Minoxidil (Loniten) is an orally effective vasodilator. It is more potent and longer acting than hydralazine and does not accumulate significantly in patients with renal insufficiency. It depends on in vivo metabolism by he-patic enzymes to produce an active metabolite, minoxi-dil sulfate. Minoxidil sulfate activates potassium chan-nels, resulting in hyperpolarization of vascular smooth muscle and relaxation of the blood vessel.
Peak concentrations of minoxidil in the blood occur 1 hour after oral administration, although the therapeutic effect may take 2 or more hours to manifest. This is probably related to the time it takes to convert minoxi-dil to minoxidil sulfate. The antihypertensive action af-ter an oral dose of minoxidil lasts 12 to 24 hours. The long duration of action allows the drug to be adminis-tered only once or twice a day, a regimen that may be beneficial for compliance. Interestingly, the therapeutic half-life is considerably longer than the plasma half-life. This may be, as has been suggested for hydralazine, a re-sult either of accumulation of the drug and its active metabolite in arterial walls or a longer plasma half-life of the sulfated metabolite, or both.
The ultimate disposition of minoxidil depends prima-rily on hepatic metabolism and only slightly on renal ex-cretion of unchanged drug. Because of this, pharmacolog-ical activity is not cumulative in patients with renal failure
The hemodynamic effects of minoxidil are generally similar to those of hydralazine, with the noteworthy ex-ception that a greater decrease in peripheral vascular resistance and consequently a larger reduction in blood pressure can be achieved with minoxidil. Minoxidil pro-duces no important changes in either renal blood flow or glomerular filtration rate. It has little or no effect on venous capacitance and does not inhibit the reflex acti-vation of the sympathetic nervous system. Orthostasis and other side effects of sympathetic blockade are therefore not a problem. As with hydralazine, there is a significant increase in cardiac output that is secondary to reflex increases in sympathetic activity, hyperrenine-mia, and salt and water retention. These effects can sub-stantially reduce the effectiveness of minoxidil when it is used alone. The addition of a β-blocker and a diuretic to the therapeutic regimen will preserve minoxidil’s an-tihypertensive action while attenuating some of the un-desirable side effects.
The major indications for the use of minoxidil are severe hypertension that may be life threatening and (2) hypertension that is resistant to milder forms of therapy. Compromises in renal function do not prolong either the plasma or the therapeutic half-life of minoxi-dil, and therefore, it seems to be particularly important for hypertensive patients with chronic renal failure.
Signs of toxicity common to vasodilator therapy in gen-eral also occur with minoxidil; they are attributable to vasodilation and reflex increases in sympathetic nerve activity. These include headache, nasal congestion, tachycardia, and palpitations. These effects do not have great clinical importance, since minoxidil is almost al-ways administered in combination with a β-blocker, which antagonizes the indirect cardiac effects. A more troublesome side effect, particularly in women, is the growth of body hair, possibly due to a direct stimulation of the growth and maturation of cells that form hair shafts. Apparently, minoxidil activates a specific gene that regulates hair shaft protein. In any case, this partic-ular side effect has been capitalized upon, and minoxi-dil is now marketed as Rogaine for the treatment of male pattern baldness.