1

ADRENOCEPTOR AGONISTS AND

ANTAGONISTS
BIETE LUNDAU LUKE
DipPharm,BPharm, Mclinpharm
ADRENOCEPTOR AGONISTS 2

 Adrenoceptor agonists are a large group of drugs with diverse

pharmacological action making them suitable for treatment of a wide
spectrum of clinical conditions ranging from cardiovascular
emergencies to common colds

 While some of these drugs exert their effects on multiple organ systems,
others target a specific organ

 These drugs mimic the effect of sympathetic nervous system and hence
they are also called sympathomimetic drugs
 3
Classification of Adrenoceptor Agonists
1. Direct – Acting Adrenoceptors
a) Catecholamines
b) Non - catecholamines

2. Indirect-Acting Adrenoceptor Agonists

3. Mixed-Acting Adrenoceptor Agonists

 4

1. Direct – Acting adrenoceptor agonists

i. Catecholamines
a) Dobutamine
b) Dopamine
c) Epinephrine
d) Isoproterenol
e) Norepinephrine
 5

ii. Non catecholamines

a) Albuterol (Salbutamol)
b) Apraclonidine
c) Clonidine
d) Midodrine
e) Oxymetazoline
f) Phenylephrine
 6

2. Indirect – Acting adrenoceptor agonists

 Amphetamine
 Cocaine

3. Mixed – Acting Adrenoceptor agonists

 Ephedrine
 Pseudoephedrine
Adrenoceptors 7
 There are two main types of adrenoceptors i.e. and β with
their subtypes whose classification was done based on the
relative potency of agonists in different tissues

 Epinephrine and norepinephrine are more potent than

isoproterenol at adrenoceptors in smooth muscles and these
were designated as – adrenoceptors

 Isoproterenol is more potent than epinephrine and

norepinephrine at adrenoceptors in cardiac tissues and
these were called β – adrenoceptors
 8
Alpha adrenoceptors
 Stimulation of 1 receptors mediates contraction of vascular smooth
muscle, iris dilator muscle, muscle in the lower urinary tract (bladder,
urethra, prostate)

 Activation of the 2 receptors in the sympathetic neurons lead to feedback

inhibition of norepinephrine release from nerve terminals

 α2 receptors are also found in the platelet, ocular, adipose, intestinal,

hepatic, renal and endocrine tissue

 In platelets α2 mediate platelet aggregation while in the pancreas they

mediate the inhibition of insulin secretion that occurs when the
sympathetic nervous system is activated
Beta adrenoceptors
9
 Activation of β1 receptors produces cardiac stimulation leading to positive
chronotropy (increased heart rate), a positive inotropy (increased
contractility), positive dromotropy (increased cardiac conduction velocity)

 Activation of β1 receptors also increases renin secretion from renal

juxtaglomerular cells

 Β2 adrenoceptors mediate relaxation of bronchial, uterine, and vascular and

also potassium uptake in the skeletal muscle

 Where as epinephrine and norepinephrine are equally potent on β1

adrenoceptors in cardiac tissue, epinephrine is more potent on β2 in smooth
muscle

 Β3 adrenoceptors is the most recent characterized one known to mediate

lipolysis, thermogenesis in skeletal muscle, uterine relaxation
Dopamine receptors 10

 These are activated by dopamine and not other adrenergic receptor

agonists

 D1 receptors mediate vascular smooth muscle relaxation

 D2 receptors modulate neurotransmitter release

 Dopamine activates D1 receptors, β1 receptors and receptors

 Unlike other catecholamines, dopamine also stimulates the release of

norepinephrine from sympathetic neurons

 For this reason, dopamine is both a direct acting and an indirect acting
receptor agonist
 11
A comparison of affinity for specific adrenoceptors

Adrenoceptor agonist Affinity for adrenoceptor

Norepinephrine 1 = 2 ; β1>β2
Epinephrine 1 = 2 ; β1 = β2
Isoproterenol Β1 = β2 >>
Dopamine D1>β1 >
Dobutamine β1 = β2 >>
Direct Acting adrenoceptor agonists
Catecholamines 12
 The naturally occurring catecholamines are norepinephrine, an endogenous
sympathetic neurotransmitter, epinephrine the principal hormone of the adrenal
medulla

 Dopamine is another neurotransmitter and a precursor to norepinephrine and

epinephrine

 Synthetic catecholamines include isoproterenol and dobutamine

Chemistry and pharmacokinetics

 They contain the catechol moiety and an ethylamine side chain

 They are rapidly inactivated by monoamine oxidase (MAO) and Catecho-O-

methyltransferase (COMT), enzymes found in the gut, liver and other tissues

 For this reason, these drugs have low bioavailability and short plasma half lives and must
be administered parenterally when systemic action is required like in management of
anaphylactic shock
Indications for catecholamines 13
 Catecholamine are used to treat several types of shock

 Shock is a condition in which circulation to vital organs is profoundly reduced

as a result of inadequate blood volume (hypovolemic shock), inadequate
cardiac function (cardiogenic shock) or inadequate vasomotor tone
(neurogenic and septic shock)

 Septic shock is associated with massive vasodilation secondary to the

production of toxins by microrganisms and it is sometimes called warm shock
to distinguish it from the others where patients’ extremities are usually cold due
to inadequate blood flow

 Anaphylactic shock results from severe immediate hypersensitivity reactions

and usually manifests by hypotension and difficult breathing caused by
bronchoconstriction
 14
Approaches to use of vasopressors
 Catecholamine drugs that increase blood pressure are called
vasopressors

 These are used to treat shock when organ function is impaired because
mean arterial blood pressure is less than 60mm Hg or simply the BP being
less than 90/60 mm Hg

 It is always important to correct hypovolemia by administering

intravenous (I.V) fluids before giving vasopressors because vasopressors
will not be effective when hypovolemia is present
Dopamine 15
 Used to treat septic or cardiogenic shock when patients remain
hypotensive despite adequate fluid administration

 Low dose (2mg/kg) is used first and then titrated to achieve the desired
blood pressure

 Though low doses of dopamine have been found to increase urine

output by augmenting renal blood flow in normal subjects, evidence
shows that these low doses are usually not effective in preventing and
treating acute renal failure

 The most effective means of protecting the kidneys in patients with

shock is the maintenance of mean arterial pressure greater than 60 mm
Hg with I.V fluids and adequate doses of vasopressors
 16
Norepinephrine

 As a potent vasoconstrictor, it is used to treat septic shock

 It is also given to patients with cardiogenic shock when the response to

dopamine is inadequate or is accompanied by tachycardia

 Norepinephrine is also used to treat hypotension caused by decreased

peripheral resistance like in persons who have received excessive doses
of vasodilator drugs
 17
Epinephrine
 Epinephrine is the treatment of choice for anaphylaxis

 By producing bronchodilation and increasing blood pressure,

epinephrine counteracts the effects of histamine and other mediators
released from mast cell and basophils during immediate hypersensitivity
reactions

 Used as a vasoconstrictor to reduce bleeding during surgery and to

prolong the action of local anesthetics by retarding their absorption into
general circulation

 Epinephrine is also used as cardiac stimulant in the treatment of cardiac

arrest and ventricular fibrillation
Isoproterenol 18
 Used to treat refractory tachycardia and atrioventricular block

 Although used in treatment of asthma, selective β2 receptor agonists like

salbutamol, terbutaline, salmetelol are more preferred as it does not
increase the heart rate as much as isoproterenol

Dobutamine
 Dobutamine is a cardiac stimulant (Inotropic agent) that also produces
vasodilation

 Used as cardiac stimulant during heart surgery and in the short term
management of acute heart failure and cardiogenic shock

 It is routinely used in treating septic shock because its vasodilator effect

further reduce vascular resistance and blood pressure
Non-catecholamines 19
 These do not have the catechol moiety neither are they substrates for
the COMT and some of them are resistant to MAO degradation

Phenylephrine
Mechanism and effects
 Phenylephrine activates 1 adrenoceptors and causes smooth muscle
contraction which produces vasoconstriction and increases vascular
resistance and blood pressure

 Ocular administration of phenylephrine leads to contraction of the iris

dilator muscle and dilatation of the pupil (Mydriasis)
Indications of Phenylephrine
20
 Used as nasal decongestant in patients with viral rhinitis caused by
different subtypes of rhinovirus (condition commonly called common
cold)

 Also used in allergic rhinitis, an inflammation by histamine released from

mast cells during allergic reaction

 The drugs vasoconstrictive effect on the nasal mucosa reduces nasal

congestion and mucus secretion thereby, opening the nasal passage
and facilitating easiness of breath

 Phenylephrine is also used in allergic conjunctivitis, an inflammation of the

eye associated to hay fever or other allergies

 When administered intravenously, phenylephrine is used to treat forms of

hypotension and shock caused by decreased peripheral resistant
Midodrine 21
 Forms an active metabolite that selectively activates 1 -
adrenoceptors in arteriolar and venous circulation

 This leads to increase in diastolic and systolic pressure in standing,

sitting and supine position

 The drug is used to treat postural (orthostatic) hypotension in person

impaired by the condition e.g. patients with severe diabetic
autonomic neuropathy

 Hypertension in supine position is the known adverse effect

Salbutamol (Albuterol), Pirbuterol, Terbutaline
 These are known β2 – adrenoceptor agonists that can be given by 22
inhalation, with salbutamol and terbutaline being available as oral
medication while terbutaline is available for injection

Mechanism and indication

 β2 – adrenoceptor agonists cause smooth muscle relaxation in several
tissues resulting in bronchodilation and hence these drugs being beneficial
in the management of asthma and chronic obstructive lung disease

 Also used off lable as tocolytics in the management of pre term

(Premature) labour which is labour before the 37th week of gestation

 The tocolytic effect relaxes the uterus and maintains pregnancy for 24 –
48hours the period enough to have corticosteroid administered to prevent
neonatal respiratory distress

 Tachycardia, muscle tremors and nervousness are known adverse effects

salbutamol and other selective β2 – adrenoceptor agonists
Imidazoline Drugs
These compounds activate - adrenergic and imidazoline receptors and mostly
23

administred by topical ocular or nasal route

Mechanism and indications

1. Oxymetazoline
 Together with similar drugs activate 1 receptors and cause vasoconstriction and
hence its use as nasal or ocular decongestant

 Because of increasing blood pressure, oxymetazoline should not be taken by

hypertensive patients

 Topical nasal decongestant should not be used for more than 3 – 5 days to avoid
nasal rebound which comes about due to vasoconstriction and tissue ischaemia

2. Brimonidine and apraclonidine

 Activate 2 in the ciliary body and reduce aqueous humor secretion by reducing
adenylyl cyclase and consequent reduction of cAMP

 Used to prevent short term elevation of intraocular pressure after cataract surgery
 24
3. Clonidine and dexmedetomidine

 These activate 2 and imdazoline receptors in the CNS and leads to

reduction to sympathetic outflow in the medulla

 Clonidine is used in the treatment of hypertension

 Also used to facilitate abstinence from opioids in persons being treated

for substance abuse

 Activation of is responsible for sedation and analgesic effects of

clonidine and dexmedetomidine and hence these drugs are used as
adjunct to anaesthesia during surgical procedure with an addition
property of preventing shivering
Indirect acting adrenoceptor agonists 25
Amphetamine and Tyramine
 Have high solubility and increase synaptic concentration of norepinephrine in the
central and peripheral nervous system and causes vasoconstriction

 Tyramine is naturally occurring found in food like bananas, cheese which

metabolized by MAO and may thus be absorbed in patients receiving MAO
inhibitors for depression and may cause exaggerated sympathetic effect

Cocaine
 A plant alkaloid which acts as local anesthetic and also stimulates sympathetic
system by preventing norepinephrine re uptake at both peripheral and central
synapses

 Cocaine also blocks the re uptake of dopamine leading to its effects and
vulnerability for abuse

 Its sympathetic effects also appears to be responsible for the severe hypertension
and cardiac damage that may occur in people who abuse cocaine
Mixed Acting Adrenoceptor Agonists 26
 pseudoephedrine and dopamine
 They indirectly increase synaptic concentration of norepinephrine like
amphetamines

Ephedrine and Pseudoephedrine

 Ephedrine is naturally occurring compound obtained plant of the genus Ephedra
which is also called ma These are drugs which act both as direct and indirect
mechanism e.g. ephedrine, huang
 Ephedrine is well absorbed from the gut and has sufficient lipid solubility to enter CNS
 Ephedrine is relatively resistant to metabolism by COMT and hence it long duration
of action

 Pseudoephedrine, an isomer to ephedrine used as nasal decongestant to treat

colds and allergies

 Availability of pseudoephedrine is now restricted in many countries because of its

newfound use in illegal making of methamphetamines for illicit sale and use
Mechanism and indications of Ephedrine and 27
Pseudoephedrine
 Ephedrine and the related drugs activate and β adrenoceptors

 Stimulation of 1 causes vasoconstriction and thus making them useful

as nasal decongestants in treatment of viral and allergic conjunctivitis

 Activation of β adrenoceptors leads bronchodilation but selective β2

adrenoceptor agonists are more safe and effective for this purpose
Mechanism and indications of Ephedrine and 28
Pseudoephedrine
 Ephedrine and the related drugs activate and β adrenoceptors

 Stimulation of 1 causes vasoconstriction and thus making them useful

as nasal decongestants in treatment of viral and allergic conjunctivitis

 Activation of β adrenoceptors leads bronchodilation but selective β2

adrenoceptor agonists are more safe and effective for this purpose

 Tachycardia and increased blood pressure are known adverse effects

of ephedrine and pseudoephedrine
 29

ADRENOCEPTOR ANTAGONISTS
Overview on adrenoceptor Antagonists 30
 Excessive sympathetic nervous system activity causes a number of diseases
including common cardiovascular disorders such as hypertension, angina
pectoris and cardiac arrhythmias

 Drugs that reduce sympathetic activity are called sympatholytics and can
be used in the management of diseases such as cardiovascular diseases
and other diseases like glaucoma, migraine headache and urinary
obstruction
 Adrenoceptor antagonists block and β adrenoceptors or both and their
therapeutic effects are almost entirely caused on 1 and β1

 Blockade of 1 relaxes the smooth muscles in tissues innervated by the

sympathetic nervous system where as blockade of β1 reduces the
sympathetic stimulation of the heart

 Blockade of 2 and β2 adrenoceptors is responsible for many of the side

effects of these drugs and hence drugs selective to and β have been
1 1

developed in an effort to avoid these adverse effects

Classification of Adrenoceptor Antagonists
1. Alpha – Adrenoceptor Antagonists 31
i. Non selective - blockers
a) Phenoxybenzamine
b) Phentolamine
ii. Selective 1 – blockers
a) Doxazosin
b) Tamsulosin
c) Alfuzosin
d) Silodosin

2. Beta Adrenoceptor Antagonists

i. Non selective β – blockers
a) Propranolol
b) Timolol
c) Pindolol
ii. Selective β1 – blockers
a) Atenolol
b) Esmolol
c) Metoprolol
3. - and β – Adrenoceptor Antagonists
a) Carvedilol
b) Labetalol
 - Adrenoceptor Antagonists
32
Non selective Blockers
 These block both 1 and 2 adrenoceptors
 Phenoxybenzamine is a non competitive antagonist while
Phentolamine is a competitive antagonist

Phenoxybenzamine
 Administered orally and undergoes non enzymatic chemical
transformation to an active metabolite

Effects and indication

 Lowers vascular resistance and lowers both supine and standing
blood pressure
 Used to treat hypertensive episodes in patients with
pheochromocytoma
Phentolamine
 Structurally related to oxymetazoline and other drugs within the midazoline
33
group

Mechanism, effect and indication

 Phentolamine is a competitive adrenoceptor antagonist that produces
vasodilation, decreases vascular resistance and decreases blood pressure

 It is used in the treatment of acute hypertensive episodes caused by -

adrenoceptor agonists

 Accidental injection of a finger with an epinephrine may result in local

vasoconstriction, ischemia and necrosis and phentolamine can be used to
treat this condition

 Phentolamine and other non selective - blockers are not used in treating
chronic hypertension as they can cause reflex tachycardia, headache,
and nasal congestion
Selective 1- Antagonists
 These selectively antagonize 1-adrenocepptors and they include alfuzosin,
34
doxazosin, prazosin, silodosin, tamsulosin, telazosin

Pharmacokinetics
 Administered orally and undergo varying amounts of first pass and systemic
circulation

Mechanism, effects and indications

 These 1- blockers relax vascular and other smooth muscles including those
of the urinary bladder, urethra and prostate

 Because they produce vasodilation and reduce blood pressure, they are
used to treat essential hypertension

 Quite helpful in treating lower urinary tract symptoms associated with

benign prostatic hyperplasia (frequency, urgency, nocturia)
Further sub categorization of specific selective 1 - Antagonists 35
 Most common adverse effects include hypotension, dizziness and
sedation

 Prazosin, terazosin and doxazosin are used for treatment of hypertension

and to relieve lower urinary tract symptoms

 It is worthy noting that terazosin and doxazosin have a longer half life
than prazosin

 On the other hand, alfuzosin, silodosin and tamsulosin are more uro-
selctive that lower urinary tract symptoms without as much hypotension,
dizziness and sedation like the other drugs
β-Adrenoceptor Antagonists
Non selective β-blockers
36
 In addition to blocking β1-adrenoceptors in the heart tissue, they block
β2 in smooth muscle, liver and other tissues
 Examples include propranolol, nadolol, pindolol and timolol

Pharmacokinetics
 The β-Adrenoceptor Antagonists are structural analogues of β-
Adrenoceptor Antagonists, all of which can be administered orally
while propranolol is also administered parenterally

Mechanisms and effects

 Non selective β-blockers competitively block the effects of
norepinephrine and other adrenoceptor agonists at β1 and β2 –
adrenoceptors while some of them exhibit intrinsic sympathomimetic
activity and membrane stabilizing (local anesthetic) activity
Specific properties 37
 Compairing the drugs; propranolol, nadolol, pindolol and timolol some
specific properties are found with individual drugs

 Pindolol is found to have intrinsic sympathomimetic activity or partial

agonist activity which enables it to exert a weak agonist effect on β –
adrenoceptors

 Although propranolol and pindolol have membrane stabilizing effects

(Local anesthetic activity), nadolol and timolol do not

 This membrane stabilizing activity causes the blockage of sodium

channels in nerves and heart tissue thereby, slowing conduction velocity

 Propranolol the first β-blocker approved (Prototype) for clinical use is

distinguished by it high lipid solubility and CNS penetration and hence a
higher incidence of side effects such as headache, psychosis, nightmares,
sleep disturbances, vertigo, visual disturbance
Indications Non selective β-blockers
Pindolol 38
 Approved for hypertension treatment

Propranolol
 Treatment of hypertension, angina pectoris and cardiac arrhythmias
 Prevention of migraine headaches and as adjunctive therapy in treatment of acute
thyrotoxicosis, acute myocardial function and pheochromocytoma

Nadolol
 Treatment of hypertension, angina pectoris and prevention of migraine headache

Timolol
 Administered orally for treatment of hypertension, to reduce risk of death in patients
with acute myocardial infarction and prevention of migraine headache

 Ocular topical application for treatment of glaucoma and is suitable because it

does not have local anesthetic effect and hence cannot anesthetize the cornea
when instilled into the eye
Selective β1-blockers
39
 These have a greater affinity for β1 than for β2 adrenoceptors and because
β1 are primarily located in the cardiac tissue, β1-blockers are also known as
cardio selective β-blockers

 Examples are acebutolol, atenolol, esmolol and metoprolol

 Comparing with non selective β-blockers, selective β1-blockers produce less

bronchoconstriction and other mediated effects

 Their selectivity for β1 adrenoceptors is not absolute and therefore,

blockade of β2 - receptors increases with dose and hence β1 should be used
with caution in patients with asthma

NB: with the last point in mind, it is important to appreciate that cardio
selectivity is not the same as cardio specificity
Specific properties and indications for selective β1-blockers 40
Acebutolol
 Administered orally for treatment of hypertension and cardiac arrhythmias

Atenolol
 Shows less variability in its oral absorption than do other β – blockers and is
largely excreted unchanged in the urine and has lower lipid solubility
 Administered orally for treatment of hypertension, angina pectoris and
acute myocardial infaction

Esmolol
 Has shorter half life compared to others β – blockers and is administered
intravenously for treatment of hypertension and acute supraventricular
tachycardia when these occur during surgery
Metoprolol 41
 Used to treat hypertension, angina pectoris and acute myocardial
infarction

 Administered orally or parenterally and is extensively metabolized by

CYP450 enzymes before undergoing renal excretion

Other β1- selective antagonists

 These include bisoprolol and betaxolol

 Both of these drugs are administered orally for treatment of hypertension

 Topical application of betaxolol also reduces aqueous humour secretion

while producing negligible systemic β-adrenoceptors and hence it is used in
treatment of chronic open angle glaucoma
 and β – Adrenoceptor Antagonists
42
 These block both and β adrenoceptors and they include carvedilol and
labetalol

Carvedilol
 Carvedilol blocks β1, β2 and 1 adrenoceptors and also possesses
antioxidant activity
 Each of these properties offer the cardioprotective effect

Antioxidant effects of carvedilol

 Inhibition of lipid peroxidation in myocardial membranes
 Scavenging of free radicals
 Prevention of neutrophil release of O2
 Additionally carvedilol has antiapoptotic effect which helps prevent
myocyte death and reduce infarct size in persons with myocardial
ischaemia
Indications of carvedilol 43
 Carvedilol is therefore referred to as third generation β-blockers and
neurohumoral antagonists and its value in treating myocardial
infarction has been established

 Carvedilol is used in management of hypertension

Labetalol
 This is a non selective β blocker and selective 1 blocker that is
primarily used in the treatment of hypertension

 Labetalol decreases heart rate and cardiac output as a result of β1-

adrenoceptor blockade and it reduces peripheral vascular
resistance as a result of 1-adrenoceptor blockade
 44

END