cause osteoporosis e.g. corticosteroids
Pharmacological
Calcium and vitamin D supplementation

Bisphosphonates
Selective oestrogen receptor modulators (SERMs)
Parathyroid hormone
Hormone replacement therapy (HRT)

Phosphate Handling LAST UPDATED: 21ST
APRIL 2019
Phosphate is abundant in the body and is an important intracellular and

extracellular anion (but is predominantly intracellular). About 65% of dietary
phosphate is absorbed, mainly in the duodenum and jejunum by a transcellular
process which is enhanced by vitamin D.
Ca2+ and PO43- precipitate to form insoluble calcium phosphate and their
concentrations in the blood are close to the saturation point at which calcium
phosphate complexes precipitate out of solution onto the bone matrix.
Therefore an increase in one of the ions results in the precipitation of some
calcium phosphate and thus some of the other ion is removed from the solution;
Ca2+ and PO43- concentrations are thus inversely proportional.
Renal Phosphate Handling
Unbound PO43- is filtered freely at the glomerulus and there is reabsorption
along the nephron. The maximum rate of reabsorption is limited and and excess
filtered phosphate above a threshold level is excreted. Of filtered phosphate,
80% is reabsorbed in the proximal tubule by a transcellular process. The distal
tubules reabsorb a further 10% of the filtered phosphate and the collecting
ducts a further 2 - 3%.
PO43- renal excretion is regulated by:
PTH (increases excretion by inhibiting reabsorption in the proximal tubule)

activated vitamin D (decreases excretion by increasing reabsorption in the
distal tubule)
acidosis (increases excretion)
glucocorticoids (increases excretion)
calcitonin (increases excretion)
Parathyroid Hormone LAST UPDATED: 6TH
DECEMBER 2021
 Bookmark
Parathyroid hormone (PTH) is a peptide hormone synthesised by the chief cells of the
parathyroid glands, located immediately behind the thyroid gland.
Release of PTH
PTH is released in response to:
decreasing plasma [Ca2+] concentration
increasing blood [PO43-] concentration (indirectly by its binding to ionised

calcium and thereby e"ective reduction of plasma calcium levels).
PTH release is thus inhibited by normal blood calcium levels and also by
hypomagnesaemia.
E!ects of PTH
PTH acts to:
BONE:
increase calcium and phosphate resorption from bone (via immediate

stimulation of osteocytic osteolysis and later, by upregulation of
osteoclast activity)
KIDNEYS:
increase calcium reabsorption in the distal tubule of the nephron (by
activating Ca2+ entry channels in the apical membrane and the
Ca2+ ATPase pump in the basolateral membrane)

increase phosphate excretion by inhibiting reabsorption in the proximal
tubule of the nephron
inhibit renal bicarbonate reabsorption stimulating a metabolic acidosis
which favours dissociation of calcium from plasma proteins
stimulate 1-alpha-hydroxylase in the kidneys to produce more activated
vitamin D
GUT:
indirectly increase calcium and phosphate absorption in the small

intestine (via activated vitamin D)
Overall PTH acts to increase plasma calcium levels and decrease plasma phosphate
levels.
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
Something wrong?
Vitamin D LAST UPDATED: 21ST

APRIL 2019
 Bookmark
Vitamin D2 (ergocalciferol), derived from plants and yeasts and Vitamin D3

(cholecalciferol), derived from animal (particularly dairy) products, are obtained
in the diet and absorbed in the small intestine. Vitamin D3 can also be
manufactured from cholesterol within the body, via a reaction that is enabled by
ultraviolet irradiation of the skin.
Production of Activated Vitamin D
The D vitamins are converted to calcifediol (25-hydroxycholecalciferol) by

vitamin D 25-hydroxylase in the liver.
This is further converted to activated vitamin D (calcitriol or 1, 25 -

dihydroxycholecalciferol) by 1-alpha-hydroxylase in the cells of the renal
proximal tubule. This final reaction is the slowest step in the process and
therefore regulates the speed of the entire chain of reactions.
The enzyme 1-alpha-hydroxylase is stimulated by parathyroid hormone (PTH)

and thus this final step is regulated by PTH.
A C TT II V
V A TT I O N
N O FF V II TTA M I N
N D . ( IM AGE M O DIF IE D BY F RC E M S U C C E S S . O R IGIN AL BY
S P O RT E X M E D I C I N E V I A WWW.F LI C K R .C O M )
E!ects of Activated Vitamin D
Activated vitamin D acts to:
GUT:
increase calcium and phosphate absorption in the small intestine

(the main action)
KIDNEYS:
increase renal calcium reabsorption (in the distal tubule via
activation of a basolateral Ca2+ ATPase pump)

increase renal phosphate reabsorption
inhibit 1-alpha-hydroxylase activity in the kidneys (negative
feedback)
PARATHYROID GLANDS:
inhibit PTH secretion from the parathyroid glands
E FF F E
E C T S O FF A
A C TT I V
V A T E D V I TTA M I N D
D .. ( IM AGE BY S P O RTE X M E DIC IN E V IA
WWW.F LIC K R .C OM )

Vitamin D Deficiency LAST UPDATED:
15TH MARCH 2019
 Bookmark
Without activated vitamin D, calcium uptake from the gut is severely

impaired to the point at which intake of the hormone is insu!cient to
maintain body stores. This leads to the increased release of PTH and
resorption of bone.
A lack of vitamin D in children leads to inadequate calcification of bones,

which become malformed (rickets). Vitamin D deficiency in adults leads to
bone wasting resulting in soft malleable bone (osteomalacia).
Vitamin D deficiency can occur in:
dietary deficiency
malabsorption e.g. coeliac disease
lack of sun exposure
chronic kidney disease
liver failure

Diabetes Mellitus LAST UPDATED: 21ST
APRIL 2019
PHYSIOLOGY / ENDOCRINE / PANCREATIC FUNCTION
 Bookmark
Diabetes mellitus is a metabolic disorder characterised by persistent hyperglycaemia

which is a result of defects in insulin secretion, insulin action or both.
Classification
Diabetes mellitus is broadly classified as type 1 or type 2 (although rarer causes of

diabetes exist):
Type 1 (5 - 10%)
Autoimmune destruction of beta-cells of the pancreas results in absolute

insulin deficiency with patients requiring insulin to survive
In absence of insulin action in muscle and adipose tissue, glucose is not
transported into cells by the GLUT4 transporter
Type 2 (90 - 95%)
Caused by both insulin resistance and a defect in insulin secretion as a

result of beta-cell dysfunction
Insulin resistance occurs in skeletal muscle, adipose tissue and liver,
resulting in reduced glucose uptake in skeletal muscle, impaired
inhibition of hepatic glucose output and increased fatty acid production
in adipose tissue, which stimulates gluconeogenesis and triglyceride
synthesis
Risk factors include obesity, lack of physical activity, increasing age,
dyslipidaemia, hypertension, certain ethnic groups, genetic
predisposition
Clinical Features
T1DM:
Osmotic symptoms
Thirst, polydipsia, polyuria

Dehydration, hypovolaemia, drowsiness
Blurred vision
Cutaneous Candida infections
Catabolic symptoms
Muscle wasting, fatigue and weight loss
Diabetic ketoacidosis (approx 25% of children with T1DM present in DKA)
Aetiology
Impairment of glucose utilisation in the peripheral tissues leads to

increased gluconeogenesis and glycogenolysis in the liver with
consequent worsened hyperglycaemia.
Simultaneous counter-regulatory hormone hypersecretion
(including cortisol, glucagon and catecholamines) in tandem with
insulin deficiency causes release of free fatty acids into the
circulation as a result of lipolysis in adipose tissue.
Free fatty acids undergo oxidation in the liver to produce ketone
bodies and subsequent ketonaemia. As ketone bodies are weakly
acidic, this causes increased plasma hydrogen ion concentrations
and metabolic acidosis.
Characterised by the biochemical triad:
Hyperglycaemia (> 11 mmol/L)

Ketonaemia (> 3 mmol/L)
Acidosis (pH < 7.3 +/- HCO3 < 15 mmol/L)
Clinical features
Symptoms
Polyuria, polydipsia, thirst, lethargy, weight loss, nausea,

vomiting, anorexia, abdominal pain, dehydration, headache,
altered mental state
Signs
Dry mucous membranes, ketotic breath, tachycardia,

hypotension, Kussmaul breathing, focal signs of precipitant
e.g. infection
Management
Fluid replacement
Insulin (+ glucose)
Monitoring of [K+] (+/- replacement)
Treat underlying cause
T2DM:
One-third of cases are detected incidentally

Diagnosis is often delayed for many years and the patient can therefore present
with complications from prolonged hyperglycaemia
Only about half of patients present with the classic symptoms of thirst,
polydipsia, polyuria and tiredness secondary to hyperglycaemia, although these
symptoms are less marked than in T1DM
Hyperglycaemic hyperosmolar state (up to 25% of patients with T2DM present
as HHS)
Aetiology
Prolonged hyperglycaemia from insulin resistance or insulin

deficiency results in an osmotic diuresis with renal sodium and
potassium loss.
This results in extracellular volume depletion and dehydration, with
a raised serum osmolality.
Ketosis/ketonaemia does not typically occur in HHS, because some
insulin is still present and hyperosmolality can inhibit lipolysis.
Characterised by triad:
Hypovolaemia
Marked hyperglycaemia (> 30 mmol/L) without significant
hyperketonaemia or acidosis
Osmolality > 320 mosmol/kg
Clinical features
Polydipsia, polyuria, impaired cognitive function, tachycardia,

hypotension, seizures
Management
Treat underlying cause

Fluid replacement (+/- insulin)
Correct electrolyte imbalance
Treat with prophylactic anticoagulation
Diagnosis
Glucose concentration criteria:
In symptomatic individuals (e.g. thirst, polyuria, polydipsia and

unexplained weight loss):
A random venous plasma glucose concentration ≥ 11.1 mmol/L OR

A fasting plasma glucose concentration ≥ 7.0 mmol/L OR
Two-hour plasma glucose concentration ≥ 11.1 mmol/L after 75g
anhydrous glucose in an oral glucose tolerance test (OGTT)
In asymptomatic individual:
At least one of the above criteria fulfilled on two separate

occasions
HbA1c criteria:
HbA1c ≥ 48 mmol/mol (6.5%) confirmed with second sample unless
individual is symptomatic with plasma glucose ≥ 11.1 mmol/L when
confirmation is not needed
N.B. Not to use in children and young people, type 1 DM, symptom onset
within 2 months, pregnancy, drugs causing hyperglycaemia (e.g. steroids)
or blood conditions a"ecting Hb (e.g. haemolytic anaemia)
Complications
Macrovascular
Ischaemic heart disease
Angina, ACS
Cerebrovascular ischaemia
TIA, stroke
Peripheral vascular disease
Intermittent claudication, acute ischaemic limb, foot ulcer
Microvascular
Autonomic neuropathy
Resting tachycardia, postural hypotension, cardiac ischaemia,

sudden cardiac death
Gastroparesis, constipation/diarrhoea, oesophageal dysmotility
Erectile dysfunction, neuropathic bladder
Mononeuropathies
Often cranial nerves III and VI, median, ulnar and radial nerves
Diabetic peripheral neuropathy
Glove and stocking distribution, foot ulceration

Diabetic nephropathy
CKD
Diabetic retinopathy
Blindness
Hypoglycaemia
Hypoglycaemia occurs when plasma glucose falls below 4 mmol/L. It commonly

occurs as a result of insulin therapy; it can also occur with certain oral hypoglycaemic
agents.
In individuals without diabetes, the normal response to hypoglycaemia comprises

reduced insulin secretion from the pancreas and increased glucagon release. A
number of counter-regulatory hormones, including noradrenaline, cortisol and growth
hormone, are also released. In patients with diabetes, these responses are reduced,
especially with recurrent hypoglycaemia and with increased duration of disease - this
can result in hypoglycaemic unawareness.
Clinical features of hypoglycaemia:
Autonomic symptoms
Sweating, feeling hot, anxiety/agitation, palpitations, shaking,

paraesthesia, dizziness
Neuroglycopaenic symptoms
Weakness, blurred vision, di#culty speaking, poor concentration, poor

coordination, drowsiness, confusion, seizures, coma
Other symptoms
Nausea, fatigue, hunger
Any suspected hypoglycaemia should be managed as an emergency, and treated

immediately to return blood glucose to the normal range.

Endocrine Pancreas LAST UPDATED: 22ND
NOVEMBER 2022
 Bookmark
The endocrine pancreas refers to those cells within the pancreas that
synthesise and secrete hormones.
The endocrine portion of the pancreas takes the form of many small clusters of
cells called islets of Langerhans or, more simply, pancreatic islets. Humans have
roughly one million islets.
Pancreatic islets house five main cell types, each of which produces a di!erent
endocrine product:
Alpha cells producing glucagon

Beta cells producing insulin (most abundant cells)
Delta cells producing somatostatin
Epsilon cells producing ghrelin
PP cells (gamma cells or F cells) producing pancreatic polypeptide
Islets are richly vascularised, allowing their secreted hormones ready access to
the circulation. Although islets comprise only 1-2% of the mass of the pancreas,
they receive about 10 to 15% of the pancreatic blood flow. Additionally, they are
innervated by parasympathetic and sympathetic neurons, and nervous signals
clearly modulate secretion of insulin and glucagon.
O
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A S LL O
OCC A LL II S A
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ANND
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AN D-AN ATOM Y-TH E-PAN C R EAS-IS-C OM P OS ED-OF-AN-EN DOAN D_F IG3_328475917)
Ghrelin
Ghrelin is a hormone that is produced and released mainly by the stomach with
small amounts also released by the small intestine, pancreas and brain. Ghrelin
has numerous functions. It is termed the ‘hunger hormone’ because it
stimulates appetite, increases food intake and promotes fat storage. It
circulates in the bloodstream and acts at the hypothalamus, an area of the brain
crucial in the control of appetite. Ghrelin has also been shown to act on regions
of the brain involved in reward processing such as the amygdala. Ghrelin also
stimulates the release of growth hormone from the pituitary gland, which, unlike
ghrelin itself, breaks down fat tissue and causes the build-up of muscle. Ghrelin
also has protective e!ects on the cardiovascular system and plays a role in the
control of insulin release.
Levels of ghrelin in the blood rise just before eating and when fasting, with the
timing of these rises being a!ected by our normal meal routine. Hence, ghrelin is
thought to play a role in mealtime ‘hunger pangs’ and the need to begin meals.
Levels of ghrelin increase when fasting (in line with increased hunger) and are
lower in individuals with a higher body weight compared with lean individuals,
which suggests ghrelin could be involved in the long-term regulation of body
weight. Eating reduces concentrations of ghrelin. Di!erent nutrients slow down
ghrelin release to varying degrees; carbohydrates and proteins restrict the
production and release of ghrelin to a greater extent than fats. Somatostatin
also restricts ghrelin release, as well as many other hormones released from the
digestive tract.

Glucagon Physiology LAST UPDATED: 9TH
JULY 2020
 Bookmark
Glucagon is produced by α cells, located peripherally within the islets of Langerhans,

in the endocrine tissues of the pancreas.
Glucagon release patterns tend to be the mirror image of those of insulin. Low blood
glucose initiates glucagon release directly and also drives nervous and hormonal
release of catecholamines which activate beta-adrenoceptors on α cells to augment
glucagon release.
Glucagon acts on guanosine triphosphate-binding protein (G-protein) coupled

receptors that stimulate the production of intracellular cyclic adenosine
monophosphate (cAMP). In liver cells, this results in the inhibition of glycogen
synthesis and the activation of glycogen breakdown systems. Similar e!ects are
obtained in muscle cells to increase circulating levels of glucose.
There are interactions between glucagon and insulin within the islets: insulin inhibits
release of glucagon, but glucagon stimulates the release of insulin, an e!ect that
ensures a basal level of insulin release regardless of glucose levels.
Comparison between Insulin and Glucagon
Hormone Insulin Glucagon
Cell Type Beta-cells Alpha-cells
Factors ↑ Blood glucose ↓ Blood glucose

that ↑ Amino acids ↑ Amino acids
Increase ↑ Fatty acids Cholecystokinin
Secretion Glucagon Catecholamines
Secretin Acetylcholine
Acetylcholine
Factors ↓ Blood glucose ↑ Blood glucose

that Somatostatin Insulin
Decrease Catecholamines Somatostatin
Secretion Fatty acids,
ketoacids
Mechanism Acts on tyrosine kinase receptor to Acts on G-protein

of Action activate intracellular pathway that coupled receptor to
results in translocation of GLUT-4 stimulate production
transporter to plasma membrane of cAMP
Major ↑ Glucose uptake into cells ↓ Glycogenesis

Actions ↑ Glycogenesis ↑ Glycogenolysis
↓ Glycogenolysis ↑
↓ Gluconeogenesis Gluconeogenesis
↑ Protein synthesis ↓ Fatty acid
↓ Protein degradation synthesis
↑ Fat deposition ↑ Lipolysis
↓ Lipolysis ↑ Ketoacid
↓ Ketoacid production production
↑ K+ uptake into cells
Overall ↓ [Glucose] ↑ [Glucose]

E!ect on ↓ [Amino acid] ↑ [Fatty acid]
Blood ↓ [Fatty acid] ↑ [Ketoacid]
Levels ↓ [Ketoacid]
↓ [K+]

Insulin Physiology LAST UPDATED: 2ND
MAY 2019
 Bookmark
Insulin is produced by β cells, located centrally within the islets of Langerhans, in the
endocrine tissues of the pancreas.
Insulin is a polypeptide hormone consisting of two short chains (A and B) linked by

disulphide bonds. Proinsulin is synthesised as a single-chain peptide. Within storage
granules, a connecting peptide (C peptide) is removed by proteases to yield insulin.
The C peptide is packaged and secreted along with insulin, and its concentration is
used to monitor β cell activity in diabetic patients who receive exogenous insulin.
Insulin release is stimulated initially during eating by the parasympathetic nervous

system and gut hormones such as secretin, but most output is driven by the rise in
plasma glucose concentration that occurs after a meal. Circulating fatty acids, ketone
bodies and amino acids augment the e!ect of glucose.
The major action of insulin is to stimulate glucose uptake, with the subsequent
manufacture of glycogen and triglycerides by adipose, muscle and liver cells.
The e!ects of insulin are mediated by the receptor tyrosine kinase. The enzyme
activates an intracellular pathway that results in the translocation of the glucose
transporter GLUT-4 and to a lesser extent GLUT-1 to the plasma membrane of the
a!ected cell, to facilitate the entry of glucose. Insulin thus decreases plasma glucose.
Insulin release is reduced as the blood glucose concentration falls, and is further
inhibited by catecholamines acting at β cell alpha-2-adrenoceptors.
II N
NSSU
U LL II N
N S II G
G N A LL TT R A N S D
DU C
C TT I O N P A TT H
H W A Y . ( IM AGE BY JAM E S FO R E M AN, U S E D WITH
P E R M IS S IO N. [C C 0], F RO M WIK IM E DIA C O M M O N S)
Comparison between Insulin and Glucagon
Hormone Insulin Glucagon
Cell Type Beta-cells Alpha-cells
Factors ↑ Blood glucose ↓ Blood glucose

that ↑ Amino acids ↑ Amino acids
Increase ↑ Fatty acids Cholecystokinin
Secretion Glucagon Catecholamines
Secretin Acetylcholine
Acetylcholine
Factors ↓ Blood glucose ↑ Blood glucose

that Somatostatin Insulin
Decrease Catecholamines Somatostatin
Secretion Fatty acids,
ketoacids
Mechanism Acts on tyrosine kinase receptor to Acts on G-protein

of Action activate intracellular pathway that coupled receptor to
results in translocation of GLUT-4 stimulate production
transporter to plasma membrane of cAMP
Major ↑ Glucose uptake into cells ↓ Glycogenesis

Actions ↑ Glycogenesis ↑ Glycogenolysis
Glycogenolysis ↑
↓ Gluconeogenesis Gluconeogenesis
↑ Protein synthesis ↓ Fatty acid
↓ Protein degradation synthesis
↑ Fat deposition ↑ Lipolysis
↓ Lipolysis ↑ Ketoacid
↓ Ketoacid production production
↑ K+ uptake into cells
Overall ↓ [Glucose] ↑ [Glucose]

E!ect on ↓ [Amino acid] ↑ [Fatty acid]
Blood ↓ [Fatty acid] ↑ [Ketoacid]
Levels ↓ [Ketoacid]
↓ [K+]

Antidiuretic Hormone LAST UPDATED: 21ST
APRIL 2019
PHYSIOLOGY / ENDOCRINE / PITUITARY FUNCTION /
RENAL / MECHANISM OF FILTRATION  Bookmark
Extracellular fluid osmolality must be closely regulated as alterations cause the

swelling or shrinking of cells and can lead to cell death. Osmoreceptors in the anterior
hypothalamus control water intake by altering thirst and control renal water excretion
by altering antidiuretic hormone (ADH) release. A rise in osmolality triggers ADH
release and stimulates thirst; a fall has the opposite e!ect.
Synthesis
Antidiuretic hormone is synthesised in the hypothalamus and transported to the

posterior pituitary within nerve fibres where it is stored in secretory granules.
Action
ADH binds V2 receptors on renal principal cells in the late distal tubule and collecting
ducts, raising cAMP levels and causing intracellular vesicles to fuse with the apical
membrane. In their membrane these vesicles have water channels called aquaporins,
which increase the water permeability allowing greater water reabsorption and
concentration of urine.
ADH also binds to V1 receptor receptors on vascular smooth muscle, causing

vasoconstriction and enhancing the e!ect of aldosterone on sodium reabsorption in
the distal tubule.
Metabolism
ADH is rapidly removed from plasma, falling by about 50% in about 10 minutes, mainly
due to metabolism in the liver and kidneys.
Stimulating Factors
ADH release is stimulated primarily by raised plasma osmolality detected by

osmoreceptors in the anterior hypothalamus. Other factors that increase ADH release
include: extracellular fluid volume depletion, angiotensin II, nausea, pain, stress,
exercise, emotion, hypoglycaemia.
Inhibiting Factors
ADH release is inhibited by low plasma osmolality, alcohol, ca!eine, glucocorticoids

and atrial natriuretic peptide (ANP).
Clinical Implications
ADH deficiency (or an inadequate response to ADH) results in diabetes insipidus.

Excess levels of ADH results in syndrome of inappropriate ADH secretion (SIADH).
FF U
UNNC
C TT II O
O N O F A N TT I D II U R E T I C
C HO
O R M O N E . ( IM AGE BY O P E N STAX C O LLEGE [C C BY 3.0

Diabetes Insipidus LAST UPDATED: 21ST
APRIL 2019
PHYSIOLOGY / ENDOCRINE / PITUITARY FUNCTION
 Bookmark
Diabetes insipidus (DI) may result from a deficiency of ADH secretion (cranial DI)
or from an inappropriate renal response to ADH (nephrogenic DI).
As a result, fluid reabsorption at the kidneys is impaired, resulting in large

amounts of hypotonic, dilute urine being passed with a profound unquenchable
polydipsia.
Biochemical Features
The biochemical hallmarks of DI are:
High plasma osmolality (> 295 mOsm/kg)

Low urine osmolality (< 300 mOsm/kg)
Hypernatraemia (> 145 mmol/L)
High urine volume
Causes
Cranial (ADH deficiency)
Inflammatory hypophysitis
Histiocytosis X
Post-pituitary surgery
Nephrogenic (ADH resistance)
Metabolic or electrolyte disturbance

Renal disease
Drugs e.g. lithium
An ADH stimulation test can distinguish between cranial and nephrogenic DI, as
nephrogenic DI shows an inability to concentrate urine even after administration
of synthetic ADH.
Management
Patients with confirmed cranial DI should be investigated for pituitary disease,

and managed as appropriate. Cranial DI typically responds well to synthetic ADH
administration and results in good clinical improvement.
In nephrogenic DI, the underlying cause should be considered and reversed

where possible. If symptoms persist, patients should drink according to thirst
and keep up with water loss. Specific measures to treat nephrogenic DI include
the use of low salt, low protein diet, diuretics and NSAIDs.

Hypernatraemia LAST UPDATED: 21ST
APRIL 2019

 Bookmark
Hypernatraemia is an increase in the serum sodium concentration > 145 mmol/L. It is

less common than hyponatraemia in clinical practice but it is a sign of significant
disease. Hypernatraemia may arise from either sodium gain or much more commonly
from water deficit (both are associated with a raised plasma osmolality).
Causes
Hypernatraemia can be thought of in relation to actual total body sodium:
Hypotonic fluid loss
The most common group of patients are those with hypernatraemia with decreased
total body sodium through loss of both water and sodium, but with a greater
proportion of water loss which may result from:
Renal losses e.g. osmotic diuresis secondary to uncontrolled diabetes mellitus,

mannitol, or renal disease
Skin losses e.g. burns, excessive sweating in hot climate or exercise
Gastrointestinal losses e.g. vomiting, diarrhoea, fistulae
Pure water depletion
Patients with hypernatraemia with normal total body sodium have a pure water deficit
which may result from:
Inadequate water intake e.g. unconscious patient, dementia, disordered thirst

perception in hypothalamic lesion
Extra-renal loss e.g. hyperventilation, hyperthyroidism, mucocutaneous loss
Renal loss e.g. diabetes insipidus or chronic kidney disease
Salt gain
Hypernatraemia with an actual increase in total body sodium is rare. Mild true
hypernatraemia may be caused by primary hyperaldosteronism, but this is not typical.
Other causes include acute salt poisoning e.g. intravenous sodium bicarbonate,
hypertonic saline, high sodium feeds in infants, near drowning in salt water, salt
ingestion.
Assessment and Management
When assessing patients with hypernatraemia:
If the hypernatraemia is mild (Na ? 150 mmol/L) and the patient has obvious
signs of dehydration it is likely the ECF volume is reduced and that the patient
has lost both sodium and water. Treatment should aim to replace the deficit of
fluid by infusing isotonic saline, or if the deficit is large, hypotonic saline.
With more severe hypernatraemia (150 - 170 mmol/L), pure water loss is likely if
the clinical signs of dehydration are mild in relation to the degree of
hypernatraemia - this is because pure water loss is distributed evenly
throughout the body compartments and the sodium content of the ECF is
unchanged. Treatment should be aimed at replacing water either orally, or with
5% dextrose.
With gross hypernatraemia ( > 180 mmol/L), an excess of sodium is likely, the
patient may present with signs of fluid overload. Treatment may be with
diuretics, or rarely, by renal dialysis.
Acute severe hypernatraemia
This is a medical emergency and requires inpatient management in a high

dependency setting. Seizures and intracranial vascular haemorrhage as a result of
brain cell crenation can occur. The cause is most commonly excessive water loss and
the key aspect of treatment is aggressive fluid replacement (typically with normal
saline as this is relatively hypotonic). If urine osmolality is low, DI should be considered
and a trial of synthetic ADH given. In patients with known DI, it is essential to ensure
synthetic ADH is given parenterally and that close fluid balance is observed.

Hyponatraemia LAST UPDATED: 16TH
JULY 2020

 Bookmark
Hyponatraemia is defined as a serum sodium concentration < 135 mmol/L. A level <
125 mmol/L is considered severe. Hyponatraemia results from a relative excess of
body water to sodium.
Clinical Features
The rate of change of sodium is more important than the absolute sodium value so
patients with chronic hyponatraemia can be asymptomatic, while patients with a
sudden drop can be very unwell.
Early symptoms are headache, nausea, vomiting and general malaise. Later signs are
confusion, agitation and drowsiness. Acute severe hyponatraemia leads to seizures,
respiratory depression, coma and death. This is due to swelling of brain cells when
water moves from the extracellular to the intracellular compartment because of
di"erences in the osmolality between brain and plasma, resulting in cerebral oedema
and raised intracranial pressure.
Diagnostic Approach
Drug history
Hydration status
Plasma osmolality
Urine osmolality
Urine sodium
Thyroid function
Assessment of cortisol reserve
Plasma osmolality
Hyponatraemia of any cause is associated with a low plasma osmolality.
If the plasma osmolality is normal, then the possibility of pseudohyponatraemia

should be considered; this is an artifactual result due to a reduction in plasma water
caused by marked hyperlipidaemia or hyperproteinaemia e.g. in multiple myeloma.
If the plasma osmolality is high, then the possibility of hyperosmolar hyponatraemia
should be considered; this may be due to hyperglycaemia or administration of
mannitol amongst other causes and reflects the shift of water out of cells into the
extracellular fluid in response to osmotic e"ects.
Urine osmolality
Once hypotonic hyponatraemia has been confirmed, urine osmolality should be

checked.
Low urine osmolality (< 100 mosmol/kg):
Primary polydipsia
Inappropriate administration of IV fluids
Malnutrition - low salt diet
Normal urine osmolality (> 100 mosmol/kg):
Urinary Na+ < 30 mmol/L
Patient hypovolaemic (true volume depletion or third space loss)
Gastrointestinal salt loss - severe diarrhoea and vomiting

Transdermal salt loss - sweating, extensive skin burns
Third space loss - pancreatitis, bowel obstruction, sepsis
Diuretics
Patient hypervolaemic (intravascular depletion in fluid overloaded state)
Congestive cardiac failure

Cirrhosis
Nephrotic syndrome
Urinary Na+ > 30 mmol/L
Patient euvolaemic (normal circulating volume)
SIADH
ACTH deficiency
Severe hypothyroidism
Patient hypovolaemic (low circulating volume)
Addison's disease
Cerebral salt-wasting
Renal salt-wasting
Vomiting (causes loss of hydrogen ions and a metabolic alkalosis
Vomiting (causes loss of hydrogen ions and a metabolic alkalosis
which is corrected by the renal excretion of sodium bicarbonate)
However, if the individual is using diuretics, or there is evidence of kidney disease, all
causes should be considered, as these can cause a low or a high urinary sodium
concentration.
Management
Treatment is cause-specific. Appropriate fluid replacement in patients with

hypovolaemic hyponatraemia with normal saline typically leads to improvement. In
patients with hypervolaemic hyponatraemia, specialist treatment of the underlying
condition is indicated.
In acute severe hyponatraemia with neurological compromise, the use of hypertonic

saline should be considered whatever the cause, with specialist input and careful
monitoring. Correction should not be too rapid, especially in chronic hyponatraemia,
as this may result in central pontine myelinolysis.

Hypothalamic-Pituitary Axis LAST UPDATED: 13TH
MARCH 2019
 Bookmark
Pituitary Hormone Hypothalamic Target E!ect

Releasing/Inhibiting Organ
Factors
Growth hormone Stimulated by Liver, bone, Direct e"ect (regulates

(GH) growth muscles growth and metabolic
hormone- rate)
releasing
hormone
(GHRH)
Inhibited by
somatostatin
(also
called growth
hormone–
inhibiting
hormone (GHIH))
Adrenocorticotropic Stimulated by Adrenal Stimulates release of

hormone (ACTH) corticotropin- gland cortisol
releasing
hormone (CRH)
Follicle-stimulating Stimulated by Gonads Stimulates release of

hormone (FSH) and gonadotropin- testosterone/oestrogen
luteinising hormone releasing and production of
(LH) hormone (GnRH) eggs/sperm
Thyroid-stimulating Stimulated by Thyroid Stimulates release of

hormone (TSH) thyrotropin gland thyroid hormones
releasing (T4/T3)
hormone (TRH)
Prolactin Weakly Mammary Direct e"ect

stimulated by glands (stimulates lactation)
TRH, oxytocin
and ADH
Inhibited by
dopamine (also
called prolactin-
inhibiting
hormone (PIH))
Antidiuretic From posterior Kidneys Direct e"ect (regulates

hormone (ADH) pituitary water balance)
Oxytocin From posterior Female Direct e"ect

pituitary reproductive (stimulates milk
system ejection in suckling and
uterine contractions in
childbirth)
H
HYYP
PO T H A L A M U
U S - P I TT U I TTA R Y A X I S . ( IM AGE BY O P E N STAX C O LLEGE [C C BY 3.0

Physiology Endocrine
Pituitary Function
Something wrong?
Pituitary Gland LAST UPDATED: 21ST

APRIL 2019
 Bookmark
Anatomical Location
The pituitary gland lies immediately beneath the hypothalamus in a bony hollow of
the sphenoid bone (the sella turcica), and it is covered by the fibrous diaphragma
sellae of the dura mater. The optic chiasm lies directly superior to the anterior
pituitary. The posterior pituitary is connected to the median eminence of the
hypothalamus by the pituitary stalk (also known as the infundibulum). The cavernous
sinuses (including cranial nerves III - VI) lie lateral to the pituitary gland. The pituitary
gland is primarily divided into two sub glands, the anterior pituitary
(adenohypophysis) and the posterior pituitary (neurohypophysis).
AANNA
ATT O
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O
OCCA
A
ATT IIIO
O
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O
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P
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U
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A
ANN
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D.. ( IM AGE BY O P E N STAX C O LLEGE
[C C BY 3.0 ( H TTP ://C R EATIV EC OMMON S.ORG/ LIC EN SES/ BY/ 3.0)], V IA WIKIMEDIA C OMMON S)
Anterior Pituitary Gland
Anterior pituitary hormones are released under the control of hypothalamic releasing
or inhibiting hormones originating from small neurons with their cell bodies in the
hypothalamus and released into the blood at the median eminence. These
hypothalamic hormones are transported directly to the anterior pituitary via
hypophyseal portal vessels and act to stimulate or inhibit release of anterior pituitary
hormones by the activation of receptors on specific groups of pituitary cells.
The anterior pituitary hormones (and the hormones released by their target organs)
inhibit further release of hypothalamic and anterior pituitary hormones by negative
feedback mechanisms.
The following hormones are secreted from the anterior pituitary gland:
Follicle-stimulating hormone (FSH)

Prolactin
Thyroid-stimulating hormone (TSH)
Adrenocorticotropic hormone (ACTH)
Luteinising hormone (LH)
Growth hormone (GH)
This can be remembered using the mnemonic: FFresh PPituitary TTastes A

Almost LLike
G
Guinness.
FFU
U NNC
C TT IIO
O
ONN O
O
OFFF TTH
HEE
E AAN
N
NTT EER
R
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O
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R P
P
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U
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A
ARR
RYY
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BY 3 .0 ( H T T P : //C R E AT I V EC O M M O N S .O RG/ L I C E N S E S/ BY/ 3 .0)] , V I A W I K I M E D I A C O M M O N S)
Posterior Pituitary Gland
The posterior pituitary gland secretes two peptide hormones:
Oxytocin
Antidiuretic hormone (ADH)
The posterior pituitary is really a direct extension of the hypothalamus. Oxytocin and
ADH are manufactured in the cell bodies of large neurons in the hypothalamus and
are transported down the axons of these cells to their terminals on capillaries
originating from the inferior hypophyseal artery within the posterior pituitary gland.
When these neurons are activated, they release oxytocin or ADH into the general
circulation from whence they can reach the relevant target tissues to produce the
required e!ect.
ADH release is controlled by negative feedback mechanisms based on plasma

osmolality and blood volume, oxytocin however is involved in positive feedback
mechanisms.
FFU
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BY 3 .0 ( H T T P : //C R E AT I V EC O M M O N S .O RG/ L I C E N S E S/ BY/ 3 .0)] , V I A W I K I M E D I A C O M M O N S)

Pituitary Hormone Dysfunction LAST UPDATED: 8TH DECEMBER 2020

 Bookmark
Hormone Stimulation Inhibition Action Clinical Excess Clinical

Deficiency
ACTH CRH Cortisol Acts on adrenal cortex Cushing's disease Secondary

to stimulate release of adrenal
glucocorticoids which insu!ciency
regulate metabolism
and stress response
TSH TRH Thyroxine Acts on thyroid gland to Secondary Secondary

stimulate release of hyperthyroidism hypothyroidism
thyroid hormones
which regulate
metabolism
FSH/LH GnRH Prolactin, Acts on gonads to Infertility Gonadal

oestrogen/testosterone stimulate production of insu!ciency
oestrogen/testosterone
and production of
eggs/sperm
GH GHRH Somatostatin Acts on liver, bone and Acromegaly in Adult GH

muscles to stimulate adults or gigantism deficiency
production of IGFs in children syndrome in
which stimulate body adults
growth and a higher or dwarfism in
metabolic rate children
Prolactin PRH, TRH Dopamine Acts on mammary Hyperprolactinemia Failure of

glands to promote milk postpartum
production lactation
ADH Raised Low plasma osmolality, Acts on kidneys to SIADH Central

plasma alcohol, ca#eine, promote water diabetes
osmolality glucocorticoids and retention and on insipidus
atrial natriuretic vascular system to
peptide (ANP) cause vasoconstriction
Oxytocin Stretch Stress Acts on female / /

receptors in reproductive system to
nipple and trigger uterine
cervix contractions during
childbirth and milk
ejection during suckling
Anterior Pituitary Hormones
ACTH
Adrenocorticotropic hormone (ACTH) acts on the adrenal cortex to stimulate glucocorticoid and androgen release.
ACTH secretion is stimulated by corticotropin-releasing hormone (CRH) from the hypothalamus.
ACTH secretion is inhibited by cortisol.
ACTH deficiency results in secondary adrenal insu"ciency.
Excess levels of ACTH due to a functioning pituitary adenoma results in Cushing's disease.
TSH
Thyroid-stimulating hormone (TSH) acts on the thyroid gland to stimulate thyroid hormone (T3 and T4) release.
TSH secretion is stimulated by thyrotropin-releasing hormone (TRH) from the hypothalamus.
TSH secretion is inhibited by raised serum levels of T3 or T4, somatostatin, dopamine, glucocorticoids, acute non-thyroidal
illness and increased human chorionic gonadotropin (e.g. in early pregnancy).
TSH deficiency results in secondary hypothyroidism.
Excess TSH (extremely rare) results in secondary hyperthyroidism.
FSH/LH
The gonadotropins, luteinising hormone (LH) and follicle stimulating hormone (FSH) act via G-protein coupled receptors on the
gonads. In the male, LH acts to stimulate production of testosterone, which acts in concert with FSH to support
spermatogenesis. In the female, LH and FSH are essential for normal menstruation and reproduction.
LH/FSH secretion is stimulated by gonadotropin-releasing hormone (GnRH) from the hypothalamus. GnRH is released in a
pulsatile fashion, which is essential for normal reproductive activity.
LH/FSH secretion is inhibited by prolactin (via GnRH) and sex steroids.
LH/FSH deficiency results in gonadal insu"ciency (decreased sex steroids).
Excess levels of FSH/LH (extremely rare) results in infertility.
Growth Hormone
Growth hormone (GH) acts on the liver to stimulate insulin-like growth factor (IGF) production to promote skeletal and muscular
growth and protein synthesis.
GH secretion is stimulated by growth hormone-releasing hormone (GHRH) from the hypothalamus.
GH secretion is inhibited by growth hormone-inhibiting hormone (somatostatin) and IGF-1.
Excess levels of GH results in acromegaly in adults and gigantism in children (if excess GH occurs prior to epiphyseal fusion).
GH deficiency results in dwarfism in children or adult GH deficiency syndrome in adults.
Prolactin
Prolactin acts on the mammary glands and reproductive organs to promote growth of these organs and initiate lactation.
Prolactin secretion is stimulated by prolactin-releasing factor (PRF) and thyrotropin-releasing hormone (TRH) from the
hypothalamus.
Prolactin secretion is inhibited by dopamine secreted by the hypothalamus.
Prolactin levels rise physiologically in pregnancy, puerperium, and breast stimulation.
Excess levels of prolactin may be caused by a prolactinoma (prolactin-secreting pituitary adenoma); compression of the pituitary
stalk by a pituitary or hypothalamic tumour preventing normal dopaminergic inhibition of prolactin release; PCOS; severe
hypothyroidism (due to increased synthesis of TRH); drugs e.g. dopamine antagonists, antipsychotics
Hyperprolactinaemia causes symptoms such as oligomenorrhoea/amenorrhoea, galactorrhoea, loss of libido, erectile
dysfunction and infertility (via inhibition of the release of GnRH from the hypothalamus).
Prolactin deficiency results in failure of postpartum lactation.
Posterior Pituitary Hormones

Posterior Pituitary Hormones
ADH
Antidiuretic hormone (ADH) acts on the kidneys to increase water permeability in the distal nephron allowing greater water
reabsorption and concentration of urine. ADH also acts on vascular smooth muscle, causing vasoconstriction.
ADH release is stimulated mainly by raised plasma osmolality detected by osmoreceptors in the anterior hypothalamus. Other
stimuli to ADH release include volume depletion, angiotensin II, hypoxia, hypercapnia, adrenaline, cortisol, sex steroids, pain,
trauma, temperature and psychogenic stimuli.
ADH release is inhibited by low plasma osmolality, alcohol, ca#eine, glucocorticoids and atrial natriuretic peptide (ANP).
ADH deficiency results in central diabetes insipidus.
Excess levels of ADH results in syndrome of inappropriate ADH secretion (SIADH).
Oxytocin
Oxytocin acts on the mammary glands to stimulate milk ejection, and the uterus to stimulate uterine contraction in childbirth.
Oxytocin release is stimulated by stretch receptors in the nipple and the cervix and by oestrogen.
Oxytocin release is inhibited by stress.

Syndrome of Inappropriate LAST UPDATED: 21ST
APRIL 2019
Antidiuretic Hormone  Bookmark
Secretion (SIADH)
Diagnosis
Syndrome of inappropriate ADH (SIADH) is characterised by:
euvolaemic hypo-osmolar hyponatraemia in the context of:
a low serum osmolality (< 275 mosmol/kg)

urine osmolality > 100 mosmol/kg and
urine sodium > 30 mmol/L.
SIADH can only be diagnosed after the exclusion of hypothyroidism, total salt
depletion and ACTH deficiency. ACTH deficiency appears identical to SIADH because it
causes reduced excretion of free water, because cortisol deficiency leads to
increased ADH activity. This is di!erent from hyponatraemia caused by
mineralocorticoid deficiency in Addison's disease.
Causes
The potential causes of SIADH are vast including:
Malignancy:
lung, lymphoma, gastrointestinal/pancreatic malignancy, genitourinary

malignancy
Neurological:
malignancy, infection, trauma, haemorrhage
Pulmonary:
pneumonia, TB, abscess, malignancy
Drugs:
SSRIs, tricyclic antidepressants, anticonvulsants
Miscellaneous:
idiopathic, HIV, MS, Guillain-Barre, Acute Intermittent Porphyria
Idiopathic SIADH is a diagnosis of exclusion.

Management
Reversal or treatment of the cause of SIADH and fluid restriction are the key aspects
of management. Strict fluid restriction (1 - 1.5 L/day) is poorly tolerated and di#cult to
achieve. Drug treatment of SIADH includes demeclocycline and ADH antagonists.
Demeclocycline reduces renal response to ADH but its use is limited by side e!ects
and unpredictable pharmacokinetics. ADH antagonists directly block ADH action and
are of use in specific clinical situations.

Hyperthyroidism LAST UPDATED: 21ST
APRIL 2019
PHYSIOLOGY / ENDOCRINE / THYROID FUNCTION
 Bookmark
The overproduction of T3 and T4 leads to hyperthyroidism.
Causes
Graves disease (autoimmune thyroid disease)
Results from the production of TSH receptor stimulating antibodies

Most common cause of hyperthyroidism
Nodular thyroid disease
Results from autonomous secretion of T3 and/or T4, either from a solitary

toxic nodule or numerous nodules within a multinodular goitre
Second most common cause of hyperthyroidism
Thyroiditis (e.g. viral, postpartum, drugs)
Results from inflammation of the thyroid gland causing a destructive

release of thyroxine
Less common
Clinical Features
Symptoms
Weight loss (often with increase appetite)

Insomnia, irritability and anxiety
Heat intolerance
Palpitations
Tremor
Pruritus
Increased bowel frequency and loose motions
Menstrual disturbance
Reduced fertility
Signs
General
Resting tachycardia (sinus rhythm or AF)

Warm peripheries
Proximal myopathy
Resting tremor
Hyperreflexia
Lid lag
Hypertension and flow murmur
Agitation and restlessness
Goitre
Graves disease
Thyroid eye disease (in order of increasing severity)
Dry/gritty eyes
Eyelid swelling, chemosis and periorbital oedema
Proptosis and lid retraction
Diplopia
Exposure keratopathy and compressive optic neuropathy
Skin changes
Pretibial myxoedema
Thyroid acropachy
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PRRO
OPP TT O
OS I S A N
ND L I D
D R
RE T R
R A C T II O N II N G R
RAAV
V E S D II S E A S E . ( IM AGE BY JO N ATH AN
TROBE, M.D. - UN IV ER SITY OF MIC H IGAN KELLOGG EYE C EN TER ( TH E EYES H AV E IT) [C C BY
3.0 ( H TTP S://C R EATIV EC OMMON S.ORG/ LIC EN SES/ BY/ 3.0)], V IA WIKIMEDIA C OMMON S)
TT H
HYYR
R O II D
D ACR
RO P A
AC H Y A N
ND P
PR E
E T II B I A L M Y X
XO E
ED E
E M A . ( IM AGE BY H E R B E RT L. F R E D, M D
AN D H EN DR IK A. VAN DIJK ( H TTP : //C N X .ORG/C ON TEN T/ M 14924/ LATEST/ ) [C C BY 2.0
( H TTPS://CREATIV ECOMMON S.ORG/ LICEN SES/ BY/2.0)], V IA WIKIMEDIA COMMON S)
Investigations
T3, T4 and TSH
Elevated T4 and T3 with suppressed TSH = Primary hyperthyroidism

Elevated T3 with suppressed TSH = T3 toxicosis
Normal T4 and T3 with suppressed TSH = Subclinical hyperthyroidism
Elevated T4 and T3 with non-suppressed TSH = Consider assay
interference or secondary hyperthyroidism e.g. TSHoma or thyroid
hormone resistance
Thyroid antibodies (e.g. thyroid peroxidase (TPO) and TSH receptor stimulating
antibodies)
Thyroid ultrasound scan
Nuclear imaging (technetium or iodine uptake isotope scan)
Management
Anti-thyroid medication
Thionamides (carbimazole and propylthiouracil) reduce synthesis of T3

and T4 and can be used in a 'titration' or 'block and replace' regimen
Beta-blockers can be used to control symptoms until patient becomes
euthyroid
Definitive treatment
Surgery
Radioactive iodine (RAI)
Thyroid Storm
This is a rare medical emergency that presents with high output cardiac failure and
extreme agitation. It has a high mortality and requires high dependency care.

Hypothyroidism LAST UPDATED: 21ST
APRIL 2019
 Bookmark
Hypothyroidism is characterised by reduced circulating T3 and T4.
Causes
Primary hypothyroidism
Autoimmune (atrophic and Hashimoto's)

Iatrogenic (thionamides, radioactive iodine, surgery, radiation)
Hypothyroid phase of thyroiditis
Drugs (lithium, amiodarone, interferon)
Iodine deficiency
Secondary hypothyroidism
TSH deficiency secondary to hypothalamic-pituitary disease
Clinical Features
Symptoms
Weight gain
Cold intolerance
Fatigue
Constipation
Depression
Muscle cramps
Carpal tunnel syndrome
Menstrual disturbance
Reduced fertility
Signs
Alopecia
Bradycardia
Dry skin
Brittle nails
Peri-orbital myxoedema
Goitre
Pre-tibial myxoedema
C
C LL II N
N II C A
AL F E AT U R
RE S
S OF H
HY P
PO T H
HY R O
O I D I S M . ( IM AGE BY M IK AE L H ÄGGSTRÖ M, U S E D
WITH P ER M IS S ION. [C C 0], F ROM WIK IM EDIA C OM M ON S)
Investigations
T3, T4 and TSH
Low T4 with elevated TSH = Primary hypothyroidism

Normal T4 with elevated TSH = Subclinical hypothyroidism
Low T4 with non-elevated TSH = Secondary hypothyroidism (exclude
pituitary disease)
Thyroid antibodies (e.g. TPO antibodies)
Management
Thyroxine replacement to normalise TFTs and resolve symptoms
Myxoedema Coma
Myxoedema coma is a rare medical emergency with a high mortality requiring
treatment in a high dependency setting characterised by:
Hypotension
Pericardial e!usion
Bradycardia
Reduced consciousness
Hypoventilation
Hyponatraemia
Renal impairment
Coagulopathy

Thyroid Function LAST UPDATED: 2ND
MAY 2019
 Bookmark
Anatomical Location
The thyroid gland is attached to the anterior surface of the trachea just below the
larynx. It has a right and left lobe joined by a central isthmus. Thyroid lesions can be
distinguished from other neck lumps by their movement on swallowing. The recurrent
laryngeal nerve lies laterally on each side and the parathyroid glands lie posteriorly -
both may be damaged during thyroid surgery. The thyroid gland has a rich vascular
supply from the inferior and superior thyroid arteries.
A
ANNA
AT O
OM Y
Y O FF T H E T H Y R O I D G LL A N
NDD . ( IM AGE BY O P E N STAX C O LLEGE [C C BY 3.0
Production and Transport of Thyroid Hormones

Thyroid tissue is made up of colloid which contains iodinated thyroglobulin.
Thyroglobulin is synthesised by the surrounding follicular cells and is the large
molecule from which thyroid hormones are made.
The thyroid gland produces two thyroid hormones, thyroxine (T4) and triiodothyronine
(T3). More T4 than T3 is synthesised -the average plasma concentration of T3 is
roughly one-sixth that of T4 - however, T4 is converted peripherally to the more
potent and shorter-acting T3.
The hormones are released under the control of thyroid-stimulating hormone (TSH)
from the anterior pituitary, which itself is regulated by thyrotropin-releasing hormone
(TRH) from the hypothalamus in response to thermoreceptor and metabolic signals,
and circulating levels of T3 and T4 detected by both the hypothalamus and pituitary
(negative feedback).
Most of the thyroid hormones in the blood are bound tightly to proteins in the
circulation - thyroxine-binding protein (TBG), transthyretin and albumin - and are
thus unavailable to their receptors which are located inside target cells. Only the
small amounts of free T3 and T4 in plasma can readily cross the cell membranes to
bind to thyroid hormone receptors. Thyroid receptors are present in almost all tissues,
with particularly high levels in the liver.
TT H
HYYR
R O II D
D HO
ORRM O N E S
S .. ( IM AGE BY M IK AE L H ÄGGSTRÖ M [ P U B LIC DO M AIN ], V IA WIK IM E DIA
C O M M O N S)
Physiological E!ects of Thyroid Hormones
Basic levels of thyroid hormone release are essential to maintain a normal metabolic
rate. Situations requiring increased heat production, for example when the core
temperature falls, leads to enhanced activation of the thyroid axis. The e"ects take
up to 4 days to reach a maximum.
Physiological e"ects of thyroid hormones include:
Heat production (thermogenesis)

Increased basal metabolic rate
Metabolic e"ects
Increase in protein turnover (both synthesis and degradation are

increased, although overall e"ect is catabolic)
Increase in lipolysis
Increase in glycogenolysis and gluconeogenesis
Enhanced catecholamine e"ect

Increase in heart rate, stroke volume and thus cardiac output
Important role in growth and development

Structure of Gut Wall LAST UPDATED: 21ST
APRIL 2019
PHYSIOLOGY / GASTROINTESTINAL / GUT WALL
 Bookmark
The gastrointestinal system is essentially a muscular tube which maintains the same
basic structure throughout its length, although this is modified as function varies.
Layers
The layers that comprise this basic structure (from innermost to outermost) are:
The innermost mucosa composed of:
the epithelial layer (which has either secretory or absorptive functions)

the lamina propria (consisting of loose connective tissue, blood vessels
and lymph tissues)
the muscularis mucosa (a thin layer of smooth muscle)
The submucosa (containing a second layer of connective tissue, larger blood

vessels and lymphatic vessels and the submucosal plexus)
The muscularis externa composed of
the inner circular muscle layer (which, when it contracts, produces a

constriction of the lumen)
the outer longitudinal muscle layer (which, when it contracts, results in
shortening of the GI tract)
the myenteric plexus which lies between these two layers of muscle
The outermost serosa (another connective tissue layer covered with squamous
mesothelial cells)
Innervation
There are two intrinsic nerve plexuses which function as the enteric nerve system,
the activity of which is moderated by extrinsic innervations and hormones.
The submucosal plexus (Meissner's plexus) is located in the submucosal layer. The
submucosal plexus only has parasympathetic input and provides secretomotor
innervation to the mucosa, mainly regulating epithelial cell and submucosal blood
vessel function.
The myenteric plexus (Auerbach's plexus) is located between the circular and
longitudinal muscle layers of the muscularis externa. The myenteric plexus provides
motor innervation to the smooth muscle layers via sympathetic and parasympathetic
input, mainly regulating intestinal motility and sphincter function.
S
S TT R
RUUC
C TT U
UR E
E O F TT H E
E G
G U TT W A
A L LL . ( IM AGE BY GO R AN TE K-E N [C C BY-SA 3.0

Defecation Reflex LAST UPDATED: 8TH
NOVEMBER 2021
PHYSIOLOGY / GASTROINTESTINAL /
LARGE INTESTINE  Bookmark
Colonic Mass Movement
Colonic mass movement describes the intense contraction that begins halfway
along the transverse colon and pushes the intestinal contents in the proximal
colon towards the rectum. It occurs shortly after a meal due to distension of the
stomach and duodenum as part of the gastrocolic reflex and if faeces is present
in the rectum, stimulates the urge to defecate.
Defecation Reflex
The internal and external anal sphincters usually keep the anal canal closed and
are controlled both reflexly and voluntarily. The internal sphincter is made up of
circular smooth muscle innervated by the autonomic fibres, and the more distal
external sphincter is composed of striated muscle innervated by motor fibres
from the pudendal nerve.
When a critical mass of faeces is forced into the rectum, the desire for
defaecation is experienced.
Distention of the rectum causes firing of a!erent cholinergic parasympathetic

fibres which are transmitted to spinal control centres resulting in contraction of
the rectum, relaxation of the internal anal sphincter and initially contraction of
the external anal sphincter. This initial contraction is soon followed by a reflex
relaxation of the external sphincter initiated by an increase in the peristaltic
activity in the sigmoid colon and pressure in the rectum.
This reflex relaxation of the external anal sphincter can be overridden by higher
brain centre activity, leading to voluntary control over the sphincter which can
delay the expulsion of faeces. The prolonged distension of the rectum then
leads to a reverse peristalsis, which empties the rectum into the colon and
removes the urge to defecate until the next mass movement and/or a more
convenient time.
When a person decides to defecate i.e. when the external sphincter is voluntarily
relaxed, an increase in intra-abdominal pressure must be achieved to expel
faeces. Thus a breath is taken in and the glottis closes over the trachea, the
respiratory muscles contract on lungs filled with air and the abdominal muscles
contract which increases both the intrathoracic and intra-abdominal pressures,
the pelvic floor muscles relax which straightens the rectum and faeces can be
expelled.

Something wrong?
Function of Large Intestine LAST UPDATED: 21ST

APRIL 2019
LARGE INTESTINE  Bookmark
The large intestine extends from the ileocaecal valve to the anus.
Ileocecal Valve
Approximately 1.5 L of chyme enters the large intestine per day through the
ileocaecal sphincter. Distension of the terminal ileum results in the opening of
the ileocaecal sphincter and distension of the caecum causes it to close
allowing regulation of flow into the colon to maximise the function of the large
intestine, which is to concentrate faeces by absorbing water and electrolytes.
The initial 1.5 L is reduced to about 150 g of faeces consisting of 100 mL of water
and 50 g of solids.
Functional Role of Taenia Coli
The muscle layers of the large intestine are slightly di!erent from those found in
the rest of the GI tract. It still has a powerful circular muscle layer but the
longitudinal smooth muscle layer is concentrated into three bands called the
teniae coli. These bands are shorter than the circular muscle layer and gather
the caecum and colon into a series of pouch-like folds called haustra.
The caecum and ascending and transverse colon are innervated by

parasympathetic branches of the vagus nerve; the descending and sigmoid
colon, rectum and anal canal are innervated by parasympathetic branches of
the pelvic splanchnic nerves. These parasympathetic fibres innervate intramural
plexuses. The sympathetic nerves via the superior mesenteric plexus, and via
the inferior mesenteric and superior hypogastric plexuses, innervate the
proximal and distal parts of the large intestine respectively.
FF U
UNNC T I O N A
A L A N A T O M Y O F T H E L A R G E I N T E S TT I N
N E . ( IM AGE BY U N K N OWN
[ P U B LIC DOM AIN ], V IA WIK IM EDIA C OM M ON S)
Handling of Chyme
Movement of chyme through the large intestine involves both mixing (via
haustral segmental contractions) and propulsion (via peristalsis). Haustration
aids the exposure of chyme to the mucosal surface and helps the reabsorption
of water and electrolytes. Chyme usually remains in the colon for up to 20 h.
Parasympathetic stimulation causes segmental contraction whereas

stimulation of sympathetic fibres stops colonic activity.
Water Absorption
The chyme that initially enters the large intestine is isotonic, however in the
colon, more water than electrolytes is absorbed, and the fluid becomes
hypertonic, leading to water being absorbed against a concentration gradient.
The process of water absorption is controlled by Na+/K+ ATPases located in the
basolateral and lateral membranes of the epithelial cells. Na+ is pumped into
extracellular spaces and tight junctions at the luminal membrane prevent the
di!usion of Na+ and Cl- back from the extracellular space into the lumen. This
leaves a hypertonic solution close to the lumen, causing water to follow by
osmosis.
The electrolytes are absorbed by a variety of mechanisms (similar to those of
the small intestine), with essentially a net movement of K+ and HCO3- into the
lumen of the large intestine, because of the potential di!erence set up by the
asymmetrical absorption of Na+ and Cl- across the epithelium.
Intestinal Flora
Commensal intestinal bacterial flora have a role in:
Keeping pathogenic bacteria at bay by competing for space and nutrient

Converting conjugated bilirubin to urobilinogen (some of which is
reabsorbed and excreted in urine) and stercobilinogen which is excreted
in the faeces
The synthesis of vitamins K, B12, thiamine and riboflavin
The breakdown of primary bile acids to secondary bile acids
The breakdown of cholesterol, some food additives and drugs

Bile LAST UPDATED: 21ST
APRIL 2019
LIVER AND GALLBLADDER  Bookmark
Bile is an aqueous, alkaline greenish-yellow liquid containing bile acids,

cholesterol, phospholipids, bile pigments, electrolytes, mucus and water.
Function
Bile functions to eliminate endogenous and exogenous substances from the

liver, to neutralise gastric acid in the small intestine, and to emulsify fats in the
small intestine and facilitate their digestion and absorption.
Production
Bile is secreted by hepatocytes. It is isotonic and resembles plasma ionically.

This fraction of bile is called the bile acid-dependent fraction. As it passes along
the bile duct, the bile is modified by epithelial cells lining the duct by the
addition of water and bicarbonate ions; this fraction is called the bile acid-
independent fraction. Overall, the liver can produce 500 - 1000 mL of bile per
day. The bile is either discharged directly into the duodenum or stored in the
gallbladder. The bile acid-independent fraction is made at the time it is required
i.e. during digestion of chyme. The bile acid-dependent fraction is made when
the bile salts are returned from the GI tract to the liver, and is then stored in the
gallbladder until needed.
Storage
The gallbladder not only stores bile but concentrates it by removing non-
essential solutes and water, leaving bile acids and pigments, mainly by active
transport of Na+ into the intercellular spaces of the lining cells which, in turn,
draws in water, HCO3- and Cl- from the bile and into the extracellular fluid.
Within a few minutes of a meal, particularly when fatty foods have been
consumed, the gallbladder contracts and releases bile into the bile duct. The
sphincter of Oddi is relaxed, allowing the bile to pass into the duodenum
through the ampulla of Vater. The gallbladder empties completely 1 h after a fat-
rich meal, and maintains the level of bile acids in the duodenum above that
necessary for the function of the micelles.
Regulation
The formation of bile is stimulated by:
Bile salts
Secretin
Glucagon
Gastrin
The release of bile stored in the gallbladder is stimulated by:
Cholecystokinin
Vagal stimulation (to a lesser extent)

Bile Acids LAST UPDATED: 6TH
DECEMBER 2020
LIVER AND GALLBLADDER  Bookmark
Bile acids are detergents which emulsify lipids. They have a hydrophobic and a
hydrophilic end and in aqueous solution, bile salts orient themselves around
droplets of lipid forming micelles to keep the lipid droplets dispersed.
Production
Bile acids are synthesised from cholesterol by hepatocyte and excreted into bile.
Synthesis of new bile acids occurs as needed to replace bile acids that are
excreted in the faeces.
The principal primary bile acids are cholic acid and chenodeoxycholic acid. They
are made more soluble by conjugation with taurine or glycine in the liver.
Enterohepatic Circulation
Of the bile acids excreted into the intestine, about 95% are reabsorbed into the
portal circulation by active transport mechanisms in the distal ileum and
recycled by the liver.
Many of the bile salts are reabsorbed unaltered, some are converted by
intestinal bacteria into secondary bile acids (deoxycholic acid and lithocholic
acid) and then reabsorbed and a small proportion escapes reabsorption and is
excreted in the faeces.
Function
The main functions of bile acids are:
Emulsification of lipids to increase the surface area available for digestion
by pancreatic lipase
Micelle formation to facilitate lipid transport and absorption
Stimulation of bile production by osmotically attracting water and
electrolytes into the bile canaliculi
Regulation of bile acid synthesis via negative feedback

Function of Liver LAST UPDATED: 21ST
APRIL 2019
 Bookmark
LIVER AND GALLBLADDER
Functional Anatomy
The liver consists of four lobes, each made up of hexagonal lobules, the functional
unit of the liver. Each lobule consists of a central vein that eventually becomes part of
the hepatic vein. Surrounding the central vein are single columns of hepatocytes
radiating outwards; between the hepatocytes are small canaliculi which drain into the
bile duct on the periphery of the lobule. At each of the six corners of the lobules lies a
'portal triad' comprising branches of the hepatic artery, the portal vein and the bile
duct.
FU
UN C T I O N A L A N A
AT O
OM Y O F T H
HE L I V
V E R . ( IM AGE BY O P E N STAX C O LLEGE [C C BY 3.0

Functions
The main functions of the liver are:
Foetal haematopoiesis
Protein metabolism
synthesis and secretion of albumin, synthesis of plasma proteins,

formation of urea from ammonia, deamination of amino acids, synthesis
of coagulation factors, metabolism of polypeptide hormones
Fat metabolism
formation of lipoproteins and fatty acids, synthesis of cholesterol,

conversion of cholesterol to bile salts, conversion of carbohydrates and
protein to fat ketogenesis, metabolism and excretion of steroid hormones
Carbohydrate metabolism
gluconeogenesis, glycogenesis, glycogenolysis
Bile production
synthesis of bile salts, production of alkaline fluid for neutralisation of

gastric acid in the intestines, excretion of waste metabolites and
detoxified substances from the body in bile
Storage of vitamins and minerals
folate, B12, fat-soluble vitamins, iron, copper
Bone metabolism in the form of hydroxylation of vitamin D

Biotransformation and detoxification of drugs and exogenous substances,
steroid hormones and nitrogenous gut toxins
Protection by filtration of portal blood
Phagocytosis of bacteria/antigens by Kup!er cells

Mastication LAST UPDATED: 4TH
MARCH 2019
MOUTH AND OESOPHAGUS  Bookmark
Mastication is the process of systematic mechanical breakdown of food in the

mouth. Mastication breaks up large food particles, mixing them with salivary
secretions and aiding subsequent digestion. Certain foods require more
chewing than others e.g. red meat or chicken compared to fish, eggs or rice in
order to be fully digested and absorbed by the gastrointestinal tract.
Mastication involves the coordinated activity of the teeth, jaw muscles,

temporomandibular joint, tongue and other structures such as the lips, palate
and salivary glands.
During mastication, three main pairs of glands secrete saliva; the parotid,
submandibular and sublingual glands.
At rest, saliva is predominantly produced by the submandibular gland (65%, with

only 20% from the parotid gland), but when stimulated, saliva is increasingly
produced by the parotid gland (50%, compared to only 30% from the
submandibular gland). The parotid gland produces a more watery proteinaceous
saliva, rich in electrolytes and enzymes with little mucus, compared to the
submandibular gland.
Following mastication, the tongue propels the bolus of food along the palate
towards the pharynx, initiating the swallowing reflex.

Saliva LAST UPDATED: 16TH
DECEMBER 2019
Sites of Production
Three main pairs of glands: the parotid, submandibular and sublingual glands secrete
saliva. About 1 - 2 L of saliva is produced per day, and almost all is swallowed and
absorbed.
Salivary gland Contribution at Contribution when

rest stimulated
Parotid gland 20% 50%
Submandibular 65% 30%

gland
Sublingual gland 7-8% 10%
Minor glands 7-8% 10%

S
SAA LL II V
VAAR Y
Y G
GL A
ANN D S .. ( IM AGE BY B LAU S E N.C O M STAF F (2 0 14) . "M E DICAL GALLE RY O F
B LAU S E N M E D I CAL 2 0 1 4". WI K I JO U R N AL O F M E D I C I N E 1 (2) . D O I : 1 0.1 5 3 47/ WJM /2 0 1 4.0 1 0.
ISSN 2002-4436. (OWN WOR K) [C C BY 3.0
Composition
Saliva is hypotonic and alkaline, and contains a mixture of both inorganic and organic
constituents. Saliva composition varies according to the rate and site of production,
but the main components are:
Water (99%)
Mucus
Digestive enzymes e.g. amylase, lingual lipase
Antibacterial enzymes e.g. lysozyme
Secretory immunoglobulins e.g. IgA
Electrolytes (high K+ and HCO3- concentration)
Control of Secretion
Secretion of saliva is under the control of the autonomic nervous system. There is a
baseline level of secretion (about 0.5 mL/min) due to ongoing low-level
parasympathetic stimulation which prevents the mouth and pharynx from drying out.
On top of the baseline, increases in salivary secretion can occur in response to food
activating gustatory receptors or mastication activating mucosal mechanoreceptors
or in response the sight, smell and anticipation of food. However salivation is initiated,
the impulses to the salivary glands travel via the autonomic nerves.
The sympathetic control of salivary production is via the superior cervical ganglion.
Sympathetic innervation causes increased protein secretion resulting in increased
production of a thick mucoid saliva. There is variable sympathetic innervation
between the salivary glands and generally this system is far less important than the
parasympathetic innervation in terms of regulating production of saliva.
The parasympathetic outflow is coordinated via centres in the medulla, and

innervation occurs via the facial and glossopharyngeal nerves. This results in the
following e!ects: increased production of saliva by acinar cells, increased secretion of
bicarbonate by ductal cells, increased blood flow to the salivary glands and
contraction of myoepithelium to increase the rate of expulsion of saliva. Overall,
increased parasympathetic stimulation results in an increased flow of saliva that is
more watery in composition. Saliva production is decreased by inhibition of the
parasympathetic nervous system e.g. by sleep, dehydration, anticholinergic drugs and
fear.
Function
Functions of saliva in health include:
General cleansing and protection of the buccal cavity by washing away food
particles
Moistening of the buccal cavity for speech
Lubrication of ingested food for bolus formation and swallowing
Dissolving of chemicals in food allowing them to interact more e"ciently with
taste buds
Dilution and neutralisation of acid in food (and produced by bacteria)
Secretion of digestive enzymes (particularly amylase for early starch digestion)
Secretion of the antibacterial enzyme lysozyme
Secretion of IgA to protect against invasion of microorganisms

Swallowing LAST UPDATED: 21ST
APRIL 2019
Swallowing is the controlled transport of a food bolus from mouth to stomach,

involving a sequential reflex, which is coordinated by the swallowing centre in the
medulla and pons and consists of three phases: the buccal, pharyngeal and
oesophageal phases. Fibres in the vagus and glossopharyngeal nerves carry
information between the gastrointestinal tract and the brainstem.
Buccal Phase (voluntary)
During the buccal phase, food is chewed and mixed with saliva to form a food bolus.
Tongue movements then push this food bolus upwards and backwards against the
hard palate, forcing it into the pharynx.
Pharyngeal Phase (involuntary)
The pharyngeal phase lasts about 1 second and is initiated by the food bolus
stimulating mechanoreceptors in the pharynx and firing impulses via the
glossopharyngeal nerve (CN IX) and the vagus nerve (CN X) to the swallowing centre.
In the pharyngeal phase:
The soft palate elevates, closing o" the nasopharynx

The base of the tongue retracts, pushing the bolus against the pharyngeal
walls
Laryngeal muscles contract to close the glottis and elevate the larynx, closing
o" the airway
Breathing is inhibited
The tip of the epiglottis moves over the tracheal opening, closing o" the airway
The pharyngeal constrictor muscles contract sequentially from top to bottom,
squeezing the bolus downwards
The upper oesophageal sphincter relaxes to permit the food bolus to enter the
oesophagus
As the bolus enters the oesophagus, these changes reverse, the larynx opens and
breathing continues.
Oesophageal Phase (involuntary)
The oesophageal phase involves transport of the bolus along the oesophagus to the
stomach by peristalsis. A coordinated wave of relaxation in front of the food bolus and
contraction behind the bolus of the circular and longitudinal muscles of the
oesophagus propels the food bolus along. Gravity accelerates the movement.
The lower oesophageal sphincter relaxes as the food bolus approaches the lower end
of the oeosphagus, opening and allowing the bolus to pass into the stomach.
The sphincters and the peristaltic waves are principally controlled by activity in the
vagus nerve and aided by a high degree of coordination of the activity within the
enteric nerve plexuses within the tract itself.
P
PHHA S
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OF S W A
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OWWI N
N G .. ( IM AGE BY B O U M P H R E YF R [C C BY-SA 3.0

Cholecystokinin LAST UPDATED: 21ST APRIL
2019
PHYSIOLOGY / GASTROINTESTINAL / PANCREAS
 Bookmark
Cholecystokinin (CCK) is secreted by I-cells of the duodenal and jejunal mucosa.
Stimulating Factors
Cholecystokinin release is stimulated by:
The presence of small peptides and amino acids in the duodenum

The presence of fatty acids and monoglycerides in the duodenum
Inhibitory Factors
The release of cholecystokinin is inhibited by somatostatin.
Function
CCK acts to:
Increase production of bile

Stimulate release of stored bile via contraction of the gallbladder and relaxation of the sphincter
of Oddi
Potentiate secretin-induced stimulation of pancreatic HCO3- secretion
Stimulate pancreatic enzyme secretion
Inhibit gastric emptying
Inhibit gastric acid production
Stimulate secretion of pepsinogen from chief cells
Hormone Released Stimulated by: Inhibited by: Acts to:

from:
Gastrin G-cells in The presence of small Low gastric pH, Stimulate

the pyloric peptides and amino somatostatin, acid
antrum acids in the stomach, secretin, secretion
gastric distension, cholecystokinin, from gastric
raised gastric pH, gastric parietal
vagal stimulation inhibitory cells,
polypeptide stimulate
pepsinogen
from gastric
chief cells,
increase
gastric
motility,
stimulate
growth of
gastric
mucosa
Cholecystokinin I-cells in The presence of fatty Somatostatin Increase

(CCK) the acids/monoglycerides production
duodenum and small of bile,
and peptides/amino acids stimulate
jejunum in the duodenum release of
stored bile,
increase
pancreatic
bicarbonate
secretion,
stimulate
pancreatic
enzyme
secretion,
inhibit
gastric
emptying,
inhibit
gastric acid
production,
stimulate
pepsinogen
secretion
Secretin S-cells in A low pH and the Somatostatin Inhibit

the presence of fatty gastric acid
duodenum acids in the secretion,
duodenum inhibit
gastric
emptying,
stimulate
pepsinogen
secretion,
stimulate
pancreatic
bicarbonate
secretion,
increase
pancreatic
enzyme
secretion,
increase bile
production
Gastric K-cells in The presence of fatty Somatostatin Inhibit

inhibitory the acids, amino acids gastric acid
polypeptide duodenum and orally secretion,
(GIP) and administered glucose stimulate
jejunum in the duodenum insulin
release

Function of Exocrine LAST UPDATED: 21ST
APRIL 2019
Pancreas  Bookmark
The exocrine pancreas secretes a major digestive fluid called pancreatic juice, which
is secreted into the duodenum via the pancreatic duct. When food is present in the
duodenum the sphincter of Oddi relaxes, allowing both bile and pancreatic secretions
to enter the duodenum.
FF U
UNNC
C TT II O
O N A LL A
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O M Y O F TT H
HE P
PA N C R E
E A S .. ( IM AGE BY O P E N STAX C O LLEGE [C C BY 3.0
Pancreatic Juice
The pancreas secretes about 1 L of fluid per day. The bulk of the fluid is a sodium and
bicarbonate rich hypertonic alkaline fluid secreted by pancreatic ductal cells, which
together with secretions from the gallbladder and the intestinal juices, neutralises
acid entering the duodenum from the stomach.
Digestive Enzymes
The acinar cells secrete a small volume of fluid rich in digestive enzymes.
These enzymes include:
Pancreatic amylase
Pancreatic lipase
Ribonuclease and deoxyribonuclease
Proteolytic enzymes including trypsin, chymotrypsin, elastase and
carboxypeptidase
Most of the proteolytic enzymes are secreted in an inactive proenzyme form to

protect the pancreas from autodigestion, and are activated in the duodenum.
Regulation of Secretions
Pancreatic exocrine secretion is controlled by:
Parasympathetic stimulation which enhances secretion of both the enzyme

and aqueous components
Sympathetic stimulation which inhibits pancreatic secretion
Secretin which stimulates secretion of the alkaline-rich fluid from ductal cells
Cholecystokinin which stimulates secretion of the enzyme-rich fluid from
acinar cells
Somatostatin which inhibits secretion from both acinar and ductal cells

Secretin LAST UPDATED: 21ST APRIL
2019
 Bookmark
Secretin is secreted by S-cells in the duodenum.
Stimulating Factors
Secretin secretion is stimulated by:
A low pH in the duodenum

The presence of the products of fat digestion in the duodenum
Inhibitory Factors
Secretin release is inhibited by somatostatin.
Function
Secretin acts to:
Decrease gastric acid secretion by gastric parietal cells (through inhibition of gastrin release)
Inhibit gastric emptying
Stimulate the release of pepsinogen by gastric chief cells
Stimulate pancreatic HCO3- secretion
Potentiate cholecystokinin-induced stimulation of pancreatic enzyme secretion
Stimulate HCO3- and H2O secretion by the liver and increase bile production

from:

gastric distension, cholecystokinin, from gastric
raised gastric pH, gastric parietal
vagal stimulation inhibitory cells,
polypeptide stimulate
pepsinogen
from gastric
chief cells,
increase
gastric
motility,
stimulate
growth of
gastric
mucosa

stored bile,
increase
pancreatic
bicarbonate
secretion,
stimulate
pancreatic
enzyme
secretion,
inhibit
gastric
emptying,
inhibit
gastric acid
production,
stimulate
pepsinogen
secretion

duodenum inhibit
gastric
emptying,
stimulate
pepsinogen
secretion,
stimulate
pancreatic
bicarbonate
secretion,
increase
pancreatic
enzyme
secretion,
increase bile
production

release

Somatostatin LAST UPDATED: 5TH
MARCH 2019
PHYSIOLOGY / GASTROINTESTINAL / PANCREAS /

 Bookmark
SMALL INTESTINE / STOMACH
Somatostatin is secreted from D-cells in the pyloric antrum, the duodenum and
pancreatic islets.
Somatostatin is secreted by cells throughout the GI tract in response to H+ in the

lumen.
Somatostatin secretion is inhibited by vagal stimulation.
Somatostatin acts to inhibit gastric acid secretion both directly at the parietal cell via
a G-protein coupled receptor and indirectly via inhibition of gastrin and histamine
secretion.
Somatostatin also acts to inhibit secretion of all GI hormones including:
Insulin
Glucagon
Cholecystokinin
Secretin
Gastric inhibitory polypeptide (GIP)
Somatostatin thus mediates:
Decreased gastric and intestinal motility

Decreased gastric and intestinal secretions
Decreased pancreatic exocrine function
Decreased pancreatic endocrine function
Decreased bile production and release

Carbohydrate Handling - MRCEM Success 28/03/2023, 12:16 PM
Carbohydrate Handling LAST UPDATED: 21ST

APRIL 2019
PHYSIOLOGY / GASTROINTESTINAL / SMALL INTESTINE
 Bookmark
Carbohydrates are the main energy source of most diets. They provide 17 kJ (4 kcal) of
energy per gram. Carbohydrate is digested in the mouth and small intestine.
Dietary Carbohydrate
Most dietary carbohydrate is in the form of polysaccharides. The principal ingested

polysaccharides are starch which is derived from plant sources and glycogen which is
derived from animal sources. Other sources of carbohydrate are monosaccharides
(glucose, fructose and galactose) and disaccharides (maltose, sucrose and lactose).
Dietary fibre consists of indigestible carbohydrate (found in plant foods) such as

cellulose, lignin and pectin. Although it does not provide energy, fibre adds bulk to the
bowel contents and increases gut motility (and decreases absorption of toxic
compounds due to its binding properties, including some carcinogens).
Carbohydrate Digestion
Polysaccharides are digested by amylases, produced initially by salivary glands and

later by the pancreas, to produce maltose, maltotriose and limit dextrins with short
branches. These are broken down further by enzymes released from the intestinal
brush border (maltase, isomaltase, sucrase and lactase) into the final products of
carbohydrate digestion, the monosaccharides (glucose, fructose and galactose),
which can be absorbed by the enterocyte.
The monosaccharides are transported across the apical membrane of the enterocyte
by means of cotransporter molecules, such as the sodium-glucose co-transporter
(SGLT-1), that link their inward movement with that of Na+ down its concentration
gradient (the Na+ gradient being maintained by the Na+/K+ ATPase pump). At the
basolateral membrane, monosaccharides leave the cell either by simple or facilitated
di"usion down the concentration gradient and enter the circulation via the rich
capillary network in the villus.
https://mrcemsuccess.com/explanation/carbohydrates/?_sft_qc=physiology&sf_paged=2 Page 2 of 3
Carbohydrate Handling - MRCEM Success 28/03/2023, 12:16 PM
C
CAAR
RBBO
OHHY D R
RAT E H A
AN D L I N
NGG .. ( IM AGE BY S O N AB I (OWN WO R K ) [C C BY-SA 4.0
https://mrcemsuccess.com/explanation/carbohydrates/?_sft_qc=physiology&sf_paged=2 Page 3 of 3
Fat Handling LAST UPDATED: 15TH
MAY 2019
 Bookmark
Dietary Fat
Dietary fat is chiefly composed of triglycerides (esters of free fatty acids and glycerol
which may be saturated or unsaturated). The essential fatty acids are linoleic acid and
alpha-linolenic acid, which cannot be manufactured in the body. The body is e!cient
at manufacturing fats (triglycerides, sterols and phospholipids) and will lay down
subcutaneous fat stores. Dietary fat provides 37 kJ (9 kcal) of energy per gram. Fats
are digested almost entirely in the small intestine and are only released from the
stomach into the duodenum at the rate at which they can be digested.
Fat Digestion
Lingual and gastric lipase begin the hydrolysis of triglycerides (although this is not
physiologically significant unless pancreatic lipase is deficient).
In the duodenum fat is emulsified by bile acids, a process where larger lipid droplets
are broken down into much smaller droplets providing a greater surface area for
enzymatic digestion. Pancreatic lipase digests triglycerides into monoglycerides and
free fatty acids. These breakdown products form tiny particles with the bile acids
called micelles.
Micelles are arranged so that hydrophobic lipid molecules lie in the centre,
surrounded by bile acids arranged such the outer region is hydrophilic. This
arrangement allows the micelles to enter the aqueous layers surrounding the
microvilli, and the products of fat digestion (fatty acids and monoglycerides),
cholesterol and fat-soluble vitamins can then di"use passively into the enterocytes,
leaving the bile salts within the lumen of the gut where they are reabsorbed from the
ileum or excreted in faeces.
S
S TT R
RUUC
C TT U
UR E
E OF A
A M
M II C
C E L LL E
E .. ( IM AGE BY B ILE1.P N G: F R AN K B O U M P H R E Y, M D DE R IVATIV E
WO R K : H A Z M AT 2 ( T H I S F I L E WAS D E R I V E D F RO M B I L E1 .P N G : ) [C C BY-SA 3 .0
Fat Absorption
Once inside the epithelial cell, lipid is taken into the smooth endoplasmic reticulum
where much of it is re esterified. Dietary and synthesised lipids are then incorporated
into chylomicrons in the Golgi body, which are exocytosed from the basolateral
membrane to enter lacteals. Some small-chain fatty acids may be absorbed directly
into the blood.
FF A
ATT H
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NDD LL II N
NGG .. ( IM AGE BY O P E N STAX C O LLEGE [C C BY 3.0
Chylomicrons
From lacteals, chylomicrons pass into the lymphatic system and eventually reach the
bloodstream via the thoracic duct. Chylomicrons consist mainly of triglyceride with
small amounts of cholesterol and cholesteryl esters in the centre with a phospholipid
coat studded with apolipoproteins.
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S TT R
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C TT U
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ONN . ( IM AGE BY AJC 1 [ P U B LIC DO M AIN ], V IA WIK IM E DIA
C O M M O N S)

Function of Small Intestine LAST UPDATED: 28TH
NOVEMBER 2019

 Bookmark
The small intestine is the main site for digestive and absorptive processes. Motility of
the small intestine (via peristalsis and segmental contraction) facilitates mixing of
intestinal contents, the bringing of the intestinal contents into contact with the
absorptive intestinal brush border and the forward propulsion of the contents. The
small intestine absorbs water, electrolytes, carbohydrates, amino acids, minerals, fats
and vitamins.
Duodenal Chyme
The chyme that first enters the duodenum is acidic, hypertonic and only partially
digested. There is an osmotic movement of water across the freely permeable wall
which leads to the contents becoming isotonic, and addition of both bicarbonate from
the pancreas and bile from the liver which neutralises the acidity, allowing further
digestion of the chyme performed by the addition of enzymes from the pancreas, liver
and intestine itself.
Functional Anatomy
The mucosa of the small intestine has a much greater surface area for absorption
than in other parts of the gastrointestinal tract.
Factors increasing the surface area include:
The small intestine is very long - about 5 m in length.

The inner wall of the small intestine is covered by numerous folds of mucous
membrane called plicae circulares.
The lining of the small intestine is folded into many finger-like projections called
villi.
The surface of the villi is covered with a layer of epithelial cells which, in turn,
have many small projections called microvilli that project towards the lumen of
the intestine (forming the brush border).
The microvilli are covered by a glycocalyx which contains many enzymes which are
involved in digestion and transport. Each villus contains a single, blind-ended
involved in digestion and transport. Each villus contains a single, blind-ended
lymphatic vessel called a lacteal and also a capillary network, via which nutrients are
absorbed.
F U N C T I O N A L A N A T O M Y O F T H E S M A L L I N T E S T I N E . ( IM AGE BY O P E N STAX C O LLEGE
Water Absorption and the Sodium Pump
As the contents of the intestine are isotonic with body fluids and mostly have the
same concentration of the major electrolytes, their absorption is active. Water cannot
be moved directly, but follows osmotic gradients set up by the transport of ions,
primarily mediated by the sodium pump.
Na+/K+ ATPase located on the basolateral membrane of the epithelial cells pumps
three Na+ ions from the cell in exchange for two K+ ions, against their respective
concentration gradients. This leads to a low intracellular concentration of Na+ and a
high intracellular concentration of K+. The low intracellular concentration of Na+
ensures a movement of Na+ from the intestinal contents into the cell down its
concentration gradient by both membrane channels and transporter protein
mechanisms. Na+ is then rapidly pumped again by the basolateral sodium pump. K+
leaves the cell across the basolateral membrane down its concentration gradient
linked to an outward movement of Cl- against its concentration gradient (Cl- having
entered the cell across the luminal membrane down its concentration gradient).
These movements set up an osmotic gradient between the lumen and the blood,
leading to water absorption following the movement of Na+ and Cl- across the
luminal membrane. Up to 9 L of water is absorbed from the gastrointestinal tract per
day, most of it from the small intestine, especially the jejunum.

Iron Handling LAST UPDATED: 21ST
APRIL 2019
SMALL INTESTINE  Bookmark
The total amount of iron in the body is about 3 - 4 g, of which about two-thirds
is in haemoglobin.
Iron Absorption
Iron exists in two forms, the ferrous state (Fe2+) or the ferric state (Fe3+). Most
dietary iron is in the form Fe3+, which is reduced by ferrireductase in the

mucosa assisted by ascorbic acid and HCl in gastric secretions to the more
soluble Fe2+ and then absorbed by the duodenum and jejunum.
Fe2+ is taken across the enterocyte apical membrane by the divalent metal
transporter (DMT1). In the enterocyte, Fe2+ is oxidised to Fe3+ and then either
stored in enterocyte epithelial cells bound to apoferritin, or released into the
plasma via the molecule ferroportin on the basolateral membrane.
Iron Transport
Iron in the plasma is bound to the transport protein transferrin. Iron is

transferred to the bone marrow for erythropoiesis or to the liver or other
parenchymal cells for storage as ferritin or haemosiderin. The iron released from
the breakdown of senescent red blood cells, some of which is stored by the
macrophages in the liver and spleen, provides most of the iron on transferrin,
only a small proportion of transferrin iron comes from dietary iron.
Regulation of Iron Absorption
The normal Western diet contains about 10 - 20 mg of iron per day and typically
about 5 - 10% of this is absorbed (to replace that lost by intestinal epithelial cell
shedding). Iron absorption is tightly regulated as excess iron is potentially toxic,
and the body has no physiological mechanism for upregulating excretion.
Iron absorption can be increased when body stores are low or when there is a
need to increase erythropoiesis e.g. an increase in absorption may be seen
about 3 - 4 days following haemorrhage.
Hepcidin is the main hormonal regulator of iron homeostasis; it inhibits iron

release from macrophages in the reticuloendothelial system and from intestinal
epithelial cells and inhibits intestinal iron absorption. Hepcidin is suppressed by
erythropoietin, ine!ective erythropoiesis, pregnancy and hypoxia, but
upregulated in inflammation and iron overload.

Protein Handling LAST UPDATED: 21ST
APRIL 2019

 Bookmark
Protein is composed of amino acids linked by peptide bonds. Nine amino acids are
essential (required from the diet) for protein synthesis and nitrogen balance, the
other necessary amino acids can be manufactured in the body. Proteins provide
about the same amount of energy as carbohydrate but are not as easily utilised. The
protein requirement of a normal healthy adult is about 40 g/day. Protein is digested in
the stomach and small intestine.
Protein Digestion
Digestion of dietary protein begins in the stomach where pepsin hydrolyses protein to
polypeptides, and continues in the duodenum where pancreatic proteases (trypsin
and chymotrypsin) continue the process of hydrolysis forming oligopeptides.
These are further broken down into small peptides and amino acids by pancreatic
carboxypeptidases and aminopeptidases located on luminal membrane epithelial
cells. Free amino acids are absorbed by secondary active transport coupled with Na+
transport. Amino acids cross the basal membrane into the capillaries by facilitated
di!usion.
PR
ROO TT E I N
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NDD LL I N
NGG .. ( IM AGE BY S O N AB I (OWN WO R K ) [C C BY-SA 4.0

Somatostatin LAST UPDATED: 5TH
MARCH 2019
PHYSIOLOGY / GASTROINTESTINAL / PANCREAS /

 Bookmark
SMALL INTESTINE / STOMACH
Somatostatin is secreted from D-cells in the pyloric antrum, the duodenum and
pancreatic islets.
Somatostatin is secreted by cells throughout the GI tract in response to H+ in the

lumen.
Somatostatin secretion is inhibited by vagal stimulation.
Somatostatin acts to inhibit gastric acid secretion both directly at the parietal cell via
a G-protein coupled receptor and indirectly via inhibition of gastrin and histamine
secretion.
Somatostatin also acts to inhibit secretion of all GI hormones including:
Insulin
Glucagon
Cholecystokinin
Secretin
Somatostatin thus mediates:
Decreased gastric and intestinal motility

Decreased gastric and intestinal secretions
Decreased pancreatic exocrine function
Decreased pancreatic endocrine function
Decreased bile production and release

Vitamin B12 Handling LAST UPDATED: 5TH
MARCH 2019
SMALL INTESTINE  Bookmark
On ingestion, vitamin B12 is bound to R protein found in saliva and gastric

secretions, which protects it from digestion in the stomach.
Once vitamin B12 has been separated from R protein in the duodenum by the
action of pancreatic proteases, vitamin B12 binds to intrinsic factor (IF) secreted
by gastric parietal cells.
Receptors for the IF-B12 complex are present in the membrane of epithelial cells
of the terminal ileum, which bind the complex and allow uptake of vitamin B12
across the apical membrane by endocytosis. Vitamin B12 is then transported
across the basal membrane into the portal blood where it is bound to
transcobalamin II and processed by the liver.
In pernicious anaemia, there are autoantibodies against gastric parietal cells

and intrinsic factor, resulting in vitamin B12 deficiency anaemia.

Vitamins LAST UPDATED: 21ST
APRIL 2019

 Bookmark
Vitamins are classified as fat soluble or water soluble. Vitamins A, D, E and K are fat
soluble, the other vitamins (B and C) are water soluble .
Absorption of fat-soluble vitamins is dependent upon absorption of dietary fat, and

they are stored in fatty tissue in the body, mainly in the liver. Sources of fat-soluble
vitamins include meat, fish and vegetable oil.
The water-soluble vitamins are mainly absorbed by di!usion or mediated transport

(other than vitamin B12). Body stores of water-soluble vitamins (other than vitamin
B12) are smaller than the stores of fat-soluble vitamins. Sources of water-soluble
vitamins include milk, meat, fruit and vegetables.
Clinical e!ects of vitamin deficiency include:
Vitamin C deficiency - Scurvy

Thiamine (Vitamin B1) deficiency - Beriberi/Wernicke-Korsako! syndrome
Vitamin B12 deficiency - Megaloblastic anaemia/Subacute combined
degeneration of spinal cord
Folate (B9) deficiency - Megaloblastic anaemia
Vitamin D deficiency - Osteomalacia/Rickets
Vitamin K deficiency - Defective clotting
Vitamin A deficiency - Blindness

Function of Stomach LAST UPDATED: 28TH
NOVEMBER 2019
PHYSIOLOGY / GASTROINTESTINAL / STOMACH
 Bookmark
The stomach receives food and fluid from the oesophagus, mixes it with digestive
juices to form chyme and releases its contents into the duodenum. The stomach acts
as a reservoir for food as it is very distensible; when empty it has a volume of about
50 mL but it has capacity of up to 3 - 4 L.
There are two sphincters at each of the gastric orifices, the lower oesophageal
sphincter protects the oesophagus from reflux of the gastric contents and the pyloric
sphincter controls the flow of gastric contents into the duodenum.
Functions
The main functions of the stomach are to:
Store food temporarily (as it can be ingested more rapidly than it can be
digested)
Chemically and mechanically digest food using acids, enzymes and churning
movements
Regulate the release of the resulting chyme into the small intestine
Secrete intrinsic factor which is essential for absorption of vitamin B12
Gastric Cell Types
Cell Type Function
Parietal cell Secretes HCl and intrinsic factor
Chief cell Secretes pepsinogen
G cell Secretes gastrin
Enterochroma!n-like cell Secretes histamine
Surface mucous cell Secretes mucus

G
GA S
S T R II C
C CE
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S .. ( IM AGE BY O P E N STAX C O LLEGE [C C BY 3.0

Gastric Acid LAST UPDATED: 24TH
FEBRUARY 2020

 Bookmark
The acid environment in the stomach provides a defence mechanism against

ingested microorganisms, aids protein digestion by activation of pepsinogen and
denaturation of dietary protein, and stimulates flow of bile and pancreatic juice.
Mechanism of Secretion
In the parietal cells, CO2 and H2O are converted to H+ and HCO3- catalysed by
carbonic anhydrase.
H+ is secreted into the lumen of the stomach in exchange for K+ by the H+/K+
ATPase pump (proton pump) on the apical membrane of the parietal cell. Cl- is
secreted along with H+; thus the secretion product of the parietal cells is HCl.
The HCO3- produced in the cells is absorbed into the bloodstream in exchange for Cl-
(Cl-/HCO3- exchange) across the basolateral membrane. Eventually, this HCO3- will
be secreted in pancreatic secretions to neutralise H+ in the small intestine.
Factors Stimulating Secretion
The secretion of HCl is stimulated by:
Vagal stimulation
Directly through the neurotransmitter acetylcholine acting at muscarinic

(M3) receptors on the parietal cell
Indirectly through the neurotransmitter gastrin-releasing peptide
(GRP) stimulating release of gastrin from G cells
Histamine acting at H2 receptors on the parietal cell (released from

enterochroma"n-like cells in response to vagal activity and gastrin)
Gastrin released from antral G cells acting at the CCKB receptor on parietal cells
Factors Inhibiting Secretion
The secretion of HCl is inhibited by:

Low pH (< 3) in the stomach
Prostaglandins
Somatostatin (both directly through inhibition at parietal cells and indirectly
through inhibition of gastrin and histamine release)
Enterogastrones
Secretin
Cholecystokinin
Vagotomy
Drugs
H2-receptor blockers e.g. cimetidine

Proton pump inhibitors e.g. omeprazole
Muscarinic receptor antagonists e.g. atropine
GGAASSTTRRIICC AAC
C IIDD SSEECCRREETTIIO
O NN.. ( IM AGE BY U N K N OWN [ P U B LIC DO M AIN ], V IA WIK IM E DIA
C O M M O N S)
Gastric Emptying LAST UPDATED: 21ST
APRIL 2019
 Bookmark
Gastric Motility
Mixing of the food with gastric secretions takes place in the distal body and
antrum of the stomach where the muscularis externa layer is thicker. The
stomach has an additional inner oblique smooth muscle layer (in addition to the
inner circular layer and outer longitudinal layer), allowing peristaltic contractions
and thorough mixing. Gastric contractions are increased by vagal stimulation
and decreased by sympathetic stimulation.
Gastric Emptying
The presence of chyme in the pyloric antrum distends it and causes antral
contractions and opening of the pyloric sphincter. The rate of gastric emptying
is regulated, which leads to a precise supply of chyme to the intestine at an
appropriate rate for digestion. Gastric emptying varies with di"erent food
types; carbohydrates are emptied more quickly, proteins more slowly and fatty
foods even more so, liquids empty more rapidly than solid foods.
Gastric emptying is increased by:
Distension of the pyloric antrum

A fall in the pH of chyme in the stomach
Parasympathetic stimulation
Gastric emptying is decreased by:
Enterogastric inhibitory reflexes stimulated by
Distension of the duodenum

The presence of fats in the duodenum (by stimulating release of
cholecystokinin)
A fall in the pH of chyme in the duodenum
An increase in the osmolality of chyme in the duodenum
Irritation of the mucosal lining of the duodenum
Hormones
Cholecystokinin
Secretin
Gastric emptying can also be delayed pathologically by mechanical obstruction

e.g. tumours or stenosis or by non-mechanical causes e.g. myotonic dystrophy
or autonomic neuropathy.

Gastric Juice LAST UPDATED:
18TH APRIL 2019
 Bookmark
The average adult produces 2 - 3 L of gastric fluid every 24 hours.
Gastric fluid contains:
Mucus
Hydrochloric acid (HCl)
Digestive enzymes
pepsinogen
gastric lipase
Intrinsic factor
Mucus
Mucus is secreted by surface mucous cells. The alkaline, mucin-rich

fluid forms a water-insoluble gel that adheres to the surface of the
stomach lumen and plays an important role in protection of the
stomach against its acid contents and autodigestion by pepsin. In
addition, local mediators, such as prostaglandins, are released when the
mucosa is irritated, and these increase the thickness of the mucus layer
and stimulate the production of bicarbonate which neutralises acid.
Hydrochloric Acid
Hydrochloric acid is secreted by gastric parietal cells.
Digestive Enzymes
Proteins in food are broken down into polypeptides in the stomach by

enzymes called pepsins. Pepsin is secreted in the form of its inactive
precursor, pepsinogen, from chief cells in the gastric mucosa, and is
converted to its active form by the acid environment in the stomach.
Gastric lipase is of little physiological importance except in pancreatic
insu"ciency.
Intrinsic Factor
Intrinsic factor is produced by parietal cells, and is essential for vitamin

B12 absorption. Intrinsic factor binds to vitamin B12, allowing it to
escape degradation in the stomach and intestine and to be safely
transported to the terminal ileum where it is absorbed.

Gastric Mucosal Barrier LAST UPDATED: 21ST
APRIL 2019
Mechanisms  Bookmark
Mechanisms to protect the gastric mucosa include:
Secretion of mucus by mucous neck cells and goblet cells which

forms a water-insoluble gel that coats the gastric mucosa
protecting it from the acidic gastric contents and autodigestion by
e.g. pepsin
Secretion of HCO3- by surface epithelial cells which forms part of

the mucosal gel layer raising the pH around the mucus layer
A compact epithelium lining with tight junctions between cells and
fast cell turnover
Production of prostaglandins which inhibit acid secretion and
increase mucus and HCO3- secretion
IgA secretion which helps prevent against invasion by ingested
microorganisms
Mucosal protection may be impaired by:
Excess acid secretion e.g. Zollinger-Ellison syndrome

NSAIDs which inhibit prostaglandin production and hence reduce
mucus secretion
Helicobacter pylori infection
Hypercalcaemia
Alcohol
Chronic nicotine exposure in smoking

Gastrin - MRCEM Success 28/03/2023, 5:45 PM
Gastrin LAST UPDATED: 21ST APRIL

2019
 Bookmark
Gastrin is secreted by antral G-cells and acts on cholecystokinin B (CCKB) receptors.
Stimulating Factors
Gastrin secretion is stimulated by:
The presence of small peptides and amino acids in chyme

Gastric distension
Vagal stimulation directly via acetylcholine and indirectly via gastrin-releasing peptide (GRP)
Raised gastric pH
Inhibiting Factors
Gastrin secretion is inhibited by:
Low gastric pH (negative feedback mechanism)

Somatostatin
Secretin
Cholecystokinin
Function
Gastrin acts to:
Stimulate acid secretion from parietal cells (both directly and indirectly by stimulating release
of histamine from ECL cells)
Stimulate pepsinogen secretion from chief cells
Increase gastric motility
Stimulate growth of gastric mucosa
from:
https://mrcemsuccess.com/explanation/gastrin/?_sft_qc=physiology&sf_paged=7 Page 2 of 4

gastric distension, cholecystokinin, from
raised gastric pH, gastric gastric
vagal stimulation inhibitory parietal
polypeptide cells,
stimulate
pepsinogen
from
gastric
chief cells,
increase
gastric
motility,
stimulate
growth of
gastric
mucosa

stored bile,
increase
pancreatic
bicarbonate
secretion,
stimulate
pancreatic
enzyme
secretion,
inhibit
gastric
emptying,
inhibit
gastric acid
production,
stimulate
pepsinogen
secretion

duodenum inhibit
gastric
emptying,
stimulate
pepsinogen
secretion,
stimulate
pancreatic
bicarbonate
secretion,
increase
pancreatic
enzyme
secretion,
increase
bile
production

release
Phases of Gastric Secretion LAST UPDATED: 21ST
APRIL 2019
 Bookmark
Stimulation of gastric secretion occurs in three phases.
Cephalic Phase
The cephalic phase is the shortest phase and is initiated by the sight, smell and taste
of food, mediated by the activation of the vagus nerve and its action on the enteric
plexus. It usually begins before the meal and lasts up to 30 minutes into the meal.
Acid secretion is upregulated by acetylcholine released from postganglionic

parasympathetic fibres in the myenteric plexus which acts directly by stimulating
parietal cells and indirectly by stimulating the release of gastrin (from antral G -cells)
and histamine (from enterochroma!n-like cells) which themselves also upregulate
acid secretion from parietal cells.
Gastric Phase
The gastric phase is the longest phase, lasting for up to 3 hours after the start of the
meal. It is triggered by distension of the stomach and the chemical composition of the
food. Most acid secretion takes place during this phase, and the food in the stomach
is converted to chyme.
Mechanoreceptors in the stomach wall are stretched and set up local myenteric and
central vagovagal cholinergic reflexes. Both cause the release of acetylcholine which
stimulates the release of gastrin, histamine, and in turn, acid, pepsinogen and mucus.
Stimulation of the vagus nerve also stimulates the release of gastrin-releasing
peptide (GRP), which mainly acts directly on G-cells to release gastrin.
Whole proteins do not a#ect gastric secretions directly but the presence of their
break-down products, amino acids and peptides, directly stimulates gastrin release
from antral G-cells.
A low pH in the stomach inhibits gastrin secretion, therefore when the stomach is
empty or when acid has been secreted for some time after food has entered it, there
is inhibition of acid secretion. However, when food first enters the stomach, the pH
rises, and this leads to release of the inhibition and causes a maximum secretion of
gastrin. Thus gastric acid secretion is self-regulating.
Intestinal phase
The intestinal phase is brought about by chyme entering the duodenum through the
pyloric sphincter. Initially, there is a continuation of gastric stimulation due to the
activation of intestinal G cells by amino acids and peptides in chyme with subsequent
gastrin release.
However, this is short lived as the duodenum becomes more distended with further
gastric emptying and a series of reflexes is initiated which inhibits further release of
gastric secretion.
Secretin is released in response to acid stimulation which reaches the stomach

via the bloodstream and inhibits the release of gastrin.
The presence of fatty acids in the duodenum itself stimulates the release of
gastric inhibitory peptide (GIP) and cholecystokinin (CCK), which inhibit the
release of both gastrin and acid.
Together with mechanoreceptors in the duodenum via vagal and local reflex
pathways, the release of secretin and cholecystokinin also plays a role in the
regulation of gastric emptying.
P
PHHA S
SE S O
O F G A S TT R
RI C S E
ECC R E T I O N . ( IM AGE BY O P E N STAX C O LLEGE [C C BY 3.0

Acid-Base Disturbance LAST UPDATED: 21ST
APRIL 2019
PHYSIOLOGY / RENAL / ACID-BASE BALANCE
 Bookmark
Total body pH can be regulated by controlling the ratio of PaCO2 (acid) to [HCO3-]
(base) in plasma. Ventilation controls the CO2 level and the kidney controls the
HCO3- level. Disorders of acid-base metabolism can therefore arise from either
excess acid or base, or from diseases altering CO2 or HCO3- levels.
pH ∝ [HCO3-]/PaCO2
In a respiratory acid-base disturbance, the primary disorder alters the CO2 level
whereas in a metabolic acid-base disturbance, the primary disorder alters the
HCO3- level either directly, or by the addition of acid or base to the body. In a mixed
disorder, there may be both respiratory and metabolic disturbances. When either the
HCO3- or CO2 levels change, the pH can be brought back towards normal by altering
the other bu"er partner in the same direction.
Normal ABG Values
RCEM defines the normal values for blood gases as:
pH = 7.35 - 7.45
pO2 (on air) = 11 - 14 kPa
pCO2 = 4.5 - 6.0 kPa
HCO3- = 24 - 30 mmol/L
BE = +/- 2 mmol/L
Acid-base disturbance
Metabolic Primary Compensatory Change

Disturbance Change
Metabolic acidosis ↓[HCO3-] ↓PaCO2 (increased ventilation)

(↓pH)
Metabolic alkalosis ↑[HCO3-] ↑PaCO2 (decreased ventilation)

(↑pH)
Respiratory ↑PaCO2 ↑[HCO3-] (increased renal bicarbonate
acidosis (↓pH) reabsorption)
Respiratory ↓PaCO2 ↓[HCO3-] (decreased renal bicarbonate

alkalosis (↑pH) reabsorption)
Base Excess
Base excess is defined as the amount of strong acid that must be added to each litre
of fully oxygenated blood to return the pH to 7.40 at a temperature of 37 °C and a
pCO2 of 40 mmHg (5.3 kPa).
A base deficit (i.e. a negative base excess) can be correspondingly defined in terms of
the amount of strong base that must be added.
The predominant base contributing to base excess is bicarbonate. A typical reference

range for base excess is -2 to +2 mmol/L.
The base excess increases (or becomes more positive) in metabolic alkalosis or in
compensation for a respiratory acidosis.
The base excess decreases (or becomes more negative) in metabolic acidosis or in
compensation for a respiratory alkalosis.
Metabolic Acidosis
Metabolic acidosis arises from the gain of acid or the loss of base as bicarbonate.
increased production of H+ e.g. lactic acidosis, ketoacidosis (DKA, alcohol,

starvation)
ingestion of H+ or of drugs that are metabolised to acids e.g. salicylate

overdose, ethylene glycol poisoning
impaired renal excretion of H+ e.g. acute or chronic renal failure
loss of HCO3- in the urine e.g. renal tubular acidosis
loss of HCO3- in the gastrointestinal tract e.g. chronic diarrhoea, ileal conduits,
fistulae, small intestinal/pancreatic/biliary drains
The compensatory response to metabolic acidosis is hyperventilation, since the
increased [H+] acts as a powerful stimulant of the respiratory centre. The deep, rapid
and gasping respiratory pattern is called Kussmaul breathing. At low pH, the blood
pressure falls as a result of reduced peripheral resistance and impaired myocardial
contractility. Pulmonary oedema and ultimately ventricular arrest can occur.
Metabolic Alkalosis
Metabolic alkalosis arises from addition of bicarbonate to the blood or from loss of H+
ions from the body.
loss of H+ in the gastrointestinal tract e.g. vomiting, pyloric stenosis, NGT

drainage
loss of H+ in the kidneys e.g. diuretic therapy

ingestion of absorbable alkali e.g. sodium bicarbonate, antacid overdose
increased renal HCO3- reabsorption e.g. primary hyperaldosteronism,

secondary to volume depletion, secondary to hypokalaemia
Metabolic alkalosis is associated with hypoventilation and features of hypocalcaemia
(due to a decrease in the unbound plasma Ca2+ concentration) and hypokalaemia

(due to a shift of potassium into cells) e.g. muscle cramps, weakness, tetany,
paraesthesia.
Respiratory Alkalosis
In a respiratory alkalosis, the primary disorder is a decrease in pCO2 resulting from

hyperventilation. Respiratory alkalosis is much less common than acidosis, and it is
usually acute and uncompensated.
Causes include:
hysterical overbreathing
mechanical over-ventilation in a ventilated patient
raised intracranial pressure
pregnancy
thyrotoxicosis
sepsis
salicylate overdose
hyperthermia
liver failure
hypoxia-induced e.g. altitude acclimatisation
Clinically, there is neuromuscular irritability, with perioral and extremity paresthesia,

muscle cramps, tinnitus, hyperreflexia, tetany and seizures. Cerebral vasoconstriction
with reduced blood flow and cardiac dysrhythmias can occur.
Respiratory Acidosis
Respiratory acidosis results from a primary decrease in ventilation as a result of

depression of the respiratory centre e.g. opioid overdose, a physical impediment to
breathing such as neurological, muscular or chest wall disease, or lung disease or
injury e.g. COPD, asthma, pulmonary oedema.
An acute rise in plasma CO2 is usually associated with a fall in oxygen levels,
dyspnoea, reduced consciousness, and eventually coma. CO2 causes vasodilation,
which may increase cerebral blood flow causing headaches and increased intracranial
pressure. Systemic vasodilation reduces blood pressure, and large rises in plasma
CO2 levels reduce cardiac contractility.

Anion Gap - MRCEM Success 28/03/2023, 12:02 PM
Anion Gap LAST UPDATED: 21ST

APRIL 2019
 Bookmark
Definition
The anion gap is the di!erence between the measured cations and the measured
anions in plasma. As plasma is always electrically neutral, the anion gap determines
the presence of unmeasured anions. These are usually proteins, organic acids,
sulphate and phosphate.
The anion gap can be calculated as: ([Na+] + [K+]) - ([Cl-] + [HCO3-])
The normal anion gap is normally between about 6 - 16 mmol/L.
Clinical Relevance
In metabolic acidosis:
An increased anion gap occurs if a new acid is added to the body. This
dissociates producing free H+ (which uses up bicarbonate) and anions (which
take the place of the bicarbonate).
A normal anion gap occurs if there is a simple loss of bicarbonate. This causes a
compensatory rise in plasma chloride concentration so the anion gap is normal
(thus is sometimes referred to as hyperchloraemic acidosis).
Causes of Increased Anion Gap Metabolic Acidosis
MUDPILES can be used to remember some of the causes of a raised anion gap
acidosis:
Methanol
Uraemia (in renal failure)
Diabetic ketoacidosis
Propylene glycol overdose
Infection/Iron overdose/Isoniazid/Inborn errors of metabolism
Lactic acidosis
Ethylene glycol overdose
https://mrcemsuccess.com/explanation/anion-gap/?_sft_qc=physiology Page 2 of 3
Anion Gap - MRCEM Success 28/03/2023, 12:02 PM
Salicylate overdose
Causes of Normal Anion Gap Metabolic Acidosis
FUSEDCARS can be used to remember some of the causes of a normal anion gap
acidosis:
Fistula (pancreaticoduodenal)
Ureteroenteric conduit
Saline administration
Endocrine (hyperparathyroidism)
Diarrhoea
Carbonic anhydrase inhibitors (e.g. acetazolamide)
Ammonium chloride
Renal tubular acidosis
Spironolactone
https://mrcemsuccess.com/explanation/anion-gap/?_sft_qc=physiology Page 3 of 3
Renal Regulation of Acid- LAST UPDATED: 21ST
APRIL 2019
Base Balance  Bookmark
The pH of arterial blood is normally 7.35 - 7.45 ([H+] = 35 - 45 nmol/L).
Metabolism produces ~ 60 mmol H+ per day, most of which is excreted through the
lungs as CO2, formed by the reaction of H+ with HCO3-. The kidneys conserve and
replace HCO3- lost in this way, and fine tune H+ excretion. Physiological bu"ers
maintain a low free [H+] and prevent large swings in pH.
Bu!ers
Bu"ers are weak acids or bases that can donate or accept H+ ions respectively and
therefore resist changes in pH. Bu"ering does not alter the body's overall H+ load,
ultimately the body must get rid of H+ by renal excretion if the bu"ering capacity of
the body is not to be exceeded and a dangerous pH reached.
At a given [H+], a defined amount of bu"er exists as acid (HA) and a defined amount
as base (A-). The ratio of bu"er pairs at a given [H+] is defined by the dissociation
constant (pK) for that bu"er pair. For a given acid-base pair, altering the ratio of the
acid to the base alters the pH.
pK = ([H+][A-])/[HA], or pH = pK + log([A-]/[HA] (the Henderson-Hasselbalch equation).
Thus an increase in [A-] or a decrease in [HA] will increase pH and a decrease in pH
will decrease the ratio [A-]/[HA].
Bicarbonate and carbonic acid (formed by the combination of CO2 with water,
potentiated by carbonic anhydrase) are the most important bu"er pair in the body,
although haemoglobin provides about 20% of bu"ering in the blood, and phosphate
and proteins provide intracellular bu"ering. Bu"ers in urine, largely phosphate, allow
the excretion of large quantities of H+.

The bicarbonate system is physiologically e"ective because CO2 and HCO3- are
precisely controlled by the lungs and the kidneys respectively.
Proximal Tubule
Bicarbonate is freely filtered at the glomerulus. Less than 0.1% of filtered bicarbonate
is normally excreted in the urine (if plasma [HCO3-] increases, maximum tubular
transport is exceeded and some HCO3- is excreted in urine). About 80% of

bicarbonate is reabsorbed in the proximal tubule.
HCO3- is not transported directly, tubular HCO3- associates with H+ secreted by
epithelial Na+/H+ antiporters to form carbonic acid (H2CO3) which readily dissociates
to form carbon dioxide and water in the presence of carbonic anhydrase. CO2 and
water di"use into the tubular cells, where they recombine to form carbonic acid
which dissociates to H+ and HCO3-.
This HCO3- is transported into the interstitium largely by Na+/HCO3- symporters on
the basolateral membrane (and H+ is secreted back into the lumen). For each
H+ secreted into the lumen, one Na+ and one HCO3- are reabsorbed into the plasma.
H+ is recycled so there is little net secretion of H+ at this stage. A further 10 - 15% of
HCO3- is similarly reabsorbed in the thick ascending limb of the loop of Henle.
BICA
AR B
BOO N A T E H A N D L I N G II N
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E .. ( IM AGE BY M. KO E P P E N, V IA
Ammonia
The body can excrete acid by the urinary loss of H+ ions associated with a bu"er
(predominantly sodium phosphate) or by the excretion of H+ ions as ammonium ions.
Ammonia is produced in tubular cells by the metabolism of glutamine, which leads to

the generation of HCO3- and glucose. NH3 di"uses into the tubular fluid, or as NH4+ is
transported by the Na+/H+ antiporter. In the tubular fluid, NH3 gains H+ to
form NH4+ which cannot di"use through membranes. About 50% of NH4+ secreted by
the proximal tubule is reabsorbed in the thick ascending limb, where it substitutes
for K+ in the Na+/K+/2Cl- symporter and passes into the medullary interstitium. Here
NH4+ dissociates into NH3 and H+ and NH3 re-enters the collecting duct by di"usion.
The secretion of H+ in the collecting duct leads to conversion back to NH4+ which is
trapped in the lumen and excreted.
Distal Tubule
The secretion of H+ in the distal tubule promotes the reabsorption of any remaining
HCO3-. The combination of H+ with NH3 and phosphate prevents H+ recycling and
allows net acid excretion.
In the early distal tubule, H+ secretion is predominantly by Na+/H+ exchange but
more distally, the Na+ gradient is insu#cient so secretion is via H+ ATPase and
H+/K+ ATPase in intercalated cells, which contain plentiful carbonic acid. As secreted
H+ is derived from CO2, new HCO3- is formed and returns to the blood.
H+ secretion is proportional to intracellular [H+] which itself is related to extracellular
pH. A fall in blood pH will therefore stimulate renal H+ secretion. In the proximal tubule
secretion of H+ serves to reclaim bicarbonate from glomerular filtrate so it is not lost,

but in the distal nephron, secretion leads to net acid excretion and generation of new
bicarbonate.
SE
E C R E TT II O N O FF H Y D R O G E N I O N S I N T H E D I S
S T A L T U B U L E . ( IM AGE BY R SWAR B R IC K

Calcium Handling LAST UPDATED: 24TH
NOVEMBER 2020
Normal Values of Calcium and Rationale for Corrected Calcium

Values
RCEM defines the normal value for total serum calcium as 2.1 - 2.5 mmol/L. This is the
sum of free ionised calcium and calcium bound to albumin.
This total serum calcium measurement must be adjusted for albumin levels (as
patients with a low albumin have total serum calcium lower than the reference range
yet have normal free ionised calcium and vice versa). 0.02 mmol/L should be added to
the calcium concentration for every g/L that albumin is below 40 and 0.02 mmol/L
should be subtracted for every g/L that albumin is above 40.
Corrected calcium = Measured calcium + [(40 g/l - albumin) x 0.02]
Calcium Absorption
Calcium rich foods include: cheese, milk, yoghurt, fish and some vegetables and nuts.
Of dietary calcium, about 25 - 30% is absorbed by the gut. Ca2+ is absorbed

throughout the small intestine but mainly in the duodenum and proximal jejunum.
Absorption occurs by a transcellular process involving intracellular calcium-binding
proteins called calbindins. Gut absorption is increased by activated vitamin D.
Physiological Actions of Calcium
Calcium is essential for:
enzymatic reactions
intracellular signalling
nerve conduction
skeletal, cardiac and smooth muscle contraction
the release of neurotransmitters
the release of hormones
secretion from exocrine glands
blood clotting
bone mineralisation
Transport of Calcium in the Blood
Only unbound ionised calcium is physiologically active.
Free intracellular Ca2+ must be maintained at a very low level; most is bound to
proteins or stored in the endoplasmic reticulum and mitochondria.
Blood calcium levels in the extracellular fluid are kept within a very narrow range to
maintain normal physiological processes:
about 45% of serum calcium is bound to albumin

about 5% is complexed to other ions and
about 50% is free ionised Ca2+.
Ionised calcium binds to negatively charged sites on protein molecules, competing

with hydrogen ions for the same binding sites on albumin and other calcium-binding
proteins. This binding is pH dependent and alters the level of ionised calcium in the
blood. An increase in pH, alkalosis, promotes increased protein binding, which
decreases free calcium levels. Acidosis, on the other hand, decreases protein binding,
resulting in increased free calcium levels.
Renal Calcium Handling
Calcium that is not protein bound is freely filtered in the glomerulus, and there is
reabsorption along the nephron.
About 70% is reabsorbed in the proximal tubule.

About 20% is reabsorbed in the thick ascending limb of the loop of Henle.
This reabsorption is mainly passive and paracellular and driven by sodium
reabsorption. Sodium reabsorption causes water reabsorption, which raises
tubular calcium concentration, causing calcium to di"use out of the tubules.
The positive lumen potential also encourages calcium to leave the tubule.
About 5 - 10% is reabsorbed in the distal convoluted tubule.
Less than 0.5% is reabsorbed in the collecting ducts.
Calcium reabsorption in the distal nephron is active and transcellular and is the
major target for hormonal control.
Regulation of Renal Calcium Handling
Calcium homeostasis is primarily controlled by three hormones: parathyroid hormone,

activated vitamin D and calcitonin.
Parathyroid hormone acts on the kidneys to increase calcium reabsorption in
the distal tubule by activating Ca2+ entry channels in the apical membrane and
the Ca2+ ATPase pump in the basolateral membrane (and to decrease

phosphate reabsorption in the proximal tubule).
Activated vitamin D acts to increase calcium reabsorption in the distal tubule
via activation of a basolateral Ca2+ ATPase pump (and to increase phosphate

reabsorption).
Calcitonin acts to inhibit renal reabsorption of calcium (and phosphate).
C
CAA LL C
C II U
UMM HAND
DL I N
N G .. ( IM AGE BY AN ATO M Y & P H YS IO LO GY, C O N N E X IO N S WE B S ITE .
H TTP : //C N X .ORG/C ON TE N T/C OL11496/1.6/ , JU N 19, 20 13. (OP E N STAX C OLLEGE ) [C C BY 3.0

Phosphate Handling LAST UPDATED: 21ST
APRIL 2019
Phosphate is abundant in the body and is an important intracellular and

extracellular anion (but is predominantly intracellular). About 65% of dietary
phosphate is absorbed, mainly in the duodenum and jejunum by a transcellular
process which is enhanced by vitamin D.
Ca2+ and PO43- precipitate to form insoluble calcium phosphate and their
concentrations in the blood are close to the saturation point at which calcium
phosphate complexes precipitate out of solution onto the bone matrix.
Therefore an increase in one of the ions results in the precipitation of some
calcium phosphate and thus some of the other ion is removed from the solution;
Ca2+ and PO43- concentrations are thus inversely proportional.
Renal Phosphate Handling
Unbound PO43- is filtered freely at the glomerulus and there is reabsorption
along the nephron. The maximum rate of reabsorption is limited and and excess
filtered phosphate above a threshold level is excreted. Of filtered phosphate,
80% is reabsorbed in the proximal tubule by a transcellular process. The distal
tubules reabsorb a further 10% of the filtered phosphate and the collecting
ducts a further 2 - 3%.
PO43- renal excretion is regulated by:
PTH (increases excretion by inhibiting reabsorption in the proximal tubule)

activated vitamin D (decreases excretion by increasing reabsorption in the
distal tubule)
acidosis (increases excretion)
glucocorticoids (increases excretion)
calcitonin (increases excretion)
Function of Kidney LAST UPDATED: 21ST
APRIL 2019
PHYSIOLOGY / RENAL / FUNCTIONAL ANATOMY
 Bookmark
Macroscopic Structure of the Kidney
Each kidney is surrounded by a fibrous renal capsule. Internally each kidney is divided
into two main layers, the dark outer renal cortex and the inner lighter renal medulla
made up of the renal pyramids. The cortex contains the glomerulus and proximal and
distal tubules of the nephrons, whilst the loop of Henle and collecting ducts descend
into the medulla.
The renal vessels, lymphatics and nerves enter the medial border of the kidney via the
hilum.
The ureters arise from the renal pelvis and emerge from the hilum before continuing
to the bladder.
Within the kidney, the outer border of the renal pelvis divides into two or three major
calyces, each of which further subdivide into minor calyces, which are each indented
by a renal papilla, the apex of the medullary pyramid, and it is here that the collecting
ducts of the renal nephron empty the urine.
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Functions of the Kidney
The kidney is important for the following actions:
Excretion of waste products and drugs in urine

Regulation of body fluid and ionic composition
Regulation of acid-base balance
Metabolism of certain proteins e.g. insulin, PTH and calcitonin
Hormone production
Renin
Activated vitamin D
Erythropoietin
Prostaglandins

Juxtaglomerular Apparatus LAST UPDATED: 21ST
APRIL 2019
 Bookmark
The juxtaglomerular apparatus (JGA) is located where the renal tubule passes back
up into the cortex and lies adjacent to the renal corpuscle and arterioles of its own
nephron.
Cell Types
The juxtaglomerular apparatus consists of three main cell types:
Juxtaglomerular (granular) cells

Macula densa tubular cells
Extraglomerular mesangial cells
Juxtaglomerular cells are specialised smooth muscle cells found mainly in the walls of
the a!erent arterioles which synthesise renin.
The macula densa is an area of specialised columnar tubular epithelial cells located at
the junction of the thick ascending limb of the loop of Henle and the early distal
tubule which senses and responds to changes in tubular ion concentration
(particularly changes in the concentration of Na+ ions).
Contractile extraglomerular mesangial cells are found outside the glomerulus in

association with the JGA. Their role is uncertain.
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
Overview of Nephron LAST UPDATED: 21ST
APRIL 2019
 Bookmark
Each kidney has about 800,000 nephrons, the functional unit of the kidney. There are
two types of nephrons, cortical nephrons (85% of nephrons) and juxtamedullary
nephrons (15% of nephrons).
Functional Anatomy
Each nephron consists of a renal corpuscle (Bowman's capsule and glomerulus) and a
tubule (proximal tubule, loop of Henle, distal tubule and collecting duct):
Cortical nephrons have their renal corpuscles in the outer part of the cortex and
relatively short loops of Henle.
Juxtamedullary nephrons have their corpuscles in the inner third of the cortex,
close to the corticomedullary junction, with long loops of Henle extending into
the renal medulla.
The glomerulus is formed by the invagination of a ball of capillaries into the Bowman's
capsule, the blind end of the nephron.
The convoluted proximal tubule continues from the renal corpuscle and straightens
before becoming the loop of Henle.
The distal tubule is the continuation of the loop of Henle, ending in the collecting
ducts.
The collecting ducts empty into papillary ducts at the apices of the renal pyramids.
Functions
Main functions:
Glomerulus: Filtration
Proximal tubule: Reabsorption
Loop of Henle: Urine concentration
Distal tubule and collecting duct: Water homeostasis and acid-base balance
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Renal Blood Supply LAST UPDATED: 13TH
NOVEMBER 2019
 Bookmark
The kidneys receive about 20% of total cardiac output ( ~1 L/min).
Functional Anatomy
The renal artery enters via the hilus and divides into two or three segmental arteries
which further divide into interlobar arteries running between the renal pyramids to
the corticomedullary border, where they split into arcuate arteries. The arcuate
arteries curve parallel to the outer surface of the kidney and give rise to the
interlobular arteries which ascend into the cortex and feed the a!erent arterioles of
the glomerulus. The capillaries of the glomerulus are the site of filtration, and drain
into the e!erent arteriole. A!erent and e!erent arterioles provide the major
resistance to renal blood flow.
In the outer two-thirds of the cortex, the e!erent arterioles branch into a network of
peritubular capillaries which supply all cortical parts of the nephrons. Capillaries close
the corticomedullary border in the inner third of the cortex, loop into the medulla to
form the vasa recta surrounding the loop of Henle. The vasa recta and peritubular
capillaries drain into the renal veins.
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Regulation of Renal Blood Flow
Autoregulation
The myogenic mechanism: where an increase in intravascular pressure

stimulates stretch receptors in the vessel wall causing a reflex smooth
muscle contraction and hence vessel vasoconstriction and reduced flow.
The tubuloglomerular feedback mechanism: where an increase in tubular
flow rate (with a resultant increase in tubular NaCl concentration
detected by the macula densa) causes the juxtaglomerular apparatus to
release adenosine which produces a!erent arteriolar vasoconstriction
and reduces GFR.
Renin-Angiotensin II system
The juxtaglomerular apparatus releases renin in response to a drop in

a!erent arteriolar pressure, a fall in tubular flow rate, or a fall in tubular
NaCl concentration at the macula densa.
Other stimuli include sympathetic nerve stimulation of beta1-adrenergic
receptors on granular cells and a fall in angiotensin II levels.
Renin promotes the production of angiotensin II which acts to
vasoconstrict a!erent and e!erent arterioles (the dominant e!ect is on
e!erent arteriolar constriction so the GFR is increased).
Prostaglandins
Many peripheral vasoconstrictors stimulate the renal production of

vasodilating prostaglandins such as PGE2 and PGI2 (prostacyclin) which
protect the kidney from severe vasoconstriction.
Vasoactive peptides
Bradykinin, released in the distal tubule and glomerulus, promotes

prostaglandin synthesis and vasodilation.
Natriuretic peptides, released from cardiac cells, produce systemic
vasodilation.
Endothelin, produced in renal vascular endothelial cells and tubules, is a
potent vasoconstrictor.
Vasopressin (ADH) promotes vasoconstriction and antidiuretic action.
Adrenomedullin promotes renal vasodilation and is produced in the
kidney.
Other regulatory pathways
Renal nerves contain sympathetic neurons which release noradrenaline

which causes constriction of both a!erent and e!erent arterioles and
promotes renin release.
Dopamine at low doses has a vasodilatory e!ect. At higher
concentrations dopamine causes renal vasoconstriction and promotes
renin release.
Nitric oxide is a potent vasodilator that is synthesised in the macula
densa, endothelium and mesangial cells and upregulated in response to
mechanical shear stress.
Vasodilators Vasoconstrictors
Prostaglandins Angiotensin II
Nitric oxide Endothelin
Bradykinin Vasopressin
Low-dose dopamine Noradrenaline

Atrial Natriuretic Peptide LAST UPDATED: 21ST
APRIL 2019
PHYSIOLOGY / RENAL / MECHANISM OF FILTRATION
 Bookmark
Atrial natriuretic peptide (ANP) is released from cardiac atrial muscle cells in
response to atrial stretch caused by an increase in intravascular fluid volume
and is also produced in collecting duct cells.
Function
ANP acts to:
Inhibit Na+ reabsorption in the distal nephron (through inhibition of ENaC

in principal cells)
Suppress the production of renin
Suppress the production of aldosterone
Suppress the production of ADH
Cause renal vasodilation, increasing the glomerular filtration rate
The net result is increased excretion of water and Na+ and hence reduced blood
volume.

Creatinine Clearance LAST UPDATED:
10TH MARCH 2019
PHYSIOLOGY / RENAL /
MECHANISM OF FILTRATION  Bookmark
Clearance is defined as the volume of plasma that is cleared of a

substance per unit time.
Clearance of substance = (Urine concentration of substance x Urine

flow rate)/Plasma concentration of substance.
Clearance of a substance can provide an accurate estimate of the

glomerular filtration rate (GFR) provided that the substance is:
1. freely filtered
2. not reabsorbed in the nephron
3. not secreted in the nephron
4. not synthesised or metabolised by the kidney
Inulin is such a substance but measurement of inulin clearance is

complicated and not used in routine clinical practice.
Creatinine (which is steadily released from skeletal muscle) clearance

can be used because it is freely filtered and not reabsorbed, and there is
very little secretion, allowing relatively accurate approximation of the
GFR (except when plasma creatinine or GFR is abnormally low).
In practice, GFR is usually estimated from the plasma creatinine using a

formula e.g. the MDRD equation making an adjustment for age, sex and
race.

Distal Collecting System LAST UPDATED: 21ST
APRIL 2019
The distal nephron consists of the late distal tubule and the collecting
ducts. The distal tubule is functionally similar to the cortical collecting
ducts. Both contain principal cells which respond to antidiuretic hormone
(ADH) and intercalated cells which secrete H+ ions (involved in acid-base
balance).
About 7% of filtered NaCl and about 8 - 17% of water is reabsorbed in the

distal tubule and collecting duct.
Water Permeability
Fluid entering the distal tubule is hypotonic. More Na+ is reabsorbed in

principal cells via the Na+ channel ENaC which is inhibited by atrial
natriuretic peptide (ANP); expression of ENaC and thus Na+ reabsorption is
increased by aldosterone. The movement of Na+ through ENaC is charge
compensated by the opposite movement (secretion) of K+ through ROMK
channels.
The distal tubule and cortical collecting duct are impermeable to water
except in the presence of antidiuretic hormone (ADH), which causes water
channels (aquaporins) to insert into the apical membrane. In the presence
of ADH, water di!uses into the cortical interstitium, and the tubular fluid
becomes more concentrated. The fluid di!ers from plasma as large
quantities of Na+, K+, Cl- and HCO3- have been reabsorbed, their place
having been taken by urea. This is concentrated as water is reabsorbed,
because the distal tubule and cortical collecting duct are impermeable to
urea.
The medullary collecting duct also becomes permeable to water in the

presence of ADH. Water is reabsorbed due to the high osmolality of the
medullary interstitium. Although only 15% of nephrons have loops of Henle
that pass deep into the medulla and so contribute to the high medullary
osmolality, the collecting ducts of all nephrons pass through the medulla
and therefore concentrate urine.
and therefore concentrate urine.
Urea
The medullary collecting duct is relatively permeable to urea, which

di!uses down its concentration gradient into the medulla and then into
the ascending loop of Henle. Urea is therefore 'trapped' and partially
recycled, so maintaining a high concentration and providing ~50% of the
osmolality in the medulla. ADH increases the permeability of the medullary
collecting duct to urea and hence its reabsorption by activating epithelial
uniporters; this further increases the medullary osmolality and allows the
production of more concentrated urine.
Potassium
Potassium has been largely reabsorbed by the time the distal tubule is
reached, and so excretion is regulated by secretion in the late distal tubule.
K+ is actively transported into principal cells by basolateral Na+ pumps and
passively secreted via ROMK channels and K+/Cl- cotransport; the former
is promoted by the negative luminal charge caused by reabsorption of Na+
through ENaC. Secretion is therefore driven by the concentration gradient
between the cytosol and tubular fluid. However, secreted K+ will reduce
the gradient unless it is washed away and so K+ excretion is increased as
tubular flow increases; diuretics therefore often lead to K+ loss. K+
secretion is increased by aldosterone which enhances Na+ pump activity
and apical membrane K+ permeability. Perturbations of K+ homeostasis
are often associated with acid-base disorders.
Calcium
Calcium reabsorption in the distal tubule is regulated by parathyroid

hormone and activated vitamin D.

Diuretic Therapy LAST UPDATED: 21ST
APRIL 2019
 Bookmark
Loop Diuretics
Loop diuretics e.g. furosemide are the most potent diuretics.
They inhibit the Na+/K+/2Cl- symporter in the thick ascending limb of the loop of
Henle. This binding inhibits sodium, potassium, and chloride reabsorption, causing
diuresis with loss of these electrolytes. The transcellular voltage di"erence falls,
and paracellular calcium and magnesium reabsorption are also reduced.
Salt reabsorption in the ascending limb normally concentrates the medullary

interstitium, and by blocking this process, loop diuretics reduce the ability of the
kidney to concentrate urine. Increased sodium delivery to the principal cells in the
collecting duct increases potassium secretion in return for sodium reabsorption.
Thiazide Diuretics
Thiazide diuretics e.g. bendroflumethiazide inhibit the apical Na+/Cl- cotransporter

in the early distal tubule. More sodium is then delivered to the principal cells of the
collecting duct. Some of this excess sodium is exchanged for potassium, causing
hypokalaemia. Reduced sodium reabsorption lowers intracellular sodium
concentration, promoting basolateral sodium-calcium exchange and therefore
calcium reabsorption.
Osmotic Diuretics
Osmotic diuretics e.g. mannitol are filtered in the glomerulus and then cannot be
reabsorbed e"ectively. As the filtrate passes along the nephron, water is reabsorbed
and the concentration of the osmotic diuretic rises until its osmotic e"ect opposes
further water reabsorption. Sodium is then reabsorbed without water. Eventually

sodium reabsorption is also inhibited because the sodium gradient between filtrate
and plasma increases to the point at which sodium leaks back into the lumen.
Potassium-Sparing Diuretics
Aldosterone promotes sodium reabsorption and potassium secretion by increasing
transcription of the ENaC channel and the Na+/K+ ATPase. Aldosterone antagonists
e.g. spironolactone block aldosterone receptors so reducing Na+ reabsorption and
K+ secretion in the distal nephron.
Carbonic Anhydrase Inhibitors
Carbonic anhydrase inhibitors e.g. acetazolamide block the reaction of carbon
dioxide and water and so prevent Na+/H+ exchange and bicarbonate reabsorption.
The increased bicarbonate levels in the filtrate oppose water reabsorption. Proximal
tubule sodium reabsorption is also reduced because it is partly dependent on
bicarbonate reabsorption.

Glomerular Filtration Barrier LAST UPDATED: 6TH
DECEMBER 2020
 Bookmark
Structure of the Glomerulus
The glomerulus is a ball of capillaries surrounded by the Bowman's capsule.
The glomerulus is interspersed with mesangial cells which act to:
provide structural support for the capillaries

exhibit phagocytic activity
secrete extracellular matrix
secrete prostaglandins
help regulate blood flow through the glomerular capillaries through their
contractile activity
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Glomerular Filtration Barrier
Plasma is selectively filtered through the glomerular capillary wall into the
Bowman's capsule. The solution that arrives in the Bowman's capsule is called
ultrafiltrate which then passes into the proximal tubule.
Selective filtration is dependent on the filtration barrier, which has three main
layers:
1. The glomerular capillary endothelium
Perforated by pores (fenestrations) which allow plasma

components with a molecular weight of < 7000 Da to pass freely.
2. A specialised capillary basement membrane
Layer of connective tissue containing negatively charged

glycoproteins, thought to be the main site of ultrafiltration.
3. Modified epithelial lining of the Bowman's capsule
Single layer of specialised cells called podocytes which have long

extensions that engulf the capillaries and numerous foot-like
processes (pedicels) directly contacting the basement membrane.
The regular gaps between pedicles are called filtration slits. Across
these slits, a protein network forms slit pores in the epithelial
lining which prevent the passage of larger molecules through
this final layer. Podocytes maintain the basement membrane and,
like mesangial cells, may be phagocytic and partially contractile.
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O RI GIN AL I MAG E BY M KO M OR N IC ZA K [CC BY-SA 3 .0

Factors a!ecting Permeability of the Filtration Barrier
Molecular weight is the main factor in determining whether a substance is

filtered or not - molecules < 7000 Da in molecular weight pass freely e.g.
glucose, amino acids, urea, ions but larger molecules are increasingly restricted
up to 70 kDa, above which filtration is insignificant.
Negatively charged molecules are further restricted, as they are repelled by

negative charges, particularly in the basement membrane. Albumin has a
molecular weight of 69 kDa and is negatively charged, thus only very small
amounts are filtered (and all of the filtered albumin is reabsorbed in the proximal
tubule), whereas small molecules such as ions, glucose, amino acids and urea
pass the filter without hindrance. This means that ultrafiltrate is virtually protein
free, but otherwise has an identical composition of that of plasma.

Glomerular Filtration Rate LAST UPDATED: 21ST
APRIL 2019
 Bookmark
Glomerular Filtration Rate
The glomerular filtration rate (GFR) is the amount of ultrafiltrate produced from
plasma flowing through the glomerulus per unit time.
The normal glomerular filtration rate is about 120 mL/min. The total amount filtered
per day is about 180 L/day.
The normal renal plasma flow (RPF) is about 600 mL/min.
Therefore the filtration fraction (FF = GFR/RPF), the proportion of plasma that is
filtered, is about 20%.
Factors Determining the GFR
The GFR is dependent on the di!erence between the hydrostatic and oncotic
pressures in the glomerular capillaries and Bowman's capsule, as determined by
Starling's equation.
The glomerular capillary pressure is greater than that elsewhere (~45 mmHg) because
of the unique arrangement of a!erent and e!erent arterioles, with low a!erent but
high e!erent resistances. As the pressure in the Bowman's capsule is ~10 mmHg, the
net hydrostatic force driving filtration is ~35 mmHg.
This is opposed by the oncotic pressure of capillary plasma (~25 mmHg); the filtrate
oncotic pressure is essentially zero (no protein).
Therefore, GFR = [Glomerular capillary hydrostatic pressure (Pc) - Bowman's capsule

hydrostatic pressure (Pb)] - Capillary oncotic pressure (?c) = 35 mmHg - 25 mmHg =
10 mmHg
It should be noted that as fluid is filtered and plasma proteins are not filtered, the
oncotic pressure in the capillary will rise as blood traverses the glomerulus, reducing
(but not abolishing) filtration. It is this raised oncotic pressure (together with a
relatively low hydrostatic pressure) that promotes reabsorption in the peritubular and
vasa recta capillaries.
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Regulation of Glomerular Filtration Rate
Glomerular capillary hydrostatic pressure and thus GFR is strongly dependent on the
relative resistance of the a!erent and e!erent arterioles. High pressure in the
glomerular capillaries forces filtrate through the filtration barrier. This pressure is
reduced by a!erent arteriolar constriction and increased by e!erent arteriolar
constriction.
The glomerular filtration rate (GFR) is constant over a wide range of blood pressures
(90 - 200 mmHg) because of substantial renal autoregulation, such that if systemic
BP falls and renal perfusion pressure falls, GFR is maintained.
Renal disease, circulating and local vasoconstrictors, and sympathetic activation all
reduce GFR, although angiotensin II preferentially constricts e!erent arterioles,
increasing the glomerular capillary hydrostatic pressure and thus increasing the GFR.
Loop of Henle LAST UPDATED: 21ST
APRIL 2019
 Bookmark
The loop of Henle consists of a single layer of flattened squamous cells (transitioning
to columnar cells in the thick ascending segment), which form a thin-walled hairpin-
shaped tube. At the point at which the loop associates with the juxtaglomerular
apparatus after re-entering the cortex, the wall is formed from modified macula
densa cells.
About 25% of filtered Na+ and Cl-, and 15% of filtered water and cations such as K+,
Ca2+, Mg2+ are reabsorbed in the loop of Henle.
The generation of high osmolality in the medulla depends on the di!erential

permeabilities to water and solutes in di!erent regions, the active transport of ions in
the thick ascending limb and the countercurrent multiplier. Tubular fluid is isotonic
with plasma when it enters the loop of Henle, hypertonic at the tip of the hairpin
(where it reaches equilibrium with the hypertonic interstitial fluid), and hypotonic
when it leaves to enter the distal nephron.
Di!erential Permeabilities to Water and Solutes in Di!erent

Regions
The thin descending limb of the loop of Henle is permeable to water and
impermeable to NaCl and urea.
The thin ascending limb is impermeable to water, but highly permeable to urea
and NaCl.
The thick ascending limb is impermeable to water and actively reabsorbs NaCl
from tubular fluid.
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Active Transport of Ions in the Thick Ascending Limb
In the thick ascending limb, Na+ and Cl- ions are actively reabsorbed from the tubular
fluid via the Na+/K+/2Cl- symporter on the apical membrane. The Na+ ions are
primarily transported across the basolateral membrane by Na+ pumps and the Cl-
ions by di!usion. K+ leaks back into the tubular fluid via apical ROMK K+ channels
creating a positive charge that drives the reabsorption of cations (Na+, K+, Ca2+,
Mg2+) through paracellular pathways. As the thick ascending limb is impermeable to

water, the reabsorption of ions reduces the tubular fluid osmolality, and increases the
interstitial fluid osmolality, creating an osmotic di!erence.
Countercurrent Multiplier
This increased interstitial fluid osmolality causes water to move passively out of the
thin descending limb, concentrating the tubular fluid. As this concentrated fluid
descends, it travels in the opposite direction to fluid returning from the still higher
osmolality regions of the deep medulla. This countercurrent arrangement creates an
osmotic gradient, causing Na+ and Cl- to di!use out of the ascending limb (diluting
the ascending fluid) and water to di!use out of the descending limb (further
concentrating the descending fluid). This e!ect is potentiated by the fact that the
ascending limb is impermeable to water but highly permeable to Na+ and Cl-, and also
by the recycling of urea between the collecting ducts and ascending limb, which
makes an important contribution to urine concentration. At the tip of the loop of
Henle, the interstitial fluid reaches its highest osmolality due in equal parts to NaCl
and urea.
The blood supply to the medulla is prevented from dissipating the osmotic gradient
between the cortex and medulla by the countercurrent exchanger arrangement of
the vasa recta capillaries. The vasa recta also removes water reabsorbed from the
loop of Henle and medullary collecting ducts.
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
Proximal Tubule LAST UPDATED: 21ST
APRIL 2019

 Bookmark
The proximal tubule continues from the renal corpuscle. The wall of the proximal
tubule is composed of a single layer of columnar epithelial cells which interdigitate
extensively at the basal surface increasing their surface area and are connected by
tight junctions at their luminal surface limiting di!usion through gaps between cells.
The luminal surface of each cell is made up of millions of microvilli, forming a dense
brush border that increases the surface area available for reabsorption of tubular
filtrate.
The main function of the proximal tubule is reabsorption. The proximal tubule
reabsorbs most glucose, amino acids, phosphate and bicarbonate together with
about 60 - 70% of filtered Na+, K+, Ca2+, Cl-, urea and water.
Sodium
The concentration of Na+ in the filtrate is ~ 140 mmol/L, but is much lower in the
cytosol of epithelial cells, which is also negatively charged. Tubular Na+ is thus
absorbed into the epithelial cells of the proximal tubule down its electrochemical
gradient, providing the driving force for the secondary transport of other substances.
About 80% of the Na+ is reabsorbed via the Na+/H+ antiporter (this secretion of H+ is
critical for HCO3- reabsorption) and some is coupled with the transport of other
substances e.g. glucose, amino acids and phosphate ions.
Na+ is removed from tubular cells into the interstitial fluid by Na+/K+ ATPase pumps
on the basolateral membrane, thus maintaining the electrochemical gradient for
reabsorption of further Na+. However only about 20% of transported Na+ di!uses into
the capillaries, as there is a significant back flux into the tubule via paracellular
pathways.
Water
Water is reabsorbed by osmosis via both transcellular and paracellular pathways,
following absorption of Na+ and HCO3- as the osmolality of the peritubular interstitial
following absorption of Na+ and HCO3- as the osmolality of the peritubular interstitial
fluid increases and the osmolality of the tubular fluid decreases. The reabsorption of
water increases tubular concentration of Cl-, K+, Ca2+ and urea which are therefore
reabsorbed into the peritubular space passively down their concentration gradients,
largely via paracellular pathways, although the route for Ca2+ may be transcellular.
Glucose
Glucose is reabsorbed by cotransport with Na+ across the apical membrane of

epithelial cells and then di!uses out of the cells into the peritubular interstitium.
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
Renal Handling of Water LAST UPDATED:
21ST APRIL 2019
and Urea  Bookmark

MECHANISM OF FILTRATION
Renal Handling of Water
The kidney regulates body water and sodium content in parallel to

maintain body volume and osmolality (normally 285 - 295 mOsmol/kg).
In the glomerulus, water and ions are freely filtered. As the filtrate
moves along the tubules, ions are reabsorbed and water follows by
osmosis. Water reabsorption is influenced by the water permeability of
the tubular epithelium and the osmotic gradient across the epithelium.
Proximal tubule:
The proximal tubule is highly water permeability and about 65% of

filtered water is reabsorbed here by osmosis, following the reabsorption
of ions.
Loop of Henle:
In the loop of Henle, the descending limb is permeable to water, but not
ions, whereas the ascending limb is permeable to ions but not water.
Sodium and chloride are transported out of the thick ascending limb
into the medullary interstitium. This raises the osmolality of the
interstitium which promotes water movement out of the descending
limb. Within the loop, the transport of water and ions is separated with
reabsorption of about 25% of filtered sodium and chloride but only 10%
of filtered water, producing a dilute urine and a hypertonic medullary
interstitium.
Distal tubule:
The distal convoluted tubule has low water permeability and does not
reabsorb water. However, reabsorption of ions further dilutes the
tubular fluid.
Collecting ducts:
The hypotonic urine passes down the collecting ducts, where water
permeability is controlled by antidiuretic hormone (ADH).
Role of Urea
Urea is freely filtered at the glomerulus. In the proximal tubule, about

50% of the filtered urea is reabsorbed passively, mainly through
paracellular routes.
Urea is secreted into the ascending limb from the medullary interstitium
down its concentration gradient, increasing tubular urea concentration.
The distal tubule, cortical collecting ducts and the outer medullary
ducts are impermeable to urea. As it continues along the nephron,
tubular urea therefore becomes more concentrated as further solutes
and water are reabsorbed, and thus in the inner medullary collecting
ducts (which are permeable to urea), urea is passively reabsorbed by
urea transporters (activated by ADH) into the medullary interstitium.
The recycling of urea between the medullary collecting ducts and the
ascending limb plays an important role in the creation of a hypertonic
medullary interstitium, accounting for about half of the medullary
interstitial osmolality that drives water reabsorption from the
descending limb and medullary collecting duct. ADH increases the
permeability of the inner medullary collecting ducts to urea, further
increasing the medullary osmolality and allowing further concentration
of urine.

Something wrong?
Renal Tubular Transport LAST UPDATED: 2ND

MAY 2019
Modes of Tubular Transport
Reabsorption and secretion involves the transport of substances across

the tubular epithelium; this occurs either by di!usion through tight
junctions and lateral intercellular spaces (paracellular pathway), driven by
concentration, osmotic or electrical gradients, or by transport through the
epithelial cells themselves (transcellular pathway).
The latter usually involves an active process on either the apical or

basolateral cell membrane, with passive di!usion across the opposite
membrane driven by the concentration gradient so created.
The movement of solutes between the peritubular space and capillaries is

by bulk flow and di!usion; the movement of water is influenced by
Starling's forces.
Active transport involves transporter proteins, and may be primary (which

uses ATP directly as an energy source) or secondary (which uses the
concentration gradient created by primary active transport as an energy
source)
The rate of di!usion across cell membranes is enhanced by ion channels

and uniporters which e!ectively increase membrane permeability to
specific substances; this is termed facilitated di!usion, and may be
modulated by hormones or drugs.
Maximal Tubular Transport
There is a limit to the rate at which any transporter can operate and so for
any substance, there is a maximum rate of absorption or secretion, called
the tubular transport maximum (Tm).

Glucose is normally completely reabsorbed in the proximal tubule via
secondary active transport by the Na+/glucose symporter and none

excreted in the urine. However, when filtrate glucose concentration rises
above the renal threshold concentration, the transporters start to saturate
and glucose appears in the urine. Once tubular maximum transport is
reached, excretion increases linearly with filtration. The threshold
concentration for glucose (~ 11 mmol/L) is somewhat lower than that
required to reach tubular transport maximum (~21 mmol/L) because of the
variation in transport maxima between nephrons; this is called splay.

Renin-Angiotensin- LAST UPDATED: 21ST
APRIL 2019
Aldosterone System  Bookmark

As plasma osmolality is strongly regulated by the osmoreceptors and ADH, changes in
the major osmotic component of extracellular fluid, i.e. Na+, will result in changes in
extracellular volume. The control of total body Na+ content by the kidney is therefore
the main regulator of body fluid volume.
Sensing Blood Volume
Atrial and other cardiopulmonary stretch receptors detect a fall in central venous
pressure (CVP) which reflects the blood volume. A fall in blood volume su"cient to
reduce the blood pressure activates the baroreceptor reflex.
In both cases, increased sympathetic stimulation causes:
peripheral vasoconstriction increasing the total peripheral resistance

renal vasoconstriction decreasing the GFR
stimulation of ADH release increasing water reabsorption
stimulation of granular cells to release renin
Renin
Renin is produced by granular cells of the juxtaglomerular apparatus and released in

response to:
A fall in extracellular fluid volume, central venous pressure or arterial blood

pressure
Decreased perfusion pressure and thus wall tension in the renal a#erent
arterioles
Decreased tubular NaCl concentration detected by the cells of the macula
densa
A reduced glomerular filtration rate (GFR)
Renin cleaves plasma angiotensinogen (produced in the liver) into angiotensin I.

Angiotensin I is converted by angiotensin-converting enzyme (ACE) on pulmonary
endothelial cells to angiotensin II.
Angiotensin II
Angiotensin II is the primary hormone for Na+ homeostasis and has several important
functions.
Angiotensin II acts to:
Stimulate release of aldosterone from the zona glomerulosa of the adrenal

cortex (which in turn acts to increase sodium reabsorption)
Cause systemic vasoconstriction
Cause vasoconstriction of the renal arterioles (predominant e#erent e#ect thus
intraglomerular pressure is stable or increased, thereby tending to maintain or
even raise the GFR)
Directly increase Na+ reabsorption from the proximal tubule (by activating
Na+/H+ antiporters)
Stimulate synthesis and release of ADH from the hypothalamus and posterior
pituitary respectively
Stimulate the sensation of thirst
Potentiate sympathetic activity (positive feedback)
Inhibit renin production by granular cells (negative feedback)
Aldosterone
Aldosterone acts mainly at the renal distal convoluted tubule (DCT) to cause sodium
retention and potassium loss. It increases the synthesis of transport mechanisms in
the distal nephron including the Na+ pump, Na+/H+ symporter, and Na+ and
K+ channels in principal cells, and H+ ATPase in intercalated cells. Na+ (and thus
water) reabsorption and K+ and H+ secretion are thereby enhanced.

R
R E N II N
N -- A N G I O T E N S I N
N - A LL D
DOOS
ST E
ERRO
ONNE S Y
YSS T E M .. ( IM AGE BY A. R AD (OWN WO R K ) C C-BY-
SA-3.0 ( H TTP ://C R EATIV EC OMMON S.ORG/ LIC EN SES/ BY-SA/ 3.0/ )], V IA WIKIMEDIA C OMMON S)

Sodium Handling LAST UPDATED: 21ST
APRIL 2019
 Bookmark
Sodium is the major extracellular cation and its concentration is tightly controlled.
Na+ is freely filtered at the glomerulus, a large amount is absorbed in the proximal
tubules and the loop of Henle, and the little that is left is reabsorbed in a precisely
regulated manner by the distal tubules and collecting ducts to maintain accurate salt
balance.
The basolateral membranes of the tubular cells contain Na+/K+ ATPases that actively
pump sodium into the peritubular interstitial fluid. From here, sodium ions pass freely
into the blood. The continual pumping of sodium out of the cells and its subsequent
removal by the blood creates a Na+ gradient between the tubular filtrate and the cell
cytoplasm. This gradient allows Na+ from the filtrate to enter the cells passively at
their apical membrane, provided that suitable channels or transporters are present.
Sodium Handling in the Proximal Tubule
Of the filtered sodium, about 65% is reabsorbed in the proximal tubule.
In the early tubule, the sodium gradient drives the cotransport of sodium with
bicarbonate, amino acids, glucose or other organic molecules. The Na+/H+ exchanger
uses the sodium gradient to drive sodium reabsorption from the filtrate and H+
secretion into the filtrate. As carbonic anhydrase is present in the cell cytoplasm and
tubular lumen, the secretion of H+ is equivalent to the reabsorption of bicarbonate.
The apical secretion of H+ is balanced by the basolateral exit of bicarbonate with

sodium.
Chloride concentration rises along the proximal tubule. When the positively charged
sodium ions leave the lumen with neutral organic molecules, the lumen is left with a
negative charge. This repels negatively charged chloride ions which leave the lumen
through the paracellular route between cells. By the time the filtrate reaches the late
proximal tubule, most organic molecules and bicarbonate have already been removed
and sodium ions are reabsorbed mainly with chloride ions.
Sodium Handling in the Loop of Henle
About 25% of filtered sodium is reabsorbed in the the loop of Henle.

The thin descending limb is permeable to water but not to sodium, so water leaves
the tubule passively to enter the hypertonic medullary interstitium. In contrast, the
thin ascending limb is permeable to sodium but not to water and as there is a high
tubular concentration of NaCl, both ions di"use out.
In the thick ascending limb, the Na+/K+/2Cl- cotransporter uses the sodium gradient
to actively reabsorb one sodium, one potassium and two chloride ions. As the
potassium ions can re-enter the tubule via an ROMK channel, the net e"ect is the
removal of one sodium and two chloride ions, leaving the tubular lumen positively
charged. This positive potential drives the paracellular transport of positively charged
ions, including sodium, potassium, calcium, magnesium and ammonium.
Sodium Handling in the Distal Nephron
The early distal tubule reabsorbs a further 5% of the filtered sodium, mainly via the
Na+/Cl- symporter. As the fluid in the lumen in this portion of the nephron is negative,
there is also some paracellular movement of negatively charged chloride ions.
About 2 - 5% of filtered sodium is reabsorbed in the late distal tubule and collecting
ducts. Sodium reabsorption by principal cells and chloride reabsorption by
intercalated cells are the final stages in sodium chloride reabsorption before urine
leaves the kidney.

Hyperkalaemia LAST UPDATED: 21ST
APRIL 2019
PHYSIOLOGY / RENAL / POTASSIUM BALANCE
 Bookmark
RCEM defines normal values for total serum potassium as 3.0 - 4.5 mmol/L.
Causes
The causes of hyperkalaemia may be divided into:
Renal retention
Renal failure
Hypoaldosteronism (e.g. Addison's disease)
K+ sparing diuretics
ACE inhibitors/ARBs
NSAIDs
Trimethoprim and pentamidine therapy
Increased intake
Excess dietary K+
Transcellular shift of K+ out of cells
Metabolic acidosis
Insulin deficiency
Beta-blockers
Cellular injury/rhabdomyolysis
Tumour lysis syndrome, trauma, burns, crush syndrome,

chemotherapy
Pseudohyperkalaemia
Prolonged tourniquet time

Di"culty collecting the sample
Test tube haemolysis
Length of storage of the specimen
Sample from limb receiving IV fluids containing potassium
Clinical Features
Clinical features of hyperkalaemia may include:
Asymptomatic
Paraesthesia
Muscle weakness or paralysis
Cardiac conduction abnormalities and dysrhythmias
ECG Changes
Hyperkalaemia causes a rapid reduction in resting membrane potential leading

to increased cardiac depolarisation and muscle excitability. This in turn results
in ECG changes which can rapidly progress to ventricular fibrillation or asystole.
Classic ECG changes:
Tall peaked T waves

Shortening of the QT interval
Lengthening of the PR interval
Widening of the QRS complex
Loss of the S-T segment
Loss of p waves
Sine wave appearance

Hypokalaemia LAST UPDATED: 21ST
APRIL 2019
 Bookmark
RCEM defines normal values for total serum potassium as 3.0 - 4.5 mmol/L.
Causes
Causes of hypokalaemia can be divided into:
Increased loss
Renal loss:
Thiazide or loop diuretics

Renal tubular acidosis
Hypomagnesaemia
Hyperaldosteronism
Transporter mutations (rare)
Drugs such as penicillins, aminoglycosides, amphotericin
GI loss:
Diarrhoea, vomiting
Transcellular shift of K+ into cells
Metabolic alkalosis
Insulin excess or overdose
Catecholamines in acute stress e.g. acute MI
Beta-2 sympathomimetics
Decreased intake
Inadequate replacement whilst NBM or on TPN, malnutrition,

anorexia nervosa, hypocaloric diets
Clinical Features
Clinical features of hypokalaemia may include:
Asymptomatic
Muscle weakness
Muscle cramps, rhabdomyolysis and myoglobinuria
Ascending paralysis resulting in respiratory failure
Constipation
Gut ileus with distension, anorexia, nausea and vomiting
Impaired ADH action with polyuria and polydipsia
ECG changes and cardiac arrhythmias
ECG Changes
Hypokalaemia increases automaticity and delays repolarisation of cardiac cells.

This predisposes the heart to dysrhythmias such as ectopic beats,
atrioventricular block and atrial and ventricular fibrillation.
Classic ECG changes:
Progressive lengthening of the PR interval

ST segment depression
Flattening of the T wave
Prominent U waves
Prolongation of QT interval

Potassium Handling LAST UPDATED: 21ST
APRIL 2019
 Bookmark
Potassium is the major intracellular cation. The potassium concentration inside

cells is around 150 mmol/L, compared with around 4 mmol/L (3.0 - 4.5 mmol/L)
in extracellular fluid. The K+ gradient across the cell membrane largely

determines the electrical potential across that membrane. As this electrical
potential influences the electrical excitability of tissues such as nerves and
muscles, including the cardiac muscle, potassium levels must be precisely
controlled within safe limits.
The average daily intake of potassium in the diet is around 40 - 120 mmol, but
the kidney filters around 800 mmol each day. To maintain potassium balance,
the kidney therefore excretes only 5 - 15% of the filtered potassium. Potassium
is freely filtered in the glomerulus, almost entirely reabsorbed before the filtrate
reaches the collecting tubules, and is then secreted into the collecting duct
before being excreted in urine.
Renal Potassium Handling
K+ is freely filtered at the glomerulus.
Proximal tubule:
Approximately 65 - 70% of filtered K+ is reabsorbed in the proximal tubule.

Potassium reabsorption is tightly linked to that of sodium and water. The
reabsorption of sodium drives that of water, which may carry some potassium
with it. The potassium gradient resulting from the reabsorption of water from
the tubular lumen drives the paracellular reabsorption of potassium and may be
enhanced by the removal of potassium from the paracellular space via the
Na+/K+ ATPase pump. In the later proximal tubule, the positive potential in the
lumen also drives the potassium reabsorption through the paracellular route.
Loop of Henle:
Some K+ moves into the filtrate in the thin descending limb of the loop of Henle,
but this is counterbalanced by movement of K+ out of the loop and into the
medullary collecting ducts. The net result is some recycling of this potassium
across the medullary interstitium. Around 30% of filtered K+ is reabsorbed in the

thick ascending limb of the loop of Henle, primarily via the luminal
Na+/K+/2Cl- cotransporter, but there is also significant paracellular

reabsorption, encouraged by the positive potential in the tubular lumen.
Distal tubule:
The distal tubule can reabsorb more potassium and 95% of filtered K+ is
reabsorbed in a sodium-dependent fashion before the filtrate reaches the
collecting ducts.
Collecting tubule and ducts:
In the distal nephron, the principal cells secrete potassium, whereas the
intercalated cells reabsorb potassium; potassium secretion far outweighs its
reabsorption in this part of the nephron, and it is here that regulation of
potassium excretion primarily occurs (mainly as a result of changes in
potassium secretion by the principal cells).
Reabsorption of K+ by intercalated cells is driven by the apical H+/K+ ATPase
pump; K+ leaves these cells through basolateral potassium channels.
Secretion of K+ by principal cells is driven by the basolateral Na+/K+ ATPase
pump; K+ is secreted into the lumen through apical K+ channels or via
K+/Cl- cotransporters down a concentration gradient. The negative potential in
the tubular lumen due to Na+ reabsorption also promotes K+ secretion (thus
increased sodium reabsorption promotes potassium secretion). As potassium
secretion is occurring down a concentration gradient, it can continue only if the
concentration of potassium in the filtrate is kept low, hence an increased tubular
flow rate results in increased K+ secretion and excretion (seen in hypokalaemia

secondary to diuretic therapy).
Control of Renal Potassium Excretion

Aldosterone: A rise in [K+] in the extracellular fluid of the adrenal cortex
directly stimulates aldosterone release. Aldosterone promotes the
synthesis of Na+/K+ ATPases and the insertion of more Na+/K+ ATPases

into the basolateral membrane, and also stimulates apical sodium and
potassium channel activity, overall acting to increase sodium reabsorption
and potassium secretion.
pH changes: Potassium secretion is reduced in acute acidosis and
increased in acute alkalosis. A higher pH increases the apical K+ channel
activity and the basolateral Na+/K+ ATPase activity – both changes that
promote K+ secretion.
Flow rates: Increased flow rates in the collecting duct reduce
K+ concentration in the lumen and therefore enhance K+ secretion.

Increased flow also activates BK potassium channels, and ENaC channels
which promote potassium secretion and sodium reabsorption
respectively.
Sodium delivery: Decreased Na+ delivery to the collecting ducts results in
less Na+ reabsorption and hence a reduced gradient for K+ secretion.

ADH: ADH reduces urinary flow rates that would reduce potassium
secretion, however it also stimulates the apical potassium channel
activity, which helps maintain normal potassium secretion.
Magnesium: Intracellular magnesium can bind and block K+ channels
inhibiting K+ secretion into the tubules. Therefore magnesium

deficiency reduces this inhibitory e"ect and so allows more potassium to
be secreted into tubules and can cause hypokalaemia.

Central Control of LAST UPDATED: 11TH
APRIL 2019
Respiration  Bookmark
PHYSIOLOGY / RESPIRATORY /
CONTROL OF RESPIRATION
Control of breathing involves a central pattern generator that sets the

basic rhythm and pattern of ventilation and controls the respiratory
muscles. It is modulated by higher centres and feedback from central and
peripheral chemoreceptors and peripheral mechanoreceptors.
Brainstem and Central Pattern Generator
The brainstem includes di!use groups of respiratory neurones in the pons

and medulla that act together as the central pattern generator.
The medulla contains dorsal and ventral respiratory groups that receive
input from the chemoreceptors and lung receptors and drive the
respiratory muscle motor neurones. The medullary respiratory groups also
provide ascending input to, and receives descending input from the
pneumotaxic centre in the pons.
The pneumotaxic centre receives input from the hypothalamus and higher
centres, coordinates medullary homeostatic functions with factors such
as emotion and temperature and a!ects the pattern of breathing.
Voluntary control of breathing is mediated by motor neurones from the

cortex contained in the pyramidal tracts, which bypass the pneumotaxic
and medullary respiratory centres.

Chemoreceptors LAST UPDATED: 11TH
APRIL 2019
CONTROL OF RESPIRATION  Bookmark
Chemical control of ventilation is mediated via central and peripheral chemoreceptors

which detect arterial PCO2 and pH (central and peripheral) and PO2 (peripheral only),
and modulate ventilation via a distributed network of neurones in the brainstem.
Factors A!ecting Ventilation
PCO2 is the most important factor. An increase in PACO2 causes ventilation to rise in
an almost linear fashion.
A metabolic acidosis (e.g. lactic acidosis in strenuous exercise) causes the

relationship between PCO2 and ventilation to shift to the left (where ventilation
increases more for any given rise in PACO2) and a metabolic alkalosis causes a shift to
the right.
PO2 normally stimulates ventilation only when it falls below around 8 kPa. However,
when a fall in PO2 is accompanied by an increase in PCO2, the resultant increase in

ventilation is far greater than would be expected from the e"ects of either alone;
there is thus a synergistic relationship between PO2 and PCO2.
Central Chemoreceptors
The central chemoreceptor consists of a di"use collection of neurones located near

the ventrolateral surface of the medulla. These are sensitive to the pH of the
surrounding cerebrospinal fluid (CSF), thus indirectly respond to blood PCO2 (but do
not respond to changes in PO2).
CSF is separated from the blood by the blood-brain barrier. This barrier is
impermeable to polar molecules such as H+ and HCO3- but CO2 can di"use across it
easily. The pH of CSF is therefore determined by the arterial PCO2 and the CSF
HCO3- and is not a"ected by blood pH. Stimulation of the central chemoreceptor by a
fall in CSF pH (with a rise in blood PCO2) causes an increase in ventilation to blow o"
CO2; the response is delayed because CO2 has to di"use across the blood-brain
barrier.
The central chemoreceptor is responsible for about 80% of the ventilatory response
to changes in PCO2 in humans.
Peripheral Chemoreceptors
The peripheral chemoreceptors are found within the carotid body, innervated by the
glossopharyngeal nerve and located at the bifurcation of the common carotid
arteries, and the aortic bodies, innervated by the vagus nerve and located on the
aortic arch. The aortic bodies are functionally less important. Carotid bodies respond
to increased PCO2 and decreased blood pH in addition to reduced PO2. They are
responsible for about 20% of the ventilatory response to increased PCO2.

Lung Receptors LAST UPDATED: 11TH
APRIL 2019
CONTROL OF RESPIRATION  Bookmark
Various types of lung receptors provide feedback from the lungs to the
respiratory centre.
Stretch Receptors
Stretch receptors are located in smooth muscle of the bronchial walls.

Their a!erent nerves ascend via the vagus nerve. Stimulation of stretch
receptors causes short, shallow breaths, and delay of the next inspiratory
cycle. These receptors are largely responsible for the Hering-Breuer reflex
where excessive lung inflation inhibits inspiratory muscle activity to
prevent over inflation.
Juxtapulmonary (J) Receptors
Juxtapulmonary or 'J' receptors are located on alveolar and bronchial walls

close to the capillaries. Their a!erents are small unmyelinated C-fibres or
myelinated nerves in the vagus nerve. Activation causes depression of
somatic and visceral activity by producing apnoea or rapid shallow
breathing, a fall in heart rate and blood pressure, laryngeal constriction
and relaxation of skeletal muscles via spinal neurones. J receptors are
stimulated by increased alveolar wall fluid, pulmonary congestion and
oedema, microembolism and inflammatory mediators. J receptors are
thought to be involved in the sensation of dyspnoea in lung disease.
Irritant Receptors
Irritant receptors are located throughout airways between epithelial cells,

with rapidly adapting a!erent myelinated fibres in the vagus nerve.
Receptors in the trachea lead to cough, those in the lower airway to
hyperpnoea. Stimulation also causes reflex bronchial and laryngeal

constriction. Irritant receptors are stimulated by irritant gases, smoke and
dust, rapid inflation/deflation, airway deformation, pulmonary congestion
and inflammation. Irritant receptors are responsible for deep augmented
breaths or sighs seen every 5 - 20 minutes at rest, which reverse the slow
collapse of the lungs that occurs in quiet breathing.
Carbon Dioxide Transport - MRCEM Success 28/03/2023, 12:17 PM
Carbon Dioxide Transport LAST UPDATED: 11TH

APRIL 2019
GAS TRANSPORT IN CIRCULATION  Bookmark
Carbon dioxide is transported in the blood from tissues to the lungs in three ways
as bicarbonate ions, as carbamino compounds with proteins or simply dissolved in
plasma.
Bicarbonate Ions
About 60% of CO2 is transported in the form of bicarbonate ions.
CO2 generated in the tissues and water combine to form carbonic acid which readily
dissociates to form HCO3- and H+. The first part of this reaction is very slow in plasma,
but is accelerated dramatically by the enzyme carbonic anhydrase present in red

blood cells. Bicarbonate is therefore formed preferentially in red cells, from which it
freely di"uses down its concentration gradient into plasma where it is transported to
the lungs. The red cell membrane is impermeable to H+ ions which remain in the cell.
To maintain electroneutrality, Cl- ions di"use into the cell to replace HCO3-, an e"ect
known as the chloride shift. Deoxygenated haemoglobin acts as a bu"er for H+,
allowing the reaction to continue.
In the lungs, all of the above reactions occur in reverse. Oxygenated haemoglobin
does not bind H+ as well as it is more acidic and so in the lungs H+ dissociates from
haemoglobin and shifts the CO2-HCO3- equation to the left, assisting CO2 unloading
from the blood. This contributes to the Haldane e"ect which states that for any given
PCO2, the CO2 content of deoxygenated blood is greater than that of oxygenated
blood.
Carbamino Compounds
About 30% of CO2 is transported as carbamino compounds. CO2 combines rapidly

with terminal amine groups on proteins to form carbamino compounds, primarily with
haemoglobin forming carbaminohaemoglobin. Reduced haemoglobin forms
carbamino compounds more readily than oxygenated haemoglobin and this also
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Carbon Dioxide Transport - MRCEM Success 28/03/2023, 12:17 PM
contributes to the Haldane e"ect.
Dissolved Carbon Dioxide
CO2 is 20 times more soluble than O2 in plasma and about 10% of CO2 is transported
dissolved in solution.
TT R
RAAN S
SPPO
OR T O
OF C A R
RBBO N D I O X I D
D E . ( IM AGE BY O P E N STAX C O LLEGE [C C BY 3.0
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Oxygen Transport LAST UPDATED: 11TH
APRIL 2019
GAS TRANSPORT IN CIRCULATION  Bookmark
The solubility of oxygen in blood plasma is low and only a very small percentage of the
body's requirement can be carried in the dissolved form (< 10 mL), therefore most
oxygen is carried bound to haemoglobin in red blood cells.
Haemoglobin
Each gram of haemoglobin binds with up to 1.34 mL oxygen, so with a haemoglobin

concentration of 150 g/L, blood contains a maximum of 200 mL/L oxygen bound to
haemoglobin; this is the oxygen capacity, which varies with [Hb]. The actual amount
of oxygen bound to haemoglobin depends on the PO2. Low PO2 in tissue capillaries
promotes oxygen release from haemoglobin, whereas the high PO2 in pulmonary
capillaries promotes oxygen binding.
Each molecule of haemoglobin can bind up to four molecules of oxygen, at which

point it is said to be saturated. Haemoglobin binds oxygen in a cooperative fashion;
this means as each oxygen molecule binds, there is a conformational change in its
protein structure and its a"nity for oxygen increases, making it easier to bind the
next oxygen molecule.
Oxygen-Haemoglobin Dissociation Curve
The oxygen dissociation curve is a graph that plots the proportion of haemoglobin in
its oxygen-laden saturated form on the vertical axis against the partial pressure of
oxygen on the horizontal axis.
Cooperative binding is responsible for the steepness of the oxygen-haemoglobin

dissociation curve in the middle. The curve flattens again at partial pressures above
about 8 kPa because there are few unfilled haemoglobin binding sites. Thus for a
normal arterial PO2 (about 13 kPa) and [Hb], the blood is about 97% saturated and any
increase in PO2 will have little e#ect on the blood oxygen content. On the steep part
of the curve however (< 8 kPa), small changes in PO2 will have large e#ects on the
blood oxygen content. The PO2 at which the haemoglobin is 50% saturated is known
as the P50 (the P50 is higher for a right-shifted curve and lower for a left-shifted
curve).
O
OXXY G
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E M O G LL O
OBBI N
N D II S
SS O C I AT I O
O N C U R V E . ( IM AGE M O DIF IE D BY F RC E M S U C C E S S .
O RI G I N AL BY PETER SOUTH WO OD (OWN WORK) [C C 0], V IA WIKIMEDIA C OMMO N S)
Factors A!ecting Oxygen-Haemoglobin Curve
The a"nity of haemoglobin for oxygen, and hence the position of the dissociation
curve, varies with local conditions.
A decreased a"nity of haemoglobin for oxygen (and hence increased ease of

dissociation), shown by a right shift in the oxygen dissociation curve, is caused by a
fall in pH, a rise in PCO2 (the Bohr e#ect) and an increase in temperature. These
changes occur in metabolically active tissues such as in exercise, and encourage

oxygen release. The metabolic by-product 2,3-diphosphoglycerate (2,3 -DPG) also
causes a right shift; 2, 3 -DPG may also be raised in chronic anaemia, chronic lung
disease, or at high altitude.
Conversely, an increased a"nity of haemoglobin for oxygen, shown by a left shift in

the oxygen dissociation curve, is caused in the lungs by a rise in pH, a fall in PCO2 and
a decrease in temperature.
Anaemia
In anaemia, at any given PO2, the oxygen capacity is reduced because of the reduced
concentration of haemoglobin binding sites. The dissociation curve would not be

altered if it was drawn as Saturation (y-axis) versus PO2 (x-axis) but if drawn as
Oxygen content (y-axis) versus PO2(x-axis), the oxygen content value at each PO2
would be reduced. In chronic anaemia, red cell 2,3 -DPG levels rise and the curve will
be right shifted.
Carbon Monoxide
Carbon monoxide (CO) binds 240 times more strongly than O2 to haemoglobin and by
occupying O2-binding sites, reduces oxygen capacity. CO also increases oxygen
a"nity, shifting the oxygen haemoglobin curve to the left and making O2 release to
tissues more di"cult.
Foetal Haemoglobin
Foetal haemoglobin (HbF) binds 2, 3 -DPG less strongly than does adult haemoglobin
(HbA), and so the HbF dissociation curve lies to the left of that for HbA, reflecting its
higher oxygen a"nity. This helps transfer oxygen from mother to foetus.
A
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LT V
VSS FOE
E TTA
A LL O X Y G E
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O P E N STAX CO LLEG E [CC BY 3 .0 ( H TT P ://C REATI V ECO MMON S .ORG/ LIC EN S ES/ BY/ 3.0)], V I A

Alveolar Di!usion LAST UPDATED: 11TH
APRIL 2019
GAS TRANSPORT IN LUNGS  Bookmark
Gas exchange between alveolar air and blood in the pulmonary capillaries takes
place by di!usion across the alveolar-capillary membrane. Di!usion occurs from
an area of high partial pressure to an area of low partial pressure, thus the
driving force for di!usion is the alveolar-capillary partial pressure gradient.
Di!usion occurs until equilibrium is reached, but random movement of particles
continues to occur and this is known as dynamic equilibrium.
Fick's Law
Di!usion occurs across a membrane and is therefore governed by Fick's law.
The rate of gas flow = permeability x surface area of gas exchange x di!erence
in partial pressures (where permeability depends on the membrane thickness,
gas molecular weight and it's solubility in the membrane).
Fick's law tells us that the rate of di!usion of a gas increases:
the larger the surface area involved in gas exchange

the greater the partial pressure gradient across the membrane
the thinner the membrane
the more soluble the gas in the membrane
the lower the molecular weight of the gas
Although CO2 is larger than O2, it is is much more soluble and di!uses 20 times
more rapidly. The average surface area of the alveolar-capillary membrane is
about 50 - 100 m2, and the average thickness is 0.4 mm. This allows an
enormous surface area for gas exchange and a very short di!usion distance.
Transfer Factor
For gas transfer across the lungs, the permeability and surface area are
commonly combined as the di!using capacity (or transfer factor) for that gas, a
measure of the alveolar-capillary membrane function.
The di!using capacity for oxygen (DLO2) cannot be measured directly but the
rate of di!usion in the lungs can be estimated by measuring the di!using
capacity of the lungs for carbon monoxide (DLCO).
Factors a!ecting transfer factor:
DLCO is reduced by reduced alveolar-capillary membrane area (as in

emphysema, pulmonary embolism or lung resection).
DLCO is reduced by increased membrane thickness (as in pulmonary
oedema or pulmonary fibrosis).
DLCO is reduced in anaemia.
DLCO is increased in polycythaemia.
DLCO is increased in exercise (due to increased pulmonary blood volume
increasing the e!ective area).
DLCO is not a!ected by hypoventilation.
Limitations of Gas Transfer
The rate of transfer of a gas may be di!usion or perfusion limited.
The solubility of nitrous oxide in the blood is low and it does not undergo
chemical combination with any component of blood, thus the partial pressure in
the blood rapidly reaches equilibrium with alveolar air, there is no alveolar-
capillary partial pressure gradient and di!usion ceases along the capillary;
uptake can only be increased by increased capillary blood flow and thus transfer
is perfusion-limited.
Carbon monoxide is rapidly taken up and bound tightly to haemoglobin thus

pulmonary capillary PCO changes little and the alveolar-capillary partial
pressure gradient is maintained along the capillary. Improved ease of di!usion,
with reduced thickness or increased area of the alveolar-capillary membrane
would increase CO uptake, and thus transfer is di!usion-limited.
Oxygen transfer lies between these two extremes, but is normally perfusion-
limited.

Gas Transport LAST UPDATED: 11TH
APRIL 2019
GAS TRANSPORT IN LUNGS  Bookmark
Fractional Concentration and Partial Pressure of Gases in a

Gas Mixture
Dalton's law states that when two or more gases, which do not react chemically,
are present in the same container, the total pressure is the sum of the partial
pressures of each gas.
In the atmosphere, the partial pressure of a gas is the contribution to barometric

pressure exerted by that gas. The total pressure exerted by the atmosphere at
sea level is 760 mmHg (101 kPa).
The partial pressure of each gas is determined by the fractional concentration of

that gas. Dried air contains 21% oxygen, 78.1% nitrogen and 0.9% inert gases
such as helium and argon. The small amount of CO2 in air (< 0.04 %) is usually
ignored.
Therefore the partial pressure of oxygen in dry inhaled air = 0.21 x 760 (101) =
159 mmHg (21.2 kPa) and the partial pressure of nitrogen = 0.78 x 760 (101) = 593
mmHg (78.8 kPa).
At altitude, the oxygen fraction is unaltered but the barometric pressure and
thus partial pressure of oxygen is reduced.
Oxygen and Carbon Dioxide Partial Pressures in Respiration
Typical values for a resting young healthy male (in kPa) are shown below:
Inhaled air: PO2 21.2, PCO2 0.0

Inspired air in airways (after humidification): PO2 19.9, PCO2 0.0
Alveolar air (after equilibrium with pulmonary capillaries): PO2 13.3, PCO2
5.3
Exhaled air (after mixing with anatomical dead space air): PO2 15.5, PCO2
4.3
Gases Dissolved in Body Fluids
If a gas is exposed to a liquid to which it does not react, gas particles will move
into that liquid. Henry's law states that the number of molecules dissolving into
the liquid is directly proportional to the partial pressure at the surface of the
gas.
The constant of proportionality is the solubility of the gas in the liquid, and it is
determined by the gas, the liquid and the temperature:
Content of dissolved gas X in liquid Y = (Solubility of X in Y) x (Partial pressure of

X at surface)

Airway Resistance LAST UPDATED: 11TH
APRIL 2019
PHYSIOLOGY / RESPIRATORY / LUNG MECHANICS
 Bookmark
Airflow is driven by and is directly proportional to, the mouth-alveolar pressure

gradient generated by the respiratory muscles.
Flow through airways is described by Darcy's law: Flow = (P1 - P2)/R where P1 is the
alveolar pressure, P2 is the mouth pressure and R is the resistance to airflow.
Airway resistance is primarily determined by the airway radius according to

Poiseuille's law, and whether the flow is laminar or turbulent. The major site of airway
resistance is the medium-sized bronchi. The smallest airways would seem to o!er the
highest resistance, but they do not because of their branching parallel arrangement.
Factors A!ecting Airway Resistance
Factors causing bronchoconstriction:
Via muscarinic receptors
Parasympathetic stimulation
Stimulation of irritant receptors
Inflammatory mediators e.g. histamine, prostaglandins, leukotrienes
Beta-blockers
Factors causing bronchodilation:
Via beta2-adrenoceptors
Sympathetic stimulation
Adrenaline (epinephrine)
Beta2-adrenergic agonists e.g. salbutamol
Anticholinergic and muscarinic antagonists e.g. ipratropium
Pollutants, and substances released from mast cells and eosinophils can increase
airway resistance via bronchoconstriction, mucosal oedema, mucus hypersecretion,
mucus plugging and epithelial shedding - all of which are important in asthma.

Expiratory Flow Rates LAST UPDATED: 19TH
APRIL 2020
 Bookmark
Lung volumes can be measured with spirometry. Airway resistance and lung
compliance can be assessed indirectly by measuring the forced expiratory flows and
volumes.
Peak Expiratory Flow Rate
The easiest and quickest measurement is the peak expiratory flow rate (PEFR). PEFR
is reduced if airway resistance is increased in obstructive disease and is commonly
used to monitor asthma. It is dependent on the initial lung volume and therefore on
the patient's age, sex and height.
N
NOOR
RMMA
A LL V
V A LL U E
ES F O
OR P E A K E
EXXP
PI R A
ATT O R Y F L O W ( E X
X A M P L E ) . ( IM AGE BY H ÄGGSTRÖ M,
M I K AE L (2 0 1 4) . "M E D I CAL GALLE RY O F M I K AE L H ÄGGST RÖ M 2 0 1 4". WI K I JO U R N AL O F
M E D I C I N E 1 (2) . D O I : 1 0.1 5 3 47/ WJM /2 0 1 4.0 0 8. I S S N 2 0 0 2- 4 4 3 6. P U B LI C D O M AI N )
Forced Vital Capacity
The forced vital capacity (FVC) is the volume of air that can forcibly be blown out after
a maximum inspiration.
Forced Expiratory Volume
The forced expiratory volume in 1 second (FEV1) is the volume of air that can forcibly
be blown out after maximal inspiration in one second.
This is normally expressed as a ratio to FVC to correct for lung volume.
FEV1/FVC Ratio
The FEV1/FVC ratio is usually 0.75 - 0.90.

The FEV1/FVC ratio can be used to distinguish between obstructive (increased airway
resistance) and restrictive (decreased lung compliance) disease.
In obstructive disease, slowing of expiratory flow means that a low proportion of the
FVC is expired in the first second and thus the FEV1/FVC ratio is reduced (normally <
0.7).
In restrictive disease, FEV1 and FVC are both reduced, but the FEV1/FVC ratio is
normal or even increased due to greater elastic recoil.
Disease Obstructive Restrictive Disease

Disease
Pathophysiology Increased Impaired ability of the lungs to expand

airway caused by decreased lung compliance
resistance
caused by
narrowing of
the airways
Examples COPD, Intrinsic causes: interstitial lung

asthma, disease, pulmonary oedema,
emphysema, pneumonia, parenchymal lung tumours;
bronchiectasis Extrinsic causes: pleural e!usion,
pleural adhesions, pneumothorax,
chest wall deformities, neuromuscular
disease, connective tissue disease,
obesity or pregnancy
FVC Normal or low Low (< 0.8)
FEV1 Low (< 0.8) Low (<0.8)
FEV1/FVC ratio Low (< 0.7) Normal or high (>0.7)
Vital capacity Low Low
Residual volume High Normal or low
Total lung Normal or high Low

capacity

Lung Compliance LAST UPDATED: 11TH
APRIL 2019
 Bookmark
In order for inspiration to occur, the respiratory muscles must overcome the
impedance o!ered by the lungs and chest wall, mainly in the form of frictional
airway resistance and elastic resistance to stretching of the lung and chest wall
tissues and the fluid lining the alveoli.
Compliance describes the distensibility or ease of stretch of lung tissue when an

external force is applied to it. Like lung volumes, compliance is a!ected by a
person's age, sex and height.
Static Compliance
The static compliance (CL) of the lungs is defined as the change in lung volume
per unit change in distending pressure.
Compliance = ΔV/ΔP
The distending pressure is the transmural pressure di!erence across the lung,
which equals alveolar - intrapleural pressure.
Alveolar pressure cannot easily be measured, but when no air is flowing, alveolar
pressure must be zero (i.e. equal to atmospheric pressure). The transmural
pressure is then equal to the intrapleural pressure.
Intrapleural pressure can be measured with an oesophageal balloon. The subject

breathes in steps and measurements are taken while the breath is held and
plotted as a static pressure-volume (P-V) curve. The static lung compliance is
the slope of the steepest part of this static P-V curve in the region just above
the functional residual capacity.
The pressure-volume curve demonstrates hysteresis where the inspiratory
curve is slightly di!erent from the expiratory curve even at the same volumes.
This is because expiration is deemed a passive process due to the elastic recoil
of the lung whereas there is a need to overcome surface tension forces when
inflating the lungs.
Dynamic Compliance
Dynamic compliance is measured during continuous breathing and therefore

includes a component due to airway resistance. The dynamic pressure-volume
loop has a point at each end where the flow is zero: the slope of the line
between these points is the dynamic compliance. In health, dynamic
compliance is similar to static compliance but is some diseases it may be lower.
Between the two zero flow points, the dynamic P-V loop appears fatter than the
static P-V loop, as intrapleural pressure must change more to drive airflow. In
fact, the area of the dynamic loop is a measure of the work done against airway
resistance.
Factors A!ecting Compliance
Compliance changes at di!erent lung volumes. Initially at lower lung volumes

the compliance of the lung is poor and greater pressure change is required to
cause a change in volume. This occurs if the lungs become collapsed for a
period of time. At functional residual capacity (FRC) compliance is optimal since
the elastic recoil of the lung tending towards collapse is balanced by the
tendency of the chest wall to spring outwards. At higher lung volumes the
compliance of the lung again becomes less as the lung becomes sti!er. At all
volumes, the base of the lung has a greater compliance than the apex.
Other factors increasing compliance:
Old age
Emphysema
Other factors decreasing compliance:
Pulmonary fibrosis
Pulmonary oedema
Atelectasis
Extremes of lung volumes

Something wrong?
Respiratory Epithelial LAST UPDATED: 30TH

MARCH 2020
Function  Bookmark
Mucociliary Clearance
The respiratory tract from the trachea down until the respiratory bronchioles is
lined with ciliated columnar epithelial cells. Goblet cells and submucosal glands
secrete a thick, gel-like mucus. Synchronous beating of the cilia moves the
mucus and associated debris to the mouth where it is swallowed or
expectorated, a process known as mucociliary clearance.
Impaired Mucociliary Clearance
Factors that increase the viscosity of the mucus (e.g. cystic fibrosis, asthma,
inflammation or poor humidity) or factors that impair ciliary activity (e.g.
smoking, pollutants, infection or general anaesthetics) lead to defective
mucociliary clearance and recurrent infections.
Mucus contains substances that protect the airway from pathogens and from
destructive proteases released from dead bacteria and immune cells e.g. alpha-
1-antitrypsin, lysozyme, IgA. Genetic deficiency of alpha-1-antitrypsin leads to
early-onset emphysema as a result of uninhibited protease activity in the lung
resulting in destruction of elastin in the alveoli.
Epithelial Cells
The single layer of epithelial cells forming the walls of the alveoli and alveolar
ducts are non ciliated squamous cells, predominantly very thin type I alveolar
pneumocytes joined by tight junctions lying on a basement membrane. These
form the gas exchange surface with the pulmonary capillary endothelium.
A few type II alveolar pneumocytes make up a small proportion of the alveolar
surface area and secrete surfactant which bathes the alveoli, reducing the
surface tension and preventing alveolar collapse.
Macrophages in the airways ingest foreign materials and destroy pathogens. In

the alveoli, alveolar macrophages take the place of cilia by clearing debris.
S
ST R
RU C
C TT U R
REE O
O FF A
ANN A LLV
VEEO
O LL U S
S . ( IM AGE M O DIF IE D BY F RC E M S U C C E S S . O R IGIN AL
S O U RC E D F RO M WI K I M E D I A C O M M O N S . )

Alveolar Interface LAST UPDATED:
15TH OCTOBER 2022
LUNG MECHANICS  Bookmark
Alveolar Air-Fluid Interface
The surface tension of the fluid lining the alveoli contributes to lung
sti!ness, as the attraction of water molecules for each other at the air-
fluid interface creates a collapsing pressure that is directly proportional to
surface tension and inversely proportional to alveolar radius.
This is a manifestation of Laplace's law which states that the pressure (P)
in a bubble (or alveolus) is proportional to the surface tension (T)/radius (r).
A small bubble will therefore have a higher collapsing pressure than a
larger one, and be more di"cult to keep open. The inward force created by
this surface tension also tends to suck fluid into the alveoli (transudation).
In the lungs, pulmonary surfactant secreted by type II pneumocytes aims

to minimise these problems.
Pulmonary Surfactant
Pulmonary surfactant is a mixture of phospholipids that floats on the

alveolar fluid surface and reduces surface tension. As the alveoli shrink
during expiration, the e!ective concentration of surfactant increases,
further lowering the surface tension (which more than balances the
increased tendency for alveoli to collapse as they shrink). Alveolar stability
is also aided by the connection and mutual pull of neighbouring alveoli, a
phenomenon known as alveolar interdependence.
Surfactant prevents alveolar collapse, increases lung compliance and

prevents transudation of fluid into alveoli. Infant respiratory distress
syndrome, with sti! lungs, lung collapse and transudation, occurs in
premature babies (< 34 weeks gestation) due to a deficiency of surfactant
production.
Something wrong?
Dead Space LAST UPDATED: 11TH

APRIL 2019
LUNG VOLUMES AND PRESSURES  Bookmark
Total Ventilation (minute ventilation) = Tidal Volume (TV) x Respiratory Rate

(RR)
With each tidal volume, about one third of the total amount of gas flowing
into the airway and lung does not participate in gas exchange. This is the
physiological dead space. Dead space can thus be defined as the volume
of gas in the respiratory tract which does not take part in gas exchange.
Anatomical Dead Space
The anatomical dead space includes the respiratory tract down to and
including the terminal bronchioles. These conducting airways have a
function in warming, filtering and humidifying inspired air. The anatomical
dead space is normally about 150 mL. Fowler's method is used to measure
anatomical dead space.
Alveolar Dead Space
The alveolar dead space refers to alveoli incapable of gas exchange; in

health, it is negligible but it may become significant in V/Q mismatch, for
example in pulmonary embolism where certain alveoli lose their blood
supply and no longer take part in gas exchange.
Physiological Dead Space
The physiological dead space is the sum of the anatomical and alveolar
dead space (in health, all alveoli take part in gas exchange, so physiological
dead space = anatomical dead space). The Bohr equation is used to
measure physiological dead space.

Functional Residual Capacity LAST UPDATED: 21ST
APRIL 2019
Definition
The volume left in the lungs at the end of a normal breath is called the functional
residual capacity (FRC). At FRC, the respiratory muscles are relaxed and its volume is
determined by the elastic properties of the chest wall (tending to spring outwards)
and the lungs (tending to collapse).
If the elastic recoil of either the lungs or chest wall is abnormally large or small, the
FRC will be abnormal. In fibrosis, the lungs are sti! and have decreased compliance,
and so the FRC is reduced. In emphysema, there is loss of alveolar tissue, and with it
elastic recoil of the lungs and hence the FRC is increased. As such, patients with
emphysema often have noticeably broader chests due to the relatively unopposed
outward recoil of the chest wall.
Factors A!ecting FRC
Factors increasing FRC:
Emphysema
Air trapping in asthma
Ageing (due to loss of elastic properties)
Increasing height of patient
Factors decreasing FRC:
Restrictive ventilatory defects e.g. pulmonary fibrosis

Posture - lying supine
Increased intra-abdominal pressure (e.g. obesity, pregnancy, ascites)
Reduced muscle tone of diaphragm e.g. muscle relaxants in
anaesthesia, neuromuscular disease

Something wrong?
Lung Volumes LAST UPDATED: 11TH

APRIL 2019
IRV Inspiratory
Reserve
Volume
(IRV)
Inspiratory
Capacity
(IC) Vital
Total
Capacity Lung
(VC)
Capacity
Tidal (TLC)
VC
TV Volume
(TVorV)t
Expiratory
Reserve
ERV Volume Functional
(ERV Residual
Capacity
(FRC)
FRet
Residual Residual
Volume Volume
RV (RV) (RV)
LLU
UNNG
G VVO
O
OLLU
U
UMME
ESS .. ( IM AGE BY V IH SADAS AT E N.WIK IP E DIA DE R IVATIV E WO R K :
R S C OTTWE E K LY ( LU N GVO LU M E .JP G) [C C BY-SA 3.0
( H TTP://CREATIV ECOMMON S.ORG/ LICEN SES/ BY-SA/ 3.0)], FROM WIKIMEDIA COMMON S)
Volumes
The tidal
tidal volume
volume (TV)
(TV) is the volume of air drawn into and out of the lungs during
normal breathing, i.e. the volume change of the lung between a resting inspiration
and a resting expiration.
The inspiratory
inspiratory reserve
reserve volume
volume (IRV)
(IRV) is the volume of air that can be inspired at
the end of a normal inspiration, i.e. the di"erence in volume between a resting and
maximum inspiration.
The expiratory
expiratory reserve
reserve volume
volume (ERV)
(ERV) is the volume of air that can be expelled at
the end of a normal expiration, i.e. the di"erence in volume between a resting and
maximum expiration.
The residual
residual volume
volume (RV)
(RV) is the volume of air remaining in the lungs after a
maximal expiration.
Capacities
The vital
vital capacity
capacity (VC)
(VC) is the maximum tidal volume when an individual breathes in
and out as far as possible i.e. the volume change of the lung between a
maximum inspiration and a maximum expiration.
VC = IRV + TV + ERV.
The inspiratory
inspiratory capacity
capacity (IC)
(IC) is the volume of air that can be breathed in by a
maximum inspiration at the end of a resting expiration.
IC = TV + IRV.
The functional
functional residual
residual capacity
capacity (FRC)
(FRC) is the volume of air remaining in the lungs
at the end of a resting expiration.
FRC = ERV + RV.
The total
total lung
lung capacity
capacity (TLC)
(TLC) is the volume of air in the lungs after a maximum
inspiration.
TLC = VC + RV.
Measuring Lung Volumes and Capacities
Lung volumes vary with age, sex and height.
Most lung volumes (except RV) can be measured directly using spirometry.
Residual volume (and thus FRC and TLC) can be measured using helium dilution or
body plethysmography.
Lung Volume Typical Value (70 kg Male)
Tidal volume (TV) 500 mL
Vital capacity (VC) 5500 mL
Inspiratory reserve volume (IRV) 3300 mL
Expiratory reserve volume (ERV) 1700 mL

Expiratory reserve volume (ERV) 1700 mL
Total lung capacity (TLC) 7300 mL
Functional residual capacity (FRC) 3500 mL
Residual volume (RV) 1800 mL

Right to Left Shunt LAST UPDATED: 11TH
APRIL 2019
VENTILATION-PERFUSION RELATIONSHIP  Bookmark
Anatomical Right to Left Shunts
Part of the venous e!uent of the bronchial and coronary circulations

bypasses the lungs and enters the pulmonary vein and left ventricle
respectively. Oxygenated blood from the lungs is therefore diluted by
venous blood. In healthy people, these anatomical shunts are equivalent to
2% or less of the cardiac output but they explain why arterial PO2 is less
than alveolar PO2 even though pulmonary capillary blood equilibrates with
alveolar air.
Right to Left Shunts in Disease
Shunting may become significant in some disease states when regions of

the lung are not ventilated (e.g. atelectasis, pulmonary oedema,
pneumonia) or due to cyanotic congenital heart disease where blood
bypasses the pulmonary circulation completely (e.g. tetralogy of Fallot).
The shunted blood will not have been oxygenated or been able to o!oad
CO2 and thus its levels of PO2 and PCO2 are that of mixed venous blood.
Changes in PCO2 and PO2 stimulate the chemoreceptors and increase
ventilation, so that arterial PCO2 returns to normal. However, increased
ventilation cannot increase blood O2 content, as the haemoglobin of the
blood passing through the lungs is already close to saturation. Thus right
to left shunts commonly result in a low arterial PO2 but a normal or low
PCO2.
Treatment with high-flow oxygen in these patients is of little benefit,

as since blood is being shunted, the oxygen-enriched air fails to reach the
shunted blood and the arterial PO2 will remain low.

Ventilation-Perfusion LAST UPDATED: 8TH
AUGUST 2021
Mismatch  Bookmark
VENTILATION-PERFUSION RELATIONSHIP
At rest, total alveolar ventilation and total pulmonary blood flow are similar, each
being around 5 L/min. To achieve e!cient gas exchange, it is essential that the flow
of gas (ventilation, V) and the flow of blood (perfusion, Q) are closely matched
throughout all regions of the lung. Ideally, local ventilation-perfusion (V/Q) ratios
should be as close to 1 as possible.
V/Q Mismatch
When there are significant regional variations in ventilation or perfusion, this is

referred to as ventilation-perfusion (V/Q) mismatch.
There are two extremes of V/Q mismatch:
1. Dead space
Lung region with normal alveolar ventilation but absent perfusion
Caused by large pulmonary embolus for example
Q = 0, therefore V/Q = ∞
The Po2 and Pco2 of alveolar gas will approach their values in inspired
air
2. True shunt
Lung region with normal perfusion but absent alveolar ventilation
Caused by complete collapse or consolidation of a lung region for

example
V = 0, therefore V/Q = 0
The Po2 and Pco2 of pulmonary capillary blood (and, therefore, of

systemic arterial blood) will approach their values in mixed venous
blood
E!ect of V/Q Mismatch on Arterial Gases
Regions of the lung with V/Q > 1 have excessive ventilation relative to perfusion with a
dead space e#ect, and blood derived from them will have raised PaO2 and low
PaCO2. This may be seen in emphysematous areas where capillaries are destroyed or
where pulmonary emboli are partially blocking blood flow.
Regions of the lung with V/Q < 1 have reduced ventilation relative to perfusion with a
shunt e#ect, and blood derived from them will have low PaO2 and raised PaCO2. This
may be seen when airways are partly blocked by bronchoconstriction, inflammation or
secretions.
Regions of high V/Q cannot compensate for regions of low V/Q and the net e#ect of
mixing blood from areas with V/Q mismatch is a low PaO2 and a normal/low PaCO2.
Hypoxic vasoconstriction helps to reduce the severity of V/Q mismatching by
diverting blood from regions with low V/Q ratios to regions that are better ventilated.
For an alveolus with a V/Q between 0-1 (V/Q mismatch but not true shunt), there is
perfusion but relatively less ventilation, therefore blood passing through this alveolus
will be partially oxygenated and increasing oxygen fraction can significantly improve
arterial oxygen content (assuming no di#usion limitation). However in a true shunt
(V/Q = 0) increasing oxygen fraction has no e#ect because the oxygen-enriched air
fails to reach the shunted blood.
Gravitational E!ects on V/Q Mismatch
Both ventilation and perfusion increase towards the lung base, because of the e#ects
of gravity, but the gravitational e#ects are greater on perfusion than ventilation and
therefore there is a regional variation in V/Q ratio from lung apex (high V/Q) to lung
base (low V/Q). In young people, this gravitational e#ect is modest and has little e#ect
on blood gases, but the V/Q mismatch increases with age and contributes to the
reduction in PaO2 seen in the elderly.
Regional ventilation and perfusion can be visualised by inhalation and infusion of

appropriate radioisotopes on a V/Q scan.
A-a gradient
The cause of a hypoxia can be classified by the alveolar-arterial PO2 gradient (A-a
gradient). The alveolar gradient is calculated as PAO2 – PaO2.
A normal A-a gradient is seen in alveolar hypoventilation or low inspired PO2 (e.g. at
high altitude). An increased A-a gradient reflects a di#usion defect (rare), V/Q
mismatch or a right-to-left shunt.
In healthy young people, there is a small A-a gradient (< 2 kPa) arising from the
normal anatomical right-to-left shunts. The normal value for the A-a gradient
increases with age.

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Neurochemical Synaptic LAST UPDATED: 25TH

Action potentials in incoming neurons are transmitted by the release of

The neurotransmitter is synthesised and stored in vesicles in the terminal bouton of

causes opening of voltage-gated Ca2+ channels in the presynaptic membrane, and a

subsequent influx of Ca2+, which causes the neurotransmitter-containing vesicle to

After activation at the postsynaptic membrane, neurotransmitters must be removed

Noradrenaline and other catecholamines in the circulation are metabolised

( H TTP://CREATIV ECOMMON S.ORG/ LICEN SES/ BY-SA/4.0)], V IA WIKIMEDIA COMMON S)

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( H TTP://CREATIV ECOMMON S.ORG/ LICEN SES/ BY-SA/4.0)], V IA WIKIMEDIA COMMON S)

PHYSIOLOGY / BASIC CELLULAR /  Bookmark

Electrical events in biological tissues are caused by the

A membrane potential is a property of all cell membranes, but

The value of the membrane potential depends on the relative

The resting membrane is more permeable to K+ and Cl- than to

charge attracts K+, leading to accumulation of K+ within the

cell. However, the consequent increase in the K+ concentration

These fixed anions also attract Na+ and the electrochemical

gradient for Na+ is strongly inwards, however the

resting membrane is relatively impermeable to Na+ and only a

small amount of Na+ can leak in. A consequence of this setup is

that if Na+ permeability were suddenly increased to more than

Sympathetic preganglionic neurons originate in the lateral horn of segments

Parasympathetic preganglionic neurons originate in the brainstem from which

Both sympathetic and parasympathetic preganglionic neurons release acetylcholine

Sympathetic postganglionic neurons terminate in the e!ector organs where they

Parasympathetic postganglionic neurons release acetylcholine

Action potentials are initiated in nerves by activation of ligand-gated Na+ channels by

neurotransmitters. Opening of these Na+ channels results in a small influx of sodium

If the stimulus is su!ciently strong, the resting membrane depolarises enough to

becomes positive, the voltage-gated Na+ channels inactivate preventing further

Voltage-gated K+ channels are also activated, causing the K+ permeability to again be

Delayed closure of these rectifier K+ channels causes a transient hyperpolarisation.

Following this there is a relative refractory period where the temporary

Coagulation Cascade LAST UPDATED: 11TH

Blood coagulation involves a biological amplification system in which a few initiation

The generation of thrombin is a complex network of amplification and negative

Coagulation is initiated after vascular injury by the interaction of the membrane

Thrombin activates a short cascade that leads to activation of factor IX (also

( H TTPS://CREATIV ECOMMON S.ORG/ LICEN SES/ BY/ 3.0)])

PHYSIOLOGY / BASIC CELLULAR /

Normal adult haemoglobin (HbA) makes up about 96 - 98 % of total adult

Hb Structure Normal adult %

HbA α2β2 96 - 98%

HbA2 α2δ2 1.5 - 3.5%

HbF α2γ2 0.5-0.8%

S T R U C T U R E O F H A E M O G L O B I N . ( IM AGE BY O P E N STAX C O LLEGE [C C BY 3.0

( H TTPS://CREATIV ECOMMON S.ORG/ LICEN SES/ BY/ 3.0)], V IA WIKIMEDIA COMMON S)

PHYSIOLOGY / BASIC CELLULAR /

Haemopoietic Stem Cells

PHYSIOLOGY / BASIC CELLULAR /

Immediate vasoconstriction of the injured vessel and reflex constriction of adjacent

Platelet Reactions and Primary Haemostatic Plug Formation

Stabilisation of the Platelet Plug by Fibrin

Definitive haemostasis is achieved when fibrin, formed by blood coagulation, is added

converts soluble plasma fibrinogen into fibrin monomers, potentiates platelet

( H TTPS://CREATIV ECOMMON S.ORG/ LICEN SES/ BY/ 3.0)])

Physiological Limitation of Blood Coagulation

Unchecked, blood coagulation would lead to thrombosis, of the protective

Coagulation Factor Inhibitors:

Protein C and Protein S:

Protein C and protein S are inhibitors of coagulation cofactors V and VIII.