Continuing Education Activity

Minoxidil, also known as 2,4-pyrimidinediamine, 6-(1-piperidinyl)-, 3-oxide, was initially developed in the 1970s as a potent peripheral vasodilator agent for the treatment of severe refractory hypertension. Minoxidil exerts its antihypertensive effect by opening adenosine triphosphate (ATP)-sensitive potassium channels, thereby reducing peripheral resistance and lowering blood pressure levels in patients. However, owing to the significant adverse effects of taking oral minoxidil, this drug is currently used only for patients with resistant hypertension who do not adequately respond to the maximum doses of 3 different classes of antihypertensive medications. In 1987, a topical formulation of minoxidil was developed to treat androgenic alopecia, initially targeting males and later expanding its use to include females. This activity comprehensively reviews the indications, contraindications, mechanism of action, pharmacokinetics, adverse effects, and other crucial aspects of topical and oral minoxidil therapy in a clinical setting. This activity aims to improve the collaboration and the competence of the interprofessional healthcare team members to provide quality care for patients experiencing hair loss and resistant hypertension.

Objectives:

• Differentiate between oral and topical minoxidil therapy based on patients' medical history, risk factors, and specific conditions.

• Screen patients' eligibility considering contraindications and potential drug interactions before prescribing minoxidil.

• Assess patients' response to minoxidil therapy, monitoring for adverse effects, therapeutic outcomes, and patient satisfaction.

• Communicate with patients about minoxidil therapy, explaining its potential benefits, risks, expected outcomes, and self-monitoring techniques to enable shared decision-making among healthcare providers.

Indications

Minoxidil, also known as 2,4-pyrimidinediamine,6-(1-piperidinyl)-, 3-oxide, was initially developed as a potent peripheral vasodilator agent for treating severe refractory hypertension. However, owing to the significant adverse effects of oral minoxidil use, this drug is currently used only for patients with resistant hypertension who do not adequately respond to the maximum doses of 3 different antihypertensive medications.

Furthermore, approximately one-fifth of patients undergoing oral minoxidil treatment developed hypertrichosis. In 1987, a topical formulation of minoxidil was developed to treat androgenic alopecia, initially targeting males and later expanding its use to include females. This topic focuses on the clinical application of topical minoxidil therapy for androgenic alopecia and oral minoxidil therapy for resistant hypertension.[1][2]

Topical minoxidil is available in both liquid solution and foam formulations. The liquid form of topical minoxidil contains alcohol and propylene glycol, the 2 crucial molecules that help dissolve the drug in a patient's body, facilitating tissue absorption. Formulations containing 2% and 5% minoxidil commonly treat scalp alopecia in individuals aged 18 and above. Long-term use of minoxidil is necessary to uphold the achieved clinical outcomes of the medication, as these effects diminish when the drug is discontinued.[3][4]

Topical Minoxidil

Androgenic alopecia is the only indication approved by the U.S. Food and Drug Administration (FDA) for topical minoxidil.

Off-label uses of topical minoxidil are as follows:

• Alopecia areata: Minoxidil has demonstrated the ability to elicit a favorable clinical response when used as a standalone treatment for alopecia areata or in conjunction with other medications, such as corticosteroids.
• Chemotherapy-induced alopecia: In this case, minoxidil has exhibited the capacity to reduce hair loss and expedite the process of hair regrowth.
• Hair transplant: Hair loss, also known as telogen effluvium, is a common observation after a hair transplant. Minoxidil can be used before and after hair transplantation to reduce hair loss in patients. However, the treatment should be temporarily suspended for 3 days before the hair transplant to prevent excessive bleeding.
• Scarring alopecia: Minoxidil has displayed evidence of having an antifibrotic effect on this condition. Consequently, topical minoxidil treatment could be a viable therapeutic option during the initial stages of dermatoses, leading to scarring alopecia, such as those stemming from scalp burns.
• Monilethrix: Minoxidil induces the synchronization of hair follicles entering the anagen phase in patients experiencing this condition.
• Hereditary alopecia or hypotrichosis: Minoxidil has demonstrated its beneficial effects by promoting hair shaft thickening in hypotrichosis.

Oral Minoxidil

According to the American College of Cardiology and the American Heart Association (AHA), resistant hypertension is characterized by elevated blood pressure levels exceeding the target range, despite the simultaneous utilization of 3 different classes of antihypertensive medications. These classes typically include a combination of a calcium channel blocker, a renin-angiotensin-aldosterone system blocker (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker), and a diuretic. These drugs are administered at the highest daily doses a patient can tolerate. The FDA approves minoxidil for maintaining blood pressure levels in patients with resistant hypertension.[5]

Many forms of alopecia are off-label indications for oral or sublingual minoxidil. Recently, multiple studies have explored using low-dose oral minoxidil (<5 mg daily) for treating many forms of alopecia, including male-patterned and female-patterned hair loss, to treat hair loss without adverse reactions.[6] The low adverse-effect profile of low-dose oral minoxidil aids in long-term adherence to treatment and positive clinical response.[7][8] More studies are needed to test the efficacy of oral and sublingual minoxidil when treating various alopecia to improve patient outcomes and provide an alternative for those with difficulty with topical formulations.[6] 

Mechanism of Action

Topical minoxidil, with the empirical formula C₉H₁₅N₅O, is a stimulant for hair growth (see Image. Skeletal Formula of Minoxidil). The precise mechanism of action for the drug remains inadequately understood. The sulfotransferase enzyme in the human scalp converts minoxidil into minoxidil sulfate, which is the active form of the molecule. Differences in sulfotransferase activity among individuals can affect minoxidil's effectiveness, leading to inconsistencies in the therapy.[9] 

Minoxidil shortens the telogen phase to prompt the dormant hair follicles for premature transition into the anagen phase. The shortening of the telogen phase might lead to telogen effluvium following minoxidil therapy. Furthermore, minoxidil extends the anagen phase, resulting in increased hair length and thickness, thereby representing the observable outcomes of minoxidil therapy.[10]

The initial outcomes of minoxidil become apparent after approximately 8 weeks of initiating the treatment, with the maximum effects manifesting around 4 months. Minoxidil affects the potassium channels present in vascular smooth muscles and hair follicles.[10] This potassium channel activity may induce the following effects:

• Stimulation of the microcirculation around the hair follicles induces arteriolar vasodilation, thereby encouraging conditions conducive to hair growth.
• Induction of the vascular endothelial growth factor expression leads to heightened vascularization around the hair follicles, thereby promoting hair growth.
• Activation of the prostaglandin-endoperoxide synthase-1 enzyme leads to the enhancement of hair growth.
• Inhibition of androgen-related effects on androgen-sensitive hair follicles.
• Direct stimulation of the hair follicles as the drug acts as an epidermal growth factor on the matrix cells, slowing their aging process and extending their anagen phase. This process is achieved through the activation of the beta-catenin pathway.
• Display of antifibrotic characteristics due to its impact on collagen synthesis.

Hypertension

Minoxidil exerts its antihypertensive effect by opening adenosine triphosphate (ATP)-sensitive potassium channels. As a result, when the smooth muscle vasculature is relaxed, it reduces peripheral resistance, which ultimately helps to lower blood pressure levels. Consequently, this process increases plasma renin activity, which, in turn, triggers salt and water retention in a patient's body. Additionally, minoxidil triggers the activation of the sympathetic nervous system, resulting in tachycardia and heightened cardiac output. Therefore, clinicians prescribe beta-blockers and diuretics alongside minoxidil to mitigate potential adverse effects.[5]

Pharmacokinetics

Absorption: Minoxidil is absorbed from the gastrointestinal tract at a rate of 95%, and the drug achieves peak levels within the initial hour. Conversely, only 1.4% of topical minoxidil is absorbed through the skin.[7]

Distribution: Minoxidil shows no binding affinity to plasma proteins. This drug experiences broad distribution, with a distribution volume ranging from 2.8 to 3.3 L/kg.

Metabolism: Minoxidil undergoes metabolism through conjugation, sulfation, and hydroxylation processes. The resulting metabolites generally exhibit lower pharmacological activity than the parent drug. Notably, as previously mentioned, topical minoxidil is metabolized within the hair follicles by the sulfotransferase enzyme, leading to the formation of minoxidil sulfate.[11]

Elimination: Although the elimination half-life of minoxidil is around 3 to 4 hours, the hypotensive impact of the medication may persist for up to 72 hours. Notably, the excretion of minoxidil and its metabolites predominantly occurs through the kidneys.[12]

Administration

Minoxidil is available as an over-the-counter topical agent in the United States. Furthermore, the medication is marketed in an oral tablet formulation and as a topical agent in foam and solution formulations for both male and female patients.

Adult Dosage

Topical minoxidil: 

• Patients can apply a 5% aerosol formulation of topical minoxidil directly onto their scalp at a one-half capful dose. The medication should be used twice daily by male patients and once daily by female patients.
• Women should apply 1 mL of the 2% topical minoxidil solution to their scalp twice daily.
• Men should apply 1 mL of 2% or 5% topical minoxidil solution to their scalp twice daily.

Scalp massage is not required following the application of the medication. Minoxidil uptake reaches approximately 50% within an hour and increases to 75% after 4 hours. Although certain practitioners use microneedling with topical minoxidil to potentially enhance the drug's efficacy, further studies are necessary to evaluate the potential significance of this practice.[13][14][15] 

A 2% topical minoxidil solution is effective for male patients experiencing androgenic alopecia in their frontotemporal and vertex regions. However, the 5% topical minoxidil solution provides a more significant clinical benefit than the 2% solution. The clinical response to minoxidil is notably more pronounced when the onset of alopecia occurs within 5 years, primarily among young adults, and when the hair follicles are not extensively miniaturized.[16] 

Oral minoxidil: 

This formulation is supplied in tablet formulations, with options of 2.5 mg and 10 mg doses. Although the FDA does not approve the oral formulation of minoxidil for treating hair loss in individuals, clinical trials have demonstrated its effectiveness at dosages ranging from 0.25 to 2.5 mg daily for maintaining blood pressure levels in patients with resistant hypertension.[8]

The recommended initial dosage of minoxidil for hypertensive therapy is 5 mg, administered once daily to patients younger than 12, which can be gradually escalated up to a maximum of 40 mg per day. Higher doses should be equally divided and administered to individuals 2 or 3 times daily to prevent excessive hypotension. The maximum recommended dosage of oral minoxidil is 100 mg per day.[12] As per the AHA's guidelines for managing resistant hypertension, minoxidil should be prescribed alongside a loop diuretic and a beta-blocker to mitigate potential adverse effects in patients.[2]

The recommended off-label dosing of oral minoxidil for treating alopecia is 0.25 to 2.5 mg, administered once or twice daily in 1 or 2 equally divided doses.

Specific Patient Population

Patient with hepatic impairment: The product labeling for topical or oral minoxidil does not offer specific dosage adjustment information. However, caution is advised when considering its use in such cases.

Patient with renal impairment: When dosing oral minoxidil, it is advisable to consider dose reduction for individuals with renal impairment. However, specific dosage adjustment information is not supplied for topical minoxidil.

Pregnancy considerations: As animal reproductive studies have indicated specific adverse effects of minoxidil in pregnant women, it is not advisable to use this drug. Minoxidil holds an FDA pregnancy category C classification.[17]

Breastfeeding considerations: As minoxidil is excreted in breast milk, its use is not recommended in breastfeeding women.[10]

Pediatric patients: The recommended initial dosage of oral minoxidil in patients younger than 12 is 0.2 mg/kg daily. Typically, the maintenance dosage of minoxidil ranges from 0.25 to 1 mg/kg per day, and the maximum recommended dosage is 50 mg per day.[18] Clinicians may suggest topical minoxidil in children; however, it is considered an off-label drug indication.[19]

Older patients: Oral minoxidil should be initiated at a lower dose in older patients as clinicians recommend, considering comorbidities, polypharmacy, and increased risk of falls in this population. 

Adverse Effects

Although minoxidil is generally well tolerated, topical minoxidil is associated with the following adverse effects, as listed below.[10][20]

• Minoxidil-induced telogen effluvium: The shortening of the telogen phase caused by minoxidil can result in excessive hair shedding in individuals.
• Skin irritation: This condition can lead to erythema, discomfort, and a burning sensation on the scalp.
• Scaly changes of the scalp: This condition can entail irritation or a potential worsening of seborrheic dermatitis.
• Isolated pruritus: appears in the area of application.
• Allergic contact dermatitis: This can lead to symptoms such as erythema, eczematous skin reactions, and pruritus. Minoxidil and propylene glycol are the primary allergens implicated in cases of allergic contact dermatitis. Patch testing can aid in identifying the underlying causative agent. If allergic contact dermatitis arises due to propylene glycol, topical minoxidil as a foam formulation can be an alternative option, as it does not contain propylene glycol.
• Localized or generalized hypertrichosis: Both oral and topical minoxidil usage can lead to hypertrichosis. However, this effect is more frequently observed with the oral formulation and when the 5% topical minoxidil solution is used compared to the 2% solution. Research indicates that hypertrichosis is linked to minoxidil extending the anagen phase. In addition, cases of hypertrichosis have been documented in infants due to unintentional direct skin contact.[21]

Oral minoxidil is also associated with significant adverse effects, as listed below.

• Rare but severe reactions include pericarditis, pericardial effusion, cardiac tamponade, exacerbating congestive heart failure, and worsening angina.
• Oral minoxidil administration can lead to significant hypotension and potential complications such as thrombocytopenia and leukopenia in individuals taking the medication.[22] 
• Breast tenderness and gynecomastia have also been reported as adverse effects of the medication.[23]
• Hypertrichosis, edema, tachycardia, and weight gain are also caused by oral minoxidil.

Drug-Drug Interactions

• Systemic cyclosporine can exacerbate adverse effects such as hypertrichosis when combined with topical minoxidil. Notably, hypertrichosis symptoms significantly improved after discontinuing topical minoxidil for 2 months.[24]
• Coadministration of low-dose aspirin and minoxidil may diminish the effectiveness of topical minoxidil. This decrease in effectiveness is attributed to the inhibitory effect of low-dose aspirin on sulfotransferase enzymes in human hair.[25]
• Concurrent use of guanethidine with minoxidil can cause severe hypotension.[26]

Contraindications

Contraindications include the following:

• Minoxidil should not be used in patients with a known history of hypersensitivity to the drug or its constituents, including propylene glycol.
• The utilization of minoxidil is not recommended for pregnant and breastfeeding women. Although minoxidil is not recognized as a teratogenic agent, there are occasional reports of congenital anomalies.[10]
• The product intended for use in males is not recommended for use in females.
• This product is also contraindicated in patients younger than 18 and those who experience sudden, uncertain, or patchy hair loss, hair loss after childbirth, scalp infections or inflammation, or use another scalp medication.

Box Warning 

Oral minoxidil can cause serious adverse effects, including pericardial effusion, that can advance to cardiac tamponade. Reports of angina pectoris worsening have also been reported in patients using the medication. As a result, careful oversight is imperative when administering minoxidil to patients.[27] 

Patients receiving guanethidine should be admitted to a hospital for monitoring when minoxidil is administered due to the substantial risk of severe orthostatic hypotension.[26] Coadministration of beta-blockers with minoxidil is advised to help manage the elevated myocardial workload and tachycardia.[12] Oral minoxidil should be used with a loop diuretic to prevent severe fluid accumulation in a patient's body.[28]

Monitoring

Patients using topical minoxidil should undergo regular monitoring for any alterations in the scalp and the occurrence of localized or generalized hypertrichosis.[29] Hypotension is a rare occurrence in patients using topical minoxidil. Nonetheless, some clinicians advise consistent monitoring of blood pressure, heart rate, and electrocardiographic changes for patients undergoing topical minoxidil therapy. Clinicians should conduct thorough assessments to eliminate secondary causes of hypertension, such as renal artery stenosis, primary aldosteronism, pheochromocytoma, and Cushing syndrome, warranting minoxidil treatment. Regular monitoring of fundoscopic examination, renal function, echocardiogram, and ankle-brachial index is recommended to assess potential target organ damage for patients taking the medication.[2]

Toxicity

Percutaneous toxicity is a rare occurrence following standard minoxidil application. In cases of significant oral ingestion, there is currently no recognized antidote for minoxidil toxicity. Unintentional oral consumption of minoxidil may lead to vomiting and, in rare instances, necessitate hospitalization. Instances of hypotension, tachycardia, and changes in the electrocardiogram have been reported following accidental ingestion. Intravenous fluids and pharmaceutical vasopressors can address malignant hypotension. In substantial inadvertent minoxidil ingestion, gastric lavage technique and activated charcoal administration might be essential to avert systemic toxicity in patients.[30] 

A case was reported where a young girl unintentionally ingested a topical solution of minoxidil prescribed to her father. After ingesting the medication, the girl encountered adverse effects such as hypotension and prolonged tachycardia.[31] Intravenous fluids are essential in cases of oral minoxidil overdose, causing hypotension in individuals. Vasopressors should be administered to patients for hypotension that does not respond to standard treatment.[32][33]

Enhancing Healthcare Team Outcomes

Topical minoxidil has been a trusted medication in the medical field for more than 30 years and is commonly prescribed by dermatologists, primary care physicians, nurse practitioners, and physician assistants. Minoxidil is also prescribed as a treatment option for resistant hypertension in patients. According to AHA, it is recommended to consult hypertension specialists for cases of resistant hypertension. A retrospective study demonstrated enhanced blood pressure control in patients with resistant hypertension under the care of hypertension specialists.[5][34][35] 

Secondary causes of hypertension require consultation with nephrologists and endocrinologists. Pharmacists are critical in ensuring no potential drug-drug interactions are of concern in patients with hypertension. Although minoxidil is regarded as a primary treatment option to promote hair growth, the efficacy of the medication can vary inconsistently depending on various cases. Some patients experience substantial improvements, whereas others observe only minimal changes. Healthcare professionals should inform patients that individual responses to minoxidil can vary and constant adherence to medication is crucial for optimal hair growth.

Emergency medicine and critical care physicians should focus on stabilizing the patient in case of a minoxidil overdose. To ensure the best outcomes for patients receiving minoxidil therapy for alopecia and hypertension, physicians, advanced practice practitioners, specialists, pharmacists, and nursing staff must work collaboratively, utilizing an interprofessional approach and open communication to facilitate effective teamwork to achieve optimal outcomes with the fewest adverse events.