A phenethyl imidazole derivative:Miconazole

DESCRIPTION 

Miconazole (Mycatins, Monistats) is a phenethyl imidazole derivative that was synthesized in 1969. It is practically insoluble in water and needs to be solubilized in polyethoxylated castor oil (1% ‘‘Cremophor’’ EL) and ethanol (10%) for intravenous (i.v.) administration. In vitro, miconazole is effective against dermatophytes, yeasts, and some molds and Gram-positive cocci and bacilli. Although it has a wide antifungal spectrum of activity in vitro, the toxicity associated with its use, limited therapeutic efficacy, and the lack of comparative trials limit its use as a systemic antifungal agent. In 1978, miconazole was marketed as an i.v. preparation for certain systemic fungal illnesses; its therapeutic role, however, was limited, and this formulation was ultimately withdrawn from the market. Hence, miconazole is primarily used topically to treat superficial fungal infections, including candidal vulvovaginitis and superficial dermatophyte infections.

MECHANISM OF DRUG ACTION

Miconazole has a fungistatic effect on susceptible fungi by inhibiting sterol C-14 demethylation of lanosterol, resulting in ergosterol depletion in the fungal cell membrane. Both the accumulation of 14 a-methyl sterols and the reduced ergosterol content affect the membrane fluidity and permeability and the activity of membrane-bound enzymes of fungi. At higher concentrations, the drug may be fungicidal and bactericidal due to direct membrane damage, resulting in inhibition of membrane-bound enzymes and mitochondrial activity and in leakage of intracellular components. Miconazole also binds strongly to erythrocyte membrane lipoproteins and can induce hemolysis of mammalian erythrocytes. Additionally, miconazole and other azole derivatives at low concentrations competitively inhibit the activity of calmodulin, which is involved in fungal infections as well as inflammatory skin diseases. Inhibition of calmodulin activity may explain the therapeutic activity of these agents in inflammatory skin disorders.

Bioavailability

Miconazole has limited bioavailability, as documented by a number of different studies. For instance, in comparison with ketoconazole cream, topical miconazole 2% cream produced drug concentrations in the stratum corneum that were 7- to 14-fold lower 1–8 h after a single dose, but were similar 24 h after drug removal. Additionally, it is minimally absorbed following intravaginal insertion of miconazole pessaries. When systemic absorption of miconazole after insertion of a 1200-mg vaginal pessary was examined in healthy volunteers, large intervolunteer variability was observed and the mean maximum serum concentration was 10.4 mg/l (o0.5% of that achieved after an i.v. dose of miconazole) and this low but detectable concentration persisted for 3 days. Following intravaginal administration of a 1200-mg miconazole nitrate vaginal ovule (miconazole nitrate in an ointment base contained in a soft gelatin capsule), peak systemic miconazole levels of 10.7 to 12 ng/ml were achieved in 16–18 h in 20 healthy premenopausal females.

Drug interactions

There is an enhanced anticoagulant effect noted when warfarin and miconazole are co-administered due to inhibition of hepatic P450 enzymes (especially P450 2C9 enzymes) responsible for the metabolism of warfarin. Since systemic absorption from the buccal mucosa after topical application of miconazole is minimal, interaction between warfarin and miconazole gel had not been considered to be problematic. However, clinically evident hemorrhage has been reported in patients on warfarin who were prescribed miconazole gel. 

Co-administration of an azole antifungal such as miconazole may inhibit the metabolism and hence increase the levels of fentanyl, pimozide, phenytoin, cyclosporine, and trimetrexate. The hypoglycemic action of sulfonylureas may be enhanced by miconazole; thus, patients receiving glimepiride should be closely monitored for hypoglycemia or loss of glycemic control when miconazole is added to or withdrawn from their regimen. Co-administration of tobramycin and intravenous miconazole may result in significant decreases in the peak serum tobramycin levels, and tobramycin concentrations should be monitored.