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Query: UMLS:C0018681 (headache)
 56,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Calcium antagonists are potent vasodilators and are widely used in the treatment of hypertension and angina pectoris. The currently available compounds belong to three classes: (1) dihydropyridines (e.g. nifedipine, amlodipine and felodipine), (2) phenylalkylamines (e.g. verapamil) and (3) benzothiazepines (e.g. diltiazem). The three classes differ in their pharmacological profile and safety. For example, verapamil and diltiazem lower heart rate, while dihydropyridines increase it or leave it unchanged. With most of the latter compounds, a marked activation of the sympathetic nervous system has been noted. Most compounds exhibit negative inotropic effects, particularly the first-generation molecules, which is disadvantageous in patients with impaired left-ventricular function. The most common side effects of these drugs are flushing, headache and edema. With verapamil, constipation may represent a problem in certain patients. Hence, in spite of a large number of calcium antagonists available, there remains a need for new compounds with enhanced efficacy and improved tolerability. A new compound should lack any negative inotropism, avoid any increase in sympathetic outflow or heart rate and exhibit a high degree of vascular selectivity. Furthermore, a low incidence of side effects, particularly ankle edema and optimal pharmacokinetics allowing once-daily dosing would be desirable. Mibefradil is a new calcium antagonist with promising pharmacological and clinical properties. The compound has a high bioavailability, lacks negative inotropic effects at therapeutic concentrations, does not exhibit reflex tachycardia during vasodilation and actually slightly decreases heart rate. It is a potent direct vasodilator efficacious in hypertension and chronic angina pectoris, elicits endothelium-dependent relaxations and facilitates the effects of nitric oxide in vascular smooth muscle. The drug is a particularly efficacious vasodilator in intramyocardial coronary arteries which may be important for its anti-ischemic effects and the lack of steal in the coronary circulation. Furthermore, mibefradil has antiproliferative properties in human vascular smooth muscle cells in culture. As a unique property, mibefradil blocks T-type calcium channels and hence represents a new class of calcium channel blockers. In patients with hypertension, mibefradil has a high efficacy in controlling blood pressure. The drug does not cause constipation and has a low incidence of ankle edema. A large trial is under way to further delineate the properties of this new calcium antagonist in patients with heart failure.
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PMID:Comparative pharmacological properties among calcium channel blockers: T-channel versus L-channel blockade. 957 Apr 24

Mibefradil, a tetralol derivative, is the first representative of a new class of calcium antagonists. It selectively blocks entry of calcium into cells through T-type channels. The efficacy and tolerability of mibefradil in the treatment of mild-to-moderate essential hypertension were evaluated in four placebo-controlled, double-blind, dose-finding studies involving over 1000 patients. Two trials involved patients from the general population, one examined a subpopulation of elderly patients, and one evaluated patients receiving chronic hydrochlorothiazide (HCTZ) treatment. Based on these studies, the recommended doses of mibefradil are 50 mg and 100 mg. Doses >100 mg/day were associated with small gains in efficacy and an increased incidence of adverse effects. Response (sitting diastolic blood pressure normalization to < or =90 mm Hg or reduction by > or =10 mm Hg) rates to mibefradil ranged from 46.0% to 68.6% with 50 mg, and from 60.0% to 93.2% with 100 mg. Normalization rates paralleled the response rates, ranging from 34.0% to 62.9% with 50 mg, and from 42.5% to 81.8% with 100 mg. The effects on sitting systolic blood pressure were similar. Treatment was associated with a slight, potentially beneficial reduction in heart rate. Results were similar across all populations, indicating that no dose adjustment is required for elderly and for HCTZ-treated patients. The frequency of adverse events was similar to that reported for placebo groups, with headache being the most common complaint. In comparative trials, mibefradil was more effective than nifedipine SR and diltiazem CD, and at least as effective as amlodipine and nifedipine GITS. Overall, mibefradil was better tolerated than the comparison drugs. Mibefradil, at the recommended doses of 50 to 100 mg/day, is safe and effective for the treatment of mild-to-moderate hypertension.
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PMID:Mibefradil, a T-channel-selective calcium antagonist: clinical trials in hypertension. 960 72

Mibefradil is the prototype of a new class of calcium antagonists that selectively block T-type voltage-gated plasma membrane calcium channels in vascular smooth muscle. The drug is structurally and pharmacologically different from traditional calcium antagonists. It does not have negative inotropism at therapeutic concentrations, and is not associated with reflex activation of neurohormonal and sympathetic systems. In clinical studies of hypertension, mibefradil 50 and 100 mg/day reduced trough sitting diastolic and systolic blood pressures in a dose-related manner. Dosages exceeding 100 mg/day generally did not result in significantly greater efficacy, but were associated with a higher frequency of adverse events. No first-dose hypotensive phenomenon was observed. Mibefradil has antiischemic properties resulting from dilation of coronary and peripheral vascular smooth muscle, and a slight reduction in heart rate. In clinical studies of chronic stable angina pectoris, dose-related increases in exercise duration, time to onset of angina, and time to 1-mm ST-segment depression during exercise tolerance tests occurred. Mibefradil reduced the number and duration of ischemic events recorded by 48-hour ambulatory electrocardiograph (ECG) monitoring, as well as number of anginal episodes and nitroglycerin consumption. Favorable hemodynamic and clinical profiles are reported, including high trough:peak ratios (> 80%), high oral bioavailability, and long elimination half-life (17-25 hrs) permitting once/day dosing. Dizziness, headache, leg edema, and lightheadedness are frequently reported, but overall the agent is well tolerated. First-degree atrioventricular block and sinus bradycardia are the most frequent ECG changes caused by the drug. In vitro studies indicate mibefradil inhibits cytochrome P450 1A2, 2D6, and 3A4, resulting in elevated plasma concentrations of drugs metabolized by those isoenzymes. Therefore, it is contraindicated in patients receiving terfenadine, astemizole, cisapride, lovastatin, or simvastatin.
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PMID:Mibefradil, a pharmacologically distinct calcium antagonist. 962 98