Direct Vasodilators and their Role in Hypertension Management: Minoxidil

Abstract

Minoxidil is a direct vasodilator that has been in use for over two decades. It is used primarily to reduce blood pressure in hypertensives who have been poorly controlled on various multidrug regimens. Although minoxidil is extremely effective, its usefulness is limited by its tendency to increase the pulse rate and to trigger salt and water retention. The latter may be incapacitating in some patients. Therefore, minoxidil is typically administered with both a diuretic and an agent that can control the pulse rate, such as a β blocker. Minoxidil has several other side effects that may limit its use, including hypertrichosis, aggravation of myocardial ischemia and/or left ventricular hypertrophy, and (infrequently) pericardial effusions. If a patient's hypertensive pattern is sufficiently severe to warrant contemplation of minoxidil therapy, referring the patient to a hypertension specialist should be strongly considered.

Direct vasodilator drugs are generally reserved for stage III hypertensive patients who have not responded to conventional three‐ or four‐drug antihypertensive regimens. In some circumstances, however, they can be effectively used at an earlier stage of hypertension. Hydralazine and minoxidil are orally administered drugs of this class; minoxidil is the more potent vasodilator. ¹ Although typically reserved for resistant hypertension, minoxidil can also be prescribed to rapidly control blood pressure in patients with accelerated hypertension (Table). ²

Table TABLE.

PHARMACOLOGY OF DIRECT VASODILATORS

Available Compounds Minoxidil

Modes of Action

Direct arterial vasodilatation with minimal venodilatation

Reflex activation of sympathetic nervous and renin‐angiotensinaldosterone systems

Indications

Requirement for multidrug therapy for otherwise resistant hypertension

Refractoriness to other agents, particularly in patients with renal insufficiency

Minoxidil loading over 24–36 hours is useful in rapidly establishing blood pressure control in resistant hypertensives

Contraindications

Pericardial effusion

Side Effects

Fluid retention

Tachycardia

Pericardial effusion

Hypertrichosis

MECHANISM OF ACTION

There is evidence to suggest that minoxidil acts by opening cardiovascular adenosine triphosphate‐sensitive potassium channels in vascular smooth muscle cells. This mechanism is similar to that of other potassium channel openers, such as pinacidil. ³ The predominant action of minoxidil is arterial; because venodilation does not occur, postural hypotension is uncommon. The arteriolar vasodilation induced by minoxidil activates the peripheral sympathetic nervous system (SNS) via carotid and aortic baroreceptor reflexes. In tandem with activation of the SNS, both the pulse rate and cardiac output increase, although after prolonged treatment, cardiac output and heart rate usually return to pretreatment levels. ⁴ Minoxidil administration evokes an increase in plasma renin activity, largely due to activation of the SNS. ⁵ , ⁶ , ⁷ The activation of the renin‐angiotensin axis elicits an increase in plasma and urinary aldosterone levels. ⁵ , ⁶ , ⁷ Over time, plasma aldosterone levels normalize, presumably because of enhanced hepatic metabolic clearance of aldosterone secondary to hepatic vasodilation. ⁸ Although minoxidil is effective in reducing blood pressure, the aforementioned hemodynamic and neurohumoral changes can offset the beneficial effect of arteriolar vasodilatation. ⁵

PHARMACOKINETICS

Minoxidil is completely and rapidly absorbed from the gastrointestinal tract, although its absorption is delayed in the presence of advanced renal failure. ⁹ Minoxidil is metabolized primarily by hepatic glucuronidation to a renally cleared active metabolite. ¹⁰ Because minoxidil concentrates in extravascular tissues, such as arterial smooth muscle cells and the myocardium, its volume of distribution exceeds that of total body water. ¹¹ Minoxidil is minimally protein‐bound and therefore can be readily dialyzed. ¹²

The elimination half‐life of minoxidil ranges from 3–4 hours, but its hypotensive effect may endure for as long as 12–72 hours, allowing oncedaily administration. ¹³ , ¹⁴ Although there appears to be a relationship between the dose and the extent of blood pressure reduction, there is no clear relationship between plasma levels and drug activity.

CLINICAL USE

Numerous clinical studies have documented the effectiveness of minoxidil in the resistant hypertensive patient. In an early study of minoxidil use, ¹⁵ 11 hypertensive patients treated with minoxidil alone experienced blood pressure reductions from 188/124 mm HG to 159/108 mm Hg. With the addition of propranolol, blood pressure dropped further, to 134/86 mm Hg. There were no signs of orthostatic hypotension and fluid retention was easily controlled with diuretics.

Minoxidil is frequently necessary in patients with renal insufficiency, many of whom are refractory to all other medications, ⁹ , ¹⁶ , ¹⁷ , ¹⁸ and it is effective regardless of the severity or etiology of hypertension or the level of renal function. ⁵ , ¹⁹ , ²⁰ It is noteworthy that before minoxidil became available, bilateral nephrectomy was almost inevitable in advanced renal failure patients as a last treatment option for uncontrolled hypertension. ⁹ , ²¹ Minoxidil does not alter renal function in the majority of patients with hypertension and normal renal function. ²² In patients with established renal insufficiency, some studies have actually shown stabilization or even reversal of the decline in renal function when blood pressure was effectively controlled. ¹⁶ , ²² , ²³ Occasionally, patients who require hemodialysis for acute or chronic renal failure attributable to malignant hypertension may discontinue dialysis as a consequence of effective blood pressure control realized with aggressive minoxidil therapy. ¹⁷ , ²² , ²³

Minoxidil is routinely administered with a β blocker and a potent diuretic. Dosage adjustments for both diuretic and β blocker therapy are commonly necessary for optimization of volume and pulse rate control. When this triple‐drug regimen is correctly instituted, more than 75% of hypertensive patients who were previously resistant to multiple drugs are controlled. ²⁴ , ²⁵ Occasionally, the volume expansion with minoxidil is of sufficient severity to warrant combination therapy with a loop diuretic and metolazone. In a minoxidil‐treated patient who is β blocker‐intolerant, pulse rate control can be accomplished with either a central a agonist, such as clonidine, or a pulse rate‐reducing calcium channel blocker, such as verapamil or diltiazem. ⁹ , ²⁶

Dosage

The starting dose of minoxidil can be as low as 2.5 mg; the maintenance dose is generally in the range of 10–40 mg/day. Minoxidil can be given once or twice daily. The twice‐daily dosing regimen is preferred in patients receiving high doses of minoxidil, in the interest of avoiding the excessive peak hypotensive effect that can occur with a large single dose. A few patients, particularly those with advanced renal failure, require doses of minoxidil in excess of 40 mg/day. Although the manufacturer's maximum recommended dose is 100 mg/day, in our experience very few patients have required more than 20 mg in a single dose or more than 40 mg/day.

The starting dose of minoxidil can be increased in different ways. For example, it can be increased by 5–10 mg every 3–4 days until blood pressure is controlled, or the dose may be titrated upward every 1–2 weeks. The latter approach is favored in patients who experience side effects.

Rapid titration of minoxidil over several days may be followed by a gradual loss of blood pressure control over the next several days as salt and water retention and tachycardia evolve. This should be anticipated and measures taken to pre‐emptively control volume and pulse rate. Significant weight gain secondary to salt and water retention can occur quickly with minoxidil. If significant edema develops, it is prudent to temporarily discontinue minoxidil rather than give large doses of a loop diuretic. Thereafter, minoxidil may be restarted at a lower dose, with appropriate diuretic support.

An accelerated dosing schedule can be used with minoxidil to achieve rapid blood pressure control in patients with symptomatic diastolic hypertension higher than 120 mm Hg. ² , ⁷ , ²⁷ For example, Alpert and Bauer ² administered a 20‐mg loading dose of oral minoxidil to nine symptomatic patients whose diastolic blood pressure exceeded 120 mm Hg 2 hours after they had received a combination of 40 mg of oral propranolol and 40 mg of oral furosemide. A booster dose of 5–20 mg, calculated on the basis of individual responses to the loading dose of minoxidil, was given at 4 hours if the diastolic blood pressure still exceeded 100 mm Hg. With this approach, a progressive and significant reduction of systolic and diastolic blood pressure was achieved over the next several hours.

These results suggest that an orally administered regimen of propranolol, furosemide, and loading/booster doses of minoxidil produces prompt, progressive, and sustained blood pressure reduction in patients with severe hypertension who require prompt blood pressure control. However, this and other early studies with minoxidil were conducted almost two decades ago; since then, current treatment considerations for accelerated or symptomatic hypertension have prompted caveats to this approach. First, this approach is not a substitute for parenteral therapy of symptomatic hypertension, but rather a complementary strategy to facilitate the switch from intravenous to oral medications. Second, minoxidil loading should always involve prior β blockade, since minoxidil tends to increase the pulse rate, particularly at the doses recommended in some of these regimens. ² , ⁷ , ²⁷ Finally, this approach is recommended only under supervised conditions because occasionally, prolonged hypotension occurs after an initial 10‐mg minoxidil dose. ²⁸

Minoxidil has also been used topically (Rogaine®) for male‐pattern baldness. Topically applied minoxidil can be absorbed: over a several‐month period of treatment, increases in left ventricular end‐diastolic volume, cardiac output, and left ventricular mass can occur. ²⁹ For this reason, the manufacturer's instructions for topical minoxidil include a specific warning to stop its use and consult a physician in the event of chest pain, rapid heartbeat, swelling, or significant weight gain. ³⁰ This warning describes the overt symptomatology that may occur with topically absorbed minoxidil; the more significant cardiac effects that have been described can be detected only under appropriate clinical vigilance.

SIDE EFFECTS

Fluid retention and tachycardia are the predominant symptoms that occur with minoxidil therapy, and they are dose‐dependent. ³¹ The mechanisms of the salt and water retention with minoxidil are not purely hemodynamic and/or neurohumoral, but rather involve a direct tubular effect. ¹⁵ Fluid retention may be of sufficient severity to require discontinuation of the medication. Careful monitoring of patients' weight after initiation of therapy can identify proneness to marked fluid retention. Early recognition of fluid retention in a minoxidil‐treated patient is an important practical consideration: it is usually much easier to treat the fluid retention before it has reached the severe stage. Although pericardial effusions have been reported in as many as 3% of patients receiving minoxidil therapy, ³² the true incidence is difficult to estimate, since many minoxidil‐treated patients have renal insufficiency and no pretreatment echocardiogram. In many cases, drug‐related pericardial effusion is simply an extension of the generalized volume overload that often accompanies minoxidil therapy. In some cases, though, it is an idiopathic, volume‐independent phenomenon that recurs when patients are rechallenged with minoxidil. ³³ In these cases, therapy should be permanently discontinued.

During the first 2 weeks of treatment with minoxidil, ST segment depression and T wave flattening or inversion are present on electrocardiography in as many as 90% of patients. ⁴ , ¹¹ , ³⁴ After several months of therapy the abnormalities may spontaneously resolve. These electrocardiographic findings may represent minoxidil‐induced myocardial ischemia or the evolution or worsening of left ventricular hypertrophy (LVH). It has been observed ³⁵ that despite good control of hypertension with triple therapy, including minoxidil, the β blocker betaxolol, and furosemide, left ventricular size may continue to increase. The association of minoxidil with LVH has been further explored in a small, comparative study in hypertensive patients with echocardiographically documented LVH who were treated with the β blocker bopindolol and guanfacine and either cilazApril, cilazApril and minoxidil, or minoxidil alone. ³⁶ In these patients, minoxidil‐associated LVH was significantly attenuated by coadministration of the angiotensin‐converting enzyme (ACE) inhibitor cilazApril, which suggests that an ACE inhibitor may be an important adjunct to minoxidil treatment.

The reflex tachycardia that occurs with minoxidil can precipitate myocardial ischemia. ⁴ , ¹⁹ , ²⁰ If symptoms of myocardial ischemia occur in a minoxidiltreated patient and the severity of hypertension requires continuation of therapy, aggressive β blocker therapy is a necessity. Elevated pulmonary artery pressures have been observed in patients receiving chronic minoxidil therapy—an effect less likely to occur with concurrent administration of a β blocker. It is probable that pulmonary hypertension in minoxidil‐treated patients reflects the presence of high pulmonary vascular resistance prior to the start of minoxidil and not a direct medication effect. ³⁷

Hypertrichosis is inevitable with minoxidil and can be disfiguring. ³⁸ Hair growth begins within 3–6 weeks of initiation of therapy, initially over the temples and eyebrows, then between the eyebrows and the hairline or sideburn region, and finally on the trunk, extremities, and scalp. Hair growth can be extensive and has even been noted in the ear canal, to the extent that it can cause hearing loss. ³⁹ In women, the unwanted cosmetic effect seriously limits minoxidil use. The specific mechanism for minoxidil‐induced hair growth is not known, but it is probably related to increased blood flow in affected areas and is not a hormonal mechanism. Hypertrichosis disappears within a few weeks after discontinuation of the drug, and in some cases there is less hair than before the drug was started. ⁴⁰ Generalized hair growth can also occur with application of topical minoxidil, which is available in both 2% and 5% solutions, but this generally requires higher doses than are currently recommended. ⁴¹ Hypertrichosis can be treated with conventional depilatory agents, although it is a time‐consuming and costly remedy.

In conclusion, minoxidil—usually given in combination with a β blocker and a loop diuretic, is effective therapy for stage III hypertension. Although significant fluid retention and tachycardia can occur with minoxidil treatment, these effects can be successfully avoided in most patients. However hypertrichosis and cardiac abnormalities, such as LVH, ischemia, and pericardial effusion, often limit the usefulness of minoxidil.