Minoxidil

The initial design of minoxidil (also called 2,4-pyrimidinediamine, 6-(1-piperidinyl)-, 3-oxide) was as a potent peripheral vasodilator agent for the treatment of severe refractory hypertension in the 1970s. Due to its serious side effects, oral minoxidil was reserved for cases of severe hypertension that were reluctant to maximum doses of three antihypertensive agents. 

Additionally, about one-fifth of patients under oral minoxidil treatment developed hypertrichosis. In 1987, a topical form was developed for the treatment of androgenic alopecia, initially for males and subsequently also for females. This article focuses specifically on topical minoxidil, the most commonly used form of the molecule.[1][2][3][4]

Topical minoxidil is available in two forms: a solution (liquid form) and a foam. The solution contains alcohol and propylene glycol, two molecules necessary to dissolve minoxidil and increase its uptake in the tissues. Formulations containing 2% and 5% minoxidil are generally used in scalp alopecia in patients who are over 18 years of age. Clinicians can use minoxidil in children; however, it is considered off-label use. Long-term use of minoxidil is necessary to maintain the clinical results, as these effects regress with drug discontinuation.[5][6]

Current uses of topical minoxidil include:

• Androgenic alopecia (the only FDA-approved indication)
• Alopecia areata: Minoxidil has been shown to induce a positive clinical response, either used alone or combined with other medications such as corticosteroids.
• Alopecia induced by chemotherapy: Minoxidil has demonstrated minimization of hair loss and acceleration of hair regrowth.
• Hair transplant: Telogen effluvium is a frequent observation after a hair transplant. Minoxidil, when administered before and after hair transplant, minimizes hair loss. Treatment should be temporarily suspended three days before the transplant to avoid excessive bleeding.
• Scarring alopecia: Minoxidil has shown evidence to exhibit an antifibrotic action. Therefore, topical minoxidil treatment can be a therapeutic choice in the early course of dermatoses leading to scarring alopecia, such as scalp burning disease.
• Monilethrix: Minoxidil leads to synchronization of the entry of hair follicles into the anagen phase.
• Hereditary alopecia/hypotrichosis: The use of minoxidil has demonstrated to be beneficial by inducing a thickening in hair shafts.

Topical minoxidil (empirical formula C9H15N5O) is a hair growth stimulator. Its mechanism of action is not well-established. Scalp sulfotransferase changes minoxidil into minoxidil sulfate, the active form of the molecule. Variations between individuals in sulfotransferase activity may be the cause of the discrepancy in minoxidil efficiency.[7]

Minoxidil acts by shortening the telogen phase and thus causing the quiescent hair follicles to enter prematurely into the anagen phase. The shortening of the telogen phase may induce telogen effluvium after the initiation of minoxidil therapy. Also, minoxidil extends the duration of the anagen phase. Lastly, increased hair length and diameter is a clinical effect of minoxidil.

The initial effects of minoxidil occur after approximately eight weeks of treatment, and maximal effects take place after four months.

Minoxidil appears to act on the potassium channels of vascular smooth muscles and hair follicles, which may induce the following effects:

• Stimulation of the microcirculation near the hair follicles by inducing arteriolar vasodilation, which may cause hair growth
• Induction of vascular endothelial growth factor (VEGF) expression which increases vascularization around the hair follicles, thus contributing to hair growth
• Activation of the prostaglandin-endoperoxide synthase one which stimulates hair growth   
• Inhibition of androgen effects on the androgen-sensitive hair follicles
• Direct stimulation of the hair follicles: Minoxidil may act as an ‘epidermal growth factor’ on matrix cells delaying their aging, thus prolonging the duration of the anagen phase, via the activation of the beta-catenin pathway  

Minoxidil has demonstrated to possess anti-fibrotic properties secondary to its effect on collagen synthesis.

Minoxidil is available in the United States as an over-the-counter topical agent. Dosing is twice daily (1 ml each dosage). No scalp massage is necessary after use. Minoxidil uptake is about 50% after an hour and 75% after 4 hours. Some practitioners associate micro-needling with topical minoxidil to enhance its efficiency, but more studies are needed to assess the value of this potential relationship.[8][9][10]

While oral minoxidil is not FDA-approved for hair loss, clinical trials have displayed effectiveness using oral minoxidil at various doses (0.25 to 2.5 mg daily).

Studies have shown that 5% minoxidil is more effective than 2% minoxidil in the treatment of alopecia. Clinical response to minoxidil is more pronounced if the onset of alopecia is within five years (mainly in young adults), and the hair follicles are not deeply miniaturized.

Minoxidil is generally well tolerated. However, some adverse effects reported by patients include:

• Minoxidil-induced telogen effluvium: Minoxidil causes the shortening of the telogen phase subsequently leading to marked shedding
• Skin irritation: Erythema, discomfort and a burning sensation
• Scaly changes of the scalp: Irritation or exacerbation of seborrheic dermatitis
• Isolated pruritus
• Allergic contact dermatitis: Erythema, eczematous skin reaction, and pruritus. Minoxidil and propylene glycol are the two major allergens in allergic contact dermatitis. Patch testing may help reveal the causative agent. In the case of allergic contact dermatitis to propylene glycol, minoxidil foam (lacks propylene glycol) is an option.
• Localized or generalized hypertrichosis: This effect can occur with both oral and topical minoxidil. However, it is more commonly seen with the oral form, and with 5% versus 2% minoxidil. Research suggests that hypertrichosis is related to minoxidil's prolongation of the anagen phase. 

Minoxidil is contraindicated in patients who have a history of hypersensitivity to the drug or its components (such as propylene glycol).

The use of minoxidil is not advised in pregnant and breastfeeding women. While minoxidil is not known to be teratogenic, reports exist of rare cases of congenital disabilities.