Azoles

The antibacterial, antiprotozoal and anthelminthic members of this group are described in the appropriate sections. Antifungal azoles comprise the following:

• Imidazoles (ketoconazole, miconazole, fenticonazole, clotrimazole, isoconazole, tioconazole) interfere with fungal oxidative enzymes to cause lethal accumulation of hydrogen peroxide; they also reduce the formation of ergosterol, an important constituent of the fungal cell wall which thus becomes permeable to intracellular constituents. Lack of selectivity in these actions results in important adverse effects.

• Triazoles (fluconazole, itraconazole) damage the fungal cell membrane by inhibiting a demethylase enzyme; they have greater selectivity against fungi, better penetration of the CNS, resistance to degradation and cause less endocrine disturbance than do the imidazoles.

Ketoconazole

Ketoconazole is well absorbed from the gut (poorly where there is gastric hypoacidity, see below); it is widely distributed in tissues but concentrations in CSF and urine are low; its action is terminated by metabolism by cytochrome P450 3A (CYP 3A) (t'/2 8 h). Ketoconazole is effective by mouth for systemic mycoses (see Table 14.2) but has been superseded by fluconazole and itraconazole for many indications largely on grounds of improved pharmacokinetics, unwanted effect profile and efficacy. Impairment of steroid synthesis by ketoconazole has been put to other uses, e.g. inhibition of testosterone synthesis lessens bone pain in patients with advanced androgen-dependent prostatic cancer.

Adverse reactions include nausea, giddiness, headache, pruritus and photophobia. Impairment of testosterone synthesis may cause gynaecomastia and decreased libido in men. Of particular concern is impairment of liver function, ranging from transient elevation of hepatic transaminases and alkaline phosphatase to severe injury and death.

Interactions. Drugs that lower gastric acidity, e.g. antacids, histamine H2 receptor antagonists, impair the absorption of ketoconazole from the gastrointestinal tract. Like all imidazoles, ketoconazole binds strongly to several cytochrome P450 isoenzymes and thus inhibits the metabolism (and increases effects of) oral anticoagulants, phenytoin and cyclosporin, and increases the risk of cardiac arrhythmias with terfenadine. A disulfiram-like reaction occurs with alcohol. Concurrent use of rifampicin, by enzyme induction of CYP 3A, markedly reduces the plasma concentration of ketoconazole.

Miconazole is an alternative. Clotrimazole is an effective topical agent for dermatophyte, yeast, and other fungal infections (intertrigo, athlete's foot, ringworm, pityriasis versicolor, fungal nappy rash).

Econazole and sulconazole are similar. Tioconazole is used for fungal nail infections and isoconazole and fenticonazole for vaginal candidiasis.

Fluconazole

Fluconazole is absorbed from the gastrointestinal tract and is excreted largely unchanged by the kidney (tV2 30 h). It is effective by mouth for oropharyngeal and oesophageal candidiasis, and i.v. for systemic candidiasis and cryptococcosis (including crypto-coccal meningitis; it penetrates the CSF well). It is used prophylactically in a variety of conditions predisposing to systemic Candida infections, including at times of profound neutropenia after bone marrow transplantation, and in patients in Intensive Care Units who have intravenous lines in situ, are receiving antibiotic therapy and have undergone bowel surgery. It may cause gastrointestinal discomfort, headaches, elevation of liver enzymes and allergic rash, but is generally very well tolerated. Animal studies demonstrate embryotoxicity and fluconazole ought not to be given to pregnant women. High doses increase the effects of phenytoin, cyclosporin, zidovudine and warfarin.

Itraconazole

Itraconazole is available for oral and i.v. administration. Absorption from the gut is about 55% and is variable. It is improved by ingestion with food, but decreased by fatty meals and therapies that reduce gastric acidity, and is often reduced in patients with AIDS; to assure adequacy of therapy, serum concentrations should be assayed during prolonged use for critical indications. It is heavily protein bound and virtually none is found within the CSF. Itraconazole is almost completely oxidised by the liver (it is a substrate for CYP 3A), and excreted in the bile; little unchanged drug enters the urine (t1/ 25 h, increasing to 40 h with continuous treatment). Itraconazole is used for a variety of superficial mycoses, as a prophylactic agent for aspergillosis and candidiasis in the immunocompromised, and i.v. for treatment of histoplasmosis. It is licensed in the UK as a second line agent for Candida, Aspergillus and Cryptococcus infections, and it may be convenient as 'follow on' therapy after systemic aspergillosis has been brought under control by an amphotericin preparation. It appears to be an effective adjunct treatment for allergic bronchopulmonary aspergillosis.

Adverse effects are uncommon, but include transient hepatitis and hypokalemia. Prolonged use may lead to cardiac failure, especially in those with preexisting cardiac disease. Co-administration of a calcium channel blocker adds to the risk.

Interactions. Enzyme induction of CYP 3A, e.g. by rifampicin, reduces the plasma concentration of itraconazole. Additionally, its affinity for several P450 isoforms, notably CYP 3A4, causes it to inhibit the oxidation of a number of drugs, including phenytoin, warfarin, cyclosporine, tacrolimus, midazolam, triazolam, cisapride and terfenidine (see above), increasing their intensity and/or duration of effect.

Voriconazole and posaconazole appear to be more active than itraconazole against Aspergillus.

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Responses

  • anya
    Do all azoles cause disulfiram reaction?
    2 years ago

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