Irreversible antagonists/blockers

An example of an irreversible antagonist with a very long action (usually many hours) is phenoxybenzamine, which blocks a-adrenoceptors and, less potently, H,-histamine and muscarinic receptors. Its structure is shown below. Also illustrated is benzilylcholine mustard, a highly active and selective irreversible blocker of muscarinic receptors. 

Listing of antidepressants grouped by principal mechanism of action in the synapse. Abbreviations MAOI—irreversible = irreversible monoamine oxidase inhibitor MAOI—reversible = reversible monoamine oxidase inhibitor NDRl = norepinephrine/ dopamine reuptake inhibitor NRI = norepinephrine reuptake inhibitor NSRl = norepinephrine/serotonin reuptake inhibitor NSSA = norepinephrine/specific serotonin agonist SRI = serotonin reuptake inhibitor SRl/serotonin-2 blocker = serotonin reuptake inhibitor and serotonin-2 receptor antagonist. 

The superiority of omeprazole-like irreversible HVK -ATPase inhibitors over H2-receptor antagonists in acid-related disorders of the upper gastrointestinal tract is quite obvious. Their clinically relevant advantages are related to their different mode of action which is independent of the kind of acid stimulation and to their longer duration of action. Reversible H /K -ATPase inhibitors share the secretagogue independent mode of action with the irreversible inhibitors but show a duration of action which is comparable with that of Hj-receptor antagonists. Their clinical advantage over irreversible inhibitors has still to be proven. Other H /K -ATPase inhibitors such as Cl channel blockers are, at present, of experimental interest only. 

Examples of ai-blockers include compounds of diverse structures, such as the synthetic heterocyclics prazosin, indoramin, phentolamine the ergot alkaloids crgotamine and dil droergotamine and the haloalkylamine irreversible alkylators, e.g. phenoxybenzamine. Examples of antagonists relatively selective for a2-receptors over a,-receptors, are the natural indolealkylamine alkaloid yohimbine and its diastereoisomer rauwoisdnc (though they also have affinity for 5-HT receptors). However, mariy of the tt -blockers (especially prazosin) also have some affinity at the a2-adrenoceptor site. 

NSC 77370 CP 10188) is an ENZYME INHIBITOR, a selective irreversible tryptophan hydroxylase inhibitor, thereby depleting 5-HT in the brain. As an indirect 5-HT antagonist, it has been given to patients with carcinoid syndrome to relieve some of the symptoms, fendiline [inn] is a methylbenzylamine, a CALCIUM-CHANNEL BLOCKER and calmodulin antagonist, with coronary VASODILATOR properties. 

B, Mechanisms and Effects Ketanserin and cyproheptadine are competitive pharmacologic antagonists. Phenoxybenzamine is an irreversible blocker. 

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