Minoxidil

Minoxidil is a Vasodilator which acts an antihypertensive agent used in the treatment of resistant hypertension that is symptomatic or has caused end-organ damage. It also stimulates hair growth in adult men and women with a certain type of baldness.

Minoxidil is absorbed 90% from the GI tract (oral); 0.3-4.5% from intact scalp (topical).It gets distributed when it enters breast milk. It is extensively metabolised through hepatic via glucuronidation and excreted via urine as metabolites with an elimination half-life of approximately 4.2 hr.

The common side effects are headache, nausea, gynaecomastia, breast tenderness, polymenorrhoea, allergic rashes, Stevens-Johnson syndrome, Contact dermatitis, pruritus, local burning, flushing, changes in hair color or texture.

Minoxidil is available in dosage form such as topical solution, foam and tablets.

Minoxidil is available in China, South Korea, India, Japan, U.S

Minoxidil, when used as a vasodilator, acts by opening adenosine triphosphate-sensitive potassium channels in vascular smooth muscle cells. This vasodilation may also improve the viability of hair cells or hair follicles.

Minoxidil may stimulate the growth of human hairs by prolonging anagen through these proliferative and anti-apoptotic effects on DPCs.

The Duration of Action of Minoxidil was within 2.8 to 4.2 hours,

The onset of Action of Minoxidil was within 30 minutes (Oral)

The Tmax was about 0.5 hour and Cmax was about 16.8 and 37.2 ng/mL

Minoxidil is available in the form of topical solution, foam and tablets.

Minoxidil reduces elevated systolic and diastolic BP by decreasing peripheral vascular resistance via vasodilation. Applied topically, it stimulates hair growth secondary to vasodilation, increases cutaneous blood flow and stimulates resting hair follicles.

Minoxidil is a Vasodilator which acts an antihypertensive agent used in the treatment of resistant hypertension that is symptomatic or has caused end-organ damage.It is also used to stimulate hair growth in adult men and women with a certain type of baldness.

Minoxidil is approved for use in the following clinical indications

• Severe Hypertension:

Adult: In conjunction w/ a β-blocker or methyldopa, and a diuretic: Initially, 5 mg daily, gradually increase at intervals of at least 3 days to 40 mg or 50 mg as a single or in 2 divided doses daily depending on response. Max: 100 mg daily. For rapid control of BP: Dose increments of 5 mg 6 hrly may be given w/ careful monitoring.

Elderly: Initially, 2.5 mg daily, increase gradually.

Although not approved there have been certain off label indication documented for Minoxidil which includes:

• Male pattern baldness

Adult:

Male: As 2% or 5% soln: Apply 1 mL to the scalp bid. As 5% foam or aerosol: Apply ½ capful to the scalp bid.

Female: As 2% soln: Apply 1 mL to the scalp bid. As 5% foam or aerosol: Apply ½ capful to the scalp once daily.

The dosage and the duration of treatment should be as per the clinical judgment of the treating physician

Minoxidil is available in various dosage strengths of 2.5mg, 5 mg, 10 mg, 2%, 5%

Minoxidil is available in the form of dosage form such as topical solution, foam and tablets.

Minoxidil should be used for the treatment of resistant hypertension that is symptomatic or has caused end-organ damage.

Hypertension: It has been observed that the low-salt Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure. Sometimes after a few weeks, its effects on blood pressure become noticeable.

The dietary restriction should be individualized as per the patient requirements.

Minoxidil may be contraindicated in the following

• Minoxidil is contraindicated in patients with a history of hypersensitivity to the drug or its components (such as propylene glycol).
• The use of minoxidil is not advised in the pregnant and breastfeeding women. While minoxidil is not known to be teratogenic, reports exist of rare cases of congenital disabilities.
• The product labeled for use on men is contraindicated to use on women.
• This product is also contraindicated if the reason for hair loss is unknown, if there is no prior family history of hair loss if hair loss occurs suddenly and/or patchy; if hair loss is linked with the childbirth, if the patient is less than 18 years old, if the scalp is infected or inflamed; or another medication is already applied on the scalp.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows.

Warnings

• Salt and Water Retention

Congestive Heart Failure-concomitant use of an adequate diuretic is required-Minoxidil tablets must usually be administered concomitantly with a diuretic adequate to prevent fluid retention and possible congestive heart failure; a high ceiling (loop) diuretic is almost always required. Body weight should be monitored closely. If minoxidil is used without a diuretic, retention of several hundred milliequivalents of salt and corresponding volumes of water can occur within a few days, leading to increased plasma and interstitial fluid volume and local or generalized edema. Diuretic treatment alone, or in combination with restricted salt intake, will usually lower fluid retention, although reversible edema did develop in approximately 10% of nondialysis patients so treated. Ascites has also been reported. Diuretic effectiveness was limited mostly by disease-related impaired renal function. The condition of patients with pre-existing congestive heart failure occasionally deteriorated in association with fluid retention although because of the decrease in blood pressure (reduction of afterload), more than twice as many improved than worsened. Rarely, refractory fluid retention may require discontinuation of minoxidil . Provided that the patient is under close medical supervision, it may be possible to resolve the refractory salt retention by discontinuing minoxidil for 1 or 2 days and then resuming the treatment in conjunction with vigorous diuretic therapy.

· Concomitant Treatment to Prevent Tachycardia is Usually Required

Minoxidil increases the heart rate. Angina may worsen or appear for the first time during minoxidil treatment, probably because of the increased oxygen demands associated with increased heart rate and cardiac output. The increase in rate and the occurrence of angina generally can be prevented by the concomitant administration of a beta-adrenergic blocking drug or other sympathetic nervous system suppressant. The ability of beta-adrenergic blocking agents to lower papillary muscle lesions in animals is further reason to utilize such an agent concomitantly. Round-the-clock effectiveness of the sympathetic suppressant should be ensured.

• Pericarditis, Pericardial Effusion, and Tamponade

There have been reports of pericarditis occurring in association with the use of minoxidil . The relationship of this association to renal status is uncertain. Pericardial effusion, occasionally with tamponade, has been observed in about 3% of treated patients not on dialysis, especially those with inadequate or compromised renal function. Although in many cases, the pericardial effusion was associated with a connective tissue disease, the uremic syndrome, congestive heart failure, or marked fluid retention, there have been instances in which these potential causes of effusion were not present. Patients should be observed closely for any suggestion of a pericardial disorder, and echocardiographic studies should be carried out if suspicion arises. More vigorous diuretic therapy, dialysis, pericardiocentesis, or surgery may be required. If the effusion persists, withdrawal of minoxidil should be considered in light of other means of controlling the hypertension and the patient’s clinical status.

• Interaction with Guanethidine

Although minoxidil does not itself cause orthostatic hypotension, its administration to patients already receiving guanethidine can result in profound orthostatic effects. If at all possible, guanethidine should be discontinued well before minoxidil is begun. Where this is not possible, minoxidil therapy should be started in the hospital, and the patient should remain institutionalized until severe orthostatic effects are no longer present or the patient has learned to avoid activities that provoke them.

• Hazard of Rapid Control of Blood Pressure

In patients with very severe blood pressure elevation, too rapid control of blood pressure, especially with intravenous agents, can precipitate syncope, cerebrovascular accidents, myocardial infarction and ischemia of special sense organs with resulting decrease or loss of vision or hearing. Patients with compromised circulation or cryoglobulinemia may also suffer ischemic episodes of the affected organs. Although such events have not been unequivocally associated with minoxidil use, total experience is limited at present.

Any patient with malignant hypertension should have initial treatment with minoxidil carried out in a hospital setting, both to assure that blood pressure is falling and to assure that it is not falling more rapidly than intended.

Precautions

General Precautions

• Monitor fluid, electrolyte balance and body weight.
• Observe patients for signs and symptoms of pericardial effusion.
• Use after myocardial infarction-Minoxidil tablets have not been used in patients who have had a myocardial infarction within the preceding month. It is possible that a reduction of arterial pressure with minoxidil might further limit blood flow to the myocardium, although this might be compensated by decreased oxygen demand because of lower blood pressure.
• Hypersensitivity-Possible hypersensitivity to minoxidil , manifested as a skin rash, has been seen in less than 1% of patients; whether the drug should be discontinued when this occurs depends on treatment alternatives.
• Renal failure or dialysis patients may require smaller doses of minoxidil and should have close medical supervision to prevent exacerbation of renal failure or precipitation of cardiac failure.

Alcohol consumption with Minoxidil may increase the risk of low blood pressure and cause adverse effects, such as dizziness, fainting, light-headedness, or headache.

Minoxidil use in breastfeeding patients is not recommended.

Pregnancy Category C.

Oral administration of minoxidil has been associated with evidence of increased fetal resorption in rabbits, but not rats, when administered at five times the maximum recommended oral antihypertensive human dose. There was no evidence of teratogenic effects in rats and rabbits. Subcutaneous administration of minoxidil to pregnant rats at 80 mg/kg/day was maternally toxic but not teratogenic. Higher subcutaneous doses produced evidence of developmental toxicity. There are no adequate and well controlled studies in pregnant women. Minoxidil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Limit or reduce the salt in the diet while taking minoxidil. Do not use potassium supplements or salt substitutes.

The adverse reactions related to molecule Minoxidil can be categorized as

• Common Adverse effects:

Reflex tachycardia, fluid retention, changes in ECG, hypertrichosis, pericardial effusion and tamponade, pericarditis, exacerbation of angina pectoris, headache, nausea, gynaecomastia, breast tenderness, polymenorrhoea, allergic rashes, Stevens-Johnson syndrome.

• Less Common adverse effects:

Asymptomatic and symptomatic hypotension, burning, crawling, itching, numbness.

• Rare adverse effects:

Thrombocytopenia and leucopenia, Topical: Contact dermatitis, pruritus, local burning, flushing, changes in hair colour or texture.

The clinically relevant drug interactions of Minoxidil is briefly summarized here.

Additive effect w/ other hypotensive drugs. Risk of orthostatic hypotension w/ sympathetic blocking drugs (e.g. guanethidine). Topical: Enhanced absorption w/ other topical medical preparations (e.g. corticosteroids, retinoids or occlusive ointment bases).

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

Symptoms:

Exaggerated hypotension.

Management:

Admin IV normal saline. Phenylephrine, angiotensin II and vasopressin may be given if inadequate perfusion of a vital organ is evident.

Pharmacodynamics:

Minoxidil is an orally effective direct acting peripheral vasodilator that reduces elevated systolic and diastolic blood pressure by decreasing peripheral vascular resistance. Minoxidil is also used topically to treat androgenetic alopecia. 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. The predominant site of minoxidil action is arterial. Venodilation does not occur with minoxidil; thus, postural hypotension is unusual with its administration. The antihypertensive activity of minoxidil is due to its sulphate metabolite, minoxidil sulfate.

Pharmacokinetics:

• Absorption:

Minoxidil is at least 90% absorbed from the GI tract in experimental animals and man.; 0.3-4.5% from intact scalp (topical). Distribution: Enters breast milk.

• Metabolism:

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.

• Excretion:

Via urine as metabolites. Elimination half-life: Approx 4.2 hr.

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