Gallopamil: A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Potential in Ischaemic Heart Disease

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Abstract

Synopsis

Gallopamil is a methoxy derivative of verapamil. As is typical of the phenylalkylamine class of calcium antagonists, it acts on the vascular system, and on the heart and its nodal structures. In the treatment of stable angina pectoris, gallopamil is at least as effective as nifedipine and diltiazem, though apparently better tolerated than nifedipine. Typical of calcium antagonists there is little or no tolerance to the antiischaemic effects of gallopamil.

Synopsis

Preliminary studies indicate that gallopamil, like other calcium antagonists, has cardioprotective potential. However, further investigation is required to explore the clinical relevance of the improved myocardial regional perfusion and free fatty acid utilisation in reversibly ischaemic regions, and the potential of delayed ischaemia during angioplasty that is observed during gallopamil administration.

Synopsis

Gallopamil is well tolerated, exhibiting a low propensity for causing cardiovascular and gastrointestinal adverse effects, thus making it a suitable alternative to other calcium antagonists for the treatment of patients with ischaemic heart disease.

Pharmacodynamic Properties

Gallopamil, a phenylalkylamine calcium antagonist, is typical of its class in acting on the vascular system, and the heart and its nodal structures. When administered at usual oral therapeutic dosages, gallopamil generally caused little change in resting heart rate, reduced the gain in heart rate during exercise, and decreased systolic and diastolic blood pressure in patients with coronary artery disease, particularly those who developed ischaemia, both at rest and during exercise. The effect of gallopamil on rate-pressure product has varied between studies, but this parameter decreased or remained unchanged more frequently than it increased.

Pharmacodynamic Properties

In animal studies, gallopamil inhibited contraction of major extramural and peripheral arteries induced by potassium, acetylcholine or adrenaline (epinephrine), as well as autoregulatory constriction of peripheral resistance vessels, with a potency intermediate between those of verapamil and nifedipine. The concentration of gallopamil required to relax potassium-induced contracture of canine veins was much lower than that required to relax arteries from the same body region.

Pharmacodynamic Properties

In patients with normal coronary arteries, intracoronary administration of gallopamil 1.5 or 3 μg/kg produced dose-related coronary vasodilatation, while a 26% increase in the calibre of stenosed arteries followed intravenous administration of a 2mg dose. When administered orally or intravenously, gallopamil does not significantly influence normal or mildly impaired left ventricular function in patients with coronary artery disease, and improves relaxation and left ventricular filling in patients with acute myocardial infarction or hypertrophic cardiomyopathy, reflecting improved left ventricular diastolic function.

Pharmacodynamic Properties

Changes in intracellular calcium may be a primary event in the sequence of metabolic and ionic changes that characterise acute ischaemia. In animal studies, gallopamil attenuated the release of creatine phosphokinase and noradrenaline (norepinephrine) during reperfusion, maintained mitochondrial function, reduced microcirculatory changes induced by repetitive ischaemia, and limited the extent of myocardial necrosis when administered soon after the beginning of occlusion.

Pharmacodynamic Properties

Initial studies in patients with coronary artery disease suggest that oral treatment with gallopamil 50mg 3 times daily improves regional myocardial perfusion and fatty acid utilisation, and myocardial microperfusion in previously ischaemic areas of left ventricle, similarly to verapamil 80mg, diltiazem 180mg and nifedipine 60mg (all 3 times daily).

Pharmacodynamic Properties

Electrophysiological investigations during His bundle electrocardiography revealed that within 20 minutes of intravenous administration of gallopamil 0.06 mg/kg there was an increase in sinus rate, nodal conduction time, Wenckebach point, and functional and effective refractory period of the AV node. Sinoatrial node recovery time was prolonged only in patients thought to have sick-sinus syndrome.

Pharmacodynamic Properties

Oral administration of gallopamil to obese males with hypertension and impaired glucose tolerance did not influence glucose metabolism, whereas gallopamil 1mg intravenously delayed the release of insulin and C peptide after an oral glucose load in healthy volunteers.

Pharmacokinetic Properties

The pharmacokinetic properties of gallopamil administered as the racemate have been studied in small groups of healthy volunteers and in patients with chronic stable angina pectoris. Single dose administration of gallopamil 50 and 100mg as conventional tablets resulted in mean maximum plasma concentrations (Cmax) of about 30 and 50 μg/L, respectively. Mean Cmax values increased to 68.3 μg/L in healthy volunteers receiving 50mg 3 times daily for 12 days. In a comparison of single doses of conventional (50mg) and sustained release (SR) tablets (100mg), mean Cmax and area under the plasma concentration-time curve (AUC) were 21.3 μg/L and 66.8 μg/L · h, respectively, after the conventional preparation, and 13 μg/L and 161.7 μg/L · h after the sustained release tablet. Mean trough plasma concentrations were 20.3 and 33.7 μg/L in patients treated twice daily with SR gallopamil 75 and 100mg, respectively. Despite almost complete oral absorption, systemic availability is low at 15% after a single dose and about 23% after repeated doses, due to extensive first-pass hepatic metabolism.

Pharmacokinetic Properties

Protein binding of gallopamil in vitro in serum of healthy volunteers is about 93% and independent of drug concentration over a range of 10 to 100 μg/L, but is influenced by pH.

Pharmacokinetic Properties

Gallopamil is largely eliminated by metabolism. The principal metabolite is norgallopamil, which is thought to be pharmacologically inactive. Mean total plasma clearance is 66 to 72 L/h after intravenous administration. Reported values for mean terminal elimination half-life were between 2.5 and 5.5 hours or between 4 and 8 hours after oral administration of conventional tablets, depending on assay method. Following administration of SR gallopamil, elimination half-life was reported to be between 5.3 and 8 hours. After oral administration of radiolabelled gallopamil, about 48 to 55% of cumulative 14C excretion appeared in the urine and 40 to 50% in faeces in the form of metabolites. Only 0.2 to 2% of a dose was excreted unchanged in the urine.

Pharmacokinetic Properties

Preliminary studies in patients with liver cirrhosis given a single oral dose of gallopamil indicated that total plasma clearance was reduced, absolute bioavailability increased, and elimination half-life prolonged to an extent suggesting the need for a dosage reduction in patients with liver cirrhosis.

Therapeutic Efficacy

The therapeutic efficacy of gallopamil administered orally as a conventional or sustained release product has been studied in double- or single-blind short term trials involving generally small numbers of patients with confirmed coronary artery disease and stable exertional angina pectoris. Gallopamil 50mg 3 times daily or 100mg twice daily (SR) is more effective than placebo in improving exercise time and tolerance, delaying the ischaemic threshold and decreasing the extent of ST-segment depression at comparable and maximum workload during exercise tests. Relative to placebo, gallopamil increased the duration of exercise by 9 to 44%, exercise tolerance by 24 to 57%, and decreased the ST-segment depression by 42 to 70%, Treatment with conventional or SR gallopamil reduces the mean incidence of spontaneous asymptomatic as well as exercise-induced episodes of ischaemia during 24-hour ambulatory electrocardiographic monitoring.

Therapeutic Efficacy

In small numbers of patients studied for periods of 1 to 4 weeks, the overall efficacy of gallopamil 50mg 3 times daily was generally similar to that of nifedipine 10mg 3 times daily, although in one study gallopamil tended to be more effective. SR gallopamil (100mg twice daily) was superior to SR nifedipine 20mg twice daily in delaying the onset of ST segment depression. In some of the small number of crossover trials conducted, gallopamil 50mg 3 times daily was more effective than diltiazem 60mg 3 times daily in improving exercise duration, the extent of ST-segment depression and anginal attack frequency.

Therapeutic Efficacy

Long term noncomparative studies of up to 2 years' duration indicated that objective and subjective improvement achieved in the first 1 to 3 months of gallopamil therapy was maintained for the duration of the study.

Therapeutic Efficacy

Preliminary studies suggest the potential of intravenously administered gallopamil for the symptomatic control of unstable and variant angina.

Tolerability

In the treatment of patients with coronary artery disease, therapeutic dosages of gallopamil have been well tolerated by most patients. In large short term noncomparative trials involving a total of over 33 000 patients, gastrointestinal symptoms, including nausea, constipation, epigastric pain and other complaints, occurred in 4.4 to 8.3% of patients. Orthostatic hypotension, flushing and peripheral oedema were reported in 2 to 2.4%. Other cardiovascular complaints included bradycardia (0.5%), first and second degree AV block (0.3%), and tachycardia (0.2%). Aggravation of existing heart failure occurred in only 0.03% of patients. Adverse effects necessitated withdrawal of gallopamil in 1.4 to 3% of patients.

Dosage and Administration

The usual oral dosage of gallopamil in the treatment of patients with chronic stable angina pectoris is 50mg 3 times daily when administered as a conventional tablet and 100mg once or twice daily as a sustained release preparation, although individualised dosages have ranged from 75 to 200mg and 100 to 200mg daily administered as conventional and sustained release preparations, respectively. In patients with unstable or variant angina, an intravenous bolus of gallopamil 30 to 60 μg/kg has been followed by continuous intravenous infusion of 0.3 to 1 μg/kg/min. Dosage should be reduced in patients with liver cirrhosis.

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