Imidazoles

Imidazoles alter the cell membrane permeability of susceptible yeasts and fungi by blocking the synthesis of ergosterol (demethylation of lanosterol is inhibited), the primary cell sterol of fungi. The enzyme targeted is a fungal cytochrome P450 (CYP450). Other enzyme systems are also impaired, such as those required for fatty acid synthesis. Because of the drug-induced changes of oxidative and peroxidative enzyme activities, toxic concentrations of hydrogen peroxide develop intracellularly. The overall effect is cell membrane and internal organelle disruption and cell death. The cholesterol in host cells is not affected by the imidazoles, although some drugs impair synthesis of selected steroids and drug-metabolizing enzymes in the host. Because imidazoles impair synthesis, a lag time to efficacy occurs. This lag time may be prolonged because of the long half-life of these drugs.

Sensitivity to the imidazoles varies greatly between various strains of yeasts and fungi, but neither natural nor acquired resistance appears to be prevalent.

The antifungal imidazoles also have some antibacterial action but are rarely used for this purpose. Miconazole has a wide antifungal spectrum against most fungi and yeasts of veterinary interest. Sensitive organisms include Blastomyces dermatitidis, Paracoccidioides brasiliensis, Histoplasma capsulatum, Candida spp, Coccidioides immitis, Cryptococcus neoformans, and Aspergillus fumigatus. Some Aspergillus and Madurella spp are only marginally sensitive.

Ketoconazole has an antifungal spectrum similar to that of miconazole, but it is more effective against C immitis and some other yeasts and fungi. Itraconazole and fluconazole are the most active of the antifungal imidazoles. Their spectrum includes dimorphic fungal organisms and dermatophytes. They are also effective against some cases of aspergillosis (60%–70%) and cutaneous sporotrichosis. Clotrimazole and econazole are used for superficial mycoses (dermatophytosis and candidiasis); econazole also has been used for oculomycosis. Thiabendazole is effective against Aspergillus and Penicillium spp, but its use has largely been replaced by the more effective imidazoles. Voriconazole is approved for human use in treatment of Aspergillus but is effective against many other fungal organisms.Posaconazole may be more effective than itraconazole or fluconazole but may be associated with more adverse effects.

The imidazoles are rapidly but sometimes erratically absorbed from the GI tract; plasma levels peak within 2 hr after administration PO. Fluconazole is an exception, being close to 100% bioavailable after administration PO. Except for fluconazole, an acidic environment is required for dissolution of the imidazoles, and a decrease in gastric acidity can reduce bioavailability after administration PO. The rate of absorption appears to be increased when the drug is given with meals, but reports are conflicting. Because oral bioavailability can be very poor with noncommercial imidazole products, caution is recommended with compounded products, and monitoring is recommended if a compounded preparation is used.

Imidazoles appear to be widely distributed in the body, with detectable concentrations in saliva, milk, and cerumen. CSF penetration is poor except for fluconazole, which reaches 50%–90% of plasma concentrations. Most imidazoles (except fluconazole) are highly protein bound in the circulation (>95%), most to albumin. The highest concentrations of imidazoles are found in the liver, adrenal glands, lungs, and kidneys.

Hepatic metabolism is the primary route of elimination. Metabolism of ketoconazole and most other imidazoles by oxidative pathways is extensive. Only ~2%–4% of a dose administered PO appears unchanged in the urine. Itraconazole is metabolized to an active metabolite that may contribute significantly to antimicrobial activity. The biliary route is the major excretory pathway (>80%); ~20% of the metabolites are eliminated in the urine. Fluconazole (in people) is eliminated (≥90%) unchanged in the urine. The kinetics of voriconazole have not yet been evaluated in animals.

The rate of elimination of ketoconazole appears to be dose dependent—the greater the dose, the longer the elimination half-life. There is also a biphasic elimination pattern, with rapid elimination in the first 1–2 hr, then a slower decline over the next 6–9 hr. Ketoconazole is usually administered bid. The half-life of itraconazole is longer (up to 48 hr in cats), thus allowing treatment once to twice daily. Because of the long half-life and mechanism of action (impaired synthesis of the fungal cell membrane), time to efficacy may take longer than drugs that have more rapid actions (such as amphotericin B).

The imidazoles given PO result in few adverse effects, but nausea, vomiting, and hepatic dysfunction can develop. Ketoconazole in particular is associated with hepatotoxicity, especially in cats. Because imidazoles also inhibit CYP450 associated with steroid synthesis, as a result, sex steroids, including testosterone and adrenal steroid (cortisol), metabolism is inhibited. Adrenal responsiveness to adrenocorticotropic hormone (ACTH) will be decreased, particularly with ketoconazole. Reproductive disorders related to ketoconazole administration may be seen in dogs. Voriconazole is associated with a number of adverse effects in people, including vision disturbances.

Imidazoles, in general, inhibit the metabolism of many drugs. Although ketoconazole has the broadest inhibitory effects, fluconazole followed by itraconazole also inhibit metabolism. Concurrent administration of these drugs with other drugs metabolized by the liver and potentially toxic should be done only with extreme caution. Imidazoles also are substrates for P-glycoprotein transport protein and may compete with other substrates, causing higher concentrations. Many of the substrates for P-glycoprotein are also substrates for CYP450. Rifampin, which is a P-glycoprotein substrate, decreases serum ketoconazole because of microsomal enzyme induction. The absorption of the imidazoles, except for that of fluconazole, is inhibited by concurrent administration of cimetidine, ranitidine, anticholinergic agents, or gastric antacids. The risk of hepatotoxicity is increased if ketoconazole and griseofulvin are administered together. Imidazoles might be used concurrently with other antifungals to facilitate synergistic efficacy.

Treatment with imidazoles increases AST, ALT, plasma bilirubin, and plasma cholesterol. Adrenal responsiveness is altered.