ENDOCRINE

PHARMACOLOGY

MOKE, EMUESIRI GOODIES

DEPARTMENT OF PHARMACOLOGY, DELTA STATE UNIVERSITY, ABRAKA.
• INTRODUCTION TO THE ENDOCRINE SYSTEM

• HORMONAL REGULATION FEEDBACK MECHANISM

• HYPOTHALAMIC AND PITUITARY HORMONES

• THE THYROID GLAND AND ITS HORMONES

• PHARMACOLOGICAL MANAGEMENT OF THYROID DYSFUNCTIONS

• ADRENOCORTICAL HORMONES

• PANCREAS AND DIABETES MELLITUS

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• INTRODUCTION TO THE ENDOCRINE SYSTEM

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• Endocrine gland – It is a group of cells, which secretes messenger molecules
(hormones) directly into the bloodstream.
• Endocrinology – It is the study of endocrine glands and their secretions.
• Hormones – It is the bioactive messenger molecule secreted by an endocrine gland.
• Endocrine – It relates to hormone action on target cells at a distance from source.
• Paracrine – It relates to hormone action on nearby target cells.
• Autocrine – It relates to hormone having an effect on its own immediate source.

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• The endocrine system is a control system of ductless glands that secretes hormones
within specific organs.
• These hormones act as messenger and are carried by the bloodstream to different
cells in the body.
• These cells interpret the messages and act on them.
• The ability to maintain homeostasis and respond to stimuli is largely due to
hormones secreted within the body.
• Without hormones, one could not
1) grow,
2) maintain a constant temperature
3) produce offspring or
4) perform the basic actions and functions that are essential for life.

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• The endocrine and the nervous system are closely involved in homeostasis.
• The endocrine system provides an electrochemical connection from the
hypothalamus of the brain to all the organs that control the body metabolism,
growth and development, and reproduction.

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 Table: Differences between the endocrine and the nervous system

S/N Endocrine System Nervous System

1. Hormones are released. Neurotransmitters are released.
2. The hormones are released into the Neurotransmitters are released across
bloodstream. synapse.
3. The endocrine system is ductless. The nervous system makes use of nerve
cells.
4. Its effect can be on many target cells Its effect is restricted to those target cells
spread throughout the body. actually innervated.
5. Effects will take place over a relatively long Effects will be generated within
time (ranging from seconds to days). milliseconds.

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Types and Location of the endocrine glands
• Pituitary gland is attached to the hypothalamus of the lower forebrain.
• Thyroid gland consists of two lateral masses connected by a cross bridge that are
attached to the trachea and it is slightly inferior to the larynx.
• Parathyroid gland are four masses of tissues, two embedded posteriorly in each
thyroid gland.
• One adrenal gland is located on top of each kidney. The cortex is the outer layer and
the medulla is the inner layer.
• Pancreas is along the lower curvature of the stomach close to where it meets the
duodenum.
• Gonads are found in the pelvic cavity.

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• HORMONAL REGULATION FEEDBACK MECHANISM

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• Regulation of the concentration of hormone molecules in the blood and fluids within
the tissues of the body is an important part of homeostasis.
• Homeostasis is the ability of a system or living organism to adjust its internal
environment to maintain a stable equilibrium or balance.
• The main body system involved in hormone regulation by feedback mechanisms are;
a. The nervous system – signals input to and output from the control center
are either nerve impulses which are part of the nervous system or chemical
signals.
b. The endocrine system – which produces and secretes hormones.

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FEEDBACK MECHANISM
• Feedback is (generally) information about actions.
• A feedback mechanism (feedback loop) is a biological occurrence wherein the output
of a system amplifies or inhibit the system.
• For example, temperature is continually monitored and adjusted as appropriate to
keep a safe range so as to maintain proper body function.

Types
There are two types of feedback mechanism:
1. Negative feedback
2. Positive feedback
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Negative feedback mechanism
• Negative feedback mechanisms act like a thermostat in the home. As the temperature
rises, the thermostat detects the change and triggers the air conditioning to turn on
and cool the house. Once the temperature reaches its thermostat setting (ideal
normal value), the air conditioning turns off.
• An example of negative feedback mechanism is the regulation of the blood calcium
level. The parathyroid glands secrete parathyroid hormone, which regulates the blood
calcium amount.
• If the calcium decreases, the parathyroid glands sense the decrease and secrete more
parathyroid hormone. The parathyroid hormone stimulates calcium release from the
bones and increase the calcium uptake into the bloodstream from the collecting
tubules in the kidneys.

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• Conversely, if the blood calcium increases too much, the parathyroid glands reduce
parathyroid hormone production.
• Both responses are examples of negative feedback because in both cases, the effects
are negative (opposite) to the stimulus.
• Most endocrine glands are under the control of negative feedback mechanisms.

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INPUT PROCESS OUTPUT

Negative feedback mechanism

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Positive Feedback Mechanism
• Positive feedback mechanisms control self- perpetuating events that can be out of
control and do not require continuous adjustment.
• In positive feedback mechanisms, the original stimulus is promoted rather negated.
Unlike negative feedback that maintains hormone levels within narrow ranges,
positive feedback is rarely used to maintain homeostatic functions.

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Positive Feedback Mechanism
• An example of positive feedback can be found in childbirth.
• The hormone oxytocin stimulates and enhances labour contractions. As the baby
moves towards the vagina (birth canal), pressure receptors within the cervix send
messages to the brain to produce oxytocin.
• Oxytocin travels to the uterus through the bloodstream, stimulating the muscles in
the uterine wall to contract stronger. The contractions intensify and increase until the
body is outside the birth canal.
• When the stimulus to the pressure receptor ends, oxytocin production stops and
labour contractions cease.

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INPUT PROCESS OUTPUT

Positive feedback mechanism

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• HYPOTHALAMIC AND PITUITARY HORMONES

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HYPOTHALAMIC AND PITUITARY HORMONES
• The control of metabolism, growth and reproduction is mediated by a combination of
neural and endocrine systems located in the hypothalamus and pituitary gland.
• The pituitary gland weighs about 0.6g and rests at the base of the brain in the body
sella turnica near the optic chiasm and the convernous sinuses.
• The pituitary consists of:
• An anterior lobe (adenohypophysis)
• A posterior lobe (neurohypophysis)

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HYPOTHALAMIC AND PITUITARY HORMONES
• The pituitary is connected to the overlying hypothalamus by a stalk of neurosecretory
fibers and blood vessels, including a portal venous system that drains the
hypothalamus and perfuse the anterior pituitary. The portal venous system carries
small regulator hormones from the hypothalamus to the anterior pituitary.
• The posterior lobe hormones are synthesized in the hypothalamus and transported
via the neurosecretory fibers in the stalk of the pituitary to the posterior lobe, from
which they are released into the circulation.

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HYPOTHALAMAIC HORMONES
• The hypothalamic hormones regulate the secretions of the anterior pituitary
hormones. They include;

1. Growth Hormone-Releasing Hormone (GHRH or GHRF) :

 GHRH stimulates growth hormone production.
 Its analogue, sermorelin, has been introduced as a diagnostic test tool for growth
hormone secretion.
 It is given intravenously, subcutaneously or intranasally.
 Onset of action is within few minutes and peak in 60 minutes.
 Its action is selective for the somatotrophs in the anterior pituitary and no other
pituitary hormone.
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2. Somatostatin (SST):
 It is a peptide of 14 amino acid residues. It inhibits the release of growth hprmone
and thyroid – stimulating hormone from the anterior pituitary and insulin and
glucagon from the pancreas. It is also decreases the release of most
gastrointestinal hormones.
 Octreotide and Lanreotide are analogues of SST.
 Octreotide is a long-acting analogue useful for the treatment of tumors secreting
vasoactive intestinal peptide, carcinoid tumors, glucagonomas and various
pituitary adenomas. Also usefyl in therapy of aeromegaly (oversecretion of growth
hormone in an adult).
 Given subcutaneously, with adverse effects of pain at injection site and GI
disturbances.

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3. Thyrotrophin-Releasing Hormone (TRH):
 TRH releases thyroid –stimulating hormone (TSH) from the anterior pituitary.
 Protirelin is a synthetic TSH used for the diagnosis of thyroid disorders.

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4. Corticotrophin-Releasing Hormone (CRH, CRF):
 CRH is a peptide that releases adrenocorticotrophic hormone (ACTH) and β-
endorphin from the anterior pituitary.
 Its action and release are inhibited by glucocorticoids.
 Synthetic analogues have been used to test the ability of the pituitary to secrete
ACTH, and to assess whether ACTH deficiency is caused by a pituitary or a
hypothalamic defect.

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5. Gonadotrophin-Releasing Hormone (GnRH):
 It is a decapeptide that releases both follicle –stimulating hormone (FSH) and
luitenising hormone (LH).
 Gonadorelin is a synthetic preparation.
 Its primary clinical utility is in the treatment of infertility.

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6. Dopamine (DA):
 Dopamine is a cathecholamine which inhibits the production of prolactin.
 It acts through the D2 –subtype of dopamine receptors. Agonists of dopamine
include bromocriptine, cabergoline and pergolide.

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Pharmacological application of drugs that mimic or block the effects of
hypothalamic and pituitary hormones includes;
1. Useful as replacement therapy for hormone deficiency states

2. Useful as antagonists for diseases that result from excess production of pituitary
hormones.

3. Useful as diagnostic tools for identifying several endocrine abnormalities.

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ANTERIOR PITUITARY HORMONES
Anterior pituitary hormones include:
 Growth hormone (GH)
 Thyroid –stimulating hormone (TSH)
 Adrenocorticotropic hormone (ACTH)
 Follicle-stimulating hormone (FSH)
 Luteinizing hormone (LH)
 Prolactin (PRL)

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POSTERIOR PITUITARY HORMONES
 Oxytocin
 Anti-diuretic Hormone

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• THE THYROID GLAND AND ITS HORMONES

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THE THYROID GLAND
• The thyroid gland secretes three (3) main hormones
 Triiodothyronine(T3)
 Thyroxine (T4)
 Calcitonin

• However, T3 and T4 are regarded as the true thyroid hormones

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• T4 and T3 are critically important for normal growth (through stimulation of growth
hormone synthesis) and energy metabolism.
• Calcitonin is involved in the control of plasma calcium ion.
• The thyroid gland has follicle also called ascinus as its functional unit. Each follicle
consists of a single layer of epithelial cells around a cavity (the follicle lumen), which is
filled with a thick colloid containing thyroglobulin.
• The follicular cells of the thyroid gland synthesize and glycosylate thyroglobulin before
secreting it into their lumen.

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• Iodination of the tyrosine residues on the thyroglobulin is catalyzed by thyroid
peroxidase, and this results in the formation of monoiodotyrosine (MIT) or
diiodotyrosine (DIT).
• The coupling of MIT and DIT results in formation of T3 (Triiodothyronine) while the
coupling of two DIT forms T4 (Thyroxine). This coupling is also catalyzed by thyroid
peroxidase.
• The thyroglobulin is then endocytosed into the follicular cells, where it is broken down
by lysosomes to release T3, T4, MIT and DIT. T3 and T4 are secreted into the plasma
while MIT and DIT are metabolized within cells and their iodide is recycled.

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• The iodide required for the synthesis of T3 and T4 comes normally form the diet in the
form of iodide.
• Through the action of a thyrotropin-dependent pump, iodide is concentrated in the
follicular cells, where it is converted into iodine by thyroid peroxidase.
• Iodide uptake is an energy dependent process occurring against a gradient. Iodide is
captured from the blood and moved to the lumen by two transporters;
 Na+/I- symporter (NIS)
 I-/Cl- porter, Pendrin (PDS).
Genetic mutation of these transporters may result into thyroid disease.

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 3 FOLLICULAR
LUMEN
4
1
8 2
FOLLICULAR LUMEN

PLASMA
FOLLICULAR
CELL
7
6
5

Figure.: Synthesis Of Thyroid Hormones 41

Control of thyroid hormone
• The production of thyroid hormone is slow but constant.
• The hypothalamus contains thyroid receptors that are able to detect and respond to
decreased levels of T3 and T4 by causing the release of thyrotrophin-releasing hormone
(TRH).
• TRH reaches the anterior pituitary via the portal circulation, and it stimulates the
secretion of thyroid-stimulating hormone (TSH)via TRH receptors on thyrotroph cells.
• TSH reaches the thyroid gland through the systemic circulation, where it stimulates
thyroid hormone secretion.
• T3 and T4 exerts negative feedback upon the hypothalamus and pituitary.

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THYROID DYSFUNCTIONS
A. Hypothyroidism
• Hypothyroidism is thyroid insufficiency. Hypothyroidism is relatively common in adults.
It is associated with lethargy and tiredness, weight gain, intolerance to cold, dry skin,
bradycardia and mental impairment.
• In Children, it manifests delayed bone growth, whereas in a case of deficiency in utero,
it results in mentally retarded infants, this condition is Cretinism.
• Hashimoto's thyroiditis is an autoimmune disease resulting in fibrosis of the thyroid
gland. It has the most common cause of hypothyroidism.
• Other causes of hypothyroidism include: iodine deficiency or excess, inborne errors of
thyroid hormone synthesis, pituitary disease, thyroid hormone resistance and
radioactive iodine ingestion.
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 Management of hypothyroidism
a) Levothyroxine
• Thyroxine is given as thyroxine sodium in maintenance therapy. It has a half-life of 6
days and a peak onset of action of 9 days.
Mechanism of action
• Thyroxine (Levothyroxine) is converted to T3 in vivo.
• It is administered orally and used in hypothyroidism.
Contraindication
• Thyroxine should not be given to people with thyrotoxicosis and it should be used with
caution to those who have cardiovascular diseases.
Adverse effects
• Arrhythmia, Tachycardia, Angina, Pain, Cramp, Headache, Restlessness, Sweating, and
weight loss
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 Management of hypothyroidism
b) Liothyronine (L-triiodothyronine sodium)
• Liothyronine is slightly bounded to globulin, thus it has a rapid onset of effect and a
shorter duration of action than levothyroxine.
Mechanism of action
• It is rapidly metabolized in vivo to T3. It has a half-life of 2-5 days and peak onset of
action of 1-2days. It is administered orally and intravenously. Liothyronine is given for
severe hypothyroidism, where a rapid effect is needed.
Contraindication
• It is contraindicated in people in people with cardiovascular disorders.
Adverse effects
• Arrythmia, Tachycardia, Angina, Pain, Cramp, Headache, Restlessness, Sweating and
weight loss
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B.) Hyperthyroidism
• Hyperthyroidism (thyroid excesses, or thyrotoxicosis) results either from the
overproduction of endogenous hormone or exposure to excess exogenous hormone.
Symptoms include:
• Increase basal metabolic rate with consequent weight loss
• Increase appetite
• Increase body temperature and sweating
• Nervousness
• Tremor
• Tachycardia
• Classical ophthalmic signs

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B.) Hyperthyroidism
• Graves' disease (diffused toxic goitre) is the most common cause of hyperthyroidism. It
is an autoimmune disease caused by the activation of TSH receptors by antibodies. It
results in an enlargement of the gland and thus excess hormone production.
• Toxic nodular goitre is the second most cause of hyperthyroidism, this is due to
adenoma. Simple non-toxic goitre is as a result of excess iodine resulting in over
production of the hormone.

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 Management of hyperthyroidism
a) Thioureylenes
• Examples are; carbimazole, methimazole and propylthiouracil.
• They are the first line drugs for the treatment of hyperthyroidism.
• In the body, carbimazole is rapidly converted to the active compound methimazole.
Mechanism of action
• The thioureylenes cause inhibition of thyroid peroxidase with a consequent reduction
with thyroid hormone synthesis and storage. Propylthiouracil also inhibits the
peripheral deiodination of T4 to T3.
Route of administration
• Oral

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 Management of hyperthyroidism
a) Thioureylenes
Contraindication
• Thioureylenes are contraindicated in people with large goitre.
• Propylthiouracil should be given at a reduce dose in patients with renal insufficiency.
Adverse effect
• Nausea and headache
• Allergic reactions including rashes
• Hypothyroidism
• In rare cases hepatoxicity, bone marrow suppression and alopecia.
• Patient that are sensitive to carbimazole are given propylthiouracil.

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 Management of hyperthyroidism
b) Anion Inhibitors
• Examples are iodine, iodide, and potassium perchlorate.
• Potassium percholate inhibits the uptake of iodine by the thyroid, however it is no longer
in use because of the risk of aplastic anemia.
• Iodide is the most rapidly acting treatment against thyrotoxicosis and it is given in
thyrotoxicosis crisis.
Mechanism of action
• Iodine and iodide cause inhibition of conversion of T4 to T3 and of hormone secretion.
They also reduce the size and vascularity of the gland, which is resident after 10-14 days.

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 Management of hyperthyroidism
b) Anion Inhibitors
PK
• They are given orally
• Usefully in thyrotoxicosis
• Contraindicated in breastfeeding women, as they can cause goitre in infants.
Adverse effects
• Hypersensitivity reactions includes rashes
• Headache, Lacrimation, Conjunctivitis, Bronchitis and laryngitis
• Depression, insomnia and impotency can occur following long term treatment.

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 Management of hyperthyroidism Route of administration
c) Β-Adrenoceptor Antagonists • Oral
• Examples are propranolol and atenolol Clinical uses
• They are used to attenuate the symptoms • Thyrotoxic crisis
of increased thyroid hormone levels, and Contraindications
the effect of increased numbers of
adrenoceptors caused by thyroid hormone. • Asthmatic patients
Mechanism of action Adverse effects
• They reduce tachycardia, nervousness, and • Hypotension, bronchoconstriction, heart
tremor. failure

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 CALCITONIN
• It is a hormone secreted by the specialized C cells found in the thyroid follicle.
• The main action of calcitonin is on bone, where it inhibits bone resorption (breakdown)by
binding to a specific receptor on osteoclast and inhibiting their action.
• In the kidney, it decreases the reabsorption of both calcium ion and phosphate in the
proximal tubules. Its overall effect is to decrease the plasma calcium ion concentration.

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 CALCITONIN
Route of drug administration
• Subcutaneous or Intramuscular
Clinical uses
• Hyperkalemia
• Paget disease of bone
• Bone pain in neoplastic disease
• Calcitonin is contraindicated in renal impairment or history of allergy.
Adverse effect
• Nausea
• Vomiting
• Flushing
• Diarrhoea
• Tingling of the hands
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ENDOCRINE PANCREAS

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CONTROL OF PLASMA GLUCOSE
• Blood glucose levels are maintained at a concentration of about 5
mmol/L, and usually do not exceed 8 mmol/L.
• A plasma glucose concentration of 2.2 mmol/L or less may result in
hypoglycaemic coma and death due to a lack of energy reaching the
brain.
• A plasma glucose of more than 10 mmol/L exceeds the renal
threshold for glucose, which means that glucose will be present in the
urine. Osmotic diuresis then occurs. (1 mmol/L equals 18 mg/dl)
• The islets of Langerhans, located in the pancreas, contain glucose
receptors, and they secrete the hormone glucagon and insulin.
• These hormones are short-term regulators of plasma glucose levels
with opposite effects. In addition, their release can be influenced by
gastrointestinal hormones and autonomic nerves. 57
CONTROL OF PLASMA GLUCOSE
• Glucose receptors are also found in the ventromedial nucleus and
lateral areas of the hypothalamus. These are able to regulate appetite
and feeding, and they also indirectly stimulate the release of a variety
of hormones, including adrenaline, growth hormone, and cortisol, all
of which affect glucose metabolism.
• The hormones involved in glucose regulation target the liver, skeletal
muscle, and adipose tissue.

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INSULIN
• Insulin is a 51-amino-acid-residue peptide made up of an α- and a β-
chain linked by disulphide bonds. It has a half-life of 3-5 minutes and
it is metabolized to a large extent by the liver (40-50%), but also by
the kidneys and muscles.
• In response to high blood glucose levels (as occurs after a meal), as
well as to glucosamine, amino acids, fatty acids, ketone bodies, and
sulphonylureas, the β-cells of the endocrine pancreas secrete insulin
along with a C-peptide.
• Insulin release is mediated by ATP-dependent potassium channels,
located in the membrane of the β-cells. These close in response to
elevated cytoplasmic ATP and decreased cytoplasmic ADP levels,
resulting in depolarization of the membrane. This triggers calcium
entry into the cell through voltage-dependent calcium channels, and
subsequent insulin release. 59
INSULIN
• Insulin release is inhibited by low blood glucose levels, growth
hormone, glucagon, cortisol, and sympathetic nervous system
activation.
• The insulin receptor consists of two α- and two β-subunits linked by
disulphide bonds. Insulin binds to the extracellular α-subunits,
resulting in the internalization of the receptor, and its subsequent
breakdown.
• The β-subunits display tyrosine kinase activity upon the binding of
insulin to the receptor. Autophosphorylation of the β-subunits ensues,
resulting in the phosphorylation of phospholipase C with subsequent
liberation of diacylglycerol (DAG) and inositol triphosphate (IP3).

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Table: Metabolic effects of insulin on fuel homeostasis:
Carbohydrates • Increase glucose transport
• Increase glycogen synthesis
• Increase glycolysis
• Inhibit gluconeogenesis
Fats • Increase lipoprotein lipase activity
• Increase fat storage in adipocytes
• Inhibit lipolysis (hormone-sensitive lipase)
• Increase hepatic lipoprotein synthesis
• Inhibit fatty acid oxidation
Proteins • Increase protein synthesis
• Increase amino acid transport

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DIABETES MELLITUS
• Diabetes mellitus (DM) involves an inability to regulate plasma
glucose within the normal range. It is characterized by an absolute or
relative insulin deficiency, leading to
• hyperglycaemia,
• glycosuria (glucose in urine)
• polyuria (production of large volumes of dilute urine) associated
with cellular potassium depletion, and
• polydipsia (intense thirst).
• There are two forms of diabetes mellitus: insulin-dependent and non-
insulin-dependent.
• The long-term consequences of both types of diabetes are similar,
and include increased risk of cardiovascular and cerebrovascular
events, peripheral and autonomic neuropathy, nephropathy, and
retinopathy. 63
DIABETES MELLITUS
Insulin-dependent DM (IDDM) - (Type 1)
• In IDDM, pancreatic β-cells are destroyed by an autoimmune T-cell
attack. This leads to a complete inability to secrete insulin, and
ketoacidosis is a problem.
• Some untreated IDDM patients have a plasma glucose concentration
of up to 100 mmol/L due to insulin deficiency. In this situation,
lipolysis is increased, as is the production of ketone bodies from fatty
acids. This leads to ketonuria and metabolic acidosis; body fluids
become hypertonic, resulting in cellular dehydration, and eventually
in hyperosmolar coma.
• IDDM is apparent at a young age.

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DIABETES MELLITUS
Non-insulin-dependent DM (NIDDM) – (Type 2)
• In NIDDM, insulin is often secreted as on average 50% of the β-cells
remain active, though there is also peripheral resistance to insulin.
• Unlike IDDM, this is relatively common in all populations enjoying
affluent lifestyle.
• The prevalence of NIDDM increase with age and the degree of
obesity.
• Ketosis is not a feature of NIDDM as ketone production is suppressed
by the small amounts of insulin produced by the pancreas.
Hyperosmolar non-ketone coma is the NIDDN equivalent to
ketoacidosis, and it can be fatal if untreated, though it responds
rapidly to fluids and insulin.
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DIABETES MELLITUS
Secondary DM
• Not to be confused with NIDDM, secondary diabetes mellitus
accounts for less than 2% of all new cases of diabetes, and it is most
commonly due to pancreatic disease (pancreatitis, carcinoma, cystic
fibrosis), endocrine disease (Cushing’ syndrome, acromegaly), or
drug-induced (thiazide diuretics or corticosteroid therapy).

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Table: Features of insulin-dependent and non-insulin-dependent diabetes
mellitus
IDDM NIDDM
0.5% prevalence in adults 5% prevalence in adult
Juvenile onset (< 30 years) Maturity onset (> 30 years)
Absolute lack of insulin Relative lack of, or excess, insulin
Not associated to obesity Often associated with obesity
Insulin therapy Oral agents (sulphonylureas)
usually suffice
Ketoacidosis frequent Ketoacidosis uncommon
Linked to the presence of islet cell No known autoimmune origin
antibody and genetic markers
(HLA antigens)
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MANAGEMENT OF DIABETES MELLITUS
A. INSULIN
• The aim of exogenous insulin preparations is to mimic basal levels of
endogenous insulin and meal-induced increases in insulin.
• Insulin preparations can be human (recombinant), porcine, or bovine
in origin, and they are available as short-, intermediate-, and long-
acting preparations.
• Short-acting insulin are soluble. These preparations most resemble
endogenous insulin, and they can be given intravenously in hospital.
The rapid-acting insulins (aspart and lispro) have a faster onset and
shorter duration of action than the traditional short-acting insulin.

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INSULIN
• Intermediate- and long-acting insulins are not as soluble as the short-
acting ones. Their solubility is decreased by precipitating the insulin
with zinc or protamine (a basic protein), which prolongs their release
into the bloodstream.
• The intermediate- and long-acting preparations include:
• Isophane insulin
• Biphasic isophane insulin
• Insulin zinc suspension
• Protamine zinc insulin

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INSULIN
Mechanism of action
• Insulin preparations mimic endogenous insulin.
Route of administration
• Insulin must always be given parenterally (intravenously, intramuscularly or
subcutaneously), as it is a peptide and thus destroyed in the gastrointestinal tract.
• Short-acting insulin is given intravenously in emergencies, but administration of
the insulin preparations in maintenance treatment is usually subcutaneous.
Indications
• Type 1 diabetes; type 2 diabetes uncontrolled by other means.
Adverse effects
• Local reactions and, in overdose, hypoglycaemia. Protamine can cause allergic
reactions. Rarely, there may be immune resistance.
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INSULIN
Therapeutic regime
The following regime are recommended depending on the patient:
• Short-acting insulin three times daily (before breakfast, lunch, and dinner)
and intermediate-acting insulin at bedtime.
• Short-acting insulin and intermediate-acting insulin mixture twice daily before
meals
• Short-acting insulin and intermediate-acting insulin mixture before breakfast,
short-acting insulin before dinner, and intermediate-acting insulin before
bedtime.
• Short-acting insulin and intermediate-acting insulin mixture before breakfast
is adequate for some NIDDM patents needing insulin.
• Preparation are now available that contains short- and intermediate-
and long-acting insulins, allowing the patient to inject themselves
only once at a time.
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INSULIN
Table: Insulin preparations (subcutaneous)

Insulin action Peak activity (h) Duration (h)

preparation
Rapid-acting Very rapid 0-2 3-4
insulin
Short-acting Rapid 1-3 3-7
insulin
Isophane insulin Intermediate 2-12 12-22

Insulin zinc Prolonged 4-24 24-28

suspension

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B. ORAL HYPOGLYCAEMICS
• The oral hypoglycaemics are administered orally, and like insulin, they
act to lower plasma glucose.
• The sulphonylureas and the biguanides are the main drugs use from
this class

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SULPHONYLUREAS
• Gliclazide, tolbutamide, chlorpropamide, and glibenclamide are
examples.
Mechanism of action
• Sulphonylureas are given for diabetes mellitus, in patients with
residual β-cell activity.
Contraindications
• Breastfeeding women, or people with ketoacidosis.
• Long-acting sulphonylureas (chlorpropamide, glibenclamide) should
be avoided in the elderly and in those with renal and hepatic
insufficiency, as these drugs can induce hypoglycaemia.

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SULPHONYLUREAS
Adverse effects
• Weight gain
• Sensitivity reactions, including rashes
• Gastrointestinal disturbances
• Headache
• Hypoglycaemia
Therapeutic regime
• Tolbutamide; 500 mg two or three times daily; duration of 6 hours
• Chlorpropamide; 100-250 mg daily; duration of 12 hours
• Glibenclamide; 2.5-15 mg daily; duration of 12 hours
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BIGUANIDES
• Metformin is the only drug in this class.
Mechanism of action
• Metformin increases the peripheral utilization of glucose, by
increasing uptake, and decreasing gluconeogenesis. To work,
metformin requires the presence of endogenous insulin; therefore,
patients must have some functioning β-cells.
Route: Oral
Clinical uses
• NIDDM where dieting and sulphonylureas have proved ineffective
Contraindications
• Hepatic or renal impairment (owing to the risk of lactic acidosis)
• Heart failure 76
BIGUANIDES
Adverse effects
• Anorexia, headache, nausea and vomiting, lactic acidosis, and
decreased B12 absorption.
Therapeutics regime
• Metformin is given at 500 mg two or three times daily.
• It can be used alone or with sulphonylureas.
• Metformin should be taken with or after food.

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ALPHA-GLUCOSIDASE INHIBITORS
• Acarbose is the only available drug in this class.
Mechanism of action
• Acarbose inhibits intestinal α-glucosidase, and it delays the
absorption of starch and sucrose.
Route
• Oral
Clinical uses
• Diabetes mellitus inadequately controlled by diet alone or in
combination with other oral hypoglycaemics.
Contraindications
• Pregnancy, breatfeeding, bowel disease
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ALPHA-GLUCOSIDASE INHIBITORS
Adverse effects
• Flatulence, diarrhea
Therapeutic notes
• Like metformin, acarbose is particularly useful in obese diabetic
patients.

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THIAZOLIDINEDIONES
• Rosiglitazone and pioglitazone belong to the thiazolidinediones.
Mechanism of action
• These agents are believed to reduce peripheral insulin resistance,
leading to a reduction in plasma glucose.
Route: Oral
Clinical uses
• Uncontrolled NIDDM.
Contraindications
• Hepatic impairment; history of heart failure.
Adverse effects
• GI disturbance, weight gain. Potentially liver failure.
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C. DIET AND FLUID REPLACEMENT
Dietary Control
• Dietary control is important for both IDDM and NIDDM.
• The diet should aim to derive its energy from the following
constituents, in the following amount:
• 50% carbohydrate (slowly absorbed forms).
• 35% fat.
• 15% protein.
• This regimen aims to reduce total fat intake, increase protein intake,
and increase the intake of high fibre foods, which slow the rate of
absorption from the gut.
• Simple sugars, as found in sweet drinks and cakes, should be avoided.
• Meals should be small and regular, thus avoiding large swings in blood
glucose levels. 81
C. DIET AND FLUID REPLACEMENT
Rehydration Therapy
• In the acute diabetic patient, the fluid deficit can be as high as 7-8 L.
Rehydration therapy is essential in order to regain fluid and electrolyte
balance, and this takes precedence over the administration of insulin.
• Untreated diabetic patients suffer from hyperkalaemia as potassium
requires insulin to enter cells. As soon as insulin is administered,
however, potassium follows glucose into cells, and hypokalaemia
becomes the danger. The rehydration fluid should, therefore, contain
potassium, and plasma potassium concentration should be measured
hourly.
• Diabetic patients are also at risk of metabolic acidosis due to excessive
ketone production. If the acidosis is severe (pH < 7.0), bicarbonate can
be administered intravenously, though evidence to support this is
weak. 82
HYPOGLYCAEMIA
• Hypoglycaemia is an uncommon presentation in the untreated diabetic
patient, though very common in those taking insulin and
sulphonylureas.
• The symptoms of hypoglycaemia are driven by the sympathetic nervous
system and include:
• Sweating
• Tremor
• Anxiety
• Altered consciousness
• The history may reveal the patient has not eaten as scheduled,
exercised, or taken too much insulin.

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HYPOGLYCAEMIA
• Management depends upon the consciousness of the patient.
• If the patient is alert, glucose can be given orally as a syrup, or as
simple sugar.
• If consciousness is altered, oral administration of glucose is dangerous,
and there is a risk of the patient aspirating. In this situation, glucose
should be administered intravenously, or glucagon can be given by
intramuscular or intravenous injection.

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MANAGEMENT OF
HYPOGLYCAEMIA
GLUCOSE (DEXTROSE MONOHYDRATE)
• Glucose is administered parenterally as dextrose monohydrate
Mechanism of action
• Dextrose mimics endogenous glucose, and it is utilized by cells.
Route: Intravenous
Clinical uses
• Hypoglycaemia, as part of rehydration therapy.
Contraindications
• Hyperglycaemia
Adverse effects
• Venous irritation and thrombophlebitis. Hypokalaemia may occur. 85
MANAGEMENT OF
HYPOGLYCAEMIA
GLUCAGON
• Glucagon is a polypeptide hormone, normally secreted by the pancreatic
α-cells
Mechanism of action
• Glucagon acts on the liver to convert glycogen to glucose, and to
synthesize glucose from non-carbohydrate precursors (gluconeogenesis).
The overall effect is to raise plasma glucose levels.
Route: Parenteral
Clinical uses
• Insulin-induced hypoglycaemia.

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MANAGEMENT OF
HYPOGLYCAEMIA
GLUCAGON
Contraindications
• Phaeochromocytoma
• Adverse effects
• Nausea, vomiting, diarrhoea, and hypokalaemia

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