Description
Minoxidil(38304-91-5) is a peripheral vasodilator that directly relaxes vascular smooth musculature, thus, lowering systolic and diastolic pressure. Its action is linked to the activation of calcium channels. Open calcium channels cause hyperpolarization of smooth muscle cells, which in turn, reduces the flow of calcium ions into the cell, which is necessary for supporting vascular tonicity. However, when taking minoxidil, tachycardia, elevated renin secretion, and water and sodium ion retention all appear simultaneously with hypotension.
Chemical Properties
White Crystalline Solid
Originator
Loniten ,Upjohn ,US ,1979
Uses
A selective ATP dependent K+ (Kir6) channel activator
Uses
antihypertensive, antialopecia agent
Uses
Used as an antihypertensive and antialopecia agent. Minoxidil activates ATP-activated K+ channels
Definition
ChEBI: A pyrimidine N-oxide that is pyrimidine-2,4-diamine 3-oxide substituted by a piperidin-1-yl group at position 6.
Manufacturing Process
Barbituric acid is reacted with phosphorus oxychloride then with 2,4,6-trichloropyrimidine and that product with ammonia to give 4-chloro-2,6-diaminopyritnidine.
A 30 g (0.15 mol) quantity of 4-chloro-2,6-diaminopyrimidine is dissolved in600 ml of hot 3A alcohol, the solution cooled to 0°C to 10°C and 41.8 g (0.24mol) of m-chloroperbenzoic acid is added. The mixture is held at 0°C to 10°Cfor 4 hours and filtered. The solid is shaken for 2 hours in 0.24 mol of 10%sodium hydroxide and filtered. The solid is washed with water and dried toyield 193 g of crude product. This product is extracted for 1 hour with 900 mlof boiling acetonitrile to yield 14.8 g (44.7% yield) of 6-amino-4-chloro-1,2-dihydro-1-hydroxy-2-iminopyrimidine, melting point 193°C.
A mixture of 3.0 g (0.019 mol) of 6-amino-4-chloro-1,2-dihydro-1-hydroxy-2-iminopyrimidine and 35 ml of piperidine is refluxed for 1.5 hours, cooled andfiltered. The solid is shaken for 20 minutes in a solution of 0.8 g of sodiumhydroxide in 30 ml of water and filtered. The solid is washed with water andextracted with 800 ml of boiling acetonitrile and filtered to yield 3.5 g (89%)yield of 6-amino-4-chloro-1,2-dihydro-1-hydroxy-2-iminopyrimidine, meltingpoint 248°C, decomposition at 259°C to 261°C.
Brand name
Loniten (Pharmacia & Upjohn); Rogaine (Pharmacia
& Upjohn); Minodyl (Quantum Pharmics).
Therapeutic Function
Antihypertensive
General Description
Minoxidil, 2,4-diamino-6-piperidinopyrimidine-3-oxide . It is converted to minoxidil sulfate in the liver bya sulfotransferase enzyme.
The antihypertensive properties of minoxidil are similarto those of hydralazine hydrochloride, in that minoxidil candecrease arteriolar vascular resistance. Minoxidil exerts itsvasodilatory action by a direct effect on arteriolar smoothmuscle and appears to have no effect on the CNS or on theadrenergic nervous system in animals. The serum half-lifeis 4.5 hours, and the antihypertensive effect may last up to24 hours.
Biological Activity
Antihypertensive. Antialopecia agent. K + channel (K ATP ) activator.
Biochem/physiol Actions
Activates ATP-activated K+ channels; vasodilator; slow or stop hair loss and promote hair regrowth.
Mechanism of action
Potassium channel openers are drugs that activate (i.e., open) ATP-sensitive K+
channels in the VSM. By
opening these potassium channels, there is increased efflux of potassium ions from the cells, causing hyperpolarization
of VSM, which closes the voltage-gated calcium channels and, thereby, decreases intracellular calcium. With less
calcium available to combine with calmodulin, there is less activation of MLCK and phosphorylation of myosin light
chains. This leads to relaxation and vasodilation. Because small arteries and arterioles normally have a high degree of
smooth muscle tone, these drugs are particularly effective in dilating these resistance vessels, decreasing systemic
vascular resistance, and lowering arterial pressure. The fall in arterial pressure leads to reflex cardiac stimulation
(baroreceptor-mediated tachycardia).
Minoxidil, as its active metabolite minoxidil O-sulfate, prolongs the opening of the potassium channel, sustaining
greater vasodilation on arterioles than on veins. The drug decreases blood pressure in both the supine and standing
positions, and there is no orthostatic hypotension. Associated with the decrease in peripheral resistance and blood
pressure is a reflex response that is accompanied by increased heart rate, cardiac output, and stroke volume, which
can be attenuated by the coadministration of a β-blocker. Along with this decrease in peripheral resistance is
increased plasma renin activity and sodium and water retention, which can result in expansion of fluid volume, edema,
and congestive heart failure. The sodium- and water-retaining effects of minoxidil can be reversed by coadministration
of a diuretic. When minoxidil is used in conjunction with a β-adrenergic blocker, pulmonary artery pressure remains
essentially unchanged.
Pharmacokinetics
Minoxidil is absorbed from the GI tract and is metabolized to its active sulfate metabolite. Plasma concentrations for
minoxidil sulfate peak within 1 hour and then decline rapidly. Following an oral dose of minoxidil, its hypotensive effect
begins in 30 minutes, is maximal in 2 to 8 hours, and persists for approximately 2 to 5 days. The delayed onset of the
hypotensive effect for minoxidil is attributed to its metabolism to its active metabolite. The drug is not bound to plasma
proteins. The major metabolite for minoxidil is its N-O-glucuronide, which unlike the sulfate metabolite is inactive as a
hypotensive agent. Approximately 10 to 20% of an oral dose of minoxidil is metabolized to its active metabolite,
minoxidil O-sulfate, and approximately 20% of minoxidil is excreted unchanged.
Clinical Use
Minoxidil is used for severe hypertension that is difficultto control with other antihypertensive agents. The drug hassome of the characteristic side effects of direct vasodilatorydrugs. It causes sodium and water retention and may requirecoadministration of a diuretic. Minoxidil also causes reflextachycardia, which can be controlled by use of a -adrenergicblocking agent.
Minoxidil topical solution is used to treat alopecia androgenitica(male-pattern baldness). Although the mechanismis not clearly understood, topical minoxidil is believed to increasecutaneous blood flow, which may stimulate hairgrowth. The stimulation of hair growth is attributed to vasodilationin the vicinity of application of the drug, resultingin better nourishment of the local hair follicles.
Side effects
Adverse reactions include local irritation and contact dermatitis.
If the treatment is discontinued, clinical regression occurs within 3 months
to the state of hair thinning that would have occurred had the treatment
not been started. Twice-daily treatment is more efficacious than once-daily
application. Women who use the5%concentrationmay note the development
of facial hair, which is reversible on discontinuation of the medication. The
5% concentration can be more irritating than the 2% solution.
Synthesis
Minoxidil, 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine
(22.8.5), is synthesized from barbituric acid, the reaction of which with phosphorous oxychloride
gives 2,4,6-trichloropyrimidine (22.8.1). Upon reaction with ammonium, this
turns into 2,4-diamino-6-chloropyrimidine (22.8.2). Next, the resulting 2,4-diamino-6-
chloropyrimidine (22.8.2) undergoes reaction with 2,4-dichlorophenol in the presence of
potassium hydroxide, giving 2,4-diamino-6-(2,4-dichlorophenoxy)-pyrimidine (22.8.3).
Oxidation of this product with 3-chloroperbenzoic acid gives 2,4-diamino-6-(2,4-
dichlorophenoxy)pyrimidine-3-oxide (22.8.4), the 2,4-dichlorophenoxyl group of which
is replaced with a piperidine group at high temperature, giving minoxidil (22.8.5).
Drug interactions
When minoxidil is administered with diuretics or other hypotensive drugs, the hypotensive effect of minoxidil increases,
and concurrent use may cause profound orthostatic hypotensive effects.
Metabolism
Extensively metabolised by the liver. It requires
sulphation to become active, but the major metabolite is a
glucuronide conjugate.
Excreted mainly in the urine in the form of metabolites.
Minoxidil and its metabolites are dialysable, although the
pharmacological effect is not reversed.
References
1) Meisheri et al. (1988), Mechanism of action of minoxidil sulfate-induced vasodilation: a role for increased K+ permeability; J. Pharmacol. Exp. Ther., 245 7
2) Messenger and Rundegren (2004) Minoxidil:mechanisms of action on hair growth; Br. J. Dermatol., 150 186
