Chemistry:Terbinafine

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Terbinafine, sold under the brand name Lamisil among others, is an antifungal medication used to treat pityriasis versicolor, fungal nail infections, and ringworm including jock itch and athlete's foot.[1][2][3] It is either taken by mouth or applied to the skin as a cream or ointment.[1][4]

Common side effects when taken by mouth include nausea, diarrhea, headache, cough, rash, and elevated liver enzymes.[1] Severe side effects include liver problems and allergic reactions.[1] Liver injury is, however, unusual.[5] Oral use during pregnancy is not typically recommended.[1] The cream and ointment may result in itchiness but are generally well tolerated.[2] Terbinafine is in the allylamines family of medications.[1] It works by decreasing the ability of fungi to synthesize ergosterol.[1] It appears to result in fungal cell death.[6]

Terbinafine was discovered in 1991.[7] It is on the World Health Organization's List of Essential Medicines.[4] In 2023, it was the 253rd most commonly prescribed medication in the United States, with more than 1 million prescriptions.[8][9]

Medical uses

Terbinafine is mainly effective on molds of the order Onygenales and some yeasts in the genus Candida.[citation needed]

As a cream or powder, it is used topically for superficial skin infections such as jock itch (tinea cruris), athlete's foot (tinea pedis), and other types of ringworm (tinea corporis).[10]

Tablets by mouth are often prescribed for the treatment of onychomycosis, a fungal nail infection, typically by a dermatophyte or Candida species. Fungal nail infections are located deep under the nail in the cuticle to which topically applied treatments are unable to penetrate in sufficient amounts. The tablets may, rarely, cause hepatotoxicity, so patients are warned of this and may be monitored with liver function tests. Alternatives to oral administration have been studied.[citation needed]

Terbinafine may induce or exacerbate subacute cutaneous lupus erythematosus. Persons with lupus erythematosus should first discuss possible risks with their doctor before initiation of therapy.[11]

Side effects

Many side effects and adverse drug reactions have been reported with oral terbinafine hydrochloride,[12][13] possibly due to its extensive biodistribution and the often extended durations involved in antifungal treatment (longer than two months). A comprehensive list of adverse events associated with terbinafine use includes:

  • Gastrointestinal problems: Diarrhea, constipation, nausea, fullness, abdominal pain, indigestion, dyspepsia, gastritis, cholestasis, flatulence, altered stool colour, abdominal muscular pain
  • Central nervous system or neurological problems: Headaches, dizziness, vertigo, light-headedness, decreased concentration levels, paraesthesia (pins and needles)
  • Hepatic problems: Raised liver enzyme levels, liver inflammation (hepatitis), liver damage, liver failure
  • Immune system problems: Decreased white blood cell counts including pancytopenia, leukopenia, lymphopenia, thrombocytopenia, agranulocytosis, and neutropenia, autoimmune reactions such as lupus erythematosus
  • Psychological problems: Depression, anxiety, insomnia, increased or unusual dream activity, malaise
  • Sensory problems: Complete loss of taste (ageusia), decreased taste (hypogeusia) and distorted taste (dysgeusia), often involving a metallic taste sensation and dry mouth, visual disturbances including blurred vision, green vision and double vision. In extremely rare cases, the loss or impairment of taste is permanent [14]
  • Auditory system problems: Tinnitus and hearing loss have been reported in rare cases.[15] The Netherlands Pharmacovigilance Centre Lareb and WHO's global VigiBase database both reported multiple cases of tinnitus and hearing loss associated with oral terbinafine use.[16]
  • Skin problems: Rashes, hives (urticaria), skin irritation, itching, jaundice, Stevens–Johnson syndrome
  • Other side effects: Fatigue, increased heart rate (tachycardia), hair loss (alopecia), decreased red blood cell count (anemia), muscle pain (myalgia), joint pain (arthralgia)


Pharmacology

Generic terbinafine hydrochloride pills

Like other allylamines, terbinafine inhibits ergosterol synthesis by inhibiting squalene epoxidase, an enzyme that catalyzes the conversion of squalene to lanosterol. In fungi, lanosterol is then converted to ergosterol; in humans, lanosterol becomes cholesterol. However, as fungi and animals diverged around 1.1 billion years ago - there is enough difference in this enzyme that terbinafine preferentially binds fungal squalene epoxidase, making it selective for inhibiting ergosterol production in fungi without significantly affecting cholesterol production in mammals. This is thought to fatally disrupt the fungal cell membrane.[citation needed]

Terbinafine is highly lipophilic and tends to accumulate in hair, skin, nails, and fat cells. This accumulation results in therapeutic levels of terbinafine even after 80 days following one week treatment of 250 mg/day.

Chemistry

Terbinafine is produced by coupling of 3,3-dimethyl-1-butyne (tert-butylacetylene) with acrolein as a key step, followed by coupling of the product of that reaction, 6,6-dimethylhept-1-en-4-yn-3-ol, with N-methyl-1-naphthalenemethanamine.[17] Multiple patents and publication to alternate syntheses are available.

Despite its name it does not contain terbium.

History

Terbinafine first became available in Europe in 1991 and in the United States in 1996. The U.S. Food and Drug Administration has approved the first generic versions of prescription Lamisil (terbinafine hydrochloride) tablets. The remaining patent or exclusivity for Lamisil expired on 30 June 2007.

On 28 September 2007, the FDA stated that terbinafine is now approved for use by children age four and up. The antifungal granules can be sprinkled on a child's food to treat scalp fungus.[18]

In the United States the price in 1999 was $547 for a 12-week course; this fell to $10 by 2015, after the patent had expired.[19]

Society and culture

Brand names

  • Terbinafine is sold in India as Terboderm by Omega Pharma and Tyza (Abbott Healthcare).[20]
  • Lamisil in Argentina, Australia, Bangladesh,[21] Belgium, Brazil, Canada, Chile, Colombia, Croatia, Egypt, the Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Israel, Mexico, the Netherlands, New Zealand, Norway, Pakistan, Peru, the Philippines,[22] Romania, Russia, Slovakia, Slovenia, South Africa, Sweden, Thailand, the United Kingdom, the United States, and Venezuela
  • Corbinal and Terbisil in Turkey, Pakistan, Undofen in Poland. Another alternate is Terbistad (Stada Arzneimittel).
  • As a generic oral medication, it is sold as Sebifin, Tinasil, Terbisil, Terbicor, and Tamsil in Australia, whilst the generic topical medication is sold there as SolvEasyTinea and Tamsil.[23][24]
  • It is also available as a generic medication in the United States, the United Kingdom, Belgium, Switzerland, Brazil, Mexico, Canada and France.
  • In India, terbinafine hydrochloride is available in topical form under the brand names Triabin by Medley Pharmaceuticals, Sebifin (Sun Pharma), Zimig (GSK Pharma) and mycoCeaze (Progreś Laboratories). MycoVa, developed by Apricus Biosciences, is a topical nail solution of terbinafine and DDAIP, which has completed three phase-III studies for the treatment of onychomycosis.
  • Other names include Terbinaforce (Mankind Pharma) and Tafine (Deurali Janta Pharmaceuticals Pvt Ltd.) Turbo (Apex Pharmaceuticals Pvt Ltd) in Nepal.
  • The topical form is sold as Lamisil AT in the United States.

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 "Terbinafine Hydrochloride". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/terbinafine-hydrochloride.html. 
  2. ↑ 2.0 2.1 "Lamisil 1% w/w Cream – Summary of Product Characteristics (SPC) – (eMC)". electronic Medicines Compendium (eMC). 17 March 2016. https://www.medicines.org.uk/emc/medicine/21037. 
  3. ↑ "Athlete's foot". BMJ Clinical Evidence 2009. July 2009. PMID 21696646. 
  4. ↑ 4.0 4.1 World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. 
  5. ↑ "Systematic review of severe acute liver injury caused by terbinafine". International Journal of Clinical Pharmacy 36 (4): 679–683. August 2014. doi:10.1007/s11096-014-9969-y. PMID 24986266. 
  6. ↑ "Terbinafine". https://www.drugbank.ca/drugs/DB00857. 
  7. ↑ The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. John Wiley & Sons. 2011. p. 90. ISBN 978-3-527-32669-3. https://books.google.com/books?id=iDNy0XxGqT8C&pg=PA90. 
  8. ↑ "The Top 300 of 2023". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  9. ↑ "Terbinafine Drug Usage Statistics, United States, 2014 - 2023". https://clincalc.com/DrugStats/Drugs/Terbinafine. 
  10. ↑ "Clinical inquiries. What is the most effective treatment for tinea pedis (athlete's foot)?". The Journal of Family Practice (Frontline Medical Communications) 51 (1): 21. January 2002. PMID 11927056. http://www.jfponline.com/Pages.asp?AID=1080. 
  11. ↑ "Subacute cutaneous lupus erythematosus induced or exacerbated by terbinafine: a report of 5 cases". Archives of Dermatology 137 (9): 1196–1198. September 2001. doi:10.1001/archderm.137.9.1196. PMID 11559217. 
  12. ↑ "Lamisil (terbinafine): Side Effects". Doublecheckmd.com. 16 June 2010. http://doublecheckmd.com/EffectsDetail.do?dname=Lamisil&sid=1510&eid=2237. 
  13. ↑ "Australian regulators issue warning on Novartis' Lamisil". Medical Marketing and Media (Mmm-online.com). 5 February 2008. http://www.mmm-online.com/australian-regulators-issue-warning-on-novartis-lamisil/article/104983/. 
  14. ↑ "Persistent impairment of taste associated with terbinafine". British Dental Journal 188 (6): 295–296. March 2000. doi:10.1038/sj.bdj.4800461. PMID 10800234. "Persistent loss of taste associated with terbinafine would however appear to be extremely rare.". 
  15. ↑ "Hearing Impairment in Association with Terbinafine". Drug Safety – Case Reports 1 (1): 9. 2014. doi:10.4081/dr.2018.7859. PMID 30370041. 
  16. ↑ "Hearing impairment in association with terbinafine". Netherlands Pharmacovigilance Centre Lareb. https://databankws.lareb.nl/Downloads/kwb_2011_1_terbi.pdf. 
  17. ↑ Hergert, T., Mátravölgyi, B., Örkényi, R. et al. Multistep batch-flow hybrid synthesis of a terbinafine precursor. J Flow Chem 12, 51–57 (2022), doi.org/10.1007/s41981-021-00188-9
  18. ↑ "US FDA approves oral granules for scalp ringworm". Reuters. 28 September 2007. https://www.reuters.com/article/governmentFilingsNews/idUSN2820532120070928. 
  19. ↑ "Cost-effectiveness of Confirmatory Testing Before Treatment of Onychomycosis". JAMA Dermatology 152 (3): 276–281. March 2016. doi:10.1001/jamadermatol.2015.4190. PMID 26716567. 
  20. ↑ "Terbinafine brands in India". Brand index. DrugsUpdate India. http://www.drugsupdate.com/brand/showavailablebrands/508/3. 
  21. ↑ "Lamisil". https://medex.com.bd/brands/10040/lamisil. 
  22. ↑ "Mercury Drug – The Leading Drugstore in the Philippines". https://www.mercurydrug.com/drug-info-center.html. 
  23. ↑ "Terbinafine". Pharmaceutical Benefits Scheme: A-Z list. Australian Government. http://www.pbs.gov.au/medicine/item/2285G-2804N-4011D. 
  24. ↑ "PI and CMI Trade Names and Active Ingredients containing Terbinafine". Therapeutic Goods Administration. Australian Government. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/PICMI?OpenForm&t=&q=Terbinafine&r=https://www.ebs.tga.gov.au/. 



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