Terconazole

Terconazole
Systematic (IUPAC) name
1-[4-[ [(2S,4S)-2-(2,4-Dichlorophenyl)-2- (1,2,4-triazol-1-ylmethyl)- 1,3-dioxolan-4-yl]methoxy]phenyl]- 4-propan-2-yl-piperazine
Clinical data
Trade names Terazol
AHFS/Drugs.com monograph
MedlinePlus a688022
Pharmacokinetic data
Protein binding 94.9%
Identifiers
67915-31-5 Yes
G01AG02
PubChem CID 441383
DrugBank DB00251 Yes
ChemSpider 390122 Yes
UNII 0KJ2VE664U Yes
KEGG D00888 Yes
ChEBI CHEBI:9451 
ChEMBL CHEMBL1306 Yes
Chemical data
Formula C26H31Cl2N5O3
532.462 g/mol
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Terconazole is an antimycotic drug used to treat vulvovaginal candidiasis. It comes as a lotion or a suppository and disrupts the biosynthesis of fats in a yeast cell. It has a relatively broad spectrum compared to azole compounds but not triazole compounds. Testing shows that it is a suitable compound for prophylaxis for those that suffer from chronic vulvovaginal candidiasis.

Drug Class

Terconazole is a triazole ketal with broad-spectrum antifungal/antimycotic tendencies.

History

In 1940, the first commercial antifungal drug was available on the market. Before this, antifungal treatments were rare and expensive. This treatment was called amphotericin B. It was effective in its function but was very toxic and only used for serious infections. The drug was infused into the bloodstream and could cause kidney damage and other side effects. The first azole compounds were administered to humans under strict care. These compounds were imidazoles, a molecule containing two non-adjacent nitrogen atoms in a 5 membered ring. These were synthesized in the late 60’s early 70’s. The first oral antimycotic imidazole called Ketoconazole was available on the market in 1981. Triazole based drugs came shortly after and quickly gained popularity due to its broader spectrum of antifungal activity and less toxicity (Maertens, J. A. 2004). Terconazole was the first triazole-based antifungal drug synthesised for human use. Janssen Pharmaceutica developed it in 1983 (Heeres, J, 1983). Previously, all triazole based drugs targeted fungal infections related to plants from candida species. Since creation, terconazole has been superseded by second-generation triazoles due to their even broader spectrum and higher activity levels against resistant pathogens likeAspergillus spp. (Cauwenbergh, G., 1989). It is still used as a treatment in cases of resistance to other drugs

Indications

Terconazole is approved to treat vulvovaginal candidiasis (vaginal thrush). It works as a broad spectrum antifungal and has shown to be an effective first-line treatment against other candida species (Tolman, E. L., Isaacson, D. M., 1986). It also shows effectiveness against dermatomycoses in animal models (Sood, G., et al., 2000)

Chemical Structure, Reactivity, Synthesis

Terconazole synthesis: U.S. Patent 4,144,346 U.S. Patent 4,223,036 [1] DE 2804096

Terconazole has the chemical formula C26H31Cl2N5O3. The chemical Name for terconazole is cis-1- {p-[|2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxalan-4-yl|]methoxyphenyl}-4-isopropylpiperazine. Terconazole has a melting point of 126.30C. The molecular weight of terconazole is 532.462g/mol Terconazole is synthesised using two chemical compounds: cis-[2(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl] methyl benzoate and the sodium salt of triazole, created by mixing triazole with NaH. These are put in a solution and catalysed using Me2SO at 1300C to give many different types of triazole derivatives (Cauwenbergh, G., 1989). These are purified using alcohol and chromatography. Terconazole is non reactive except when exposed to strong oxidising agents or strong bases due to the nitrogen attached to the triazole ring. It has been found to be photosensitive (Fromtling, R. A. 1988)

Available Forms

Terconazole is a white, odourless powder. It can be purchased commercially in the following forms: • Terconazole 0.4% cream 5g applied intravaginally once a day for 7 days • Terconazole 0.8% cream 5g applied intravaginally once a day for 3 days • Terconazole 80mg vaginal suppository used once daily for 3 days (Mosby, 2012).

Mechanism of Action

Terconazole binds to the heme iron component on the cytochrome p450 enzyme lanosterol of fungi, also known as CYP3A4. The gene ERG11 controls Lanosterol creation (Yoshida, Y. 1988). Lanosterol is found within the yeast plasma membrane. It is a class of methylsterol. Within a normal yeast cell, lanosterol is demethylated using 14α-demethylation (Isaacson, D., 1987). This process creates zymosterol: a major constituent in the ergosterol biosynthesis pathway for the creation of cell membrane constituents in yeast. This structure provides the membrane with fluidity (Saccharomyces Genome Database, 2013). This occurs by transforming lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol. This stops respiration by prohibiting reduction of NADH to NAD. This stops biosynthesis of cell membrane products as well as transport and catabolism. Eventually, membrane fluidity and activity of membrane bound enzymes become depleted. It has also been shown to inhibit morphologic change of yeast as well as cell adherence and is directly toxic to yeast. Terconazole targets fungi specifically since humans do not use lanosterol In this pathway. This process does not affect all fungi such as pneumocystis carinii, which lacks lanosterol (Sobel, J., 1994)l.

Metabolism

Absorption of terconazole is 5-8% in patients that have had a hysterectomy and 12-16% in other patients. In those that administered 0.8% terconazole, plasma concentrations of the drug remained quite low with the peak plasma concentration being 0.006μg at 6.6 hours. Those metabolism rates show similar results in pregnant vulvovaginal candidiasis, non-pregnant vulvovaginal candidiasis and healthy women. The half-life of terconazole in blood is recorded to be around 6.9 hours over a range of 4.0-11.3 hours). Radioactivity of plasma terconazole is low compared to terconazole at 0.6%. Excretion of radioactivity is via two routes, renal (32-53%) and faecal (47-52%). Metabolism is extensive and is highly protein bound (94.9%) with the degree of binding being independent of drug concentration (Sheehan, D. J. et al. 1999).

Efficacy

In a review of 19 studies, it was shown that short-term rates for intravaginally administered azole treatments show mycological cure (no presence of organism) in 80% of cases in a short term follow-up and 66% over long term follow-up (Nurbhai, M., 2009). In a double-blind study by Slavin in 1992, Terconazole showed a 75% mycological cure over a short-term period (7-14 days) and 100% mycological cure over a long-term period (28-34 days). This study focussed on the drug as an 80mg vaginal suppository, taken three times overnight by 10 women (Slavin, M. B., 1992). In another placebo-controlled, double blind study by Schmidt et al., The efficacy of different concentrations of terconazole creams were tested. Cream was applied for three days to 24 women between the ages of 18-60. The results showed 0.8% terconazole mycologic cure rates were 83.3% within 1-3 days of starting treatment, 83.3% within 8-11 days of treatment and 58.3% within 30-35 days of treatment (Schmidt, C., 1990). The efficacy of the suppository is more effective after a long-term follow-up than terconazole as a cream or other intravaginal treatments (Maibach, H. I., & Farage, M. A., 2006).

Side Effects

The most common side effects of terconazole include headaches, vulvar/vaginal irritation, rash, itching, burning or discomfort (Workowski, K. A et al., 2010). Other side effects may include abdominal pain or cramps dysmenorrhea, chills, fever and allergic reactions. Flu-like symptoms have been recorded in those that take suppositories greater than 160mg (Schmidt, C., 1990). May cause birth defects if used in the first trimester. (Faro, S., 1997)

Drug Interactions

Terconazole may interact with the spermicide nonoxynol-9. A precipitate is formed upon combination of both drugs. Terconazole may weaken latex-based condoms (Pfaller, M. A. 2010).

Safety

Terconazole is not considered hazardous when handled under normal conditions. It is generally non-flammable and non-carcinogenic Generally is non-toxic, however, can emit toxic fumes when dust is set alight. Can cause respiratory distress as dust (Mancano, M. A., 2013). Can be absorbed by embryo within the first trimester of pregnancy and cause birth defects. Cross inhibition shows that there may be some toxicity. (Melbourne Sexual Health Centre. 2011)

References

Cauwenbergh, G., & Vanden Bossche, H. (1989). Terconazole. pharmacology of a new antimycotic agent.. Journal of Reproductive Medicine, 34(8), 588-592. Faro, S., Apuzzio, J., Bohannon, N., Elliott, K., Martens, M. G., Mou, S. M., Young, R. L. (1997). Treatment considerations in vulvovaginal candidiasis. The Female Patient, 22(1), 1-17. Fromtling, R. A. (1988). Overview of antifungal azoles. Clinical Microbiology Review, 1(1), 201. Heeres, J., Hendrickx, R., & Van Cutsem, J. (1983). Antimycotic azoles: 6. synthesis & antifungal properties of terconazole, a novel triazole ketal. The Journal of Medical Chemistry, 26(1), 611-613. Isaacson, D. M., Tolman, E. L., Tobia, A. J., Rosenthale, M. E., Mcguire, J. L., Van Den Bossche, H., & Janssen, P. A. (1987). Selective inhibition of 14α-desmethyl sterol synthesis in candida albicans by terconazole, a new triazole antimycotic. Journal of Antimicrobial Chemotherapy, 21(3), 333-343. Maertens, J. A. (2004). History of the development of azole derivatives. Clinical Microbiology & Infection, 10(1), 1-10. doi:10.1111/j.1470-9465.2004.00841.x Maibach, H. I., & Farage, M. A. (2006). Vulvar therapies: Evidence vs. testimony: Fungal: Candidiasis. In M. A. Farage (Ed.), The vulva: Anatomy, physiology, and pathology (1st ed., pp. 128-129). 270 Madison Avenue, New York, NY: Informa Healthcare USA Inc. Mancano, M. A., & Gallagher, J. C. (2013). Antifungal, triazole. In T. Reilly (Ed.), Frequently prescribed medications (2nd ed., pp. 312). 5 Wall Street, Burlington, MA, USA: Jones & Bartlett Learning. Melbourne Sexual Health Centre. (2011). Vaginal thrush. Retrieved 04/25, 2013, from http://www.betterhealth.vic.gov.au/bhcv2/bhcarticles.nsf/pages/Thrush Mosby. (2012). Terconazole. In K. White, & J. Watrous (Eds.), Mosby's drug reference for health professions (3rd ed., pp. 1558-1559). 3251 Riverport Lane, St. Louis, Missouri, USA: Elsevier. Nurbhai, M., Grimshaw, J., Watson, M., Bond, C. M., Mollison, J. A., & Ludbrook, A. (2009). Oral versus intra-vaginal imidazole and triazole anti-fungal treatment of uncomplicated vulvovaginal candidiasis (thrush) (review). The Chochrane Collaboration, 1(1), 1-54. Pfaller, M. A. (2010). Terconazole. In M. L. Grayson (Ed.), Kucers' the use of antibiotics: A clinical review of antibacterial, antifungal, antiparasitic & antiviral drugs (6th ed., pp. 1933-1935). 1752 N Street, NW, Wahington, USA: ASM Press. Saccharomyces Genome Database. (2013). C-4 methylsterol oxidase activity. Retrieved 02/03, 2013, from http://www.yeastgenome.org/cgi-bin/GO/goTerm.pl?goid=254#annosum Schmidt, C., Sobel, J., & Meriwether, C. (1990). Comparison of 0.8% terconazole cream in severe vulvovaginal candidiasis. Obstetrics & Gynecology, 76(3), 414-416. Sheehan, D. J., Hitchcock, C. A., & Sibley, C. M. (1999). Vulvovaginal candidiasis. Clinical microbiology reviews: Current & emerging azole antifungal treatments (12th ed., pp. 56-58). New York, NY, U.S.A.: American Society for microbiology. Slavin, M. B., Benrubi, G. I., Parker, R., Griffin, C. R., & Magee, M. J. (1992). Single dose oral fluconazole vs intravaginal terconazole in treatment of candida vaginitis. comparison and pilot study.. The Journal of the Florida Medical Association, 79(10), 693-696. Sobel, J. (1994). Mini review: Candida vaginitis. Infectious Diseases in Clinical Practice, 3(5), 334-339. Sood, G., Nyirjesy, P., Weitz, M. V., & Chatwani, A. (2000). “Terconazole cream for non-candida albicans fungal vaginitis" results of a retrospective analysis . Diseases in Obstetrics & Gynecology, 8(1), 240-243. Tolman, E. L., Isaacson, D. M., Rosenthale, M. E., McGuire, J. L., Van Cutsem, J., Borgers, M., & Van Den Bossche, H. (1986). Anticandidal activities of terconazole,a broad-spectrum antimycotic. Antimicrobial Agents & Chemotherapy, 29(6), 986-991. Workowski, K. A., & Berman, S. (2010). Sexually transmitted diseases treatment guidelines, recommendations & reports. (Review No. 59). 1600 Clifton Rd. Atlanta, GA 30333, USA: Centers For Disease Control & Prevention. Yoshida, Y. (1988). Cytochrome P450 of fungi: Primary target for azole anitfungal agents. Current Topics in Medical Mycology, 2(1), 388-389. doi:10.1007/978-1-4612-3730-3_1


References

  1. ↑ Heeres, J.; Hendrickx, R.; Van Cutsem, J. (1983). "Antimycotic azoles. 6. Synthesis and antifungal properties of terconazole, a novel triazole ketal". Journal of Medicinal Chemistry 26 (4): 611. doi:10.1021/jm00358a032.