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Non-specific Alpha Adrenergic Antagonist

  • Non-specific Alpha Adrenergic Antagonists, which include phenoxybenzamine and phentolamine, directly bind and antagonize both alpha1 and alpha2 adrenergic receptors, resulting in profound effects on the cardiovascular system. Their alpha1 blockade yields significant vasodilation and thus reduced blood pressure. Reflex tachycardia is exacerbated by blockade of alpha2 receptors, which reduces alpha2-mediated inhibition of the sympathetic nervous system. Because of these reflex responses, these non-specific alpha blockers have limited clinical utility.
Mechanisms of Actions
  • Phenoxybenzamine
    • Phenoxybenzamine is unique among the adrenergic antagonists in that it covalently binds alpha receptors and thus its antagonism is irreversible. Only new synthesis of alpha receptors can overcome its pharmacological action and thus the drugs effects are very long-lived.
  • Phentolamine
    • Phentolamine is a competitive antagonist of alpha receptors and thus its effects are much shorter in action. Furthermore, its pharmacological effects can be reversed by administration of alpha adrenergic agonists.
Pharmacological Effects
  • Alpha1 Blockade
    • Blockade of alpha1 receptors results in significant inhibition of baseline sympathetic vasocontrictive tone on the vasculature. This yields a systemic vasodilation and fall in systemic vascular resistance. In most patients this results in a fall in systemic arterial pressure that is sensed by baroreceptors which in turn trigger increased sympathetic tone to the heart, yielding increased heart rate (i.e. a reflex tachycardia). Additionally, because short-term regulation of blood pressure is largely mediated by rapid modulation of alpha1 receptors, these drugs often render patients prone to postural hypotension.
  • Alpha2 Blockade
    • Recall that presynaptic alpha2 receptors act to negatively inhibit release of endogenous norepinephrine from adrenergic nerve terminals. As a result of alpha2 blockade, these drugs yield enhanced norepinephrine release from sympathetic nerve terminals. In the context of increased sympathetic tone to the heart (Described above), this can yield hyper-stimulation of the heart, enhancing the reflex tachycardic response, and in some cases promoting arrhythmias.
Therapeutic Uses
  • Pheochromocytoma
    • The primary clinical application of phenoxybenzamine is in the pre-surgical management of pheochormocytomas. This drug is administered for several weeks prior to surgical removal of these catecholamine-secreting tumors in order to prevent any hypertensive crises resulting from leakage of catecholamines during their operative removal.
  • Hypertension
    • Non-specific alpha blockers are now rarely used in the management of hypertension due to their potential to cause significant postural hypotension and cardiac arrhythmias.