Adrenergic antagonists

Adrenergic antagonists
Also called blockers or sympatholytic agents
Sympatholytics inhibit—or LYSE—sympathetic
neurotransmitters (norepinephrine and epinephrine)
Bind to adrenoceptors but do not trigger the usual
receptor-mediated intracellular effects
Classified by the type of adrenergic receptor they
block
Alpha1 and alpha2 receptors
Beta1 and beta2 receptors
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Alpha receptor antagonists
Alpha-receptor antagonists may be:
I. Irreversible antagonists
Interact with alpha receptor
Drug-receptor bond do not dissociate and cannot be
surmounted
Phenoxybenzamine is a non-selective irreversible
antagonist of α adrenoceptor
II. Reversible antagonists
Reversible antagonists dissociate from receptors and the
block can be surmounted with sufficiently high
concentrations of agonists
A. Non-selective α antagonists
It includes drugs such as Phentolamine,
Tolazoline and Ergot derivatives
B. Selective α-antagonists
α1 Selective antagonists:
 It
includes drugs such as prazosin, doxazosin,
terazosin, and tamsulosin
α2 selective antagonists:
 Drugs such as yohimbine and idazoxan are α2
selective antagonists
Pharmacologic Effects of α-Antagonists
Cardiovascular System
α1 Receptor Antagonists
Blockade of α1 adrenergic receptors inhibits vasoconstriction
induced by endogenous catecholamines
Vasodilation may occur in both arteriolar resistance vessels and
veins
The result is a fall in blood pressure due to decreased peripheral
resistance
The magnitude of such effects depends on the activity of the
sympathetic nervous system at the time the antagonist is
administered
 Less in supine than in upright subjects and is particularly marked if there
is hypovolemia
For most α receptor antagonists, the fall in blood
pressure is opposed by baroreceptor reflexes that
cause:
Increases in heart rate and cardiac output, as well as
fluid retention
Reflexes are exaggerated if the antagonist also blocks
α2 receptors on peripheral sympathetic nerve endings
Leading to enhanced release of norepinephrine and
increased stimulation of postsynaptic β1 receptors in the
heart and on juxtaglomerular cells
α2Receptor Antagonists
Blockade of α2 receptors with selective antagonists such
as yohimbine thus can increase sympathetic outflow
Potentiate the release of norepinephrine from nerve
endings
leading to activation of β1 and α1 receptors in the heart
and peripheral vasculature with a consequent rise in
blood pressure
Other Effects
Minor effects that signal the blockade of α receptors in
other tissues include miosis and nasal stuffiness
Alpha1-receptor blockade of the base of the bladder and
the prostate is associated with decreased resistance to
the flow of urine
Non-selective α antagonists
Phenoxybenzamine
It forms a reactive ethyleneimonium intermediate that
covalently binds to receptors, resulting in irreversible
blockade
It is not specific for α-adrenoceptors and also
antagonises the actions of acetylcholine, histamine and
5-HT
Phenoxybenzamine reduces blood pressure especially
when sympathetic tone is high
 eg, As a result of upright posture or because of reduced blood
volume
Cardiac output may be increased because of reflex
effects and because of some blockade of presynaptic α2
receptors in cardiac sympathetic nerves
The major use of phenoxybenzamine is in the treatment
of pheochromocytoma
Phentolamine
It is a potent competitive antagonist at both α1 and α2
receptors
Phentolamine causes a reduction in peripheral
resistance through blockade of α1 receptors
The cardiac stimulation induced by phentolamine is due
to sympathetic stimulation of the heart resulting from
baroreflex mechanisms
Phentolamine potently blocks α2 receptors,
antagonism of presynaptic α2 receptors
Enhanced release of norepinephrine from sympathetic
nerves
Phentolamine also has minor inhibitory effects at
serotonin receptors and agonist effects at muscarinic
and H1 and H2 histamine receptors
Used in the treatment of pheochromocytoma as well
as for male erectile dysfunction
Tolazoline is an obsolete agent similar to
phentolamine
Ergot derivatives
Ergotamine and dihydroergotamine cause reversible α-
receptor blockade
 Probably via a partial agonist action
They are used in the treatment of migraine
They may also cause nausea and vomiting due to their
direct effect on CNS emetic centers
Ergot alkaloids are contraindicated in women who are or
may become pregnant
 Cause fetal distress and miscarriage
α1 selective antagonists
Prazosin
It is highly selective for α1 receptors and typically 1000-
fold less potent at α2 receptors
The major effects of prazosin result from its blockade of
α1 receptors in arterioles and veins
 This leads to a fall in peripheral vascular resistance and in
venous return to the heart
Unlike other vasodilating drugs, administration of prazosin
usually does not increase heart rate due to the following
reasons:
I. Since prazosin has little or no α2 receptor-blocking
effect at concentrations achieved clinically
 Does not promote the release of norepinephrine from
sympathetic nerve endings in the heart
II. Prazosin decreases cardiac preload and thus has little
tendency to increase cardiac output and rate
III. Prazosin appears to depress baroreflex function
 It may act in the CNS to suppress sympathetic outflow
Prazosin and related drugs in this class
Decreasing low-density lipoproteins (LDL) and
triglycerides
while increasing concentrations of high-density
lipoproteins (HDL)
Due to its shorter duration of action, the twice-daily
dosing requirement for prazosin is a disadvantage
compared with newer α1 receptor antagonists
The drug undergoes extensive hepatic metabolism followed by
excretion in the bile
It has bioavailability of about 50% to 70% after oral
administration
The half-life is normally about 3 hours
Terazosin and Doxazosin
The major distinction between these drugs and prazosin
is in their pharmacokinetic properties.
 Their bioavailability is high (90%)
 They have longer duration of action (given once)

An interesting aspect of the action of terazosin and

doxazosin in the treatment of lower urinary tract
problems in men with BPH
 Induction of apoptosis in prostate smooth muscle cells
 Apoptosis may lessen the symptoms associated with chronic
BPH by limiting cell proliferation
Tamsulosin
Tamsulosin shows some selectivity for α1A-adrenoceptor
of the bladder and causes less hypotension than drugs
such as prazosin
Blockade of 1A receptors in prostate
Efficacious in the treatment of BPH (benign prostatic
hyperplasia) with little effect on blood pressure
It has high bioavailability and a half-life of 9–15 hours
Adverse Effects of α1 selective
Antagonists
A major potential adverse effect of prazosin and its
congeners is the first-dose effect
Marked postural hypotension (manifested as dizziness
and light-headedness) and syncope
These effects occur most frequently during initial
treatment and when the dosage is sharply increased
α2 selective Antagonists
Yohimbine
It is an α2-selective antagonist
It has no established clinical role
Theoretically, it could be useful in autonomic
insufficiency
 Promoting neurotransmitter release through blockade of
presynaptic α2 receptors
Improves male sexual function (probably by virtue of its
vasodilator effect)
 Evidence for this effect in humans is limited
Yohimbine can abruptly reverse the antihypertensive
effects of an α2-adrenoceptor agonist such as clonidine
 It readily enters the CNS

 Acts to increase BP and heart rate

 Also enhances motor activity and produces tremors
Clinical Uses of the Alpha-Receptor
Blocking Drugs
Pheochromocytoma
Hypertension
Urinary Obstruction
Erectile Dysfunction
Beta-Adrenoceptor Antagonists
Beta-blocking drugs :
Occupy β receptors and competitively reduce receptor
occupancy
 For catecholamines and other β agonists
Most β -blocking drugs in clinical use are pure
antagonists
The occupancy of a β receptor by such a drug causes no
activation of the receptor
Some beta blockers are partial agonists
They cause partial activation of the receptor less
than that caused by the full agonists
Epinephrine and isoproterenol
In the presence of high catecholamine concentrations,
they inhibit the activation of β receptors
Moderately activate the receptors in the absence of
endogenous agonists
Evidence suggests that some β blockers are inverse
agonists
β drugs that reduce constitutive activity of β receptors in
some tissues
 eg, betaxolol, metoprolol
β -adrenergic receptor antagonists are classified as:
1. Non-Selective β Receptor Antagonists
 Propranolol, Nadolol, Penbutolol, Pindolol, and Timolol.
2. Selective β Receptor Antagonits
a) β 1-Selective Antagonists
 Acebutolol, Atenolol, Bisoprolol, Esmolol and Metoprolol
b) β2-Selective Antagonists
 Butoxamine (not clinically used)
3. Non-selective β blockers with additional actions at α-
adrenergic receptors
 Carvedilol, Labetalol and Carteolol
Non-selective beta antagonists
Propranolol

Interacts with 1- & 2-AR with equal affinity

Highly lipophilic and is almost completely absorbed after

oral administration
Undergoes extensive first pass effect (only about 25%

reaches the systemic circulation)

Nadolol

 A long-acting antagonist with equal affinity for

1 and 2 receptors

 Has a relatively long half-life of 12 to 24 hours

 Therapeutic use: treatment of hypertension &

angina pectoris

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Timolol

 Potent, non-subtype-selective  antagonist

 Therapeutic use: Treatment of hypertension,

congestive heart failure, and has been widely

used in the treatment of glaucoma and
intraocular hypertension

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Pindolol

 -blockers with partial agonistic activity

 Preferred as antihypertensive agents in

individuals with diminished cardiac reserve or a
propensity for bradycardia
 Such drugs produce smaller reductions in
resting heart rate and blood pressure

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Selective beta 1 antagonists
Metoprolol
 1-selective receptor antagonist

 Therapeutic Uses
 For the treatment of hypertension, treatment
of angina
 Effective in chronic heart failure
Atenolol
 1-selective antagonist

 Too hydrophilic to penetrate the CNS

 Therapeutic Uses
 Treatment of hypertension

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Esmolol
 A 1-selective antagonist with a very short
duration of action
 Administered IV is used when  blockade of
short duration is desired
 Has a half-life of about 8 minutes
 Onset and cessation of  receptor blockade
which are rapid; peak effects occur within 6 to 10
minutes of administration
 There is substantial attenuation of  blockade
within 20 minutes of stopping an infusion

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Acebutolol
 Has some ISA
 Well absorbed, and undergoes significant first-
pass metabolism to an active metabolite,
diacetolol
Bisoprolol
 A highly selective 1 receptor antagonist that
does not have ISA

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Adverse effects and precautions
Cardiovascular System
 May cause or exacerbate heart failure in susceptible
patients
 Bradycardia which may cause life-threatening
bradyarrhythmias in patients with partial or complete
atrioventricular conduction defects
 Abrupt discontinuation of -AR antagonists after
long-term treatment
 Exacerbate angina and may increase the risk of sudden
death
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Pulmonary Function
 A major adverse effect of  receptor antagonists
 Drugs with selectivity for 1-AR or those with
ISA at 2 AR may be some what less likely to
induce bronchospasm
Central Nervous System

 Include fatigue, sleep disturbances, and

depression

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Metabolism
 May delay recovery from insulin-induced
hypoglycemia
 Should d be used with great caution in patients with
diabetes who are prone to hypoglycemic reactions
Overdosage
 Hypotension, bradycardia, prolonged AV
conduction times
 Seizures and depression may occur
 Hypoglycemia is rare, and bronchospasm is
uncommon in the absence of pulmonary disease
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Drug Interactions
 Aluminum salts, cholestyramine, and colestipol
may decrease the absorption of  blockers
 phenytoin, rifampin, and phenobarbital, as well
as smoking (inducers) may decrease plasma
concentrations of  blockers (e.g., propranolol).
Therapeutic Uses of β Blockers
Cardiovascular Diseases
Ischemic Heart Disease
Hypertension,,labetalol
Glaucoma
Hyperthyroidism
Anxiety States
Migraine
Pheochromocytoma
Summary : ADRs & C\Is
Contraindications
Adverse Effects

Bronchoconstriction  Asthma
Bradycardia.  Diabettes Mellitus
Hypoglycaemia  Heart Failure
Fatigue
 Quiz
The graphs below depict the changes in blood pressure
caused by the intravenous administration of epinephrine
before and after an unknown Drug X.
Drug X is
Atropine.
Phenylephrine.
Physostigmine.
Prazosin.
Propranolol.