Minoxidil

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Minoxidil
Minoxidil-2D-skeletal.svg
Minoxidil-from-xtal-3D-balls.png
Systematic (IUPAC) name
6-Piperidin-1-ylpyrimidine-2,4-diamine 3-oxide
Clinical data
Trade namesRogaine
AHFS/Drugs.commonograph
Pregnancy cat.C
Legal statusP(UK) for topical use, otherwise POM. Cannot be prescribed on the NHS.
RoutesOral / topical
Pharmacokinetic data
MetabolismPrimarily hepatic
Half-life4.2 hours
Excretionrenal
Identifiers
CAS number38304-91-5 YesY
ATC codeC02DC01 D11AX01
PubChemCID 4201
IUPHAR ligand4254
DrugBankDB00350
ChemSpider10438564 YesY
UNII5965120SH1 N
KEGGD00418 N
ChEBICHEBI:6942 N
ChEMBLCHEMBL802 N
PDB ligand IDMXD (PDBe, RCSB PDB)
Chemical data
FormulaC9H15N5O 
Mol. mass209.251 g/mol
 N (what is this?)  (verify)
 
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Minoxidil
Minoxidil-2D-skeletal.svg
Minoxidil-from-xtal-3D-balls.png
Systematic (IUPAC) name
6-Piperidin-1-ylpyrimidine-2,4-diamine 3-oxide
Clinical data
Trade namesRogaine
AHFS/Drugs.commonograph
Pregnancy cat.C
Legal statusP(UK) for topical use, otherwise POM. Cannot be prescribed on the NHS.
RoutesOral / topical
Pharmacokinetic data
MetabolismPrimarily hepatic
Half-life4.2 hours
Excretionrenal
Identifiers
CAS number38304-91-5 YesY
ATC codeC02DC01 D11AX01
PubChemCID 4201
IUPHAR ligand4254
DrugBankDB00350
ChemSpider10438564 YesY
UNII5965120SH1 N
KEGGD00418 N
ChEBICHEBI:6942 N
ChEMBLCHEMBL802 N
PDB ligand IDMXD (PDBe, RCSB PDB)
Chemical data
FormulaC9H15N5O 
Mol. mass209.251 g/mol
 N (what is this?)  (verify)

Minoxidil is an antihypertensive vasodilator medication. It also slows or stops hair loss and promotes hair regrowth. Now off-patent, it is available over-the-counter for the treatment of androgenic alopecia. Widely used for the treatment of hair loss, it has been proven clinically effective in both the prevention of loss and in establishing varying degrees of hair re-growth in males and females suffering pattern baldness.[1][2] Minoxidil must be used indefinitely for continued support of existing hair follicles and the maintenance of any experienced hair regrowth.[1][3]

History[edit]

Originally, minoxidil was used exclusively as an oral drug (with the trade name 'Loniten') to treat high blood pressure. However, it was discovered to have an interesting side effect: hair growth.[4] Minoxidil may cause increased growth or darkening of fine body hairs, or in some cases, significant hair growth. When the medication is discontinued, the hair loss will return to normal rate within 30 to 60 days. Upjohn Corporation produced a topical solution that contained 2% minoxidil to be used to treat baldness and hair loss, under the brand name Rogaine in the United States and Canada, and Regaine in Europe and the Asia-Pacific. The patent on minoxidil expired February 11, 1996. Treatments usually include a 5% concentration solution that is designed for men, and a 2% concentration solution for women.[5] While the drug is available in the United Kingdom, it cannot be prescribed on the NHS, so patients must either buy it over-the-counter, or have a private prescription for it.[6]

Mechanism and clarification of potential efficacy[edit]

The mechanism by which minoxidil promotes hair growth is not fully understood. Minoxidil contains the nitric oxide chemical functional group and may act as a nitric oxide agonist. Similarly, minoxidil is a potassium channel opener, causing hyperpolarization of cell membranes. Minoxidil is less effective when there is a large area of hair loss. 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 (vertex) hair loss only.[7] Minoxidil is also a vasodilator.[8] Hypothetically, by widening blood vessels and opening potassium channels, it allows more oxygen, blood, and nutrients to the follicle. This may cause follicles in the telogen phase to shed, which are then replaced by thicker hairs in a new anagen phase.

Side effects[edit]

Minoxidil is generally well tolerated, but common side effects include burning or irritation of the eye, itching, redness or irritation at the treated area, as well as unwanted hair growth elsewhere on the body. Users should discontinue treatment and seek medical attention right away if they experience any of the following serious side effects: severe allergic reactions (e.g. rash, hives, itching, difficulty breathing, tightness in the chest, or swelling of the mouth, face, lips, or tongue), chest pain, dizziness, fainting, tachycardia (rapid heartbeat), sudden and unexplained weight gain, or swelling of the hands and feet.[9] Hair loss is a common side effect of minoxidil treatment.[10] Manufacturers note that minoxidil-induced hair loss is a common side effect and describe the process as "shedding". Although this phenomenon demonstrates that minoxidil is indeed affecting hair follicles, manufacturers offer no guarantee that the new hair loss will be replaced with hair growth. The speculated reason for this shedding is the encouragement of hairs already in the telogen phase to shed early.

Alcohol and propylene glycol present in some topical preparations may dry the scalp, resulting in dandruff and contact dermatitis.[11] Some formulations of minoxidil substitute lipid Nanosomes in order to reduce contact dermatitis from the alcohol and propylene glycol vehicle.[12][13]

Side effects of oral minoxidil may include swelling of the face and extremities, rapid and irregular heartbeat, lightheadedness, cardiac lesions, and focal necrosis of the papillary muscle and subendocardial areas of the left ventricle.[14] There have been cases of allergic reactions to minoxidil or the non-active ingredient propylene glycol, which is found in some topical minoxidil formulations. Pseudoacromegaly is an extremely rare side effect reported with large doses of oral minoxidil.[15]

Minoxidil is highly toxic to cats, and may cause death with just inadvertent skin contact.[16][17]

Application[edit]

Minoxidil needs to be applied twice daily, and may be used indefinitely for continued support of existing hair follicles and the maintenance of any experienced hair regrowth. To achieve maximum effect, the solution should be in contact with the scalp for at least 4 hours before allowing hair to get wet.[18] Minoxidil stimulates hair follicles and growth, but does not reduce dihydrotestosterone (DHT) or the enzyme responsible for its accumulation around the hair follicle, 5-alpha reductase, which is the primary mediator of male pattern baldness in genetically susceptible individuals.[19] Therefore, when treatment is stopped, the DHT has its expected effect of shrinking and ultimately destroying the genetically predisposed hair follicles.

Chemical synthesis[edit]

An expeditious synthesis starts with the cyanomalonamide (1); this is then converted to its methyl enol ether (2), for example, by reaction with trimethyloxonium tetrafluoroborate. Reaction of that intermediate with cyanamide leads to the imine (3).

Minoxidil synthesis.png

Condensation with hydroxylamine can occur at either cyano group; for clarity, only one alternative is shown. Addition to that on nitrogen will lead to the formation of the hypothetical hydroxyguanidine (4). Addition to the remaining nitrile leads to minoxidil (5) after bond rearrangement.[20]

Trade names[edit]

Minoxidil is marketed under many trade names, including Avogain, Rogaine, Regaine, Lipogaine, Avacor Physician's Formulation, Kirkland, Tugain, Loniten (oral), Mintop, Amexidil, Vanarex, Keranique and Obabo.

See also[edit]

References[edit]

  1. ^ a b Olsen, Elise A.; Dunlap, Frank E.; Funicella, Toni; Koperski, Judith A.; Swinehart, James M.; Tschen, Eduardo H.; Trancik, Ronald J. (2002). "A randomized clinical trial of 5% topical minoxidil versus 2% topical minoxidil and placebo in the treatment of androgenetic alopecia in men". Journal of the American Academy of Dermatology 47 (3): 377–385. doi:10.1067/mjd.2002.124088. ISSN 0190-9622. 
  2. ^ Price, Vera H.; Menefee, Emory; Strauss, Paul C. (1999). "Changes in hair weight and hair count in men with androgenetic alopecia, after application of 5% and 2% topical minoxidil, placebo, or no treatment". Journal of the American Academy of Dermatology 41 (5): 717–721. doi:10.1016/S0190-9622(99)70006-X. ISSN 0190-9622. 
  3. ^ Olsen, Elise A.; Weiner, Madeline S.; Amara, Ingrid A.; DeLong, Elizabeth R. (1990). "Five-year follow-up of men with androgenetic alopecia treated with topical minoxidil". Journal of the American Academy of Dermatology 22 (4): 643–646. doi:10.1016/0190-9622(90)70089-Z. ISSN 0190-9622. 
  4. ^ MINOXIDIL - ORAL (Loniten) side effects, medical uses, and drug interactions | MedicineNet
  5. ^ "Grant v. Pharmacia & Upjohn Co.". Retrieved 2009-01-17. 
  6. ^ Drug Tariff, 2009/04/11[full citation needed]
  7. ^ Scow, DT; Nolte, RS; Shaughnessy, AF (April 1999). "Medical treatments for balding in men". Am Fam Physician 59 (8): 2189–94. PMID 10221304. 
  8. ^ Vasodilators | MayoClinic.com
  9. ^ Rogaine Side Effects | Drugs.com
  10. ^ FAQs | Rogaine
  11. ^ "Dandruff and Seborrheic Dermatitis". Medscape.com. Retrieved 2009-10-09. 
  12. ^ Balakrishnan P, Shanmugam S, Lee WS, Lee WM, Kim JO, Oh DH, Kim DD, Kim JS, Yoo BK, Choi HG, Woo JS, Yong CS (1 February 2009). "Formulation and in vitro assessment of minoxidil Nanosomes for enhanced skin delivery". International Journal of Phermaceutics 377: 1–8. doi:10.1016/j.ijpharm.2009.04.020. PMID 19394413. 
  13. ^ Padois K, Cantiéni C, Bertholle V, Bardel C, Pirot F, Falson F (16 June 2011). "Solid lipid nanoparticles suspension versus commercial solutions for dermal delivery of minoxidil". International Journal of Pharmaceutics 416: 300–304. doi:10.1016/j.ijpharm.2011.06.014. PMID 21704140. 
  14. ^ "Minoxidil Official FDA information, side effects and uses". Drugs.com. 
  15. ^ Nguyen, K.; Marks Jr, J. (2003). "Pseudoacromegaly induced by the long-term use of minoxidil". Journal of the American Academy of Dermatology 48 (6): 962–965. doi:10.1067/mjd.2003.325. PMID 12789195. 
  16. ^ Camille DeClementi; Keith L. Bailey; Spencer C. Goldstein; Michael Scott Orser (December 2004). "Suspected toxicosis after topical administration of minoxidil in 2 cats". Journal of Veterinary Emergency and Critical Care 14 (4): 287–292. doi:10.1111/j.1476-4431.2004.04014.x. 
  17. ^ "Minoxidil Warning". ShowCatsOnline.com. Retrieved 2007-01-18. "Very small amounts of Minoxidil can result [in] serious problems or death" 
  18. ^ minoxidil (Rogaine) - drug class, medical uses, medication side effects, and drug interactions by MedicineNet.com
  19. ^ American Hair Loss Association | Men's Hair Loss | Causes of Hair Loss
  20. ^ McCall, J. M.; Tenbrink, R. E.; Ursprung, J. J. (1975). "New approach to triaminopyrimidine N-oxides". The Journal of Organic Chemistry 40 (22): 3304–3306. doi:10.1021/jo00910a040. PMID 1185310. 

External links[edit]