Adrenergic Agonists

Department of Pharmacology
College of Medicine- University of
Kirkuk
2019-2020
 Adrenergic Agonists
The adrenergic drugs affect receptors
that are stimulated by norepinephrine or
epinephrine.
Some adrenergic drugs act directly on
the adrenergic receptor (adrenoceptor) by
activating it and are said to be
(sympathomimetic).
block the action of the neurotransmitters
at the receptors (sympatholytics).
 THE ADRENERGIC NEURON
 Adrenergic neurons release norepinephrine
as the primary neurotransmitter.
 These neurons are found in the central
nervous system (CNS) and also in the
sympathetic nervous system(ANS) where
they serve as links between ganglia and the
neuro-effector tissues.
 The adrenergic neurons and receptors,
located either presynaptically on the neuron
or postsynaptically on the effector organ, are
the sites of action of the adrenergic drugs.
Neurotransmission at adrenergic neurons
 Neurotransmission in adrenergic neurons
closely resembles that already described for
the cholinergic neurons. except that
norepinephrine is the neurotransmitter
instead of acetylcholine.
 The process involves five steps:
Synthesis
Storage
Release
Receptor binding of Norepinephrine
Removal of the neurotransmitter from the
synaptic gap.
 :Synthesis of norepinephrine
 Tyrosine is transported by a Na+- linked carrier into
the axoplasm of the adrenergic neuron, where it is
hydroxylated to dihydroxyphenylalanine (DOPA) by
tyrosine hydroxylase
 This is the rate-limiting step in the formation of
norepinephrine.
 DOPA is then decarboxylated by the enzyme dopa
decarboxylase (aromatic l-amino acid decarboxylase)
to form dopamine in the cytoplasm of the
presynaptic neuron.
 :Storage of norepinephrine in vesicles
 Dopamine is then transported into synaptic vesicles
by an amine transporter system that is also involved
in the reuptake of preformed norepinephrine.
 This carrier system is blocked by reserpine
Dopamine is hydroxylated to form norepinephrine
by the enzyme, dopamine β-hydroxylase.
 Synaptic vesicles contain dopamine or
norepinephrine plus adenosine triphosphate (ATP)
and β-hydroxylase as well as other co transmitters
 In the adrenal medulla, norepinephrine is
methylated to yield epinephrine, which is stored in
chromaffin cells along with norepinephrine.
 Release of norepinephrine
 An action potential arriving at the nerve
junction triggers an influx of calcium ions from
the extracellular fluid into the cytoplasm of the
neuron.
 The increase in calcium causes vesicles
inside the neuron to fuse with the cell
membrane and expel (exocytose) their
contents into the synapse.
 Drugs such as guanethidine block this
release.
 Binding to receptors
 Norepinephrine released from the synaptic vesicles
diffuses across the synaptic space and binds to either
postsynaptic receptors on the effector organ or to
presynaptic receptors on the nerve ending.
 The recognition of norepinephrine by the membrane
receptors triggers a cascade of events within the cell,
resulting in the formation of intracellular second
messengers that act as links (transducers) in the
communication between the neurotransmitter and the action
generated within the effector cell.
 Adrenergic receptors use both (cAMP) and
phosphatidylinositol cycle to transduce the signal into an
effect.
 Norepinephrine also binds to presynaptic receptors that
modulate the release of the neurotransmitter.
 Removal of norepinephrine
 Norepinephrine may:
 Diffuse out of the synaptic space and enter the general
circulation
 Be metabolized (Methylated) by postsynaptic cell
membrane–associated Catechol O- Methyl Transferase
(COMT) to inactive metabolite in the synaptic space and
Oxidized by MAO
 Be recaptured by an uptake system (NET) that pumps the
norepinephrine back into the neuron.
 The uptake by the neuronal membrane involves a
sodium- or potassium-activated ATPase that can be
inhibited by tricyclic antidepressants, such as imipramine,
or by cocaine
 Uptake of norepinephrine into the presynaptic neuron is
the primary mechanism for termination of norepinephrine’s
effects.
 Adrenergic receptors (adrenoceptors)
 several classes of adrenoceptors can be
distinguished pharmacologically.
 Two families of receptors:
α and β, were initially identified on the basis of
their responses to the adrenergic agonists
epinephrine, norepinephrine, and isoproterenol.
 A number of receptor subtypes:
 α1 and α2 Receptors: The α- adrenoceptors show a
weak response to the synthetic agonist isoproterenol,
but they are responsive to the naturally occurring
catecholamines epinephrine and norepinephrine
 For α receptors, the rank order of potency is
epinephrine ≥ norepinephrine >>
isoproterenol.
 The α- adrenoceptors are subdivided into
two subgroups, α1 and α2, based on their
affinities for α agonists and blocking drugs.
 For example, the α1 receptors have a higher
affinity for phenylephrine than do the α2
receptors.
 Conversely, the drug clonidine selectively
binds to α2 receptors and has less effect on
α1 receptors.
Type of adrenergic Receptors
 α1 Receptors
 1-These receptors are present on the
postsynaptic membrane of the effector
organs and mediate many of the classic
effects, originally designated as α adrenergic,
involving constriction of smooth muscle.
 Activation of α1 receptors initiates a series of
reactions through the G protein activation,
resulting in the generation of (IP3) &(DAG)
from phosphatidylinositol
 α2 Receptors
 located primarily on:
 presynaptic nerve endings
 on other cells, such as the b cell of the pancreas
 on certain vascular smooth muscle cells

*Control adrenergic neuromediator and insulin output, respectively.

These are Further subdivided into:
 Alpha 1 A, B,C, and D
 Alpha 2 A, B and C
 Alpha 1 Adrenoceptors:
 They're present on postsynaptic membrane of effecter organ.
 This extended classification is necessary for understanding the selectivity of
some drugs.
 For example, tamsulosin is a selective α1A antagonist that is used to
treat benign prostate hyperplasia.
 drug is clinically useful because it targets α1A receptors found primarily in
the urinary tract and prostate gland.
 Their function: α1
 On Vessels: cause smooth muscle
contraction so there will be
Vasoconstriction of blood vessels found in
skin, splanchnic vessels and skeletal
muscles, this will cause pallor and increase
peripheral vascular resistance.
 On Eyes: contraction of radial muscles of
the iris this will lead to dilation of the pupil
Mydriasis.
contraction of smooth muscles of Vas
Deferens and seminal vesicle ejaculation
 Pregnant uterus contraction low
placental blood flow.

 Skin: contraction of Pilo erector muscle

goose flesh skin erection of hair.

 Sweat glands: are of two types:

 Apocrine gland: stimulation of this gland
leads to increased secretion
 Acrine gland or thermoregulatory gland has
muscarinic receptor even though they’re
innervated by adrenergic nerves.
 Metabolic functions: the effect on the liver
 stimulation of lipolysis
 Gluconeogenesis
 Glycogenolysis
 K+ release

• Heart: increase force of contraction ( not so

important).
 Mechanism of Activation of alpha 1
:receptors
 Stimulation of alpha 1 receptor
Activation of a G-coupling protein
Activation of phospholipase C
It acts on phosphotidyl inositol biphosphate
 The release of :
*Diacylglycerol (DAG)
*Inositol triphosphate (IP3)
Major effects mediated by α1adrenoceptors

 Vasoconstriction
 Increased peripheral resistance
 Increased blood pressure
 Mydriasis
 Increased closure of internal sphincter
of the bladder
 :Alpha 2 Adrenoceptors
Location
1-Presynaptic receptor on adrenergic nerve
terminal(auto receptor),platelets, lipocytes and
smooth muscle
Function
1-They inhibit the release of noradrenaline
2-Presynaptic receptor are present on cholinergic
nerve terminal, they are called “Hetero
receptors’’
On GIT
The relaxation of GIT smooth muscles is probably
due to Presynaptic inhibition of
parasympathetic activity (because of the
presence on alpha 2 receptors on cholinergic
terminal on GIT)
3- Postsynaptic CNS adrenoceptors are present in
the brain, e.g.: brain stem vasomotor center
Decrease sympathetic stimulation.
Some drugs used as Antihypertensive act on
these receptors for example “Clonidine”
4-On the beta cells of pancreas
Alpha 2 receptors are inhibitory, they decrease
the insulin release.
5-On platelets
They produce aggregation

6-On vascular smooth muscles

Contraction
7-On fat cells
Inhibition of lipolysis
 Mechanism of Activation of alpha 2
:receptors
 Alpha 2 receptors (with the help of
inhibitory regulatory G protein) inhibit
adenyl cyclase enzyme activity causing
decrease in intracellular cAMP.
 In addition there are other mechanisms
include:
 Activation of Potassium channels.
 Closing of Calcium channel
 Major effects mediated by α2
adrenoceptors
 Inhibition of norepinephrine release
 Inhibition of acetylcholine release
 Inhibition of insulin release
 β Receptors
 β Receptors: exhibit a set of responses different from those of the α
receptors. These are characterized by a strong response to Isoproternol,
with less sensitivity to epinephrine and norepinephrine.

 β1 receptors have approximately equal affinities for epinephrine and

norepinephrine
 whereas β2 receptors have a higher affinity for epinephrine than for
norepinephrine.

 Thus, tissues with a predominance of β2 receptors (such as the

vasculature of skeletal muscle) are particularly responsive to the
hormonal effects of circulating epinephrine released by the adrenal
medulla

 Binding of a neurotransmitter at any of the three β receptors results in

activation of adenylyl cyclase and, therefore, increased concentrations of
cAMP within the cell.
 For β receptors, the rank order of potency is isoproterenol > epinephrine
> norepinephrine.
 Major effects mediated by β1
.adrenoceptors

 Tachycardia
 Increased lipolysis
 Increased myocardial contractility
 Increased release of renin
 :Beta1 receptors
 Location
 Heart: increased Automaticity of SA node with
increased heart rate (i.e. positive chronotropic
effect).
 Increased conductivity (velocity) in conducting
tissues including AV node (i.e. positive
dromotropic effect).
 Increased excitability of AV node and muscles.
 predisposing to arythmias.
 and increased Oxygen consumption.
 Decreased Refractory Period.
 Kidney:Stimulation of Beta1 receptors on
juxtaglomerular cells will increase Renin
release (Renin converts Angiotensinogen
into Angiotensin I )
 Nerves: Presynaptic adrenergic and
cholinergic terminals.
 :Beta2 Receptors
 Distribution of receptors: Adrenergically
innervated organs and tissues tend to have a
predominance of one type of receptor. For
example, tissues such as the vasculature to
skeletal muscle have both α1 and β2
receptors, but the β2 receptors predominate.
 Other tissues may have one type of receptor
exclusively, with practically no significant
numbers of other types of adrenergic
receptors. For example, the heart contains
predominantly β1 receptors.
Major effects mediated by β2
adrenoceptors
 Vasodilatation
 Decreased peripheral resistance
 Bronchodilation
 Increased muscle and liver
Glycogenolysis
 Relaxed uterine smooth muscle
 Increased release of glucagons
 Location&Action
 Blood Vessels: Vasodilation of skeletal muscles, renal
and visceral vessels. Decreased total peripheral
resistance (TPR).
 Lung:Bronchodilation
 GIT: Smooth muscles in the intestinal wall are relaxed
 Genitourinary system: Relaxation of Bladder wall.
Pregnant uterus relaxation delay of premature labour
 Skeletal muscles:Activation of Beta2 receptors
Tremor and increased K+ by skeletal muscles
Hypokalemia
 Mast Cells: Decreased Histamine release.
 Liver: Increased Gluconeogenesis and
GlycogenolysisThis will lead to Hyperglycemia.
 Pancreas: Increase release of Glucagon lead to
Hyperglycemia
 Heart: has beta2 but much lesser than other organs.
 Mechanism of Activation of Beta
:Receptors
 Activation of all subtypes of Beta receptors activation of
adenyl cyclase increased conversion of ATP to cAMP,
both are mediated by protein Gs (stimulatory).
 cAMP is the major 2nd messenger of beta receptor activation
 In the heart, the activation of beta receptors increased influx of
calcium across cell membrane and its sequestration from
sarcoplasmic reticulum inside the cell.
 Relaxation of smooth muscle may involve the Phosphorylation
(inactivation) of myosin light chain kinase.
 Beta activation increase cAMP Phosphorylation of myosin
light chain kinase inactive form vasodilation and relaxation
 Nitrate increase cGMP dephosphorylation of myosin light
chain kinase inactive form relaxation.
 :Dopamine Receptors
 They're of 5 subtypes arranged in two
families:
Family (1) :D1 and D5
Family (2) :D2, D3 and D4

• Stimulation of D1 family stimulation of adenyl

cyclase smooth muscle relaxation renal
vessels dilation
• Stimulation of D2 family inhibit adenylyl
cyclaes and open potassium channels
modulate transmitter release
:Desensitization of receptors
 Prolonged exposure to the catecholamine
reduces the responsiveness of these receptors,
a phenomenon known as desensitization.
 Three mechanisms have been suggested:
1-sequestration of the receptors
2-down-regulation
3-inability to couple to G protein, because the
receptor has been phosphorylated on the
cytoplasmic side by either of protein kinase A or
beta adrenergic receptor kinase (BARK).
 :Supersensitivity:occure when there is
 Depletion of Noradrenaline in synaptic cleft
by receptors
 Cut off adrenergic nerve supply (de
innervation)
 Up-regulation: increase the no. of receptors
to that drug then when suddenly he stops
using that drug the effect will be much greater
than before even before the began to use the
drug.
Note:To avoid such cases we're "Tapering"
the drug. I.e. gradually decrease the doses
till stopping the drug.
Adrenergic Agonists
 :Adrenergic Agonists

 According to chemical structure.

 According to receptor sensitivity.
 According to their mode of action.
 1- According to chemical structure:
A- Catecholamine:
They're sympathomimetic amine that contains
3,4-dihydroxybenzene group like adrenaline,
Noradrenaline, dopamine, Dobutamine and
Isoprenaline.
 Both Dobutamine and Isoprenaline are
synthetic
Characteristics:
*Show the highest potency
*Shortest half-life in pharmacology (2 min)
*Do not readily penetrate into CNS
*Metabolized by COMT (postsynaptically and
in the gut wall), MAO (intraneuronally and
in the mitochondria of liver cells and gut
wall cells).
 They're ineffective if given orally except
Isoprenaline.
 B- Non-Catecholamine:
 They're phenylisopropylamines compounds lack the
catechol hydroxyl groups, They include:
 phenylephrine,
 ephedrine and
 amphetamine group.

 Characteristics:
 Not metabolized by COMT and they're poor substrates for MAO
so they are given ORALLY.

 Have prolonged duration of action.

 Have increased lipid solubility
 Have greater access to CNS due to lipid solubility and they may
act indirectly producing unwanted side effects.
 :According to receptor sensitivity -2
 Alpha-agonist
 Beta-agonist
Catecholamine:
Noradrenaline:
 Mainly affects alpha receptors.
 Has weak effect on Beta1 receptors
 Has no effect on Beta2 receptors.
 So action on alpha1 = alpha2 and beta1 >> beta2
Adrenaline: Interacts with both alpha and beta receptors
At low doses: Beta effect (vasodilation) on the vascular
system predominates.
At Higher doses: Alpha effect (vasoconstriction) is
strongest.
So action on alpha1 = alpha2 and beta1 = beta
 :Isoprenaline
 Predominantly stimulated beta adrenergic receptors, it's
action on alpha receptors is insignificant.
So; beta1 = beta2 >>>>>>>> alpha
Comparison of effect of Noradrenaline, adrenaline and
Isoprenaline:

 Heart rate :
*Adrenaline & Isoprenaline increase heart rate.
*Noradrenaline decreases heart rate due to increased blood
pressure by stimulating the baroreceptors and due to intense
vasoconstriction.
*If atropine is given before Noradrenaline, or the vagus is cut ,or
the patient is in shock then there will be tachycardia.
Note: the Baroreceptors reflex predominates over noradrenaline
effects.
 Force of contraction: ( ↑ contractility →
↑ SV )
 Noradrenaline, Adrenaline and Isoprenaline
increase contractility and stroke volume.
 The reflex compensation doesn't affect the
positive inotropic effect of Noradrenaline

 Cardiac output :
 Adrenaline and Isoprenaline increase
cardiac output .
 Noradrenaline has little or no effect on
cardiac output (due to weak beta1 effect)
 Myocardial oxygen consumption :
Increase with all (least with Noradrenaline).
Conductivity :
Increased by all and may cause arrhythmias.
 Blood vessels of skeletal muscles :
 Noradrenaline causes constriction (i.e. increase
total peripheral resistance TPR) through αlpha
action .
 Adrenaline & Isoprenaline dilate vessels going to
the skeletal muscles & liver also . the effect,
therefore, is a decreasing in TPR more evident
with Isoprenaline. (β₂ action).
 Skin blood vessels:
 Noradrenaline & Adrenaline constrict skin and mucus
membrane arterioles (αlpha action).
 Isoprenaline has no effect because ??

 Renal blood vessels :The same of the skin.

 Veins :
 Adrenaline & Noradrenaline produce vasoconstriction
which leads to increased venous return .
 Isoprenaline produces dilation of veins which leads to
decreased venous return.
 Veins contain α and β₂ receptors (alpha are more than
beta).
 Blood pressure :
 Noradrenaline increases systolic and diastolic blood
pressure (alpha action).
 Adrenaline increases systolic blood pressure (Beta1) with
slight decrease in diastolic blood pressure (Beta2
vasodilation).
 The mean blood pressure (MBP) = (2 x diastolic + systolic
blood pressure ⁄3 ) may be slightly increased because the
increase in systolic pressure is much more than the decrease
in diastolic pressure.
 So Adrenaline increases the mean blood pressure but the
increase is less with Noradrenaline.

 Isoprenaline may slightly increase systolic pressure

but it greatly reduces the diastolic pressure & the
mean arterial pressure.
 Capillaries:
 Adrenaline reduces capillary permeability due
to widening of the endothelial cells that
decreases the pores.
 Noradrenaline and Isoprenaline have no effect.

• Bronchiolar smooth muscle :

Adrenaline and Isoprenaline cause powerful
bronchodilation (β₂ effect).
 Noradrenaline has no effect, because??
 Gastrointestinal Tract:
 Noradrenaline (αlpha₂ action) , Adrenaline (alpha₂
and beta₂ action) and Isoprenaline (βeta₂ action)
cause relaxation .
 Pregnancy uterus :
 Noradrenaline (alpha action ) causes
contraction.
 Adrenaline and Isoprenaline (beta₂ action)
causes relaxation.
 Radial muscles of the iris :
 Adrenaline (alpha₁ action) causes contraction
of radial muscles (mydriasis).
 Noradrenaline has little effect because it is not
absorbed (causes severe vasoconstriction).
 Isoprenaline has no effect.
 Blood glucose: (increased by all)
 Adrenaline has significant hyperglycemic effect because
it :
 increases glycogenolysis in the liver (beta₂ effect)
 increases the release of glucagon (beta₂ effect)
 Decreases the insulin (alpha₂ effect on Beta cells of
Pancreas).
 Isoprenaline cause increase in blood sugar (β₂
effect).
 Noradrenaline may increase blood sugar.
 Lipolysis:
 Adrenaline initiates Lipolysis (through its agonist activity
on B₃ receptors).
 The increased Lipolysis induced by Isoprenaline is not
clinically significant.
 Lipolysis is least increased by Noradrenaline.
 Serum pottasium k:
 Adrenaline & Isoprenaline lead to hypokalemia because
the biochemical pump that shifts k + into the cells is
activated by beta₂ agonists.
 However Noradrenaline may cause hyperkalemia
through alpha₁ effect.
 Release of mediators from mast cells :
 The release is inhibited by Adrenaline & Isoprenaline
(beta₂ effect)
 Noradrenaline has no effect.
 Muscle tremor :
 Adrenaline & Isoprenaline cause muscle tremor (beta₂
effect) while it less with Noradrenaline.
Note: Adrenaline constricts skin blood vessels and dilates
skeletal muscle blood vessels.
:According to their mode of action -3

• 1- Direct acting agonists. Ex: (catecholamine and

phenylephrine).
 2- Indirectly acting agonists. Ex: (Amphetamine,
Tyramine). It interacts with MAO inhibitors
causing hypertensive crisis.
 These drugs are taken up into Presynaptic neurons
and cause the release of NA
 3-Mixed action some agonist have both modes of
action, they can directly stimulate Adrenoceptors and
release NA from adrenergic neurons (indirect action).
Ex: Ephedrine (mainly direct) Metaraminol (mainly
indirect)
 A- Direct acting adrenergic agonist
Direct-acting agonists bind to adrenergic
receptors on effector organs without interacting
with the presynaptic neuron. As a group, these
agents are widely used clinically.
 :Therapeutic uses of Noradrenaline
 To treat shocks:
To treat Hypovolemic shock because it increases
vascular resistance which leads to increased
blood pressure ,but it cause decrease blood flow
to the kidney. *dopamine is better
* Nor. is given by I.V. infusion 2- 4 mg⁄min .
 As a local vasoconstrictor:
Mixed with local anesthetic to prolong its action
because it delays its absorption into the blood
stream. However Adrenaline is preferred.
• Noradrenaline is not used as nasal decongestant
because it is not absorbed (it causes severe
vasoconstriction).
 Epinephrine
 In the adrenal medulla, norepinephrine is methylated to
yield epinephrine, which is stored in chromaffin cells along
with norepinephrine.
 On stimulation, the adrenal medulla releases about 80%
epinephrine and 20% norepinephrine directly into the
circulation.
 At low doses, β effects (vasodilation) on the vascular
system predominate,
 whereas at high doses, α effects (vasoconstriction) are
the strongest.
 :Therapeutic uses of Adrenaline
 Anaphylactic shock :
(Type І) hypersensitivity reaction in response to
allergens that cross-link IgE fixed to mast cells and
basophiles leading to degeneration and release of
histamine and other mediators.
 Adrenaline is the drug of choice in anaphylactic attacks.
0.2-2.5 mg IM/SC q5-15 min (1:1000 solution; 1mg/ml).
 Adrenaline is given intramuscularly or intravenously
(should only be done in patients who are profoundly
hypotensive or are in cardiopulmonary arrest refractory
to volume resuscitation and several epinephrine
injections) in patient with cardiac arrest .
 It acts as physiological antagonist to histamine.
Note:Drugs of Anaphylactic Shock: (Adrenaline,
Corticosteroids and anti-histamines).
 Acute asthma :
In the presence of bronchoconstriction, the
respiratory exchange is greatly improved within
few minutes after subcutaneous administration
of Adrenaline (beta₂ action).
 Glaucoma :
 Adrenaline solution may be used topically to
reduce(IOP) in open angle glaucoma.
 It reduces the production of aqueous humor by
vasoconstriction of the ciliary body blood
vessels and by enhanced outflow of aqueous
humor.
 In closed angle glaucoma mydriasis (including
Adrenaline)are contraindicated .
 with Local anesthetics :
 Local anesthetic solution usually contains
1:100,000 adrenaline.
The effect is to greatly increase the duration of
local anesthesia by producing vasoconstriction
at the site of injection.
Adrenaline controls bleeding during
surgery(Vasoconstriction as in dental
extraction).
 Epistaxis: very weak solution of Adrenaline
can also be used topically to vasoconstrict
mucus membranes to control oozing of
capillary blood.
 Cardiac arrest: Adrenaline is given by
intracardiac injection.
Epistaxis
:Pharmacokinetics
 Epinephrine has a rapid onset but a brief duration of
action t½ of 2 minutes (due to rapid degradation).
 The preferred route is intramuscular (anterior thigh)
due to rapid absorption. In emergency situations,
epinephrine is given intravenously (IV) for the most
rapid onset of action.
 It may also be given subcutaneously, by
endotracheal tube, and by inhalation
 It is rapidly metabolized by MAO and COMT, and the
metabolites metanephrine and vanillylmandelic acid
are excreted in urine therefore, they are given in
continuous I.V. infusion.
 :Therapeutic uses of Isoprenaline

 Complete heart block : (Stokes –Adams attack)

refers to a sudden, transient episode of syncope
 Beta blockers poisoning : Isoprenaline is used
as an antidote.
 Acute asthma: Isoprenaline is now rarely used
as bronchodilator because it's not selective and
has side effects.
Common adverse effects of
: catecholamine
 CNS disturbances: anxiety, insomnia,
headache and tremor.
 Cardiovascular disturbances: palpitation,
cardiac arrhythmias, pulmonary edema,
hypertension & sometimes cerebral
hemorrhage.
 Isoprenaline causes hypotension ,
Noradrenaline may cause tissue necrosis.
 Contra indication of Adrenaline and
:Isoprenaline
 Angina pectoris (due to increased O2
consumption).
 Cardiac arrhythmias.
 Thyrotoxicosis
 With halogenated general anesthetics
because they sensitize the heart to
catecholamine.
 Patients taking tricyclic antidepressant
TCA.
 Dopamine
 Dopamine activates D₁ receptors in peripheral
mesenteric and renal vascular beds, which leads to
Vasodilation.
 The activation of Presynaptic D₂ receptors on
adrenergic neurons , which suppresses Nor. release,
contributes to these effect (renal Vasodilation) .
 A continuous I.V. infusion of dopamine 2-5 mg⁄kg⁄min
causes increased renal blood flow, by activation of
dopaminergic receptors (mainly D₁).
 As the dose raises 5-15 mg⁄kg⁄min, dopamine activates
beta receptors in the heart with tachycardia and
increased contractility and cardiac output. It causes
increase in total peripheral resistance.
 Higher doses more than 15 mg⁄kg⁄min can cause
vasoconstriction and hypertension by activating alpha
receptors
:Therapeutic uses of dopamine

1- Shocks : dopamine is the drug of choice

for shock (hypovolemic) because:
 it raises blood pressure by stimulating the heart (beta₁
action).
 it enhances perfusion of the kidney and Splanchnic
areas, enhances GFR and causes Na+ diuresis.

2. Congestive heart failure: is an inability of

the heart to provide sufficient pump action to
distribute blood flow to meet the needs of the
body.
 : Adverse effects

 An overdose of dopamine produces the same

effects as sympathetic stimulation.
 Arrhythmias
 Angina worsening , hypertention
 tachycardia
 Nausea, Vomiting (because of the
stimulation of chemoreceptors triggers
 Dobutamine : (works on heart more
.than vessels)

 It's a synthetic direct acting catecholamine,

that is the beta₁ receptors agonist.
 It's available as racemic mixture.
 It stimulates the heart with few vascular
effects (beta₁ action).
 increases cardiac output with little
tachycardia and doesn't significantly
elevate O₂ consumption of myocardium
 : Therapeutic uses of Dobutamine

 Congestive heart failure.

 Shock: in patient with ischemic heart
diseases ??
 Fenoldopam
 Is an agonist of peripheral dopamine D1 receptors.
It is used as a rapid-acting vasodilator to treat
severe hypertension in hospitalized patients,
acting on coronary arteries, kidney arterioles, and
mesenteric arteries.
 It undergoes extensive first-pass metabolism and
has a 10-minute elimination half-life after IV
infusion.
 Headache, flushing, dizziness, nausea, vomiting,
and tachycardia (due to vasodilation) may be
observed with this agent.
 Oxymetazoline
 Is a direct-acting synthetic adrenergic
agonist that stimulates both α1- and α2-
adrenergic receptors.
 Oxymetazoline is found in many over-the-
counter (short-term uses):
nasal spray decongestants,
 as well as in ophthalmic drops for the
relief of redness of the eyes associated
with swimming, colds, and contact lenses.
Oxymetazoline directly stimulates α
receptors on blood vessels supplying the nasal
mucosa and conjunctiva, thereby producing
vasoconstriction and decreasing congestion.
 It is absorbed in the systemic circulation
regardless of the route of administration and may
produce nervousness, headaches, and trouble
sleeping.
 Local irritation and sneezing may occur with
intranasal administration.
 Rebound congestion and dependence are
observed with long-term use.
 Phenylephrine
 Is a direct-acting, synthetic adrenergic drug that
binds primarily to α1 receptors.
 Phenylephrine is a vasoconstrictor that raises
both systolic and diastolic blood pressures.
 It has no effect on the heart itself but, rather,
induces reflex bradycardia when given
parenterally.
 The drug is used to treat hypotension in
hospitalized or surgical patients (especially those
with a rapid heart rate).
 Large doses can cause hypertensive headache
and cardiac irregularities.
Phenylephrine acts as a nasal
decongestant when applied topically or
taken orally.
 Phenylephrine has replaced
pseudoephedrine in many oral
decongestants, since pseudoephedrine
has been misused to make
methamphetamine.
 Phenylephrine is also used in
ophthalmic solutions for mydriasis.
 Clonidine
 Is an α2 agonist that is used for the treatment of
hypertension.
 It can also be used to minimize the symptoms that
accompany withdrawal from opiates, tobacco smoking, and
benzodiazepines.
 Clonidine acts centrally on presynaptic α2 receptors to
produce inhibition of sympathetic vasomotor centers,
decreasing sympathetic outflow to the periphery.
 The most common side effects of clonidine are
lethargy, sedation, constipation, and xerostomia.
 Abrupt discontinuance must be avoided to prevent rebound
hypertension.
 Midodrine
 Is a prodrug that is enzymatically hydrolyzed to
desglymidodrine, a selective α1-receptor agonist.
 The peak concentration of desglymidodrine is
achieved about 1 hour after midodrine is
administered orally.
 The primary indication for Midodrine is the
treatment of orthostatic hypotension, typically due
to impaired autonomic nervous system function.
 Although the drug has efficacy in diminishing the
fall of blood pressure when the patient is
standing, it may cause hypertension when the
subject is supine.
B- Mixed acting adrenergic agonist
 :Ephedrine
 Non catecholamine, mixed action (mainly indirect). It is a plant
alkaloid , now it is made synthetically.
: It differs from adrenaline in the following
 It is a mixed action adrenergic agent.
 release stored noradrenaline from nerve endings (indirect)
 stimulate alpha & beta receptors (direct).
 It is about 100 times less potent than adrenaline.
 Has along duration of action? (t½ = 4 hours).
 Excellent absorption orally
 Penetrates to CNS causing mild stimulation ( ↑ alertness
,↓fatigue).
 Raises both systolic and diastolic blood pressure. (like Nor.)
 While adrenaline ↑ systolic & ↓ diastolic (slightly).
 Tachyphylaxis occurs.
 : Therapeutic uses
 As a presser agent (to raise blood pressure).
 As a nasal decongestant.(while Nor. is not)
 As a mydriatic agent. (alpha₁ action)
 Chronic treatment of asthma ).(it is used only in
chronic cases due to its slow action). acute→
Subcutaneous administration of Adrenaline.
 Incontinence by alpha₁ receptors.
 Heart block thus enhances contractility. (beta
action)
 Myasthenia gravis : ephedrine improves motor
function??
 : Adverse effects

 Tachycardia
 Arrhythmia
 Hypertension
 Worsening angina
 Tremor
 Hyperglycemia
Indirect acting adrenergic agonist
 Amphetamine
(non catecholamine, indirect action)
Action and adverse effects
1- CNS : it has a marked central stimulatory
action leads to ↑ alertness (euphoria), ↓
fatigue , depress appetite and insomnia
it may causes weakness , delirium , tremor ,
dizziness , panic states and suicidal
tendencies
 In higher doses it causes convulsions .
Chronic use produces a state of psychosis
resembles an acute schizophrenic attack.
2- Sympathetic nervous system
It acts indirectly through noradrenaline
release causing:
A) Hypertension (from α effect on
vasculature “↑PR” & β effect on heart
“↑CO” ).
B) Cardiac arrhythmias
C) Anginal pains
D) Headache
E) Excessive sweating
 : Therapeutic uses

 Factors that limit the therapeutic usefulness

of amphetamine include:
psychological and physical dependence
and development of tolerance to euphoric and
anorectic effects with chronic use
 attention deficit syndrome
 Narcolepsy
 Anorexiant
 Depression
 Note: there are three drugs similar to
amphetamine:
 Methamphetamine (very similar to Amphetamine).
Methylphenidate : (Amphetamine derivative)used
in children with attention deficit syndrome.
 Hydroxyamphetamine : used to differentiate
between preganglionic and postganglionic lesions
(Horner΄s syndrome : loss of sympathetic
stimulation due to destruction of the superior
cervical sympathetic ganglion).
 Anorexigenic drugs:
Amphetamine : has temporary effect , it causes
tolerance and antagonizes antihypertensive drugs.
 fenfluramine and dexfenfluramine : it causes
serotonin release and inhibited reuptake and also
stimulated (5-HT) receptors. → serotonin acts on
satiety center .
→ unfortunately, this drug induces pulmonary
hypertension and valvular lesion were reported.
 Tyramine
Is not a clinically useful drug, but it is important because it is
found in fermented foods, such as aged cheese and Chianti
wine.It is a normal by-product of tyrosine metabolism.

 Normally, it is oxidized by MAO in the gastrointestinal tract,

but, if the patient is taking MAOIs, it can precipitate serious
vasopressor episodes.

 Like amphetamines, tyramine can enter the nerve terminal

and displace stored norepinephrine. The released
catecholamine then acts on adrenoceptors.
 Cocaine
 Is unique among local anesthetics in having the ability to block
the sodium-chloride (Na+/Cl-)-dependent norepinephrine
transporter required for cellular uptake of norepinephrine into
the adrenergic neuron.
 Consequently, norepinephrine accumulates in the synaptic
space, resulting in enhanced sympathetic activity and
potentiation of the actions of epinephrine and norepinephrine.
Therefore,
 small doses of the catecholamines produce greatly magnified
effects in an individual taking cocaine.
 In addition, the duration of action of epinephrine and
norepinephrine is increased.
 Like amphetamines, it can increase blood pressure by α1
agonist actions and β stimulatory effects.