Adrenergic Antagonists

The adrenergic antagonists (also called blockers or

sympatholytic agents) bind to adrenoceptors but do not trigger
the usual receptor-mediated intracellular effects.
These drugs act by either reversibly or irreversibly attaching to
the receptor, thus preventing its activation by endogenous
catecholamines.
These drugs termed as adrenergic receptor antagonists, which
inhibit the interaction of norepinephrine, epinephrine, and other
sympathomimetic drugs with a and b receptors.


Classification of adrenoceptors
Main pharmacological classification into and subtypes,
based originally on order of potency among agonists, later on
selective antagonists.
Adrenoceptor subtypes:
Two main -receptor subtypes,
1
and
2
, each divided into
three further subtypes
Three -adrenoceptor subtypes (
1
,
2
,
3
)
All belong to the superfamily of G-protein-coupled
receptors.
Second messengers:

1
-receptors activate phospholipase C, producing inositol
trisphosphate and diacylglycerol as second messengers

2
-receptors inhibit adenylate cyclase, decreasing cAMP
formation
all types of -receptor stimulate adenylyl cyclase.
The main effects of receptor activation are as follows.

1
-receptors: vasoconstriction, relaxation of
gastrointestinal smooth muscle, salivary secretion and
hepatic glycogenolysis

2
-receptors: inhibition of transmitter release (including
noradrenaline and acetylcholine release from autonomic
nerves), platelet aggregation, contraction of vascular
smooth muscle, inhibition of insulin release

1
-receptors: increased cardiac rate and force

2
-receptors: bronchodilatation, vasodilatation, relaxation
of visceral smooth muscle, hepatic glycogenolysis and
muscle tremor

3
-receptors: lipolysis

Sympatholytics
Alpha & Beta-antagonist
e.g. Labetolol
Adrenoceptor Blockers
Alpha -antagonist
Non Selective
Phenoxybenzamine
(irreversible; long acting)
Phentolamine
(revesible and long acting)

1
selective
Prazocin
Terazocin
Doxazocin

2
selective
Yohimbine
Idazoxan
Beta -antagonist
Non-selective
Propranolol
Timolol
Pindolol

1
-selective
Atenolol
Metoprolol
Esmolol

2
-selective
Butoxamine
Inhibiting release
and uptake
Reserpine
Gaunithidine
CLINICAL PHARMACOLOGY OF THE ALPHA-
RECEPTORBLOCKING DRUGS
1. Pheochromocytoma:
This tumor is usually found in the adrenal medulla; it typically
releases a mixture of epinephrine and norepinephrine.
Patients have many symptoms and signs of catecholamine
excess, including:
Intermittent or sustained hypertension
Headaches
Palpitations
Increased sweating
Treatment:
Alpha-receptor antagonists are most useful in the preoperative
management of patients with pheochromocytoma i.e.,
phenoxybenzamine and phentolamine
2. Hypertensive Emergencies:
The alpha-adrenoceptor antagonist drugs have limited
application in the management of hypertensive emergencies,
although labetalol has been used.
In theory, alpha-adrenoceptor antagonists are most useful
when increased blood pressure reflects excess circulating
concentrations of agonists,
In pheochromocytoma
overdosage of sympathomimetic drugs
clonidine withdrawal.
However, other drugs are generally preferable.

3. Chronic Hypertension
Members of the prazosin family of alpha
1
-selective antagonists are
efficacious drugs in the treatment of mild to moderate systemic
hypertension.
4. Local Vasoconstrictor Excess
Phentolamine has been used to reverse the intense local
vasoconstriction caused by infiltration of agonists (e.g,
norepinephrine) into subcutaneous tissue during intended
intravenous administration. The antagonist is administered by local
infiltration into the ischemic tissue.
5. Urinary Obstruction
Several alpha
1
-receptor antagonists in patients with BPH(Benign
prostatic hyperplasia). E.g. Prazosin, doxazosin, and terazosin are
efficacious.


CLINICAL PHARMACOLOGY OF THE BETA-
RECEPTORBLOCKING DRUGS

1. Hypertension:
The beta-adrenoceptor-blocking drugs have proved to be
effective and well tolerated in hypertension.
The drug is often used with either a diuretic or a vasodilator.
2. Ischemic Heart Disease:
Beta-adrenoceptor blockers reduce the frequency of anginal
episodes and improve exercise tolerance in many patients with
angina.
These actions relate to the blockade of beta-cardiac receptors,
resulting in decreased cardiac work and reduction in oxygen
demand.

3. Cardiac Arrhythmias:
Beta antagonists are often effective in the treatment of both
supraventricular and ventricular arrhythmias.
4. Heart Failure:
antagonistsmetoprolol, bisoprolol, and carvedilolare
effective in treating chronic heart failure in selected patients.
5. Glaucoma :
Systemic administration of beta-blocking drugs was found to
reduce intraocular pressure in patients with glaucoma.
It was found that topical administration also reduces intra-
ocular pressure.
The mechanism appears to involve reduced production of
aqueous humor by the ciliary body, which is physiologically
activated by cAMP.
E.g, Timolol, Betaxolol, carteolol, levobunolol, and
metipranolol are approved for the treatment of glaucoma.
6. Hyperthyroidism:
Excessive catecholamine action is an important aspect of the
pathophysiology of hyperthyroidism.
They causes inhibition of peripheral conversion of thyroxine to
tri-iodothyronine.
Propranolol has been used extensively in patients with
thyroid storm (severe hyperthyroidism).
It is used cautiously in patients with this condition to control
supraventricular tachycardias that often precipitate heart
failure.
7. Neurologic Diseases:
Propranolol reduces the frequency and intensity of migraine
headache.
Propranolol may contribute to the symptomatic treatment of
alcohol withdrawal in some patients.


PREPARATIONS AVAILABLE
1.Alpha Blockers:
Alfuzosin (Uroxatral)
Oral: 10 mg tablets (extended-release)
Phenoxybenzamine (Dibenzyline)
Oral: 10 mg capsules
Phentolamine (generic, Regitine)
Parenteral: 5 mg/vial for injection
Tamsulosin (Flomax)
Oral: 0.4 mg capsule
Terazosin (generic, Hytrin)
Oral: 1, 2, 5, 10 mg tablets, capsules





2. Beta Blockers:
Atenolol (generic, Tenormin)
Oral: 25, 50, 100 mg tablets
Parenteral: 0.5 mg/mL for IV injection
Betaxolol
Oral (Kerlone): 10, 20 mg tablets
Ophthalmic (generic, Betoptic): 0.25%, 0.5% drops





Some Prototype Drugs:
Alpha-Adrenergic Antagonists:
1. Phentolamine:
An imidazoline derivative, is a potent competitive antagonist at both alpha
1

and alpha
2
receptors .
Phentolamine causes a reduction in peripheral resistance through blockade
of alpha
1
receptors and possibly alpha
2
receptors on vascular smooth
muscle.
The cardiac stimulation induced by phentolamine is due to sympathetic
stimulation of the heart resulting from baroreflex mechanisms.
Phentolamine has limited absorption after oral administration. Its
pharmacokinetic properties are not well known;
It may reach peak concentrations within an hour after oral administration
and
It has a half-life of 57 hours.
The principal adverse effects are related to cardiac stimulation, which may
cause severe tachycardia, arrhythmias, and myocardial ischemia, nasal
congestion, and headache
Phentolamine has been used in the treatment of pheochromocytoma
2. Prazosin
It is a piperazinyl quinazoline effective in the management of
hypertension.
It is highly selective for alpha
1
receptors and typically 1000-fold less
potent at alpha
2
receptors.
Prazosin is extensively metabolized in humans; because of
metabolic degradation by the liver, only about 50% of the drug is
available after oral administration.
The half-life is normally about 3 hours.
3. Terazosin:
It is another reversible alpha
1
-selective antagonist that is
effective in hypertension.
it is also approved for use in men with urinary symptoms due
to benign prostatic hyperplasia (BPH).
Terazosin has high bioavailability but is extensively
metabolized in the liver, with only a small fraction of
unchanged drug excreted in the urine.
The half-life of terazosin is 912 hours.


Beta-Adrenergic Antagonists:
1. Propranolol :
Propranolol is highly lipophilic and is almost completely absorbed
after oral administration.
It is metabolized by the liver during its first passage through the
portal circulation; on average, only about 25% reaches the systemic
circulation.
Propranolol has a large volume of distribution (4 liters/kg) and
readily enters the CNS.
Approximately 90% of the drug in the circulation is bound to
plasma proteins.
It is extensively metabolized, with most metabolites appearing in
the urine.



Therapeutic Uses:
For the treatment of :
o Hypertension and angina
o The prophylaxis of migraine
o Myocardial infarction
o Pheochromocytoma
Drug interaction: It induce bronchospasm so contra-indicated
in asthma.
It also may delay recovery from insulin-induced hypoglycemia
so should be used with great caution in patients with diabetes.
Propranolol and Ca
2+
channel blockers have additive effects on
the cardiac conducting system.
Drugs such as phenytoin, rifampin, and phenobarbital, as well
as smoking, induce hepatic biotransformation enzymes and
may decrease plasma concentrations of propranolol.
Cimetidine and hydralazine may increase the bioavailability
of agents such as propranolol and metoprolol.
2. Atenolol :
Atenolol (TENORMIN, others) is a beta
1
-selective antagonist.
Atenolol is very hydrophilic and appears to penetrate the CNS
only to a limited extent.
Its half-life is somewhat longer than that of metoprolol.
Atenolol is incompletely absorbed (about 50%), but most of
the absorbed dose reaches the systemic circulation.
The drug is excreted largely unchanged in the urine, and the
elimination half-life is about 5 to 8 hours.
The drug accumulates in patients with renal failure, and
dosage should be adjusted for patients whose creatinine
clearance is less than 35 ml/minute.


Indirect acting sympatholytics:
1. Reserpine:
Reserpine is an alkaloid from the shrub Rauwolfia, which has
been used in India for centuries for the treatment of mental dis
orders.
At very low concentration, blocks the transport of
noradrenaline and other amines into synaptic vesicles, by
blocking the vesicular monoamine transporter.
It is now used only experimentally, but was at one time used as
an antihypertensive drug.
Its central effects, especially depression, which probably
result from impairment of noradrenergic and 5-HT-mediated
transmission in the brain are a serious disadvantage.
It has a slow onset, a long duration of action, and effects that
persist for many days after discontinuation.

2. Guanethidine :
It was first discovered in the mid-1950s
It inhibits the release of noradrenaline from sympathetic nerve
terminals. It has little effect on the adrenal medulla.
Guanethidine is also concentrated in synaptic vesicles by means
of the vesicular transporter, possibly interfering with their
ability to undergo exocytosis, and also displacing noradrenaline.
It causes a gradual and long-lasting depletion of noradrenaline
in sympathetic nerve endings, similar to the effect of reserpine.
Given in large doses, it causes structural damage to
noradrenergic neurons.
they produce severe side effects associated with the loss of
sympathetic reflexes.
The most troublesome are postural hypotension, diarrhea, nasal
congestion and failure of ejaculation.
REFRENCES
Pharmacology by Rang and Dale
Katzung Pharmacology Tenth Ed
GOODMAN & GILMAN'S THE
PHARMACOLOGICAL BASIS OF
THERAPEUTICS - 11th Ed. (2006)
Lippincott's Illustrated Reviews Pharmacology, 4th
Edition
THANK YOU