Minoxidil: An Underused Vasodilator for Resistant or Severe Hypertension

Abstract

Minoxidil is a direct vasodilator introduced in the early 1970s for the treatment of hypertension. It is capable of reducing blood pressure in most persons with resistant hypertension where therapy has failed with multidrug regimens. Minoxidil's effect can be limited because of an increase in pulse rate and/or sodium (and water) retention. The latter May prove quite debilitating in some patients. Thus, minoxidil is generally administered with both a diuretic and an agent that can keep pulse rate in check, such as a β blocker or a combined α‐β blocker. The prominent tachycardia with minoxidil can aggravate myocardial ischemia and, if long‐standing, leads to left ventricular hypertrophy. Minoxidil has a particularly annoying side effect of hypertrichosis that May limit its use, particularly among women. Minoxidil use is infrequently associated with the idiosyncratic onset of a pericardial effusion. If a patient's hypertension is severe enough to warrant minoxidil therapy, a hypertension specialist should probably become involved in the patient's care. The use of this medicaion should be limited in view of the availability of effective agents with fewer side effects. There is, however, a place for minoxidil in the treatment of resistant hypertension especially in patients with advanced renal disease.

Direct vasodilator drugs, such as hydralazine and minoxidil, are generally held in reserve for patients with advanced stage 2 hypertension who have not responded to conventional multidrug antihypertensive regimens. ¹ , ² Although these compounds are typically reserved for resistant hypertension, they are well suited for patients with accelerated hypertension. In addition, there are circumstances in which they can be employed in less severe cases. For example, hydralazine in a dose of 25–100 mg twice daily was a Step 3 medication in The Antihypertensive and Lipid‐Lowering to Prevent Heart Attack Trial (ALLHAT), albeit on a per protocol basis. The rationale for the use of hydralazine in this trial related to its direct vasodilatory mode of action being different and complementary to the other drug classes in use.

MECHANISM OF ACTION

The antihyfpertensive activity of minoxidil is due to its sulphate metabolite, minoxidil sulfate. In large measure, minoxidil acts by opening adenosine triphosphate‐sensitive potassium channels in vascular smooth muscle cells. The ensuing vasodilation is comparable to that observed with other known potassium channel openers, like pinacidil. ³ The predominant site of minoxidil action is arterial. Venodilation does not occur with minoxidil; thus, postural hypotension is unusual with its administration. The arteriolar vasodilation brought about by minoxidil can stimulate the peripheral sympathetic nervous system (SNS) by way of carotid and aortic baroreceptor reflexes. In conjunction with activation of the SNS, both pulse rate and cardiac output increase with minoxidil; however, cardiac output and heart rate will tend to revert to pretreatment values with long‐term treatment. ⁴ Minoxidil administration also brings about an increase in plasma renin activity, largely due to the aforementioned activation of the SNS. ⁵ , ⁶ , ⁷ This activation of the reninangiotensin axis further prompts increased biosynthesis of aldosterone; whereas plasma and urinary aldosterone levels are increased early in the course of treatment with minoxidil, ⁵ , ⁶ , ⁷ over time these values tend to normalize presumably because of accelerated metabolic clearance of aldosterone in association with hepatic vasodilation. ⁸ Although minoxidil is effective in reducing blood pressure (BP), the counterregulatory hemodynamic and neurohumoral changes that accompany its use can completely offset (or partially attenuate) the beneficial BP‐lowering effect that ensues from arteriolar vasodilatation. ⁵

PHARMACOKINETICS

Minoxidil is completely and rapidly absorbed from the gastrointestinal tract, although its absorption can be delayed in the setting of advanced renal failure. ⁹ Minoxidil is primarily metabolized by hepatic glucuronidation to an active metabolite, which is renally cleared. ¹⁰ Because minoxidil localizes to compartments other than the intravascular space, such as arterial smooth muscle cells and the myocardium, its volume of distribution typically extends beyond that of total body water. ¹¹ Minoxidil is minimally protein bound, making it freely available for dialysis. ¹² The plasma elimination half‐life of minoxidil is in the order of 3–4 hours. This differs noticeably from the duration of its hypotensive effect, which in some patients May endure for as long as 72 hours. It is the latter effect that supports its once‐daily dosing, although there is considerable interindividual variability in the frequency with which dosing must occur. ¹³ , ¹⁴ Although there appears to be a relationship between the dose of minoxidil and the degree of BP reduction, there is a more limited correlation between plasma minoxidil levels and its BP‐reducing ability.

CLINICAL USE

The effectiveness of minoxidil in patients with resistant hypertension is well established. In one report, 11 patients with hypertension given minoxidil alone saw their mean BP fall from 188/124 mm Hg to 159/108 mm Hg. With the addition of the β blocker propranolol, BP fell to 134/86 mm Hg. In these patients there were no signs of orthostatic hypotension and fluid retention was easily controlled with diuretics. ¹⁵

Minoxidil is frequently a therapy of last resort in patients with chronic kidney disease (CKD) who have been unresponsive to other antihypertensive medications. ⁹ , ¹⁶ , ¹⁷ , ¹⁸ Most forms of hypertension, independent of severity and/or the degree of renal insufficiency, are at least partially responsive to minoxidil. ⁵ , ¹⁹ , ²⁰ In this regard, shortly after minoxidil was made available, it quickly replaced bilateral nephrectomies as the treatment of choice in advanced CKD patients with otherwise uncontrollable hypertension. ⁹ , ²¹ Minoxidil does not adversely affect renal function in the majority of patients with hypertension and a normal glomerular filtration rate (GFR). ²² In patients with established CKD, minoxidil can stabilize GFR‐if not improve renal function‐when BP is properly controlled. ¹⁶ , ²² , ²³ On occasion, patients with CKD with malignant hypertension and sudden BP control with minoxidil experience an acute further deterioration in renal function. This fall in GFR can be of sufficient magnitude to call for dialysis; however, GFR is often recoverable and discontinuation of dialysis possible if normal BP is established with minoxidil therapy. ¹⁷ , ²² , ²³

In persons with advanced stage 2 hypertension, minoxidil is almost always given as one of several antihypertensive medications. If so, the coadministered antihypertensive medications should include a diuretic (usually a loop diuretic) and a β blocker or a combined α‐β blocker such as labetalol or carvedilol. It is not appropriate to simply give these medications without having established goals for their use. In the case of concomitant diuretic therapy, the potency of the chosen diuretic and its frequency of dosing should be sufficient to keep the patient free of edema. This can prove challenging, and occasionally, the volume expansion (edema) with minoxidil can be of sufficient severity to require combination therapy with a loop diuretic and metolazone. (In many cases, large doses of a loop diuretic [i.e, furosemide >100mg/d] May be necessary to control edema.)

Concomitant β‐blocker or combined α‐β‐blocker therapy should be directed to the problem of pulse rate control. The vasodilation induced by minoxidil can provoke a significant tachycardic response, particularly at peak medication effect; thus, β blockade or combined α‐β blockade should be timed to coincide with the presumed (or determined) time of maximal pulse rate response with minoxidil. This is often easier said than done, particularly if sustained‐release compounds are being used for β blockade. In the case of tachycardia with minoxidil, which proves difficult to control, it is reasonable to empirically split‐dose the total required amount of minoxidil on a two‐ or three‐times daily basis. In theory, this will attenuate the peak pulse rate response because lower individual doses are being given.

In a patient treated with minoxidil who is β‐blocker intolerant it simply May not be possible to use this drug if the pulse rate response is too extreme; however, patients treated with minoxidil usually receive several other medications, including drugs such as the central α‐agonist clonidine and/or a pulse rate reducing calcium channel blocker such as verapamil or diltiazem. ⁹ , ²⁴ Physicians should be mindful of the fact that both of these drug classes are known to reduce heart rate and May be used to support (or occasionally substitute) for β blockade. When this triple‐drug regimen is correctly constituted, more than 75% of patients with hypertension who were previously resistant to multidrug therapy can achieve control. ²⁵ , ²⁶

DOSING CONSIDERATIONS

The beginning dose of minoxidil can be as low as 2.5 mg/d with a maintenance dose generally falling in the range of 10–40 mg/d. Minoxidil can be given from once to three times daily with the most common frequency of administration being twice daily. The twice‐daily, or occasionally the thrice‐daily, dosing regimen is preferred in patients receiving high doses of minoxidil to avoid an excessive peak hypotensive effect as May come to pass with one large daily dose. Occasionally, doses of minoxidil in excess of 40 mg/d are required to normalize BR Although the manufacturer's maximum recommended dose is 100 mg/d it is unusual for patients to require more than 20 mg in a single dose and 40 mg as a total daily dose. A starting dose of minoxidil can be safely titrated upward fairly quickly, with dose escalation every 3–4 days. If vasodilator side effects occur with a particular dose of minoxidil, dose escalation should occur at a slowed pace.

The rapid titration of minoxidil over a several‐day time span May be followed by a gradual loss of BP control over the ensuing days as sodium retention and tachycardia evolve. These counterregulatory adjustments should be anticipated even as therapy starts with minoxidil. The weight gain with minoxidil can be sudden and extreme, in part because patients are seldom advised to limit sodium intake as it is begun. Once significant edema is present a sensible step is to temporarily discontinue minoxidil (or significantly reduce the dose) and allow the edema to resolve of its own accord. This maneuver obviates the need for a high‐dose loop diuretic regimen and allows an earlier restart of minoxidil with a more reasonable diuretic regimen.

An accelerated dosing schedule can be used with minoxidil to achieve rapid BP control in patients with severe diastolic hypertension (>120 mm Hg). ² , ⁷ , ²⁷ For example, 2 hours after having received a combination of both furosemide (40 mg) and propranolol (40 mg), a 20‐mg loading dose of oral minoxidil was given to nine symptomatic patients whose diastolic BP exceeded 120 mm Hg. ² A booster dose of 5–20 mg, calculated on the basis of each patient's response to the loading dose of minoxidil, was given 4 hours hence if diastolic BP still exceeded 100 mm Hg. With this therapeutic line of attack, systolic and diastolic BPs fell progressively over the ensuing several hours.

This approach shows that an orally administered regimen of propranolol, furosemide, and minoxidil produces prompt and sustained BP reduction in patients with severe hypertension who require immediate BP reduction. These early studies with minoxidil occurred at a time when the treatment of accelerated symptomatic hypertension was constrained by the absence of intravenous therapies; thus, this approach outlined is not a substitute for the treatment of symptomatic hypertension with parenteral therapies but rather a matching strategy to ease the transition from intravenous to oral medications.

Also, minoxidil loading should always be preceded by β‐blocker or combined α‐β therapy because high‐dose minoxidil can be expected to significantly increase pulse rate and thereby increase the likelihood of (and risk from) myocardial ischemia. ² , ⁷ , ²⁷ Finally, this course of action is recommended only under strict supervision because prolonged hypotension has been occasionally seen after an initial 10‐mg minoxidil dose. ²⁸

Minoxidil topically applied for male‐pattern baldness can be transdermally absorbed. To this end, it has been observed over a several‐month period of treatment with topical minoxidil that left ventricular end‐diastolic volume, cardiac output, and left ventricular mass all can increase. ²⁹ To this end, the manufacturer of topical minoxidil in their instructions to patients provides a specific warning to stop its use and consult a physician if a patient experiences chest pain, rapid heartbeat, swelling, or a significant weight gain. ³⁰ These are self‐evident manifestations of minoxidil effect that are easily identified by a patient. The more significant cardiac structural effects that have been described with topically administered minoxidil must be identified by physicians.

SIDE EFFECTS

Fluid retention and tachycardia are dose‐dependent side effects that occur with minoxidil. ³¹ The mechanism of the sodium and water retention with minoxidil is a varying combination of renal hemodynamic and/or neurohumoral changes as well as direct tubular effects. ¹⁵ The latter May relate to minoxidil's action as a potassium channel opener.

Activation of the potassium channel in the thick ascending limb increases Na⁺/2Cl−/K⁺ co‐transporter activity and thereby increases sodium and chloride reabsorption. This occurs without major changes in potassium or calcium excretion. ³²

Fluid retention can be extreme enough to require discontinuation of the medication. Daily monitoring of a patient's weight as therapy progresses can pinpoint those experiencing the most marked fluid retention. The earlier fluid retention is identified in a patient treated with minoxidil the easier it is to manage this side effect. Pericardial effusions have also been reported in as many as 3% of patients treated with minoxidil. ³³ , ³⁴ Such effusions can spontaneously resolve, obviating the need for catheter drainage in some patients. ³⁵ The true incidence of pericardial effusion with minoxidil is difficult to estimate because many such patients have CKD (pericardial effusions can occur in advanced CKD in and of itself) and no pretreatment echocardiogram. In many cases a minoxidil‐related pericardial effusion is simply an extension of the generalized volume overload that can accompany therapy; however, in some instances it is idiopathic (and volume‐independent) and recurs with minoxidil rechallenge. ³⁵ Under these circumstances further therapy with minoxidil is ill advised.

During the first 2 weeks of treatment with minoxidil, ST‐segment depression and T‐wave flattening or inversion can be seen in up to 90% of patients.^4,11,36 These electrocardiogram abnormalities often resolve during long‐term therapy; on the other hand, their persistence can be a sign of myocardial ischemia or the onset of progressive left ventricular hypertrophy (LVH). Moreover, it has been observed that despite good control of hypertension with minoxidil, the β blocker betaxolol, and furosemide, left ventricular size often continues to increase. ³⁷ Minoxidil‐associated LVH has been further investigated in a cohort of hypertensive patients with LVH (echocardiographically determined) treated with the β blocker bopindolol and guanfacine and either cilazapril, cilazapril and minoxidil, or minoxidil alone. ³⁸ Minoxidil‐associated LVH was significantly attenuated by the coadministration of the angiotensin‐converting enzyme inhibitor cilazapril in these studies suggesting that an angiotensin‐converting enzyme inhibitor should be viewed as important adjunctive therapy in patients treated with minoxidil.

The reflex tachycardia that occurs with minoxidil can precipitate myocardial ischemia. ⁴ , ¹⁹ , ²⁰ If symptoms of myocardial ischemia occur in a patient treated with minoxidil and the severity of the patient's hypertension requires therapy to be continued, aggressive β‐blocker therapy becomes imperative. Elevated pulmonary artery pressures have been observed in patients receiving chronic minoxidil therapy, an effect less likely to occur in patients concurrently receiving β‐blocker therapy. When pulmonary hypertension is detected in patients treated with minoxidil it is not a direct medication effect; rather, it is more likely to be a sign of a pretherapy abnormality. ³⁹

Hypertrichosis is quite common with minoxidil and can be cosmetically disfiguring, particularly in women (Figure I). ⁴⁰ Hair growth begins within 3–6 weeks of starting therapy, occurring over the temples and eyebrows initially, spreading to areas between the eyebrows and hairline or sideburn regions, to finally involve the trunk, extremities, and scalp. Hair growth can be extensive, even having occurred in the ear canal with resultant hearing loss. ⁴¹ Although increased cutaneous blood flow to affected areas is one possible explanation for the increased hair growth with minoxidil; several lines of evidence, from clinical observations, animal studies and in vitro experiments, suggest that the promotion of hair growth by minoxidil is related in some way to its action as a potassium channel opener. ⁴²

Figure.

Facial hair growth in a woman receiving minoxidil therapy. Reprinted with permission from White G, Cox N, eds. Diseases of the Skin. Philadelphia, PA: WB Saunders; 2000.

Hypertrichosis disappears within a few weeks of discontinuing minoxidil, although in some cases there is less hair than before the drug was started. ⁴³ Generalized hair growth in areas that are not bald can also occur with any of the topical minoxidil solutions that are currently available in both 2% and 5% solutions. For this to occur it generally requires application of the topical solution in amounts exceeding current recommendations. ⁴⁴

In women, hypertrichosis can be treated in a number of ways. Shaving the affected areas has the fewest side effects but is usually psychologically objectionable to the patient. Women should be reassured that shaving will not cause the hair to grow faster or become darker. Other treatment options include bleaching, waxing, electrolysis, depilatories, and plucking. Finally, topical minoxidil (and oral minoxidil) should be used with care during pregnancy because topically applied minoxidil has been associated with fetal malformations. ⁴⁵ Thus, although minoxidil is a potent vasodilator and will lower blood pressure, there are significant problems that limit its use to resistant hypertension or patients with definite renal disease.