Minoxidil: A Review of its Pharmacological Properties and Therapeutic Use

Summary

Synopsis: Minoxidil¹is an orally effective vasodilator which is more potent than hydralazine. The drug induces reflex stimulation of the sympathetic nervous system and of plasma renin activity and produces fluid retention. For these reasons, minoxidil must usually be administered in combination with an antiadrenergic agent and with a diuretic. Its acceptability for use in females is limited by the frequent appearance of hypertrichosis. Minoxidil is particularly useful in the treatment of patients with severe refractory hypertension. However, its suitability in the management of male patients with moderate hypertension remains to be determined.

Pharmacodynamic Studies: Minoxidil is a potent direct vasodilator, which reduces both systolic and diastolic blood pressure by lowering peripheral resistance. The drug acts predominantly on the arterioles and has little effect on the venous capacitance vessels. Hence, minoxidil blood pressure reduction is associated with an increase in heart rate, stroke volume and cardiac index, and is usually not accompanied by orthostatic hypotension. Minoxidil produces reflex stimulation of the sympathetic nervous system, with increases in plasma noradrenaline (norepinephrine) levels and in plasma renin activity (PRA). Plasma aldosterone levels increase during acute administration of minoxidil but return to pretreatment levels during chronic treatment. The concomitant use of a β-blocker, such as propranolol or atenolol, or of a centrally acting inhibitor of sympathetic activity such as Clonidine or α-methyldopa, potentiate the antihypertensive action of minoxidil by inhibiting the reflex increase in cardiac output and in renin release. Diuretics also potentiate the antihypertensive activity of minoxidil, by antagonising the sodium-retaining effect of this drug.

As with many other antihypertensive agents, the administration of minoxidil in patients with malignant hypertension may be accompanied by a transitory continuing deterioration of renal function to a point where haemodialysis may be required. However, subsequent improvement of renal function may be observed in many patients, sometimes to a degree where haemodialysis is no longer needed. In patients with so-called ‘benign’ hypertension not responding well to ‘traditional’ therapy, better control of blood pressure with minoxidil may prevent the deterioration of renal function which occurs in the majority of such patients.

Pharmacokinetics: Peak plasma concentrations of minoxidil usually occur within 1 hour after ingestion. More than 95% of the drug is absorbed from the gastrointestinal tract. Minoxidil has a relatively large volume of distribution of approximately 200L, the drug preferentially concentrating in certain extravascular sites, such as vascular smooth muscle. Minoxidil is metabolised in the liver predominantly by conjugation with glucuronic acid. The drug and its metabolites are minimally protein bound, and are readily excreted from the kidneys or dialysed across the membranes used for haemodialysis. The drug reportedly has an elimination half-life of approximately 3 to 4 hours; however, the duration of its antihypertensive effect may exceed 72 hours. This prolonged activity may be related to the reported high affinity of this drug for vascular smooth muscles.

Therapeutic Trials: Most therapeutic trials with minoxidil have been of open design and limited to patients in whom a conventional ‘triple therapy’ regimen (a diuretic, an antiadrenergic drug and a vasodilator) had failed because of ineffectiveness or intolerable side effects. These limitations to use, imposed by the American Food and Drug Administration, were originally justified by experimental evidence of atrial haemorrhagic and degenerative lesions in the dog. These lesions have subsequently been shown to be specific for this animal species. A number of trials have shown that minoxidil can be effective in the management of the most severe and resistant forms of hypertension in adults as well as in children. Some therapeutic trials have shown that minoxidil is a more potent vasodilator and antihypertensive agent than hydralazine. In many instances, this drug has been used successfully in combination as a medical alternative to bilateral nephrectomy. A few studies have also demonstrated the efficacy of this drug in the management of patients with moderate hypertension. However, further clinical experience is needed before the risk-benefits of minoxidil in less severe forms of hypertension in male patients can be clearly ascertained; in females the occurence of hypertrichosis may preclude use of the drug in less severe forms of the disease.

Side Effects: Minoxidil therapy is frequently associated with significant side effects, some of which are particularly pronounced in patients with impaired renal function. The drug may cause renal sodium and fluid retention and stimulate thirst. This can lead to peripheral oedema and, in the most severe cases, to congestive heart failure and pulmonary oedema. When this problem becomes recurrent or refractory to diuretics or to dialysis, discontinuation of the drug may be necessary. Minoxidil administration has also been associated with pericardial effusion, particularly in patients with severe impairment in renal function. However, the real incidence of this side effect remains to be determined. The use of minoxidil may cause electrocardiographic T-wave changes during the first 2 weeks of therapy. This abnormality is usually not associated with symptoms or with cardiac enzyme elevation and reverts spontaneously. Pulmonary hypertension has been described in patients treated with minoxidil, but a cause-effect relationship is uncertain. Orthostatic hypotension is not likely to occur with minoxidil.

Reversible hypertrichosis is a common side effect which appears to some degree in nearly all patients treated with minoxidil for longer than 1 month, and constitutes a serious limitation to the use of this drug in females.

Dosage and Administration: The usual initial dose is 5 to 10mg daily in 2 divided doses. (Once-daily dosing can also be used, particularly with total daily doses of 20mg or less.) This dose can be increased slowly (5 to 10mg/day increments every 2 to 3 days) up to 100mg per day. However, the majority of patients with severe hypertension usually respond to a dose not exceeding 50mg/day. Accelerated regimens of dosage increase can be used in patients with the most severe forms of hypertension, to achieve a more rapid control of blood pressure. In patients on haemodialysis or peritoneal dialysis, minoxidil should be administered after the dialysis, since the drug is easily dialysible. Patients receiving minoxidil who are not on dialysis must also receive sufficient diuretic therapy to maintain salt and water balance. Most patients will also require a sympathetic nervous system suppressant, preferably a β, to limit reflex tachycardia.