NAZOLE CREAM

Indications

• Endogenous Cushing's syndrome
• Cushing's disease
• Topical treatment of fungal infections (limited to specific formulations)

Dosage

Children: For paediatric dosing, refer to the BNF for Children

Adults: For Cushing's syndrome, the maximum dose is 200 mg daily with concurrent use of cobicistat-boosted regimens. The dosing should be adjusted based on patient response and liver enzyme levels.

Mechanism of action

Ketoconazole interacts with 14-alpha-sterol demethylase, a cytochrome P-450 enzyme essential for converting lanosterol to ergosterol. This inhibition results in reduced ergosterol levels in the fungal cell membrane, compromising its integrity and function. The metabolic blockage also leads to the accumulation of toxic sterol precursors, which further disrupt cellular processes. Ketoconazole's fungistatic properties prevent the growth and spread of fungal cells by altering cellular membranes and increasing membrane permeability.

Pharmacodynamics

As a fungistatic agent, ketoconazole halts growth in fungal cells, preventing their proliferation. It primarily targets the ergosterol biosynthesis pathway, which is crucial for maintaining fungal cell membrane integrity. This mechanism leads to increased membrane fluidity, impairing membrane-bound enzyme systems and resulting in growth inhibition of fungal pathogens.

Pharmacokinetics

Ketoconazole is well absorbed when taken orally, but its absorption can be affected by gastric pH. It undergoes extensive hepatic metabolism, primarily via cytochrome P450 enzymes, leading to various metabolites. The drug has a half-life of approximately 2-8 hours, but this can vary based on dose and individual metabolism. Ketoconazole is excreted mainly through the feces, with some renal excretion of unchanged drug.

Contra-indications

• Acquired QTc prolongation
• Acute porphyrias
• Congenital QTc prolongation
• Cushing's syndrome

Adverse effects

• Dizziness
• Flushing
• Hyperglycaemia
• Diarrhoea
• Gastrointestinal discomfort
• Nausea
• Vomiting
• Skin reactions
• Allergic conditions
• Alopecia
• Angioedema
• Asthenia
• Drowsiness
• Headache
• Thrombocytopenia
• Fever
• Hepatic disorders
• Taste alteration
• Appetite abnormality
• Arthralgia
• Dry mouth
• Epistaxis
• Flatulence
• Fontanelle bulging
• Gynaecomastia
• Hot flush
• Insomnia
• Increased intracranial pressure
• Malaise
• Myalgia
• Nervousness
• Papilloedema
• Paraesthesia
• Peripheral oedema
• Photophobia
• Photosensitivity reaction
• Tongue discolouration

Interactions

• Severe: phenobarbital decreases ketoconazole concentration
• Severe: primidone decreases ketoconazole concentration
• Severe: rifamycins increase ketoconazole concentration
• Severe: rifabutin increases ketoconazole concentration
• Severe: nevirapine decreases ketoconazole exposure
• Severe: rifampicin decreases ketoconazole exposure
• Moderate: anti-androgens increase ketoconazole exposure
• Moderate: darolutamide increases ketoconazole exposure
• Moderate: coumarins increase anticoagulant effect
• Moderate: warfarin increases anticoagulant effect

Precautions

• High dosage may cause proximal myopathy
• Avoid in chronic therapy
• Pre-treatment liver enzymes should not exceed 2 times the normal upper limit
• Risk of adrenal insufficiency

Pregnancy

Manufacturer advises avoid-teratogenic in animal

Mechanism of action

Ketoconazole interacts with 14-α-sterol demethylase, a cytochrome P-450 enzyme necessary for the conversion of lanosterol to ergosterol. This results in inhibition of ergosterol synthesis and increased fungal cellular permeability due to reduced amounts of ergosterol present in the fungal cell membrane. This metabolic inhibition also results in accumulation of 14α-methyl-3,6-diol, a toxic metabolite. The increase in membrane fluidity is also thought to produce impairment of membrane-bound enzyme systems as components become less closely packed. Ketoconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14alpha-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. This results in an accumulation of methylated sterol precursors and a depletion of ergosterol within the cell membrane thus weakening the structure and function of the fungal cell membrane. Like other azole antifungal agents, ketoconazole presumably exerts its antifungal activity by altering cellular membranes, resulting in increased membrane permeability, secondary metabolic effects, and growth inhibition. Although the exact mechanism of action of ketoconazole has not been fully determined, it has been suggested that the fungistatic activity of the drug may result from interference with ergosterol synthesis, probably via inhibition of C-14 demethylation of sterol intermediates (e.g., lanosterol). The fungicidal activity of ketoconazole at high concentrations may result from a direct physiochemical effect of the drug on the fungal cell membrane.

Pharmacodynamics

Ketoconazole, similarly to other azole antifungals, is a fungistatic agent which causes growth arrest in fungal cells thereby preventing growth and spread of the fungus throughout the body.