Adrenergic Antagonists (Sympatholytics)

Basic stages in synaptic transmission

Inhibition of sympathetic nervous system The inhibition of Sympathetic N S is accomplished by the following mechanism: 1- Interacting with adrenergic receptors.( α& β ) 2- Interacting with synthesis of NE. 3- Interacting with storage of NE. 4- Interacting with release of NE. 5- Interacting with reuptake of NE

Inhibition of sympathetic nervous system (continued) The inhibition of Sympathetic N S is accomplished by the following mechanism: 6- Interacting with presynaptic degradation of NE. 7- Interacting with post synaptic inactivation of NE.

Adrenergic receptor blocker Adrenergic receptors (reversible or irreversible blocking of α or/and β receptors)

Adrenergic Blocking Drugs These groups are competitively inhibit α and/or β receptor sites. Can be classified into three classes: 1- α blockers (selective and None selective). 2- β blockers (selective and None selective). 3- α and β blockers (specific for both α and β)

Adrenergic Receptor Antagonist  α-Blockers: Non selective: Phenoxybenzamine & Phentolamine Selective α1-Blocker: Prazosin, Terazosin, Doxazosin & Tamsulosin Selective α2-Blocker: Yohimbine (Sympatholytic ?)  β-Blockers: Non selective: Propranolol, Timolol & Nadolol Selective β1-Blocker: Atenolol, Metoprolol & Esmolol Selective β1-Blocker with partial β2 agonist activity: Acebutolol & Pindolol  α & β Blocker: Labetalol & carvidilol

Effects of α-adrenoceptor Antagonists The most important effect is CVS effect They block α1 receptors causing decrease in peripheral resistance and consequently increase BP. The resultant hypotension provokes reflex tachycardia.

Non-selective α- blockers 1- Phenoxybenzamine: Nonselective, linking covalently to both α1-postsynaptic and α2-presynaptic receptors. The block is irreversible and noncompetitive, and the only mechanism for overcoming the block is to synthesize new adrenoceptors (NE), which requires a day or more. The actions of phenoxybenzamine last about 24 hours after a single administration. After the drug is injected, a delay of a few hours occurs before a blockade develops, because the molecule must undergo biotransformation to the active form.

Phenoxybenzamine

Cardiovascular effects: 1- By blocking α1 receptors, phenoxybenzamine prevents vasoconstriction of peripheral blood vessels by endogenous catecholamines. 2- The decreased peripheral resistance provokes a reflex tachycardia.

Phenoxy benzamine 3- The ability to block presynaptic α2 receptors in the heart can contribute to an increased cardiac output. [Note: These receptors when blocked will result in more norepinephrine release, which stimulates β1 receptors on the heart to increase cardiac output]. 4- This drug has been unsuccessful in maintaining lowered blood pressure in hypertension.

Phenoxy benzamine Therapeutic uses: Phenoxybenzamine is used in the treatment of pheochromocytoma, a catecholamine secreting tumor of cells derived from the adrenal medulla. Adverse effects: Phenoxybenzamine can cause postural hypotension, and reflex tachycardia.

Non-selective α- blockers 2- Phentolamine In contrast to phenoxybenzamine, phentolamine produces a competitive block of α1 and α2 receptors. The drug's action lasts for approximately 4 hours after a single administration. Like phenoxybenzamine, it produces postural hypotension Phentolamine-induced reflex cardiac stimulation and tachycardia Phentolamine is used for the short-term management of pheochromocytoma.

Non-selective α- blockers (Continued) The main differences between phenoxybenzamine and phentolamine are:  Phenoxybenzamine is a prodrug that takes few hrs for biotransformation while phentolamine is not a prodrug  Phenoxybenzamine bind covalently (irreversible binding) to α receptors and so the activity last for about 28 hrs. On the other hand, phentolamine is competitive blocker (reversible binding), so the activity last for 4hr.

Selective α1-blockers A- Prazosin, terazosin and doxazosin. These drugs decrease peripheral vascular resistance and lower arterial blood pressure by causing the relaxation of both arterial and venous smooth muscle. These drugs, unlike phenoxybenzamine and phentolamine, cause minimal changes in cardiac output; thus The hypotensive effect is more dramatic than the effect of non selective.

Selective α1-blockers

Therapeutic uses of Prazosin, terazosin and doxazosin Hypertension: They are used alone or in combination with other antihypertensive drugs.

Selective α1-blockers Adverse effects : dizziness, a lack of energy, nasal congestion, headache, drowsiness, and orthostatic hypotension the first dose of these drugs produces an exaggerated orthostatic hypotensive response that can result in syncope (fainting). This action, termed a first-dose effect, may be minimized by adjusting the first dose to one-third or one-fourth of the normal dose and by giving the drug at bedtime.

Selective α1-blockers B- Flomax (tamsulosin). Tamsulosin is a potent inhibitor of the α1A receptors found on the smooth muscle of the prostate. This selectivity accounts for tamsulosin's minimal effect on blood pressure. Produces smooth muscle relaxation of prostate gland and bladder neck. Minimal orthostatic hypotension.

Selective α1-blockers Medical uses of Flomax (tamsulosin) Tamsulosin is used to improve urination in men with benign prostatic hyperplasia (enlarged prostate).

Selective α1-blockers C- Priscoline (tolaxoline): Priscoline used for Pulmonary hypertension in newborn.

Selective α2- blockers Yohimbine blocks α2 causing increase in sympathetic flow and so BP. It has been abused for sexual stimulant. No approved medical uses

Orthostatic hypotension -Orthostatic hypotension is the major side effect of the most of antihypertensive drugs. -It is a problem with Prazosin analogs and to a lesser extent with Tamsulosin. -Orthostatsis is a problem that can be seen with any vasodilator that affects the tone on venous smooth muscle.

Orthostatic hypotension (continued) Orthostatic hypotension is observed with organic nitrates, hydralazine, clonidine,and minixodil. Orthostatic hypotension or postural hypotension occurs when systemic arterial blood pressure falls by more than 20 mmHg upon standing. In this situation, cerebral perfusion falls and an individual may become light headed, dizzy or fatality may occur.

Orthostatic hypotension (continued) In changing from the supine to the standing position, gravity tends to cause blood to pool in the lower extremities. However, several reflexes, including sympathetically mediated venoconstriction minimize this pooling and maintain cerebral perfusion. If these reflex actions do not occur, then orthostatic hypotension could result.

Orthostatic hypotension (continued) By blocking the α 1 -receptors associated with venous smooth muscle, prazosin-like drugs, inhibit the sympathetically mediated vasoconstriction associated with postural changes. Hence, orthostatic hypotension can occur.

Orthostatic hypotension (contued) Drugs like clonidine cause orthostasis due to its CNS actions that block the sympathetic reflexes. Vasodilators such as nitrates, minoxidil, hydralazine or impotence medications cause orthostasis because of their actions directly on the vasculature.