ADRENERGIC AGONISTS

Adrenergic agonists
• The adrenergic agonists are also called
adrenomimetic or sympathomimetic
• They affect receptors that are stimulated by
noradrenaline and adrenaline.
• The adrenomimetic drugs mimic the effects of
adrenergic nerve stimulation on sympathetic
effectors.
• The adrenomimetic drugs can be divided into
two major groups on the basis of their chemical
structure, the catecholamines and the
noncatecholamines.
 Adrenergic agonists
 The catecholamines include noradrenaline,
adrenaline, and dopamine, all of which are
naturally occurring, and several synthetic
substances, the most important of which is
isoproterenol and dobutamine.
 Non-catecholamine are
Phenylephrine ,terbutaline, clonidine,
salbutamol, ephedrine, and ritodrine.
 Catecholamines
• The catecholamines share the following properties:
 High potency in activating α- and β-receptors.
 Rapid inactivation by COMT postsynaptically and
MAO intraneuronally.
 The catecholamines have only a brief duration of
action when given parenterally.
 They are ineffective when given orally.
 Poor penetration into the CNS because
catecholamines are polar substances.
 Non-catecholamines
• The non-catecholamines share the following
properties:
 The non-catecholamines have longer half-
lives, since they are not inactivated by COMT
and MAO.
 Increased lipid solubility of many non-
catecholamines permits greater oral
administration and access to the CNS.
 Mechanism of Action
• Adrenomimetic drugs produce responses by
interacting with the adrenoceptors on effectors
cells (α1-, α2-, β1-, or β2).
• Adrenomimetic drugs vary in their affinities for
each subgroup of adrenoceptor:
• Adrenaline has a high affinity for all adrenoceptors
(α1-, α2-, β1-, or β2-receptors).
• Isoproterenol has high affinity for β1and β2.
• Noradrenaline has a high affinity for α and
β1adrenoceptor, but a relatively low affinity for β2-
receptors.
 Adrenomimetic drugs
• Adrenomimetic drugs can be divided into three
groups based on their mechanism of action

• 1.Direct–acting adrenomimetic drugs.

• These drugs act by direct stimulation of α-and
β–adrenoceptors e.g. adrenaline, noradrenaline
dopamine, isoproterenol, dobutamine,
phenylephrine, methoxamine, clonidine,
metaproterenol, terbutaline and salbutamol
(albuterol).
 Adrenomimetic drugs
• 2.Indirect–acting adrenomimetics
These drugs do not themselves interact with
adrenoceptor, but they are capable of
producing sympathetic effects by releasing
noradrenaline from neuronal storage site
(vesicles) e.g. amphetamine and tyramine.
 Adrenomimetic drugs
• 3.Mixed-acting Adrenomimetics
• Some adrenomimetic drugs act both directly
and indirectly, that is, they release some
noradrenaline from storage sites in
adrenergic neurons and also directly activate
adrenoceptor e.g. ephedrine and
metaraminol.

 
 Direct-acting Adrenergic Agonists
• Responses associated with the type of
adrenoceptors:
• Alpha-1adrenoceptors: stimulation of α1-
adrenoceptors causes arterial and arteriolar
constriction (cutaneous, visceral, skeletal, and
pulmonary), venous constriction, uterine
contraction, pupillary dilatation (contraction of
radial smooth muscle of iris) contraction of ureter,
contraction of spleen, and contraction of pilomotor
muscle.
 Direct-acting Adrenergic Agonists
• Alpha-2: stimulation of α2-adrenoceptors causes
inhibition of noradrenaline release and inhibition
of ganglionic transmission.
• Beta-1: stimulation of β1-adrenoceptors results in
increased force and rate of cardiac contraction,
stimulation of renin release, and stimulation of
lipolysis (β3).
 Direct-acting Adrenergic Agonists
• Beta-2: stimulation of β2-adrenoceptors causes
arteriolar dilatation (skeletal muscle, coronary
visceral beds), intestinal relaxation (may also
involve α-receptors), uterine relaxation, bronchial
relaxation, bladder body relaxation, stimulation of
insulin release, skeletal muscle tremor, and
stimulation of glycogenolysis.
 Cardiovascular Effects
• β1-receptors agonists increase the rate (positive
chronotropic) and force (positive inotropic) of
myocardial contraction and conduction velocity
(positive dromotropic) through the AV node.

• β2-receptor agonists cause relaxation of vascular

smooth muscle and may involve in a reflex
increase in heart rate.
 Cardiovascular Effects
• α1-receptor agonists constrict smooth muscle
of resistance vessel (e.g. in the skin and
splanchnic beds), causing increased
peripheral resistance.
• α2-receptor agonists reduce blood pressure
by presynaptic action on neurons in the CNS.
 The Eye
• β-receptor agonists cause relaxation of ciliary
muscle with some decrease in accommodation.
• Beta-adrenoceptors on ciliary epithelium facilitate
the secretion of aqueous humor.
• α-receptor agonists contract the radial muscle of
the iris and dilate the pupil (mydriasis).
• Adrenaline and β-receptor antagonists decrease
intraocular pressure and treat glaucoma.
 Gastrointestinal Tract
• α-receptor agonists relax gastrointestinal
smooth muscle.
• α-receptor agonists reduce the release of
acetylcholine by presynaptic action.
• α1-receptor agonists contract gastrointestinal
sphincters.
 Metabolic and Endocrine Effects
• β-receptor agonists increase liver and
skeletal muscle glycogenolysis (β2) and
increase lipolysis in fat cells (β1, β3).
• β1-receptor agonists increase and α-receptor
agonists decrease insulin and renin secretion.
 Lungs and Female Genitalia
• Respiratory System Effects
• β2-receptor agonists induce relaxation of
bronchial smooth muscle and decrease
airway resistance.
•  Genitourinary Tract Effects
• β2-receptor agonists induce relaxation of
uterine smooth muscle. 
 Adrenaline
• Adrenaline activates β1-, β2- and α-adrenoceptors.
• At low doses, β-receptor effects predominate; at
high concentrations, α-receptor effects
predominate.
• At low doses, adrenaline produces positive
inotropic and chronotropic effects (β1-effect) and
vasodilatation (β2)
• At high doses, adrenaline activates α-receptors
vascular beds to cause vasoconstriction.
 Noradrenaline
• Noradrenaline activates β1- α-receptors but has
little activity at β2-receptor.
• Noradrenaline increases total peripheral
resistance and diastolic blood pressure because
of its vasoconstrictor effect and lack of effect on
β2-receptors in the skeletal muscle vascular beds.
• Noradrenaline increases systolic blood pressure
• Noradrenaline is rarely used therapeutically.
 Dopamine
• Dopamine is a adrenomimetic drug.
• It exerts its cardiovascular action by:
 Releasing noradrenaline from adrenergic neurons.
 Interacting with α–and β1–adrenoceptor.
 Interacting with specific dopamine receptor.
• Dopamine receptors are D1 and D2.
• Low doses of dopamine infusion can produce
vasodilatation in the renal and coronary (D1–receptor
effect). This is antagonized by haloperidol not
propranolol
 Dopamine
• The infusion of moderately higher doses of
dopamine increases the rate and contractile
force of the heart (β1). This is antagonized by
propranolol.
• At still higher doses dopamine cause an α–
adrenoceptor–mediated vasoconstriction in
most vascular beds as well as stimulation of
the heart. This is antagonized by
phentolamine.
 Beta (β)-adrenoceptor Agonists
• Dobutamine: selective on β1 receptors so the drug
increases cardiac output
• Metaproterenol, Terbutaline, Ritodrine, Salbutamol,
Salmeterol, and Bitolterol
• These drugs are more selective β2-receptor agonists
that relax bronchial smooth muscle with fewer
cardiac effects
• Ritodrine, salbutamol, and terbutaline are used to
suppress premature labor.
• Isoproterenol: dilates bronchial smooth muscles and
increases heart rate and contractility and causes
vasodilatation
 Alpha (α)-Adrenoceptor agonists
• Phenylephrine, Methenamine, and Metaraminol
• They produce their effects by direct α-receptors
stimulation resulting in vasoconstriction.
• Metaraminol also has indirect activity; it is
taken up and released at sympathetic nerve
endings. It also releases adrenaline.
• Because they are not metabolized by COMT,
these drugs are less potent but have longer
durations of action than noradrenaline.
 Alpha (α)-Adrenoceptor agonists

• Xylometazoline, Oxymetazoline, and

Phenylpropanolamine
• These drugs have relative selective action at
α1-receptors.
• At high doses, these drugs may cause
clonidine-like effects due to their action in
the CNS.
 
 Alpha (α)-Adrenoceptor agonists
• Clonidine, Methyldopa, and Guanabenz
• These drugs activate presynaptic α2-receptors in
the vasomotor center of the medulla to reduce
sympathetic tone.
• These drugs reduce blood pressure.
• Methyldopa is a prodrug that is metabolized to
methyl dopamine and then to the active agent
α-methylnoradrenaline in nerve ending, where
it replaces noradrenaline and acts as a potent
false neurotransmitter.
 Indirect and Mixed-acting Adrenergic
Agonists
• Ephedrine and Mephenteramine
• These drugs release noradrenaline from nerve
terminals and have some direct action on
adrenoceptors (mixed-acting adrenergic
agonists).
• These drugs are effective orally and, unlike
catecholamines, penetrate the brain and can
produce mild CNS stimulation.
• After continued use, tachyphylaxis may
develop.
 
 Amphetamines
• Amphetamine, Dextroamphetamine,
Methamphetamine, Phenmetrazine,
Methylphenidate, and Hydroxyamphetamine
• These drugs produce effects similar to
adrenaline, with direct and indirect activity.
• Dextroamphetamine has more CNS-
stimulatory activity.
 Therapeutic Uses
• Overview
• α1-adrenoceptor agonists are used to treat
hypotension and to induce mydriasis, and
vasoconstriction (with local anesthetics).
• α2-adrenoceptor agonists are used to treat
hypertension (e.g. clonidine and methyldopa).
• β1-adrenoceptors agonists are used to treat cardiac
arrest.
• β2-adrenocetor agonists are used to treat bronchial
spasm and bronchial asthma,
 Uses in Cardiovascular System
• Sympathomimetics drugs are used for short-term
hypotensive emergencies (Ephedrine and
mephenteramine)
• Low to moderate doses of dopamine or dobutamine
may be useful in cases of cardiogenic or septic shock
• Adrenaline is used in anaphylactic shock and topically
to reduce superficial bleeding.
• Dobutamine is used to treat congestive heart failure.
• Isoproterenol and adrenaline are be used for
treatment of cardiac arrest and heart block.
• Adrenaline is used in combination with local
anesthetics to reduce blood flow and to prolong local
anesthesia.
 Uses in Respiratory System
• For symptomatic relief of hay fever and rhinitis
of the common cold (phenylephrine
phenylpropanolamine, oxymetazoline,
xylometazoline, tetrahydrozoline, and
pseudoephedrine) are available, many as over-
the-counter (OTC)
• When treating asthma, preferred drugs
(metaproterenol, terbutaline, salbutamol, and
bitolterol)
• Adrenaline is administered subcutaneously to
treat bronchospasm.
 Uses in Eye and Uterus
• Phenylephrine facilitates examination of the
retina because of its mydriatic effect
• Used in chronic open-angle glaucoma,
adrenaline and α-receptor agonists lower
intraocular pressure by increasing aqueous
outflow
• and terbutaline to suppress premature labor by
relaxing the uterus,
 Uses in the CNS
• Amphetamine or related analogues are used for
treatment of narcolepsy (sleep disorder
characterized by uncontrollable desire to sleep)
for their arousal effects and their ability to
increase the attention.
• They are used as adjunct therapy for obesity
because of their anorexiant effect.
• They are used to treat attention-deficient
hyperactivity disorder in children.
 Adverse Effects and Toxicity
• Overdose may result in severe hypertension,
with possible cerebral hemorrhage, pulmonary
edema, arrhythmia, and ventricular fibrillation.
• Milder effects include headache, dizziness, and
palpitations.
• Drug abuse may occur with amphetamine and
amphetamine-like drugs.
• Drug interactions include, tricyclic
antidepressant that block catecholamine
reuptake
 Drug interactions
• With tricyclic antidepressant that block
catecholamine reuptake and may potentiate
the effects of noradrenaline and adrenaline.
• Also some halogenated anesthetic agents
and digitalis may sensitize the heart β-
receptor stimulant, resulting in ventricular
arrhythmias.