Interaction between antidepressants and alpha 1-adrenergic receptor antagonists on the binding to alpha 1-acid glycoprotein.

alpha 1-Receptor antagonists and antidepressant agents are basic (cationic) drugs that are known to bind to alpha 1-acid glycoprotein (AAG). Since these drugs are frequently co-administered and since they bind to the same protein, this investigation was designed to evaluate the "in vitro" ability of antidepressants, alpha 1-receptor antagonists, and propranolol to displace [3H]imipramine and [3H]prazosin from the AAG binding site(s). Equilibrium dialysis was employed. Of the drugs studied, the following order of potency in displacing [3H]prazosin was found: trazodone greater than prazosin greater than doxazosin greater than propranolol greater than doxepin = amoxapine = trimazosin = amitriptyline greater than imipramine greater than nortriptyline = desipramine = nomifensine greater than bupropion = maprotiline. [3H]lmipramine binding from AAG was displaced with the following potency order: prazosin greater than imipramine greater than propranolol greater than doxazosin greater than nortriptyline greater than desipramine greater than trimazosin. Tricyclic antidepressants produced similar degrees of displacement of both [3H]imipramine and [3H]prazosin from AAG; whereas, alpha 1-receptor antagonists were more effective displacers of [3H]prazosin than of [3H]imipramine. Furthermore, the demethylated metabolites of imipramine and amitriptyline were less potent displacers than their parent compounds. These results suggest that more than a single binding site may be available for binding to AAG and that hydrophobic bonding is important in the binding of drugs to AAG.

Agents with tricyclic structures for treating peptic ulcer disease.

The pathogenesis, clinical signs, and conventional treatment of peptic ulcer disease (PUD) are briefly discussed, and the use of drugs with tricyclic structures in the treatment of PUD is reviewed. Peptic ulcers occur most commonly in the duodenal bulb and the stomach. Numerous factors contribute to the formation of peptic ulcers, but an imbalance between acid and pepsin secretion and mucosal resistance is considered important. Conventional drug therapy of PUD with antacids, H2-receptor antagonists, anticholinergic drugs, and sucralfate is designed to correct this imbalance by neutralizing acid, inhibiting acid secretion, preventing contact of the ulcer with acid and pepsin, and enhancing mucosal defense mechanisms. Tricyclic agents that appear to be useful in the treatment of PUD are the tricyclic antidepressants, trimipramine maleate and doxepin hydrochloride, and the selective antimuscarinic drug, pirenzepine hydrochloride. The therapeutic effects of tricyclic antidepressants may result from their anticholinergic, antidepressant, and H2-receptor blocking actions. Controlled clinical trials suggest that trimipramine 50 mg/day (as the maleate salt) and pirenzepine hydrochloride 100-150 mg/day are superior to placebo and may be as effective as cimetidine for the short-term treatment of duodenal ulcers. Limited data suggest that these drugs are also effective for treating gastric ulcers. Assessment of the apparent efficacy of doxepin in duodenal ulcer treatment requires further study. Anticholinergic side effects and sedation associated with the administration of tricyclic agents may limit their usefulness as first-line anti-ulcer agents. With further evidence of their efficacy, trimipramine, doxepin, and pirenzepine may play an important role in the treatment of patients unresponsive to conventional anti-ulcer therapy.