MINOXIDIL TABLETS, USP
Minoxidil tablets contain minoxidil, an antihypertensive peripheral vasodilator. Minoxidil occurs as a white to off-white, odorless crystalline powder that is soluble in alcohol and propylene glycol; sparingly soluble in methanol; slightly soluble in water; practically insoluble in chloroform, acetone and ethyl acetate. The chemical name for minoxidil is 2,4-pyrimidinediamine, 6-(1-piperidinyl)-,3-oxide. The structural formula is represented below:
Minoxidil tablets for oral administration contain either 2.5 mg or 10 mg of minoxidil. Inactive ingredients: colloidal silicon dioxide, anhydrous lactose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate.
1. General Pharmacologic Properties
Minoxidil is an orally effective direct acting peripheral vasodilator that reduces elevated systolic and diastolic blood pressure by decreasing peripheral vascular resistance. Microcirculatory blood flow in animals is enhanced or maintained in all systemic vascular beds. In man, forearm and renal vascular resistance decline; forearm blood flow increases while renal blood flow and glomerular filtration rate are preserved.
Because it causes peripheral vasodilation, minoxidil elicits a number of predictable reactions. Reduction of peripheral arteriolar resistance and the associated fall in blood pressure trigger sympathetic, vagal inhibitory, and renal homeostatic mechanisms, including an increase in renin secretion, that lead to increased cardiac rate and output and salt and water retention. These adverse effects can usually be minimized by concomitant administration of a diuretic and a beta-adrenergic blocking agent or other sympathetic nervous system suppressant.
Minoxidil does not interfere with vasomotor reflexes and therefore does not produce orthostatic hypotension. The drug does not enter the central nervous system in experimental animals in significant amounts, and it does not affect CNS function in man.
2. Effects on Blood Pressure and Target Organs
The extent and time-course of blood pressure reduction by minoxidil do not correspond closely to its concentration in plasma. After an effective single oral dose, blood pressure usually starts to decline within one-half hour, reaches a minimum between 2 and 3 hours and recovers at an arithmetically linear rate of about 30%/day. The total duration of effect is approximately 75 hours. When minoxidil is administered chronically, once or twice a day, the time required to achieve maximum effect on blood pressure with a given daily dose is inversely related to the size of the dose. Thus, maximum effect is achieved on 10 mg/day within 7 days, on 20 mg/day within 5 days, and on 40 mg/day within 3 days.
The blood pressure response to minoxidil is linearly related to the logarithm of the dose administered. The slope of this log-linear dose-response relationship is proportional to the extent of hypertension and approaches zero at a supine diastolic blood pressure of approximately 85 mm Hg.
When used in severely hypertensive patients resistant to other therapy, frequently with an accompanying diuretic and beta-blocker, minoxidil tablets usually decreased the blood pressure and reversed encephalopathy and retinopathy.
3. Absorption and Metabolism
Minoxidil is at least 90% absorbed from the GI tract in experimental animals and man. Plasma levels of the parent drug reach maximum within the first hour and decline rapidly thereafter. The average plasma half-life in man is 4.2 hours. Approximately 90% of the administered drug is metabolized, predominantly by conjugation with glucuronic acid at the N-oxide position in the pyrimidine ring, but also by conversion to more polar products. Known metabolites exert much less pharmacologic effect than minoxidil itself; all are excreted principally in the urine. Minoxidil does not bind to plasma proteins, and its renal clearance corresponds to the glomerular filtration rate. In the absence of functional renal tissue, minoxidil and its metabolites can be removed by hemodialysis.
4. Cardiac Lesions in Animals
Minoxidil produces several cardiac lesions in animals. Some are characteristic of agents that cause tachycardia and diastolic hypotension (beta-agonists like isoproterenol, arterial dilators like hydralazine) while others are produced by a narrower range of agents with arterial dilating properties. The significance of these lesions for humans is not clear, as they have not been recognized in patients treated with oral minoxidil at systemically active doses, despite formal review of over 150 autopsies of treated patients.
- (a)Papillary muscle/subendocardial necrosis
The most characteristic lesion of minoxidil, seen in rat, dog, and minipig (but not monkeys) is focal necrosis of the papillary muscle and subendocardial areas of the left ventricle. These lesions appear rapidly, within a few days of treatment with doses of 0.5 to 10 mg/kg/day in the dog and minipig, and are not progressive, although they leave residual scars. They are similar to lesions produced by other peripheral arterial dilators, by theobromine, and by beta-adrenergic receptor agonists such as isoproterenol, epinephrine, and albuterol. The lesions are thought to reflect ischemia provoked by increased oxygen demand (tachycardia, increased cardiac output) and relative decrease in coronary flow (decreased diastolic pressure and decreased time in diastole) caused by the vasodilatory effects of these agents coupled with reflex or directly induced tachycardia.
- (b)Hemorrhagic lesions
After acute oral minoxidil treatment (0.5 to 10 mg/kg/day) in dogs and minipigs, hemorrhagic lesions are seen in many parts of the heart, mainly in the epicardium, endocardium, and walls of small coronary arteries and arterioles. In minipigs the lesions occur primarily in the left atrium while in dogs they are most prominent in the right atrium, frequently appearing as grossly visible hemorrhagic lesions. With exposure of 1-20 mg/kg/day in the dog for 30 days or longer, there is replacement of myocardial cells by proliferating fibroblasts and angioblasts, hemorrhage and hemosiderin accumulation. These lesions can be produced by topical minoxidil administration that gives systemic absorption of 0.5 to 1 mg/kg/day. Other peripheral dilators, including an experimental agent, nicorandil, and theobromine, have produced similar lesions.
A less fully studied lesions is focal epicarditis, seen in dogs after 2 days of oral minoxidil. More recently, chronic proliferative epicarditis was observed in dogs treated topically twice a day for 90 days. In a one year oral dog study, serosanguinous pericardial fluid was seen.
- (d)Hypertrophy and Dilation
Oral and topical studies in rats, dogs, monkeys (oral only), and rabbits (dermal only) show cardiac hypertrophy and dilation. This is presumed to represent the consequences of prolonged fluid overload; there is preliminary evidence in monkeys that diuretics partly reverse these effects.
Autopsies of over 150 patients who died of various causes after receiving minoxidil for hypertension have not revealed the characteristic hemorrhagic (especially atrial) lesions seen in dogs and minipigs. While areas of papillary muscle and subendocardial necrosis were occasionally seen, they occurred in the presence of known pre-existing coronary artery disease and were also seen in patients never exposed to minoxidil in another series using similar, but not identical, autopsy methods.