Continuing Education Activity

Minoxidil (also called 2,4-pyrimidinediamine, 6-(1-piperidinyl)-, 3-oxide) was first designed 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. Also, about one-fifth of patients under oral minoxidil treatment developed hypertrichosis. In 1987, a topical form was developed to treat androgenic alopecia, initially for males and subsequently for females. This activity reviews the indications, contraindications, and adverse effects of minoxidil and highlights the interprofessional team's role in managing patients with hair loss.

Objectives:

• Identify the mechanism of action of minoxidil.
• Describe the adverse effects of minoxidil.
• Review the contraindications of minoxidil.
• Explain interprofessional team strategies for enhancing care coordination and communication to advance the safe use of minoxidil for alopecia and improve outcomes.

Indications

The initial design of minoxidil (also called 2,4-pyrimidinediamine, 6-(1-piperidinyl)-, 3-oxide) was a potent peripheral vasodilator agent to treat severe refractory hypertension in the 1970s. However, 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 to treat androgenic alopecia, initially for males and subsequently 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 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

• 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. When administered before and after a hair transplant, minoxidil minimizes hair loss. However, 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 from scalp burning.
• Monilethrix: Minoxidil leads to synchronization of the entry of hair follicles into the anagen phase.
• Hereditary alopecia/hypotrichosis: The use of minoxidil has been demonstrated to be beneficial by inducing a thickening in hair shafts.

Mechanism of Action

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, 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 are the clinical effects of minoxidil.[8]

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:[8]

• 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 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 been demonstrated to possess anti-fibrotic properties secondary to its effect on collagen synthesis.

Administration

Minoxidil is available in the United States as an over-the-counter topical agent. It is available as a foam and a solution formulation to use for men and women patients. 

• The 5% aerosol formulation is applied one-half capful once a day in women and one-half capful twice a day in men on the top of the scalp.
• The dose of 1 mL of 2% solution formulation is applied twice a day in women on the top of the scalp.
• The dose of 1 mL of 2% or 5% solution formulation is applied twice a day in men on the top of the scalp.

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 efficiency, but more studies are needed to assess the value of this potential relationship.[9][10][11]

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 treating 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.

Specific Patient Population

Patient with Hepatic Impairment: There is no dose adjustment information available from manufacturers for patients with hepatic impairment.

Patient with Renal Impairment: There is no dose adjustment information available from manufacturers for patients with renal impairment.

Pregnant Women: Some adverse effects were observed in animal reproductive studies, so minoxidil is not recommended for pregnant women. It is an FDA pregnancy category C medicine.[12]

Breastfeeding Women: Minoxidil is excreted in breast milk, so it is not recommended for breastfeeding women.[8]

Adverse Effects

Minoxidil is generally well tolerated. However, some adverse effects reported by patients include:[8][13]

• 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 5% versus 2% minoxidil. Research suggests that hypertrichosis is related to minoxidil's prolongation of the anagen phase.

Drug Interaction

• Systemic cyclosporine may enhance side effects like hypertrichosis when used with topical minoxidil. The hypertrichosis symptoms improved drastically after stopping topical minoxidil for two months.[14]
• Coadministration of baby aspirin may also reduce the topical minoxidil efficacy. This reduction in efficacy is believed to be associated with the negative inhibition of sulfotransferase enzymes by baby aspirin in the human hair.[15]

Contraindications

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 pregnant and breastfeeding women. While minoxidil is not known to be teratogenic, reports exist of rare cases of congenital disabilities.[8]

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 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.

Monitoring

Patients using topical minoxidil require regular monitoring for scalp changes and localized/generalized hypertrichosis.[16]

Hypotension is rarely reported in patients using topical minoxidil. However, some clinicians recommend monitoring blood pressure, heart rate, and changes in the electrocardiographic regularly while on topical minoxidil therapy.

Toxicity

Percutaneous toxicity is uncommon after the conventional use of minoxidil. There is no known antidote for minoxidil toxicity after massive oral ingestion. Accidental oral ingestion of minoxidil can result in vomiting and does rarely require hospitalization. There are reported cases of hypotension, tachycardia, and/or electrocardiogram (ECG) changes after accidental ingestion. Intravenous fluids and vasopressor agents may manage refractory hypotension. Gastric wash and activated charcoal may be necessary to prevent systemic toxicity in massive accidental ingestions of minoxidil.[17] A case was reported for a young girl where she accidentally ingested a minoxidil cutaneous solution intended for her father. Side effects like hypotension and persistent tachycardia were observed after ingestion.[18]

Enhancing Healthcare Team Outcomes

While the pharmaceutical industry produces several medications to manage male pattern baldness, and the effectiveness between individuals varies. Minoxidil has been present for three decades and is widely prescribed by nurse practitioners, physician assistants, primary care providers, and dermatologists. Pharmacists can verify that there are no concerning drug-drug interactions. Minoxidil is considered a first-line treatment to aid hair growth, but it shows inconsistent efficacy. Some patients see a vast improvement, while others notice minimal changes. Healthcare workers should educate patients that each individual may react to minoxidil differently, and hair growth occurs best with consistent medication adherence. All interprofessional healthcare team members need to be aware when a patient is taking or wants to try minoxidil and factor that into the overall healthcare delivery strategy for that individual to achieve optimal patient outcomes. [Level 5]

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Jimenez-Cauhe J, Saceda-Corralo D, Rodrigues-Barata R, Hermosa-Gelbard A, Moreno-Arrones OM, Fernandez-Nieto D, Vaño-Galvan S. Effectiveness and safety of low-dose oral minoxidil in male androgenetic alopecia. J Am Acad Dermatol. 2019 Aug;81(2):648-649. [PubMed: 31054970]

2.

Hunter N, Sayed K, Hay RA, Allam R, Hussein N. Comparing the Efficacy of Mesotherapy to Topical Minoxidil in the Treatment of Female Pattern Hair Loss Using Ultrasound Biomicroscopy: A Randomized Controlled Trial. Acta Dermatovenerol Croat. 2019 Mar;27(1):1-7. [PubMed: 31032783]

3.

Ahluwalia J, Fabi SG. The psychological and aesthetic impact of age-related hair changes in females. J Cosmet Dermatol. 2019 Aug;18(4):1161-1169. [PubMed: 31012988]

4.

Anouar I, Hjira N, Boui M. Loose Anagen Syndrome: A Little Response to Minoxidil. Int J Trichology. 2019 Mar-Apr;11(2):89-91. [PMC free article: PMC6463455] [PubMed: 31007480]

5.

Verma K, Tegta GR, Verma G, Gupta M, Negi A, Sharma R. A Study to Compare the Efficacy of Platelet-rich Plasma and Minoxidil Therapy for the Treatment of Androgenetic Alopecia. Int J Trichology. 2019 Mar-Apr;11(2):68-79. [PMC free article: PMC6463452] [PubMed: 31007475]

6.

Gajjar PC, Mehta HH, Barvaliya M, Sonagra B. Comparative Study between Mesotherapy and Topical 5% Minoxidil by Dermoscopic Evaluation for Androgenic Alopecia in Male: A Randomized Controlled Trial. Int J Trichology. 2019 Mar-Apr;11(2):58-67. [PMC free article: PMC6463458] [PubMed: 31007474]

7.

Freire PCB, Riera R, Martimbianco ALC, Petri V, Atallah AN. Minoxidil for patchy alopecia areata: systematic review and meta-analysis. J Eur Acad Dermatol Venereol. 2019 Sep;33(9):1792-1799. [PubMed: 30835901]

8.

Suchonwanit P, Thammarucha S, Leerunyakul K. Minoxidil and its use in hair disorders: a review. Drug Des Devel Ther. 2019;13:2777-2786. [PMC free article: PMC6691938] [PubMed: 31496654]

9.

Sharma A, Goren A, Dhurat R, Agrawal S, Sinclair R, Trüeb RM, Vañó-Galván S, Chen G, Tan Y, Kovacevic M, Situm M, McCoy J. Tretinoin enhances minoxidil response in androgenetic alopecia patients by upregulating follicular sulfotransferase enzymes. Dermatol Ther. 2019 May;32(3):e12915. [PubMed: 30974011]

10.

Sung CT, Juhasz ML, Choi FD, Mesinkovska NA. The Efficacy of Topical Minoxidil for Non-Scarring Alopecia: A Systematic Review. J Drugs Dermatol. 2019 Feb 01;18(2):155-160. [PubMed: 30794366]

11.

Fabbrocini G, Cantelli M, Masarà A, Annunziata MC, Marasca C, Cacciapuoti S. Female pattern hair loss: A clinical, pathophysiologic, and therapeutic review. Int J Womens Dermatol. 2018 Dec;4(4):203-211. [PMC free article: PMC6322157] [PubMed: 30627618]

12.

Smorlesi C, Caldarella A, Caramelli L, Di Lollo S, Moroni F. Topically applied minoxidil may cause fetal malformation: a case report. Birth Defects Res A Clin Mol Teratol. 2003 Dec;67(12):997-1001. [PubMed: 14745922]

13.

Rossi A, Cantisani C, Melis L, Iorio A, Scali E, Calvieri S. Minoxidil use in dermatology, side effects and recent patents. Recent Pat Inflamm Allergy Drug Discov. 2012 May;6(2):130-6. [PubMed: 22409453]

14.

Sever MS, Sonmez YE, Kocak N. Limited use of minoxidil in renal transplant recipients because of the additive side-effects of cyclosporine on hypertrichosis. Transplantation. 1990 Sep;50(3):536. [PubMed: 2402807]

15.

Goren A, Sharma A, Dhurat R, Shapiro J, Sinclair R, Situm M, Kovacevic M, Lukinovic Skudar V, Goldust M, Lotti T, McCoy J. Low-dose daily aspirin reduces topical minoxidil efficacy in androgenetic alopecia patients. Dermatol Ther. 2018 Nov;31(6):e12741. [PubMed: 30226287]

16.

Gargallo V, Gutierrez C, Vanaclocha F, Guerra-Tapia A. Generalized Hypertrichosis Due to Topical Minoxidil. Actas Dermosifiliogr. 2015 Sep;106(7):599-600. [PubMed: 25688008]

17.

MacMillan AR, Warshawski FJ, Steinberg RA. Minoxidil overdose. Chest. 1993 Apr;103(4):1290-1. [PubMed: 8131492]

18.

Topical minoxidil: accidental poisoning in children. Prescrire Int. 2015 Apr;24(159):97. [PubMed: 25941701]