Alpha-adrenergic blocking drugs

রাজশাহী বিশ্ববিদ্যালয়ের ফার্মেসী বিভাগের বি. ফার্ম (সম্মান) তৃতীয় বর্ষের সিলেবাস অনুযায়ী প্রণিতঃ

Syllabus
Drug Acting on ANS:
a) (i) Parasympathomimetic agents: Acetyl choline, Methacoline, Carbachol. (ii) Sympathomimetic drugs: Epinephrine, norepinephrine. (iii) Anticholinesterase agents: Physostigmine, Edrophonium. Organophosphorous compounds.
b) (i) Antimuscarinic Agents or Atropine Drugs: atropine sulfate, scopolamine hydrobromide, homatropine hydrobromide. (ii) Drugs inhibiting adrenergic nerves and structures innervated by them, Adrenergic blocking agents.
c) Ganglion Stimulating and Blocking Agents.

ADRENOCEPTORS
Drugs that produce responses by interacting with adrenoceptors are referred to as adrenoceptor agonistsor adrenergic agonists. Norepinephrine and isoproterenol are examples of such compounds. Agents that inhibit responses mediated by adrenoceptor activation are known as adrenoceptor antagonists, adrenergic antagonists, or adrenergic blocking agents. Prazosin and propranolol are examples of receptor-blocking drugs.

ADRENERGIC BLOCKING AGENTS
1. Classification of adrenoceptors
Main pharmacological classification into α and β subtypes, based originally on order of potency among agonists, later on selective antagonists.
Adrenoceptor subtypes:
two main α-receptor subtypes, α1 and α2, each divided into three further subtypes
three β-adrenoceptor subtypes (β1, β2, β3)
all belong to the superfamily of G-protein-coupled receptors.
Second messengers:
· α1-receptors activate phospholipase C, producing inositol trisphosphate and diacylglycerol as second messengers
· α2-receptors inhibit adenylate cyclase, decreasing cAMP formation
· all types of β-receptor stimulate adenylyl cyclase.

The main effects of receptor activation are as follows.
α1-receptors: vasoconstriction, relaxation of gastrointestinal smooth muscle, salivary secretion and hepatic glycogenolysis
α2-receptors: inhibition of transmitter release (including noradrenaline and acetylcholine release from autonomic nerves), platelet aggregation, contraction of vascular smooth muscle, inhibition of insulin release
β1-receptors: increased cardiac rate and force
β2-receptors: bronchodilatation, vasodilatation, relaxation of visceral smooth muscle, hepatic glycogenolysis and muscle tremor
β3-receptors: lipolysis.

2. α-Adrenoceptor antagonists
The clinically important α-blockers fall primarily into three chemical groups:
Ø the haloalkylamines (e.g., phenoxybenzamine)
Ø the imidazolines (e.g., phentolamine), and
Ø the quinazoline derivatives (e.g., prazosin).
Of these three classes of α-adrenoceptor antagonists, the quinazoline compounds are of greatest clinical utility and are much emphasized. The use of the haloalkylamines and imidazolines has diminished in recent years because they lack selectivity for α1- and α2-receptors.
The main groups of α-adrenoceptor antagonists based on their selectivity are:
# non-selective α-receptor antagonists (e.g. phenoxybenzamine, phentolamine)
# α1-selective antagonists (e.g. prazosin, doxazosin, terazosin)
# α2-selective antagonists (e.g. yohimbine, idazoxan)

Non-selective α-adrenoceptor antagonists
Phenoxybenzamine is not specific for α-receptors, and also antagonises the actions of acetylcholine, histamine and 5-HT. It is long-lasting because it binds covalently to the receptor. Phentolamine is more selective, but it binds reversibly and its action is short-lasting. In humans, these drugs cause a fall in arterial pressure (because of block of α-receptor-mediated vasoconstriction) and postural hypotension. The cardiac output and heart rate are increased. This is a reflex response to the fall in arterial pressure, mediated through β-receptors. The concomitant block of α2-receptors tends to increase noradrenaline release, which has the effect of enhancing the reflex tachycardia that occurs with any blood pressure-lowering agent. Phenoxybenzamine retains a niche (but vital) use in preparing patients with phaeochromocytoma for surgery; its irreversible antagonism and the resultant depression in the maximum of the agonist dose -response are desirable in a situation where surgical manipulation of the tumour may release a large bolus of pressor amine into the circulation.

Selective α1 antagonists
Prazosin was the first α1-selective antagonist. Similar drugs with longer half-lives (e.g. doxazosin, terazosin), which have the advantage of allowing once-daily dosing, are now available. They are highly selective for α1-adrenoceptors and cause vasodilatation and fall in arterial pressure, but less tachycardia than occurs with non-selective α-receptor antagonists, presumably because they do not increase noradrenaline release from sympathetic nerve terminals. Some postural hypotension may occur.
The α1-receptor antagonists cause relaxation of the smooth muscle of the bladder neck and prostate capsule, and inhibit hypertrophy of these tissues, and are therefore useful in treating urinary retention associated with benign prostatic hypertrophy. Tamsulosin, an α1A-receptor antagonist, shows some selectivity for the bladder, and causes less hypotension than drugs such as prazosin, which act on α1B-receptors to control vascular tone.
It is believed that α1A-receptors play a part in the pathological hypertrophy not only of prostatic and vascular smooth muscle, but also in the cardiac hypertrophy that occurs in hypertension, and the use of selective α1A-receptor antagonists to treat these chronic conditions is under investigation.

Selective α2 antagonists
Yohimbine is a naturally occurring alkaloid; various synthetic analogues have been made, such as idazoxan. These drugs are used experimentally to analyse α-receptor subtypes, and yohimbine, probably by virtue of its vasodilator effect, historically enjoyed notoriety as an aphrodisiac, but they are not used therapeutically.

PRAZOSIN

Mechanism of Action
The α-antagonism produced by prazosin and the other quinazoline derivatives is of the equilibrium-competitive type. The drugs are selective for α1-adrenoceptors, so that at usual therapeutic concentrations there is little or negligible antagonism of α2-adrenoceptors. However, selectivity is only relative and can be lost with high drug concentrations. While most of the pharmacological effects of prazosin are directly attributable to α1-antagonism, at high doses the drug can cause vasodilation by a direct effect on smooth muscle independent of α-receptors. This action appears to be related to an inhibition of phosphodiesterases that results in an enhancement of intracellular levels of cyclic nucleotides (like cGMP).

Absorption, Metabolism, Excretion
Prazosin is readily absorbed after oral administration, peak serum levels occur approximately 2 hours after a single oral dose, and the antihypertensive effect of prazosin persists for up to 10 hours.
Distribution- * Plasma half-life- 2.5 to 4 hours
* Elimination from plasma follows first-order kinetics.
* 97% bound to plasma proteins.
Biotransformation- Hepatic O-dealkylation and glucuronide formation.
Excretion- 10% of orally administered prazosin is excreted in the urine. Plasma levels of prazosin are increased in patients with renal failure; the nature of this interaction is unknown.

Pharmacological Actions
The most important pharmacological effect of prazosin is its ability to antagonize vascular smooth muscle contraction that is caused by either sympathetic nervous activity or the action of adrenomimetics. Hemodynamically, the effects of prazosin differ from those of phenoxybenzamine and phentolamine in that venous smooth muscle is not as much affected by prazosin. Postural hypotension during chronic treatment is also less of a problem. Also, increases in heart rate, contractile force, and plasma renin activity, which normally occur after the use of vasodilators and α-blockers, are much less prominent following chronic treatment with prazosin. Prazosin blocks responses mediated by postsynaptic α1-receptors but has no effect on the presynaptic α2-receptors. Thus, stimulation of the heart and renin release is less prominent with this drug.

Clinical Uses
Hypertension- Prazosin is effective in reducing all grades of hypertension. The drug can be administered alone in mild and (in some instances) moderate hypertension. When the hypertension is moderate or severe, prazosin generally is given in combination with a thiazide diuretic and a β-blocker. The antihypertensive actions of prazosin are considerably potentiated by coadministration of thiazides or other types of antihypertensive drugs.
Prazosin may be particularly useful when patients cannot tolerate other classes of antihypertensive drugs or when blood pressure is not well controlled by other drugs. Since prazosin does not significantly influence blood uric acid or glucose levels, it can be used in hypertensive patients whose condition is complicated by diabetes mellitus or gout.
Prostatic hypertrophy- Prazosin and other α-antagonists find use in the management of benign prostatic obstruction, especially in patients who are not candidates for surgery. Blockade of α-adrenoceptors in the base of the bladder and in the prostate apparently reduces the symptoms of obstruction and the urinary urgency that occurs at night.

Adverse Effects
Although less of a problem than with phenoxybenzamine or phentolamine, symptoms of postural hypotension, such as dizziness and light-headedness, are the most commonly reported side effects associated with prazosin therapy. These effects occur most frequently during initial treatment and when the dosage is sharply increased. Postural hypotension seems to be more pronounced during Na+ deficiency, as may occur in patients on a low-salt diet or being treated with diuretics, α- blockers, or both.