Minoxidil sulfate

Baker CA, Uno H, Johnson GA. Minoxidil sulfation in the hair follicle. Skin Pharmacol 1994 7(6) 335—339. 

Minoxidil (Loniten) is an orally effective vasodilator. It is more potent and longer acting than hydralazine and does not accumulate significantly in patients with renal insufficiency. It depends on in vivo metabolism by hepatic enzymes to produce an active metabolite, minoxidil sulfate. Minoxidil sulfate activates potassium channels, resulting in hyperpolarization of vascular smooth muscle and relaxation of the blood vessel. 

Minoxidil is a very efficacious orally active vasodilator. The effect results from the opening of potassium channels in smooth muscle membranes by minoxidil sulfate, the active metabolite. Increased potassium permeability stabilizes the membrane at its resting potential and makes contraction less likely. Like hydralazine, minoxidil dilates arterioles but not veins. Because of its greater potential antihypertensive effect, minoxidil should replace hydralazine when maximal doses of the latter are not effective or in patients with renal failure and severe hypertension, who do not respond well to hydralazine. 

Buhl AE, Waldon DJ, Baker CA, Johnson GA. Minoxidil sulfate is the active metabolite that stimulates hair follicles. J Invest Dermatol 1990 95 553-7. 

Minoxidil. Minoxidil increases the blood flow to the follicular dermal papilla by a direct vasodilation effect on the arteriolar blood vessels (94, 95). Vasodilation is caused by the active metabolite minoxidil sulfate. 

In the discovery phase, metabolite identification is usually performed with a combination of in vitro and in vivo experiments using samples from different species in order to compare metabolite exposures. The structural identification of major circulating metabolites formed in nonclinical animal models as well as the metabolites formed in human in vitro systems is needed for the metabolites to be synthesized and their pharmacological activities and/or toxicological implications to be determined [25], In addition, metabolite identification can lead to the discovery of candidates with satisfactory clearance/PK properties and/or improved safety profile. Following are some examples of metabolites that were later developed as drugs desloratadine from loratadine, acetaminophen from phenacetin, morphine from codeine, minoxidil sulfate from minoxidil, fexofenadine from terfenadine, and oxazepam from diazepam. 

Minoxidil (loniten) is efficacious in patients with the most severe and drug-resistant forms of hypertension. A small fraction of minoxidil is metabolized by hepatic sulfotransferase to the active molecule, minoxidil N-O sulfate. Minoxidil sulfate activates the ATP-modulated channel in smooth muscle, causing hyperpolarization and relaxation of arteriolar smooth muscle. Minoxidil produces arteriolar vasodilation with essentially no effect on capacitance vessels. Minoxidil preferentially increases blood flow to skin, skeletal muscle, the GI tract, and the heart. The disproportionate increase in blood flow to the heart may have a metabolic basis, in that administration of minoxidil is associated with a reflex increase in myocardial contractility and in cardiac output. The cardiac output can increase by as much as three- to fourfold, primarily due to enhanced venous return to the heart. The increased venous return probably results from enhanced flow in vascular beds with a fast response for venous return to the heart. The adrenergic increase in myocardial contractility contributes to the increased cardiac output, but is not the predominant factor. The renal effects of minoxidil are complex it dilates renal arteries, but systemic hypotension produced by the drug actually can decrease renal blood flow. Renal function usually improves in patients who take minoxidil for the treatment of hypertension, especially if renal dysfunction is secondary to hypertension. Minoxidil potently stimulates renin secretion, an effect mediated by renal sympathetic stimulation. 

Minoxidil is extremely efficacious and is thus reserved for severe hypertension. Minoxidil is a prodrug its metabolite, minoxidil sulfate, is a potassium channel opener that hyperpolarizes and relaxes vascular smooth muscle. The toxicity of minoxidil consists of severe compensatory responses (Table 11-2, Figure 11-2), hirsutism, and pericardial abnormalities. 

Hyperpolarization of smooth muscle through increased potassium permeability Minoxidil metabolite (minoxidil sulfate), diazoxide... 

Diazoxide is a potassium channel opener as given. Minoxidil sulfate, a metabolite of minoxidil, also acts by this mechanism. The answer is (C). 

Antihypertensive prodrug of minoxidil sulfate, a high-efficacy arteriolar vasodilator. Used in HTN topically for baldness. Tox tachycardia, salt and water retention, pericardial effusion. 

Minoxidil is absorbed from the Gl 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. 

Sulfation of hydroxylamines and hydroxyamides often leads to reactive electrophilic metabolites (Abu-Zeid et al., 1992 Banoglu, 2000), but in the case of the prodrug minoxidil, sulfation of the N-oxide yields the active drug (Anderson et al., 1998) ... 

Nevertheless, it is assumed that treatment with minoxidil lengthens and thickens the small vellus hairs and decreases shedding. Minoxidil is a potassium channel opener that causes vasorelaxation [132] and stimulates cutaneous blood flow to the scalp [133]. Minoxidil sulfate, a metabolite of minoxidil, is a potent vasodilator. Uptake and conversion of minoxidil to minoxidil sulfate occurs within the HE, suggesting a direct action on the follicle [134]. The most probable site of action of minoxidil is the DP [135], and the mechanism of action has been linked to its effects on the Kir6.1/SUR2B potassium channel expressed by the derma papilla [136-138]. 

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