Ketoconazole (KTZ)

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Chapter: Essential pharmacology : Antifungal Drugs

It is the first orally effective broad-spectrum antifungal drug, useful in both dermatophytosis and deep mycosis. The oral absorption of KTZ is facilitated by gastric acidity because it is more soluble at lower pH.


KETOCONAZOLE (KTZ)

 

It is the first orally effective broad-spectrum antifungal drug, useful in both dermatophytosis and deep mycosis. The oral absorption of KTZ is facilitated by gastric acidity because it is more soluble at lower pH. Hepatic metabolism is extensive; metabolites are excreted in urine and faeces. Elimination of KTZ is dose dependent: t½ varies from 1½ to 6 hours. Penetration in CSF is poor: not effective in fungal meningitis. However, therapeutic concentrations are attained in the skin and vaginal fluid.

 

In spite of relatively short t½, a single daily dose is satisfactory in less severe cases. The usual dose is 200 mg OD or BD; higher doses are sometimes required.

 

FUNGICIDE, NIZRAL, FUNAZOLE, KETOVATE 200 mg tab.

 

FUNGINOC 2% oint, 2% shampoo (for dandruff), KETOVATE 2% cream. NIZRAL 2% cream, 2% lotion; DANRUF 2% shampoo, HYPHORAL 2% lotion.

 

Adverse Effects

 

Ketoconazole is much less toxic than AMB, but more side effects occur than with itraconazole or fluconazole, that have largely replaced it for systemic use.

 

The most common side effects are nausea and vomiting; can be reduced by giving the drug with meals. Others are—loss of appetite, headache, paresthesia, rashes and hair loss.

 

Ketoconazole decreases androgen production from testes, and it displaces testosterone from protein binding sites. Gynaecomastia, loss of hair and libido, and oligozoospermia may be the manifestations. Menstrual irregularities occur in some women due to suppression of estradiol synthesis.

 

A dose-dependent decrease in serum hydrocortisone due to synthesis inhibition has also been noted, but without any clinical manifestations in normal individuals.

 

Mild and asymptomatic elevation of serum transaminases occurs in ~5% patients, but serious hepatotoxicity is infrequent.

 

It is contraindicated in pregnant and nursing women.

 

Interactions

 

H2 blockers, proton pump inhibitors and antacids decrease the oral absorption of KTZ by reducing gastric acidity.

 

Rifampin, phenobarbitone, carbamazepine and phenytoin induce KTZ metabolism and reduce its efficacy.

 

Ketoconazole inhibits cytochrome P450, especially CYP3A4, and raises the blood levels of several drugs including:

 

Phenytoin      

Digoxin

Diazepam      

Cyclosporine

Haloperidol   

Nifedipine and other DHPs

Warfarin       

HIV protease inhibitors

Sulfonylureas 

Statin hypolipidaemics

 

The dangerous interaction with terfenadine, astemizole and cisapride resulting in polymorphic ventricular tachycardia due to excessive rise in plasma levels of these drugs has resulted in withdrawal of these drugs from the market in many countries.

 

Use

 

Orally administered KTZ is effective in dermatophytosis because it is concentrated in the stratum corneum; is an alternative to griseofulvin, but use is restricted due to potential adverse effects.

 

Though effective in monilial vaginitis, oral therapy (for 5–7 days) with KTZ is reserved for recurrent cases or those not responding to topical agents.

 

Systemic Mycosis: Administered orally, KTZ is effective in several types of systemic mycosis, but itraconazole and fluconazole, being more active with fewer side effects, have largely replaced it for these indications except for considerations of cost.

 

KTZ is occasionally used in dermal leishmaniasis and kala azar.

 

Highdose KTZ has been used in Cushing’s syndrome to decrease corticosteroid production.

 

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