6/5/13

Phenoxybenzamine

 Phenoxybenzamine [fen-ox-ee-BEN-za-meen] is nonselective, linking covalently to both α1-postsynaptic and α2-presynaptic receptors


Figure : Covalent  inactivation of α1 adrenoceptor by phenoxybenzamine.



The block is irreversible and noncompetitive, and the only mechanism the body has for overcoming the block is to synthesize new adrenoceptors, which requires a day or more. Therefore, 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.


1. Actions: 

a. Cardiovascular effects: 

By blocking α receptors, phenoxybenzamine prevents vasoconstriction of peripheral blood vessels by endogenous catecholamines. The decreased peripheral resistance provokes a reflex tachycardia. Furthermore, the ability to block presynaptic inhibitory 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 β receptors on the heart to increase cardiac output]. Thus, the drug has been unsuccessful in maintaining lowered blood pressure in hypertension and has been discontinued for this purpose.


 b. Epinephrine reversal: 

All α-adrenergic blockers reverse the α-agonist actions of epinephrine. For example, the vasoconstrictive action of epinephrine is interrupted, but vasodilation of other vascular beds caused by stimulation of β receptors is not blocked. Therefore, the systemic blood pressure decreases in response to epinephrine given in the presence of phenoxybenzamine .


Figure : Summary of effects of adrenergic blockers on the changes in blood pressure induced by isoproterenol, epinephrine, and norepinephrine.


 [Note: The actions of norepinephrine are not reversed but are diminished, because norepinephrine lacks significant β-agonist action on the vasculature.] Phenoxybenzamine has no effect on the actions of isoproterenol, which is a pure β agonist .


2. Therapeutic uses:

Phenoxybenzamine is used in the treatment of pheochromocytoma, a catecholamine-secreting tumor of cells derived from the adrenal medulla. Prior to surgical removal of the tumor, patients are treated with phenoxybenzamine to preclude the hypertensive crisis that can result from manipulation of the tissue. This drug is also useful in the chronic management of these tumors, particularly when the catecholamine-secreting cells are diffuse and, therefore, inoperable. Phenoxybenzamine or phentolamine are sometimes effective in treating Raynaud's disease. Autonomic hyperreflexia, which predisposes paraplegics to strokes, can be managed with phenoxybenzamine.

3. Adverse effects:

Phenoxybenzamine can cause postural hypotension, nasal stuffiness, nausea, and vomiting. It can inhibit ejaculation. The drug also may induce reflex tachycardia, mediated by the baroreceptor reflex, and is contraindicated in patients with decreased coronary perfusion.



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