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Drugs

, Volume 35, Issue 1, pp 1–21 | Cite as

Bevantolol

A Preliminary Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Efficacy in Hypertension and Angina Pectoris
  • William H. Frishman
  • Renée J. Goldberg
  • Paul Benfield
Drug Evaluation

Summary

Synopsis

Bevantolol is a new β- adrenoceptor antagonist which possesses a relatively high degree of selectivity for β1- adrenoceptors. It is devoid of intrinsic sympathomimetic activity and possesses only weak local anaesthetic properties. Interestingly, bevantolol has been shown to cause a lowering effect on peripheral vascular resistance. Available clinical data indicate that bevantolol, given once or twice daily, is an effective agent in the management of mild to moderate hypertension and stable angina pectoris. In hypertension bevantolol has been shown to be of comparable therapeutic efficacy to both atenolol and propranolol, while in patients with angina pectoris the drug compared favourably with atenolol. During short and long term administration bevantolol has been well tolerated and few patients have withdrawn from treatment because of adverse effects.

However, although the properties of bevantolol may offer theoretical advantages in some patients, only a few comparative studies have been reported, and thus it is presently unclear what advantages bevantolol may offer over existing treatments for hypertension or angina pectoris.

Pharmacodynamic Properties

Studies in animals and man have shown that bevantolol is a relatively selective β1- adrenoceptor antagonist. In vitro and in vivo, bevantolol inhibited the chronotropic response to isoprenaline (isoproterenol) in various species, and in the anaesthetised dog it also inhibited tachycardia induced by adrenaline (epinephrine), carotid artery occlusion, tyramine and 1,1-dimethyl-4-phenylpiperazinium iodide. Animal studies have shown the β-adrenoceptor blocking potency of bevantolol to be between 3- and 8-fold less than that of propranolol after intravenous and oral administration. The selectivity of bevantolol for β1-adrenoceptors was demonstrated in vitro by its significantly greater antagonism of guinea-pig atrial versus tracheal response to isoprenaline. In dogs bevantolol produced more selective blockade of the chronotropic versus the depressor cardiovascular responses to isoprenaline than propranolol. In humans bevantolol 200 mg/day reduced the chronotropic effect of isoprenaline to a similar extent as atenolol 100 mg/day.

Bevantolol does not possess intrinsic sympathomimetic activity and it is only a weak local anaesthetic. In receptor binding studies bevantolol displayed weak affinity for α1-adrenoceptors and an antagonist effect has been demonstrated in vitro but it is not known whether this represents a clinically significant effect.

It has been demonstrated in animals and humans that bevantolol, mainly as a result of β1-adrenoceptor antagonism, exerts a negative chronotropic effect on the heart. In healthy human subjects single oral doses of bevantolol 50 or 100mg reduced tachycardia and elevated blood pressure caused by exercise. In patients with hypertension, administration of bevantolol 200 to 600 mg/day either as single or divided daily doses significantly reduced heart rate over a 24-hour period. In addition, during treatment of patients with angina pectoris heart rate significantly reduced after 2 weeks and this reduction was maintained for up to 12 weeks in treatment with bevantolol 300 mg/day. The results of a study in a small number of healthy subjects and patients with slight to moderate ischaemic heart disease suggest that bevantolol also exerts negative inotropic effects on the myocardium. Administration of bevantolol 200 mg/day orally to healthy subjects for 7 days caused an overall reduction in peripheral vascular resistance. The blood pressure lowering effects of bevantolol have been demonstrated in hypertensive rats, normotensive dogs and in healthy volunteers as well as patients with hypertension. In healthy subjects, administration of bevantolol 200mg daily for 7 days caused a reduction in peripheral resistance.

Several studies in animal models of myocardial ischaemia have shown that bevantolol produced increased blood flow and improved contractile function of ischaemic myocardium. It has also been shown that bevantolol decreased the extent of epicardial ST segment shift in dogs and protected the ischaemic myocardium from ventricular fibrillation in pigs.

Bevantolol, administered as single or cumulative doses, has been shown to reduce the FEV1 in small numbers of patients with asthma but the risk of bronchospasm occurring in such patients during treatment for hypertension is not known.

During 12 weeks’ administration to patients with angina pectoris bevantolol 300 mg/ day reduced the serum low density lipoprotein concentration and increased the high density lipoprotein/low density lipoprotein ratio. However, bevantolol affected neither fasting plasma insulin concentrations in these patients nor fasting blood glucose concentrations in patients with both hypertension and mild diabetes. These apparently beneficial effects of bevantolol on the blood lipid profile were not confirmed in patients with hypertension treated for 6 months.

Pharmacokinetic Properties

After single doses of bevantolol 100 to 400mg in fasted healthy subjects, peak plasma concentrations occur between 1 and 2 hours. While absorption of bevantolol is nearly complete, it undergoes presystemic metabolism — about 60% of an orally administered dose reaches the systemic circulation in unchanged form. Although food may slow the rate of absorption of bevantolol, the total amount of drug absorbed is not significantly affected. Distribution is rapid and extensive. In man, the apparent volume of distribution is 1.5 L/kg. Over 95% of plasma bevantolol is bound to glycoproteins.

Less than 10% of an oral dose of bevantolol appears unchanged in the urine. Several metabolites have been identified, although none are considered to be of clinical importance. Most (72%) of a radioactive dose of bevantolol is renally excreted over 5 days. In healthy subjects the mean elimination half-life of bevantolol was about 1.5 hours and there were no recorded changes in pharmacokinetic variables after 7 daily doses of 100 or 200mg.

Current evidence suggests that the pharmacokinetic properties of bevantolol do not change to a clinically significant extent in the elderly or patients with renal impairment.

Therapeutic Trials

In patients with mild to moderate hypertension single or divided daily doses of bevantolol 200, 300 or 400mg reduced diastolic blood pressure to a significantly greater extent than placebo. After up to 11 weeks’ treatment with bevantolol 100 to 400 mg/day between 66 and 79% of patients had attained a clinical response compared with 23 to 33% of patients administered placebo. Daily doses of bevantolol 200, 300 and 400mg appear to be therapeutically equivalent in patients with mild to moderate hypertension. Using 24-hour blood pressure recordings, it was shown that the antihypertensive effects of once or twice daily administration are similar. In addition, bevantolol blunted the early morning increase in blood pressure. Administration of twice daily doses of bevantolol 100 to 300mg or propranolol 80 to 240mg for 6 months produced equivalent antihypertensive effects. In addition, bevantolol 400 mg/day appears to be similar in antihypertensive efficacy to atenolol 100 mg/day, when both are administered as once daily regimens.

In patients with stable angina pectoris bevantolol 75 or 150mg twice daily significantly reduced both the myocardial oxygen demand during maximum workload and the proportion of patients who stopped exercising because of angina pain or ST segment depression. In addition, the frequency of angina attacks was reduced and the patients’ ‘quality of life’ improved after bevantolol. Another study showed that indices of antianginal efficacy were similarly improved after bevantolol 200 mg/day was administered as a once or twice daily dosage regimen.

Bevantolol 150mg twice daily and atenolol 100mg once daily displayed similar anti-anginal effects when administered over 12 weeks, with the exception that both resting and exercise heart rate were reduced to a greater extent after atenolol. Another study showed that once daily administration of bevantolol 400mg or atenolol 100mg for 4 weeks caused significant antianginal effects with no between-treatment differences.

Side Effects

Bevantolol has been well tolerated during short and long term studies in hypertension and angina pectoris. The most frequently reported side effects were fatigue, headache, dizziness, oedema and gastrointestinal upsets. These have generally been mild, causing only few patients to withdraw from treatment.

Dosage and Administration

Most patients with mild to moderate hypertension or angina pectoris should respond to doses of bevantolol within the ranges of 200 to 400 mg/day or 150 to 300 mg/day, respectively. A once or twice daily dosage regimen, individually titrated for optimum efficacy, may be used.

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Copyright information

© ADIS Press Limited 1988

Authors and Affiliations

  • William H. Frishman
    • 1
    • 2
    • 3
  • Renée J. Goldberg
    • 1
    • 2
    • 3
  • Paul Benfield
    • 1
    • 2
    • 3
  1. 1.Department of MedicineAlbert Einstein College of MedicineBronxUSA
  2. 2.Department of Pharmacology, Arnold and Marie Schwartz College of Pharmacy and Health SciencesLong Island UniversityBrooklynUSA
  3. 3.ADIS Drug Information ServicesMairangi Bay, Auckland 10New ZealandUSA

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