Angina

Therapeutic opportunities for NO synthons include angina, for which nitroglycerin is effectively used, as well as penile erectile dysfunction. NOS inhibitors have demonstrated some protection in cerebral ischemia models and may be potentially beneficial in alleviating cell death associated with cerebral ischemia. l-NMA is under clinical study for treatment of sepsis. 

Salts of acetarsone are used in the treatment of intestinal amoebiasis, vaginal trichomoniasis, and necrotizing ulcerative gingivitis (Vincent s angina). The diethylamine salt (acetylarsan [534-33-8]) has antisyphilitic properties. Because of toxicity problems, safer dmgs have been developed. Oral LD q in rabbits is 150 mg /kg. 

Other agents are also used for the treatment of manic-depressive disorders based on preliminary clinical results (177). The antiepileptic carbamazepine [298-46-4] has been reported in some clinical studies to be therapeutically beneficial in mild-to-moderate manic depression. Carbamazepine treatment is used especially in bipolar patients intolerant to lithium or nonresponders. A majority of Hthium-resistant, rapidly cycling manic-depressive patients were reported in one study to improve on carbamazepine (178). Carbamazepine blocks noradrenaline reuptake and inhibits noradrenaline exocytosis. The main adverse events are those found commonly with antiepileptics, ie, vigilance problems, nystagmus, ataxia, and anemia, in addition to nausea, diarrhea, or constipation. Carbamazepine can be used in combination with lithium. Several clinical studies report that the calcium channel blocker verapamil [52-53-9] registered for angina pectoris and supraventricular arrhythmias, may also be effective in the treatment of acute mania. Its use as a mood stabilizer may be unrelated to its calcium-blocking properties. Verapamil also decreases the activity of several neurotransmitters. Severe manic depression is often treated with antipsychotics or benzodiazepine anxiolytics. 

There has been a rebirth of interest in a spirin between the 1970s and 1990s as evidence accumulated from a number of clinical trials that aspirin ingestion lowers the incidence of myocardial infarction (39,40), unstable angina (41,42), and stroke (43). 

Elestolol sulfate is a nonselective, ultrashort acting P-adrenoceptor blocker. It has no ISA and produces weak inhibition of the fast sodium channel. The dmg is under clinical investigation for supraventricular tachyarrhythmias, unstable angina, and acute MI. In humans, flestolol has hemodynamics and electrophysiologic effects similar to those of other P-adrenoceptor blockers. The pharmacokinetics of flestolol are similar to those of esmolol. It is 50 times more potent than esmolol and the elimination half-life is 7.2 min. Recovery from P-adrenoceptor blockade is 30—45 min after stopping iv infusions. The dmg is hydrolyzed by tissue esterases and no active metabohtes of flestolol have been identified (41). 

Bopindolol is a long-acting, nonselective P-adrenoceptor blocker. It has mild membrane stabilizing activity and ISA. In vivo, the compound is hydrolyzed to its active metabohte. Because of this prodmg feature the onset of action is slower than other available P-adrenoceptor blockers. Preliminary pharmacokinetic studies indicate that the compound is weU absorbed, is 70% bioavailable, and peak plasma levels are achieved in about 2 h. Whereas its elimination half-life is 4—8 h, P-adrenoceptor blocking action (- 40%) is stiU apparent after 48 h. The dmg is being studied in hypertension, angina, and arrhythmias (43). 

Nitroglycerin remains the dmg of choice for treatment of angina pectoris. It has also been found useful for the treatment of congestive heart failure, myocardial infarction, peripheral vascular disease, such as Raynaud s disease, and mitral insufficiency, although the benefits of nitroglycerin in mitral insufficiency have been questioned. 

Verapamil. Verapamil hydrochloride is a pbenyl alkyl amine and is considered the prototype of the Class I calcium channel blockers. Verapamil is also a potent inhibitor of coronary artery spasm and is useful in Prinzmetal s angina and in unstable angina at rest. Verapamil produces negative chronotropic and inotropic effects. These two actions reduce myocardial oxygen consumption and probably account for the effectiveness of verapamil in chronic stable effort angina (98,99). Moreover, verapamil is an effective antihypertensive agent. 

Propranolol. Propranolol (Table 1), a Class II antiarrhythmic agent, is usefiil in the management of hypertrophic subaortic stenosis, especially for the treatment of exertional or other stress-induced angina by improving blood flow. The dmg can increase exercise tolerance in patients suffering from angina. Propranolol has been shown to have cardioprotective action in post-MI patients (37—39,98,99,108). 

Nadolol. Nadolol (Table 3) is a hydrophilic, nonselective -adrenoceptor blocking agent having no ISA and no membrane-stabilizing activity. It is useful for the treatment of hypertension and chronic stable exertional angina (98,99,108). 

Other P"Adrenoceptor Blocking Agents. Carteolol hydrochloride (Table 1) is also a Class II antiarrhythmic agent. In three separate studies in patients having angina pectoris, carteolol was considered effective as evidenced by a reduction in the frequency and severity of anginal episodes, reduction in the amount of nitroglycerin consumed, improvement of ECG parameters, or an increase in the duration of trea dmill exercise (42). 

Bisoprolol fumarate is a long-acting, cardioselective -adrenoceptor blocker, and is the most potent cardioselective -adrenoceptor blocker available. Bisoprolol has no ISA. At high concentrations it has membrane-stabilizing activity. The dmg has a "balanced clearance", ie, half is excreted by the kidneys and half is eliminated by the Hver and its excretion is not affected by functional impairment of either organ. It is approved in Europe for hypertension and is being studied in angina (43). 

Bevantolol hydrochloride is a moderately lipophilic, long-acting, cardioselective -adrenoceptor blocker. It has no ISA but has membrane-stabilizing activity. The dmg is in use in Europe for the treatment of hypertension and angina. It is rapidly absorbed from the GI tract. Peak plasma levels occur in 1—2 h. It is metabolized extensively in the Hver to a metaboHte that has some ISA. It is excreted by the Hver and the kidneys and excretion is delayed in patients having kidney failure. 

Nifedipine (Table 3) is a potent vasodilator that selectively dilates resistance vessels and has fewer effects on venous vessels. It does not cause reflex tachycardia during chronic therapy. Nifedipine is one of the first-line choices for black or elderly patients and patients having concomitant angina pectoris, diabetes, or peripheral vascular diseases. Nifedipine, sublingually, is also suitable for the treatment of hypertensive emergencies. Nifedipine does not impair sexual function or worsen blood Hpid profile. The side effects are flushing, headache, and dizziness. 

Passive transdermal dehvery systems on the market tend to be either matrix or membrane controUed. In matrix devices, the stmctural and molecular characteristics of the dmg-polymer matrix determine dmg release. Examples of polymer matrix-controUed diffusional systems for angina prophylaxis include Nitro-Dur and Nitrodisc, which provide transdermal dehvery of nitroglycerin [55-63-0], and Erandol, a tape that releases isosorbide dinitrate [87-33-2]. Matrix diffusional systems have been used for dehvering dmgs with a wide therapeutic index. 

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