Minoxidil

Minoxidil, sold under the brand names Loniten and Rogaine among others, is a medication used for the treatment of high blood pressure and pattern hair loss. It is an antihypertensive and a vasodilator. It is available as a generic medication by prescription in oral tablet form and over-the-counter as a topical liquid or foam.

Medical uses

High blood pressure

Minoxidil, when used for hypertension, is generally reserved for use in severe hypertension patients who do not respond to at least two agents and a diuretic. Minoxidil is also generally administered with a loop diuretic to prevent sodium retention and potassium retention. It may also cause a reflex tachycardia and thus is prescribed with a beta blocker.

Hair loss

Minoxidil, when applied topically, is used for the treatment of hair loss. It is effective in helping promote hair growth in people with androgenic alopecia regardless of sex. Minoxidil must be used indefinitely for continued support of existing hair follicles and the maintenance of any experienced hair regrowth.
Low-dose oral minoxidil is used off-label against hair loss and to promote hair regrowth. Oral minoxidil is an effective and well-tolerated treatment alternative for patients having difficulty with topical formulations.
Minoxidil requires at least 2 to 4months before the first benefits on hair growth can be observed. Maximal effectiveness occurs after 12months.

Available forms

Minoxidil is available in the form of oral tablets, topical solution, topical foam, and topical spray. The tablets include 2.5 and 10mg forms, the solutions include 2% and 5% forms, and the foam and spray are both 5% concentration. The topical solutions are formulated with polyethylene glycol to enhance absorption of minoxidil. The topical solution is often referred to as minoxidil topical solution and the topical foam is known as minoxidil topical foam.

Side effects

of oral minoxidil may include swelling of the face and extremities, rapid heartbeat, or lightheadedness. Cardiac lesions, such as focal necrosis of the papillary muscle and subendocardial areas of the left ventricle, have been observed in laboratory animals treated with minoxidil. Pseudoacromegaly is an extremely rare side effect reported with large doses of oral minoxidil.
Topically applied minoxidil is generally well tolerated, but common side effects include itching of the eyes, general itching, irritation at the treated area, and unwanted hair growth elsewhere on the body. Alcohol and propylene glycol present in some topical preparations may dry the scalp, resulting in dandruff and contact dermatitis.
Sublingual minoxidil may have reduced side effects with retained effectiveness compared to oral minoxidil. This is due to less minoxidil sulfate being formed during first-pass metabolism and due to local activation of minoxidil into minoxidil sulfate within hair follicles. In a preliminary clinical trial, no adverse effects or changes in blood pressure occurred with low-dose sublingual minoxidil.
Minoxidil has been implicated in causing pericardial effusions including life-threatening cases of cardiac tamponade. There have been case reports dating back to the 1980s describing this phenomenon, including topical and oral formulations. The frequency of these occurrences has previously been reported at 3%, but the true frequency is difficult to determine as a large proportion of patients in this cohort also had renal insufficiency and may have had an effusion preceding the use of minoxidil.

Overdose

In 2013 or 2014, a seven-year-old girl was admitted to a children's hospital in Toulouse in France after accidentally ingesting a teaspoon of Alopexy. The child vomited constantly after ingestion and showed hypotension and tachycardia for 40 hours. The authors of the report on the incident stressed that the product should be kept out of reach of children, and urged manufacturers to consider more secure child-resistant packaging.

Interactions

of oral minoxidil with guanethidine can result in profound orthostatic hypotension.
Low-dose daily aspirin can reduce the effectiveness of topical minoxidil for hair loss. This is thought to be because aspirin inhibits sulfotransferase activity and hence prevents conversion of minoxidil into its active form minoxidil sulfate. Salicylic acid is also a sulfotransferase inhibitor and could likewise affect the effectiveness of topical minoxidil. In addition, paracetamol is a sulfate scavenger and may inhibit minoxidil activation into minoxidil sulfate and effectiveness.

Pharmacology

Pharmacodynamics

The mechanism by which minoxidil promotes hair growth is not fully understood. Minoxidil is an adenosine 5'-triphosphate-sensitive potassium channel opener, causing hyperpolarization of cell membranes. Theoretically, by widening blood vessels and opening potassium channels, it allows more oxygen, blood, and nutrients to the follicles. Moreover, minoxidil contains a nitric oxide moiety and may act as a nitric oxide agonist. This may cause follicles in the telogen phase to shed, which are then replaced by thicker hairs in a new anagen phase. Minoxidil is a prodrug that is converted by sulfation via the sulfotransferase enzyme SULT1A1 to its active form, minoxidil sulfate. The effect of minoxidil is mediated by adenosine, which triggers intracellular signal transduction via both adenosine A₁ receptors and two sub-types of adenosine A₂ receptors. Minoxidil acts as an activator of the Kir6/SUR2 channel upon selective binding to SUR2. The expression of SUR2B in dermal papilla cells might play a role in the production of adenosine. Minoxidil induces cell growth factors such as VEGF, HGF, IGF-1 and potentiates HGF and IGF-1 actions by the activation of uncoupled sulfonylurea receptor on the plasma membrane of dermal papilla cells.
A number of in vitro effects of minoxidil have been described in monocultures of various skin and hair follicle cell types including stimulation of cell proliferation, inhibition of collagen synthesis, and stimulation of vascular endothelial growth factor, prostaglandin synthesis and leukotriene B4 expression.
Minoxidil causes a redistribution of cellular iron through its apparent capacity to bind this metal ion. By binding iron in a Fenton-reactive form, intracellular hydroxyl radical production would ensue, but hydroxyl would be immediately trapped and scavenged by the minoxidil to generate a nitroxyl radical. It is presumed that this nitroxyl radical will be capable of reduction by glutathione to reform minoxidil. Such a process would cycle until the minoxidil is otherwise metabolized and would result in rapid glutathione depletion with glutathione disulphide formation and therefore with concomitant consumption of NADPH/NADH and other reducing equivalents. Minoxidil inhibited PHD by interfering with the normal function of ascorbate, a cofactor of the enzyme, leading to a stabilization of HIF-1α protein and a subsequent activation of HIF-1. In an in vivo angiogenesis assay, millimolar minoxidil increased blood vessel formation in a VEGF-dependent manner. Minoxidil inhibition of PHD occurs via interrupting ascorbate binding to iron. The structural feature of positioning amines adjacent to nitric oxide may confer the ability of millimolar minoxidil to chelate iron, thereby inhibiting PHD. Minoxidil is capable of tetrahydrobiopterin inhibition as a cofactor for nitric oxide synthase.
Minoxidil stimulates prostaglandin E₂ production by activating COX-1 and prostaglandin endoperoxide synthase-1 but inhibits prostacyclin production. Additionally, expression of the prostaglandin E₂ receptor, the most upregulated target gene in the β-catenin pathway of DP cells, was enhanced by minoxidil, which may enable hair follicles to grow continuously and maintain the anagen phase.
Due to the anti-fibrotic activity of minoxidil inhibition of enzyme lysyl hydroxylase present in fibroblast may result in the synthesis of a hydroxylysine-deficient collagen. Minoxidil can also potentially stimulate elastogenesis in aortic smooth muscle cells, and in skin fibroblasts in a dose-dependent manner. In hypertensive rats, minoxidil increases elastin levels in the mesenteric, abdominal, and renal arteries by a decrease in elastase enzyme activity in these tissues. In rats, potassium channel openers decrease calcium influx which inhibits elastin gene transcription through extracellular signal-regulated kinase 1/2 -activator protein 1 signaling pathway. ERK 1/2 increases, through elastin gene transcription, adequately cross-linked elastic fiber content synthesized by smooth muscle cells, and decreases the number of cells in the aorta.
Minoxidil possesses α₂-adrenergic receptor agonist activity, stimulates the peripheral sympathetic nervous system by way of carotid and aortic baroreceptor reflexes. Minoxidil administration also brings an increase in plasma renin activity, largely due to the aforementioned activation of the SNS. This activation of the renin-angiotensin axis further prompts increased biosynthesis of aldosterone; whereas plasma and urinary aldosterone levels are increased early in the course of treatment with minoxidil, over time these values tend to normalize presumably because of accelerated metabolic clearance of aldosterone in association with hepatic vasodilation.
Minoxidil may be involved in the inhibition of serotonin 5-HT₂ receptors.
Minoxidil might increase blood-tumor barrier permeability in a time-dependent manner by down-regulating tight junction protein expression and this effect could be related to ROS/RhoA/PI3K/PKB signal pathway. Minoxidil significantly increases ROS concentration when compared to untreated cells.
Minoxidil treatment resulted in a 0.22 fold change for 5α-R2 in vitro. This antiandrogenic effect of minoxidil, shown by significant downregulation of 5α-R2 gene expression in HaCaT cells, may be one of its mechanisms of action in alopecia.
Minoxidil is less effective when the area of hair loss is large. In addition, its effectiveness has largely been demonstrated in younger men who have experienced hair loss for less than 5 years. Minoxidil use is indicated for central hair loss only. Two clinical studies are being conducted in the US for a medical device that may allow patients to determine if they are likely to benefit from minoxidil therapy.
Conditions such as Cantú syndrome have been shown to mimic the pharmacological properties of minoxidil.