New Class Of Calcium Antagonists Research Articles

Pharmacokinetics and Pharmacodynamics of Mibefradil in Hypertensive Patients with Varying Degrees of Renal Insufficiency

Mibefradil, the first member of the tetralol derivatives, a new class of calcium antagonists, is used for the treatment of hypertension and angina pectoris. This study was designed to investigate the effect of varying degrees of chronic renal impairment on mibefradil pharmacokinetics and pharmacodynamics. Neither pharmacokinetic nor pharmacodynamic parameters varied as a function of renal status. Additionally, hemodialysis removed only a relatively small fraction of drug from the body. It was concluded that the majority of renal-failure patients will not require a change in mibefradil dosage relative to patients with normal renal function. Following hemodialysis, supplemental mibefradil treatment should not be necessary.

Mibefradil, a T-Channel–Selective Calcium Antagonist: Clinical Trials in Hypertension

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 ≤90 mm Hg or reduction by ≥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.

Mibefradil: A New Selective T-Channel Calcium Antagonist for Hypertension and Angina Pectoris.

Calcium antagonists are an established therapy for patients with hypertension and angina pectoris, but their current usage is often limited by their pharmacologic profilers and side effects. Mibefradil is a recently developed calcium antagonist with a unique chemical structure, site of action, and set of pharmacologic effects. Unlike currently available calcium channels as well as L-type channels. It is further distinguished from the other calcium antagonists in that it is the first member of a new class of calcium antagonists, the tetralol derivatives. With chronic oral dosing, mibefradil attains steady-state plasma concentrations within 3-4 days, has a bioavailability of approximately 90%, and a plasma half-life of 17-25 hours. It has a gradual onset of action and can be administered once daily without regard to food intake. It increases coronary blood flow and lowers peripheral vascular resistance. The vasodilatory effects of mibefradil are associated with a lack of inotropic effect on myocardium, lack of neurohormonal activation, and a reduction in heart rate. In clinical trials it has been demonstrated to be an effective agent in the treatment of patients with hypertension and angina pectoris, with a good safety and tolerability profile regardless of age, gender, or race.

Mibefradil: A Selective T-Type Calcium Antagonist

Mibefradil is the first of a new class of calcium antagonists with a unique structure and pharmacology. Its novel mechanism of action is characterized by L-type and selective T-type calcium channel blockade. Mibefradil is selective for smooth muscle over cardiac muscle and selectively dilates the coronary vasculature over the peripheral vasculature. In animal studies, mibefradil increases coronary blood flow during induced ischemia. In addition, in vitro studies demonstrated that mibefradil decreases smooth muscle proliferation in response to vascular injury. The most intriguing effects of mibefradil include a lack of negative inotropy and reflex tachycardia, as well as inhibition of pathologic hypertrophy and remodeling in response to vascular injury. In clinical trials, mibefradil (100 mg) was more effective than diltiazem dual-release capsules (360 mg) and as effective as amlodipine (10 mg) in treating mild-to-moderate hypertension; mibefradil (100 mg) also resulted in a greater reduction in sitting diastolic blood pressure than did nifedipine GITS (60 mg) in patients with moderate-to-severe hypertension. In patients with chronic stable angina, mibefradil (100 mg) was as effective as diltiazem SR capsules (120 mg) twice daily and more effective than amlodipine (10 mg) in improving exercise tolerance and reducing ischemic episodes. Mibefradil improved survival in a rat model of heart failure as effectively as the angiotensin-converting enzyme (ACE) inhibitor, cilazapril. The apparent lack of negative inotropic activity and neurohormonal activity with mibefradil, as well as its favorable effects on cardiac remodeling in experimental models, suggest that this agent may be beneficial in congestive heart failure. This hypothesis is being tested in the ongoing Mortality Assessment in Congestive Heart Failure (MACH-1) trial.

Mibefradil. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the management of hypertension and angina pectoris.

Mibefradil belongs to a new class of calcium antagonists, the tetralol derivatives. It selectively blocks T-type calcium channels in contrast to other calcium antagonists which block only L-type channels. Mibefradil relaxes coronary arteries without suppressing myocardial contractility and causes a dose-related decrease in heart rate. When given orally once daily to patients with hypertension mibefradil produces a dose-related decrease in blood pressure which is sustained for 24 hours and improves exercise performance in patients with stable angina pectoris. In patients with generally mild to moderate hypertension oral mibefradil was superior to nifedipine SR and diltiazem CD, tended to be more effective than nifedipine GITS and had similar efficacy to amlodipine. Mibefradil 50 to 100mg once daily also has antianginal and anti-ischaemic effects. The drug improves the duration of symptom-limited exercise and the time to onset of ischaemia, and reduces the frequency of anginal attacks and consumption of nitroglycerin. Its efficacy is similar to that of diltiazem and tends to be greater than that of amlodipine in patients with stable angina. Mibefradil is generally well tolerated and is associated with a lower incidence of leg oedema than amlodipine and nifedipine. Thus, mibefradil is a calcium antagonist with a predictable cardiovascular profile, which, on the basis of available clinical data, is an effective alternative to other drugs widely used in the treatment of hypertension and stable angina pectoris.

Diversity of calcium antagonists

Calcium antagonists (CAs) are widely used in the management of hypertension and chronic stable angina pectoris. Currently available CAs fall into three distinct structural classes—the dihydropyridines, the benzothiazepines, and the phenylalkylamines. The diversity of these agents, even among drugs within a structural group, is apparent in their pharmacology, physiologic effects, and therapeutic uses. Traditional CAs produce their effects through blockade of the L-type calcium channel. Recently, a new CA has been developed. Mibefradil, the first member of a new class of CAs, is a tetralol derivative. It is characterized by its selective blockade of T-type calcium channels. It differs from existing CAs and may offer important therapeutic advantages.

Predictable clinical effects in the treatment of hypertension and chronic, stable angina pectoris

Drug selection criteria A drug used in the treatment of hypertension and chronic, stable angina pectoris should have simple dosing, predictable efficacy and be well tolerated. Two factors can strongly influence the achievement of these goals: the mechanism of action of the compound and its pharmacokinetic profile. Clinical features Mibefradil, the first member of a new class of calcium antagonists, preferentially blocks transient (T-type) calcium channels. The compound has high bio-availability with a long half-life, and steady-state plasma concentrations are reached within 3–4 days. These pharmacokinetic characteristics are not affected by age, sex, race, body weight or renal function. Treatment with mibefradil results in coronary and peripheral vasodilation, a slight decrease in the heart rate, no negative inotropic effect and no reflex increase in sympathetic activity or neurohormones. There is a strong correlation between the plasma concentration of mibefradil and its clinical effects. Conclusions The results of two large, multicenter, placebocontrolled, randomized trials in hypertension and chronic, stable angina pectoris confirm that the combination of mibefradil's distinct mechanism of action and favorable pharmacokinetic profile achieves the goals of a simple dose schedule, predictable effect and good tolerability. These attributes, in turn, can increase patient compliance, with treatment and physician confidence in ultimately achieving a favorable therapeutic outcome.

Effects of monatepil, a novel calcium antagonist with alpha 1-adrenergic blocking activity, on the low-density lipoprotein receptor in human skin fibroblasts.

To investigate the mechanisms of the hypolipidemic effect of monatepil, a new class of calcium antagonists with alpha 1-adrenergic blocking activity, we examined the effects of the drug on low-density lipoprotein (LDL) receptor activity and the level of LDL receptor mRNA present in cultured human skin fibroblasts. At concentrations of 2 x 10(-5) M, monatepil increased the binding (248 +/- 43%; mean +/- SD), internalization (374 +/- 18%), and degradation (145 +/- 2%) of 125I-LDL in human skin fibroblasts (n = 3, p < 0.05). Treatment of human skin fibroblasts with 2 x 10(-5) M of monatepil for 6 hours resulted in an increase in LDL receptor mRNA to 163% of the control level (n = 2), as shown by Northern blot analysis. Our results suggest that the hypolipidemic clinical effects of monatepil may be due to increased LDL receptor activity.

Reappraisal of the importance of heart rate as a risk factor for cardiovascular morbidity and mortality

Heart rate is a key determinant of myocardial oxygen consumption. Several lines of evidence support a consistent association between heart rate and cardiovascular mortality. Increments in heart rate are positively related to cardiovascular and sudden death in patients with hypertension or previous myocardial infarction and in the elderly with heart disease. This relationship is important because a number of commonly used cardiovascular agents, such as beta-blockers and calcium antagonists (CAs), can affect heart rate. Beta-blockers decrease heart rate and reduce morbidity and mortality in post-myocardial infarction patients. The CAs are a structurally diverse group of agents with different physiologic effects. The dihydropyridine CAs are not associated with a reduction in heart rate. In fact, often they can cause reflex tachycardia as a result of potent systemic vasodilator action, which may provoke angina, especially in patients with ischemic heart disease. The nondihydropyridine CAs verapamil and diltiazem reduce heart rate but are associated with negative inotropy. Mibefradil, the first member of a new class of CAs, reduces heart rate and is not associated with negative inotropic effects. This unique pharmacologic profile may be of great value in treating hypertensive patients, particularly those with coexisting ischemic heart disease, and also patients with angina pectoris alone. However, the clinical benefit of pharmacologically reducing heart rate with mibefradil needs to be demonstrated in controlled trials.

Rationale for the use of calcium antagonists in the treatment of silent myocardial ischemia

Silent myocardial ischemia, whether it occurs at rest or during exercise, is associated with an unfavorable prognosis and may lead to sudden cardiac death. Agents used to treat silent myocardial ischemia have included nitrates, beta-blockers, and calcium antagonists (CAs). Despite treatment with traditional anti-ischemic agents, studies have shown that up to 40% of patients who receive what is considered to be clinically optimal antianginal therapy continue to have daily episodes of silent myocardial ischemia. The use of nitrates and beta-blockers is sometimes confounded by issues of tolerance and tolerability. Although the CAs have been found to be effective in decreasing the duration and frequency of episodes of silent ischemia, in general beta-blockers produce a greater reduction in these variables. Thus a need for effective and tolerable anti-ischemic agents persists. A new class of CAs, the tetralol derivatives, may show promise in this regard. The first of this new class, mibefradil, is characterized by selective blockade of T-type calcium-ion channels and has been shown in a few studies to reduce the frequency and duration of asymptomatic ischemic episodes in patients with stable exertional angina pectoris. Large-scale clinical trials are necessary before the efficacy and tolerability of this new CA can be compared fully with those of the beta-blockers and currently available CAs.

Pharmacologic and Therapeutic Differences Among Calcium Channel Antagonists: Profile of Mibefradil, a New Calcium Antagonist

Calcium antagonists are a heterogeneous group of drugs, each with a different chemical structure and cardiovascular profile. Distinguishing factors include pharmacokinetics, mode of calcium mobilization affected, class and subclass of calcium channel inhibited, state-dependent interactions, and effect of disease on the drug's activity. A new calcium antagonist, mibefradil, has a unique chemical structure and cardiovascular profile compared with those currently available, and it appears to represent a new class of calcium antagonists. (Am J Cardiol 1996;78(suppl 9A):7–12)

Ab initio and molecular dynamics study of dibenzotricyclic calcium antagonists: A rigid model approach

A new class of calcium antagonists (dibenzotricyclic compounds) is studied by means of reaction field ab initio calculations and molecular dynamics simulations. The central ring of these tricyclic molecules is found to be more important to the calcium antagonistic potency than the two phenyl rings. The central ring with antagonistic potency shows hydrophobic character, thus the interaction between the drug and the binding sites is assumed to be dominated by hydrophobic interactions. Variation of the flexure angle, the angle between the two phenyl rings, does not change the hydrophobic property of the central ring significantly, therefore it is not expected to affect the interaction between the drug and binding site directly. The effect of the flexure angle on calcium antagonistic potency, the relation between drug affinity of these tricyclic molecules and their ionization energies, and the interaction of calcium ions with the central ring are discussed. © 1994 John Wiley & Sons, Inc.

Synthesis and preliminary biological evaluation of 1-aminomethyl-4-substituted-4-H-pyrrolo[2,1-C][1,4] benzothiazines, a new class of calcium antagonists.

The preparation of 4a-g , conformationally rigid calcium channel blockers related to Diltiazem, is described starting from tricyclic compounds 5a-c . On radioreceptor assay and preliminary biochemical tests some compounds show high affinity for Calcium Channel Receptors (CCRs) and calcium antagonistic activity comparable or superior to that of Diltiazem.

A new class of calcium antagonists. 2. Synthesis and biological activity of 11-[4-[4-(4-fluorophenyl)-1-piperazinyl]butyryl]amino]-6,11-dihydrodibenzo[b,e]thiepin maleate and related compounds

A series of [(epsilon-aminoalkanoyl)amino]-6,11- dihydrodibenzo[b,e]thiepins and -5H-dibenzo[a,d]cycloheptenes and related compounds were synthesized and evaluated for calcium antagonistic activity by calcium-induced constriction of potassium-depolarized rat aorta. Semiempirical molecular orbital calculations of the dibenzotricyclic systems indicated that calcium antagonistic activity increased with a decrease of the angle between the planes of the two phenyl rings. AM1 net charge calculations showed that a neutral or positive charge distribution in the bridge portion was necessary for activity. 11-[[4-[4-(4-Fluorophenyl)-1- piperazinyl]butyryl]amino]-6,11-dihydrodibenzo[b,e]thiepin maleate (16, AJ-2615) showed a more gradual and longer lasting antihypertensive effect than diltiazem and nifedipine in spontaneously hypertensive rats (SHR) administered orally. Compound 16 also possessed antianginal effects in methacholine-induced ST elevation and vasopressin-induced ST depression tests in rats. The alteration of the dibenzotricyclic system of 16 to 5H-dibenzo[a,d]cycloheptene (19, 5-[[4-[4-(4-fluorophenyl)-1-piperazinyl]-butyryl]amino]-5H- dibenzo[a,d]cycloheptene) resulted in selectivity for cardiac tissue over vascular tissue, thereby conferring antianginal activity without an effect on blood pressure. Antianginal potencies of 16 and 19 were equal to or somewhat more potent than those of diltiazem.

A new class of calcium antagonists. Synthesis and biological activity of 11-[(.omega.-aminoalkanoyl)amino]-6,6a,7,8,9,10,10a,11-octahydrodibenzo[b,e]thiepin derivatives

A series of 11-[(omega-aminoalkanoyl)amino]-6,6a,7,8,9,10,10a,11- octahydrodibenzo[b,e]thiepin derivatives were prepared and found to be a structurally new class of calcium antagonists. The structure-activity relationship studies indicated that the optimum was (6aR*,10aR*,11R*)-11-[[4-[4-(4-fluorophenyl)-1- piperazinyl]butyryl] amino]-6,6a,7,8,9,10,10a,11-octahydrodibenzo[b,e]thiepin (31,pA2 8.16), which was superior to diltiazem (pA2 7.42) in calcium antagonistic activity. Compound 31 showed antihypertensive activity in anesthetized rats, without a significant effect on the heart rate. It had also antianginal effects in vasopressin-induced ST-depression and methacholine-induced ST-elevation testings in rats. These potencies of 31 were essentially equal to those of diltiazem.