PHARMACOLOGY OF ALPHA ADRENERGIC RECEPTOR ANTAGONISTS 2002

I. Alpha Adrenergic Receptor Antagonists

A. Introduction

1. Alpha receptors mediate many important actions of endogenous catecholamines. These include:

a. alpha 1 mediated vasoconstriction,

b. alpha 2 receptor mediated inhibition of the release of NE and ACh,

c. alpha 2 mediated inhibition of insulin secretion and inhibition of lipolysis,

d. alpha 2 mediated contraction of blood vessels in skin and mucosa (these receptors are preferentially activated by circulating catecholamines, whereas alpha 1 receptors are activated by NE released at sympathetic nerve terminals).

e. alpha 2 mediated central inhibition of sympathetic tone.

2. Correspondingly therefore it should be evident that "A detailed knowledge of the autonomic nervous system and the sites of action of drugs that act on adrenergic receptors is essential for understanding the pharmacology and therapeutic uses of ..." adrenergic receptor blocking drugs (G & G, 1990,p221).

B. The most important effects of alpha 1 & 2 adrenergic antagonists are on the cardiovascular system. These cardiovascular effects are mediated in large part by the effects of the antagonists on sympathetic nerve endings, and by effects on the CNS. The antagonism which is observed in most cases is competitive.

C. Cardiovascular Effects of Alpha 1 Antagonists

1. Alpha 1 antagonists block vasoconstriction induced by endogenous catecholamines. The resulting fall in peripheral resistance leads to a fall in mean blood pressure. The magnitude of this effect is dependent upon the degree of sympathetic tone at the time the antagonist is administered. Thus there is less hypotension in the supine than in the standing patient. The decrease in blood pressure leads to a reflex tachycardia. The reflex effects are exaggerated if the drug also has alpha 2 antagonist effects, because antagonism of alpha 2 receptors facilitates release of NE presynaptically to cause a further tachycardic effect.

2. They block the vasoconstriction and hypertensive effects of exogenous sympathomimetics. For example, pressor responses to phenylephrine (a pure alpha 1 agonist) are completely blocked. Pressor responses to EPI can be transformed to depressor responses (EPI reversal) because of stimulation of beta 2 receptors by EPI.

D. Cardiovascular Effects of Alpha 2 Antagonists

1. Alpha 2 antagonists increase sympathetic outflow by an action on the CNS. This potentiates the release of NE from sympathetic nerve endings leading to activation of alpha 1 receptors in vascular smooth muscle, and beta 1 receptors in the heart among others. The net result is an increase in mean blood pressure, and a reflex bradycardia.

E. Other Actions of Alpha Adrenergic Antagonists

1. Alpha antagonists can block alpha 1 receptors that mediate contraction of nonvascular smooth muscle such as the trigone and sphincter muscles of the bladder, leading to decreased resistance to urinary outflow.

2. Activation of alpha 2 receptors causes inhibition of insulin secretion. Blockade of these receptors facilitates insulin release.

F. Pharmacology of Phenoxybenzamine

1. Phenoxybenzamine is an irreversible alpha blocker that blocks both alpha 1 and alpha 2 receptors with a slight preference for alpha 1 receptors. It causes a decrease in peripheral resistance, and a reflex tachycardia due to hypotension mediated baroreceptor effects, and also because it blocks alpha 2 receptors, resulting in increased release of NE. Hypotension is particularly prevalent when sympathetic reflexes are active, such as in the standing patient, or during stress. A major side effect therefore is postural hypotension. Also seen are cardiac arrhythmias. Phenoxybenzamine blocks pressor responses to exogenous catecholamines, and in fact causes reversal of the pressor response to EPI into a depressor response. Phenoxybenzamine also inhibits the uptake of catecholamines into nerve terminals and extraneuronal uptake sites, and irreversibly inhibits 5-HT, and histamine receptors in higher doses than those required for alpha receptor blockade. Duration of effect of this drug is many days. A major use of this drug is in the management of hypertension in pheochromocytoma prior to surgery.

G. Pharmacology of Phentolamine and Tolazoline

1. Phentolamine and tolazoline are competitive antagonists of both alpha 1 and alpha 2 receptors. As such their effects on the cardiovascular system are similar to those of phenoxybenzamine just discussed. These drugs also have a parasympathomimetic effect on GI smooth muscle and gastric secretions. Toxicity is like that of phenoxybenzamine. Phentolamine is also used in the management of hypertension in cases of pheochromocytoma prior to surgery. It is also used intradermally to prevent dermal necrosis in cases of inadvertent extravasation of an alpha adrenergic agonist. It has also been used to treat the hypertensive crisis which sometimes results from rapid withdrawal from clonidine.

H. Pharmacology of Prazosin and Related Drugs

1. Prazosin is the prototype of a family of potent and very selective alpha 1 receptor antagonists. It has 1000X greater affinity for alpha 1 vs alpha 2 receptors. It blocks all alpha one receptor subtypes equipotently. It is a short acting drug with a duration of action of about 7 to 10 hours. Prazosin causes a decrease in total peripheral resistance, but not an increase in heart rate (since alpha 2 receptors are not inhibited). Terazosin is a close structural analogue of prazosin with similar pharmacological effects, but an intermediate duration of action, ie approximately 18 hours. Doxazosin is another structural analogue with similar pharmacological effects to prazosin, but with a long duration of action, ie 36 hours. Adverse effects of these drugs include the so-called "first dose phenomenon". That is marked postural hypotension and fainting 30-90 minutes after the first dose, or with the addition of a second antihypertensive drug to a patient already taking one of these agents. Postural hypotension is another side effect. A major use of these drugs is in the treatment of hypertension. Alpha 1 receptors in the trigone muscle of the bladder and in the urethra contribute to the resistance to outflow of urine. Alpha 1 receptor blockers reduce this resistance especially when impaired bladder emptying is the result of benign prostatic hyperplasia. Tamsulosin is another alpha 1 blocker, with little effect on alpha 1-B receptors and considerable efficacy at the alpha 1-A receptor which is believed to be predominant in human bladder and prostate.. It is used in the treatment of benign prostatic hyperplasia because it decreases the resistance to urinary flow, with less hypotensive effects on blood pressure (although all the alpha blockers have been tested and are relatively effective in BPH).

I. Miscellaneous drugs with alpha adrenergic blocking activity

1. The ergot alkaloids were the first adrenergic blocking agents to be discovered.Ergot is a fungus which grows on rye which contains many biologically active components. Ergotism is a disease characterized by profound vasoconstriction , ischemia, and gangrene of the affected limb. In the Middle Ages it was known as St. Anthony's Fire, and was relieved by visiting the shrine of St. Anthony which was located in an area of France where bread was seldom contaminated with the fungus. Both ergotamine, and dihydroergotamine are structural derivatives of a compound isolated from ergot which have potent competitive alpha antagonist effects. These drugs are sometimes used in the treatment of migraine headache. However, 5HT-1 receptor agonists (ie sumatriptan) appear to be more effective and safer for migraine.

2. Phenothiazines, which are antipsychotic drugs, have potent alpha blocking actions.

J. Therapeutic Uses of Alpha Adrenergic Receptor Blockers

1. Hypertension

2. Pheochromocytoma

3. Sometimes used in treatment of peripheral vasospastic disease ie Raynauds disease to improve perfusion

4. To enhance urinary flow in benign prostatic hyperplasia. Major therapy is surgery.

5. Treatment of local excess concentration of a vasoconstrictor in order to prevent necrosis.

K. Toxicity of Alpha Blockers

1. Postural hypotension

a. First dose phenomenon with prazosin and analogues

2. Reflex tachycardia, especially with agents that also block alpha 2 receptors.

3. Other arrhythmias

4. Parasympathomimetic effects of phentolamine and tolazoline.