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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. Like the agonists, the adrenergic antagonists are classified according to their relative affinities for α or β receptors in the peripheral nervous system. [Note: Antagonists that block dopamine receptors are most important in the central nervous system (CNS) and are therefore considered in that section ).] 




The receptor-blocking drugs discussed in this chapter are summarized in Figure above 


  • α-Adrenergic Blocking Agents 

Drugs that block α-adrenoceptors profoundly affect blood pressure. Because normal sympathetic control of the vasculature occurs in large part through agonist actions on α-adrenergic receptors, blockade of these receptors reduces the sympathetic tone of the blood vessels, resulting in decreased peripheral vascular resistance. This induces a reflex tachycardia resulting from the lowered blood pressure. [Note: β receptors, including β1-adrenoceptors on the heart, are not affected by α blockade.] The α-adrenergic blocking agents, phenoxybenzamine and phentolamine, have limited clinical applications.



D. Yohimbine 





  • β-Adrenergic Blocking Agents 

All the clinically available β-blockers are competitive antagonists. Nonselective β-blockers act at both β1 and β2 receptors, whereas cardioselective β antagonists primarily block β1 receptors [Note: There are no clinically useful β2 antagonists]. These drugs also differ in intrinsic sympathomimetic activity, in CNS effects, and in pharmacokinetics


Figure : Elimination half- lives  for some α- blockers.

Although all β-blockers lower blood pressure in hypertension, they do not induce postural hypotension, because the α-adrenoceptors remain functional. Therefore, normal sympathetic control of the vasculature is maintained. β-Blockers are also effective in treating angina, cardiac arrhythmias, myocardial infarction, congestive heart failure, hyperthyroidism, and glaucoma, as well as serving in the prophylaxis of migraine headaches. [Note: The names of all β-blockers end in “-olol” except for labetalol and carvedilol
B. Timolol and nadolol: Nonselective β antagonists Timolol [TIM-o-lole] and nadolol [NAH-doh-lole] also block β1- and β2- adrenoceptors and are more potent than propranolol. Nadolol has a very long duration of action . Timolol reduces the production of aqueous humor in the eye. It is used topically in the treatment of chronic open-angle glaucoma and, occasionally, for systemic treatment of hypertension.

C. Acebutolol, atenolol, metoprolol, and esmolol: 





  •  Drugs Affecting Neurotransmitter 
Release or Uptake , some agonists, such as amphetamine and tyramine, do not act directly on the adrenoceptor. Instead, they exert their effects indirectly on the adrenergic neuron by causing the release of neurotransmitter from storage vesicles. Similarly, some agents act on the adrenergic neuron, either to interfere with neurotransmitter release or to alter the uptake of the neurotransmitter into the adrenergic nerve. However, due to the advent of newer and more effective agents, with fewer side effects, these agents are rarely used therapeutically. These agents are included in this chapter due to their unique mechanisms of action and historical value.


A. Reserpine
 Reserpine [re-SER-peen], a plant alkaloid, blocks the Mg2+/adenosine triphosphate–dependent transport of biogenic amines, norepinephrine, dopamine, and serotonin from the cytoplasm into storage vesicles in the adrenergic nerves of all body tissues. This causes the ultimate depletion of biogenic amines. Sympathetic function, in general, is impaired because of decreased release of norepinephrine. The drug has a slow onset, a long duration of action, and effects that persist for many days after discontinuation.

B. Guanethidine
Guanethidine [gwahn-ETH-i-deen] blocks the release of stored norepinephrine as well as displaces norepinephrine from storage vesicles (thus producing a transient increase in blood pressure). This leads to gradual depletion of norepinephrine in nerve endings except for those in the CNS. Guanethidine commonly causes orthostatic hypotension and interferes with male sexual function. Supersensitivity to norepinephrine due to depletion of the amine can result in hypertensive crisis in patients with pheochromocytoma.

C. Cocaine
Although cocaine inhibits norepinephrine uptake, it is an adrenergic agonist.





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