Dilevalol

Summary

Synopsis

Dilevalol, the RR-stereoisomer of labetalol, is a non-cardioselective β-adrenoceptor antagonist with substantial partial β₂-agonist and negligible α₁ -blocking activity. Reduction in blood pressure during dilevalol administration is associated with peripheral vasodilatation, and heart rate remains essentially unchanged. Following oral administration, dilevalol is completely absorbed. Once-daily administration is possible, due to a long elimination half-life.

Large well-controlled trials reveal that dilevalol is equivalent in antihypertensive efficacy to metoprolol, the ACE inhibitors captopril and enalapril, and the calcium antagonist nifedipine. Smaller noncomparative and comparative trials demonstrate the blood pressure-lowering effects of dilevalol and suggest an efficacy at least equivalent to that of the ‘pure’ β-blockers atenolol and propranolol and the α₁-blockers urapidil and doxazosin. Dilevalol appears to be well tolerated, the most frequent adverse effects being dizziness, headache and diarrhoea in only about 7% of patients each. Unlike α₁-blockers and labetalol, dilevalol is not commonly associated with orthostatic hypotension.

Thus, data suggest that dilevalol, with its distinctive pharmacological profile, is likely to be a useful addition to the options currently available for treating patients with mild to moderate essential hypertension.

Pharmacodynamic Properties

In vitro and in vivo animal studies and results obtained in humans reveal that dilevalol is a nonselective blocker of β₁ - and β₂-adrenoceptors, with a similar potency to propranolol, but has negligible antagonistic activity at α₁-receptors. As estimated from isoprenaline (isoproterenol)-induced haemodynamic effects in vivo and in isolated animal tissues, dilevalol has 3 to 6 times the β-blocking activity of its parent racemate labetalol, but is less than 25% as effective as labetalol in inhibiting α₁-mediated changes induced by norepinephrine (noradrenaline) or phenylephrine. In humans, dilevalol is about 1.75 times more effective than labetalol in blocking the effects of isoprenaline at β₁-receptors, and is significantly more potent in inhibiting stimulation of the β₂-subtype by salbutamol (albuterol). It is almost devoid of α₂-blocking activity in humans.

Dilevalol shows marked partial β₂-agonist activity in animal models by producing ICI 118,551 and/or propranolol-sensitive tracheal relaxation and peripheral vasodilatation, and falls in systemic vascular resistance in humans.

The haemodynamic profile of dilevalol is characterised by reductions in peripheral resistance and blood pressure without significant effects on heart rate in animals and in humans. Mean arterial blood pressure is reduced by 14 to 29%, and systolic and diastolic pressures by approximately 13 to 18% by dilevalol 100 to 1600 mg/day in patients with mild to moderate essential hypertension after 1 to 8 weeks of therapy (see also Therapeutic Use, below). The blood pressure lowering effects of dilevalol are maintained during the 24 hours after an oral dose in patients and in healthy subjects. A decrease in peripheral resistance of 13% is primarily responsible for the fall in blood pressure, since resting heart rate is generally unaffected or occasionally increased slightly. Although decreases in heart rate have occurred during dilevalol administration, the incidence and extent is not as great as with atenolol. Resting cardiac index is also unchanged. However, during exercise, increases in heart rate were blunted by up to 29% and cardiac index by 19%. Left ventricular function appears to improve during dilevalol treatment, as assessed by left ventricular mass index, ejection fraction and ejection time.

In animals, dilevalol enhances nodal conduction but inhibits intraventricular conduction. Dilevalol protects against lethal ventricular fibrillation elicited by methylscopolamine in animals subjected to myocardial infarction, while the anticholinergic compensates for a relative excess in parasympathetic activity — and thus bradyarrhythmia and arrest — resulting from β-blockade by dilevalol.

Glomerular filtration rate, filtration fraction and effective renal plasma flow are preserved in healthy volunteers, patients with essential hypertension and in those with renal dysfunction receiving dilevalol.

There was no significant difference between the forced expiratory volume in 1 second following placebo or single oral doses of dilevalol 200 or 400mg in patients with reversible asthma, in contrast to a significant reduction of 16% observed with metoprolol 200mg. Furthermore, isoprenaline-induced bronchodilatation was re-established after 90 minutes during concomitant dilevalol, but not metoprolol, administration.

Plasma renin activity is lowered and norepinephrine levels increased by dilevalol. There is a neutral or possibly beneficial effect on plasma lipids, with an increase in the high density lipoprotein fraction and a slight reduction in low density lipoprotein. Total cholesterol levels are unaltered by 1 month to 1 year of dilevalol therapy.

In summary, dilevalol lowers blood pressure through a decrease in peripheral resistance, with perhaps a minor contribution from decreased cardiac output.

Pharmacokinetic Properties

In healthy subjects, dilevalol is completely absorbed following oral administration. However, extensive first-pass metabolism occurs, with subsequent glucuronide conjugation such that the bioavailability of dilevalol is 30% or less, and only 1.25% of detectable urinary dilevalol is unchanged drug. Peak plasma concentrations (C_max) of unchanged drug after a single oral 400mg dose are attained within 50 minutes, and vary among individuals between 220 and 485 μg/L. After a 200mg dose administered to healthy volunteers, C_max was 61.5 μg/L after 1.4 hours, and in 15 patients with hypertension C_max values of 118, 226 and 545 μg/L occurred within 1 hour of the last dose following 5 days’ administration of dilevalol 200, 400 and 800 mg/day, respectively. A C_max of 236 μg/L was detected in 6 renally impaired patients 46 minutes after a 400mg oral dose, and increased to 387 μg/L 1.5 hours after the same dose in 6 others maintained on haemodialysis. The area under the plasma concentration-time curve also varies considerably, but a dose-proportional increase in this parameter has been established.

Although dilevalol is approximately 75% bound to human plasma proteins, it is extensively distributed into extra vascular tissue, as shown by an apparent volume of distribution of about 25 L/kg following a 50mg intravenous dose in healthy subjects. In lactating women, the plasma concentration of unchanged dilevalol after a 400mg oral dose was 2 to 3 times that detected in breast milk. Over 48 hours, a total of 0.007% of the administered dose was excreted into the milk.

At least 33% in total of an oral dose is recovered, mainly as conjugates, in the urine within 60 hours, representing the main route of excretion. Clearance of dilevalol from the plasma is essentially complete within 48 hours, with a total clearance of 23 ml/min/ kg after an intravenous dose of 50mg, the main site of plasma clearance being the liver. In healthy subjects the elimination half-life of unchanged dilevalol after single doses and at steady-state is 8 to 12 hours, increasing to 19 hours in patients with severe renal dysfunction and to 29 hours in those maintained on haemodialysis.

The blood pressure-lowering effects of dilevalol in hypertensive patients are related to plasma concentration of unchanged drug at steady-state.

Therapeutic Use

Once-daily administration of dilevalol 200 to 1600mg was equivalent in efficacy to once-daily metoprolol 100 to 400mg or enalapril 20 or 40mg, and twice-daily therapy with captopril 50mg or nifedipine 20 or 40mg after 1 month to 1 year of treatment in large numbers of patients with mild to moderate hypertension participating in well designed double-blind comparative studies.

Short term noncomparative studies involving small patient populations with essential hypertension show that dilevalol 100 to 800mg once or twice daily lowered systolic blood pressure by 8 to 13% and diastolic pressure by 11 to 16%. In most comparative trials, some of which were not strictly designed to assess antihypertensive efficacy and therefore included relatively few patients, diastolic blood pressure was reduced by 10mm Hg or more or to 90mm Hg or less in about 60% of patients receiving dilevalol. Dilevalol 50 to 1600mg once daily was superior to placebo and at least as effective as atenolol 50 to 150 mg/day, propranolol 40 to 320mg twice daily, and mean daily doses of acebutolol 444mg, tilisolol 21.7mg, urapidil 84mg and the rather low dose of doxazosin 1.7mg in these studies. Dilevalol was less effective in Black compared with White patients. Efficacy was estimated either in terms of the magnitude of the blood pressure reduction or the number of hypertensive patients achieving a diastolic pressure within normal limits.

Dilevalol 400 to 450mg administered intravenously effectively reduced blood pressure in most patients with severe hypertension, but maintenance of this effect with subsequent oral therapy with dilevalol 200 to 800mg twice daily plus hydrochlorothiazide 25 or 50 mg/day was less successful.

Adverse Effects

Data from medium and long term comparative trials demonstrate that dilevalol 100 to 1600 mg/day is well tolerated, with an overall incidence of adverse effects similar to that of placebo and less than that of metoprolol 100 to 400 mg/day and propranolol 80 to 640 mg/day. Dizziness and headache are the most frequently reported reactions, each usually occurring in about 7% of patients. A similar percentage experience diarrhoea. Adverse effects associated with β₂-blockade, such as cold extremities and dyspnoea, occur in less than 4% of recipients, and bradycardia and heart block from β₁-blockade are encountered significantly less often than with metoprolol or propranolol. Since dilevalol’s vasodilator activity is not mediated through α₁-blockade, overt orthostatic hypotension is unlikely to occur.

Serum electrolytes are unaffected by dilevalol therapy. Serum transaminase levels are elevated in 2% of dilevalol recipients, and 3% have a positive antinuclear antibody (ANA) titre, but this is not uncommon with any β-blocker therapy.

Dosage and Administration

Once-daily oral administration of 200 to 400mg, titrated up to 800mg if necessary, is the recommended dosage of dilevalol in adult patients with mild to moderate essential hypertension. Concomitant hydrochlorothiazide may also be required by some patients for adequate blood pressure control. In severe hypertension, intravenous injections of dilevalol 25 to 600mg have been used in the short term, with oral doses of 200 to 800mg twice daily plus hydrochlorothiazide 25 to 50 mg/day for longer term maintenance.

Dosage reduction may only be necessary in those patients with renal dysfunction who are maintained on haemodialysis.