Mechanism of action
According to the chemical structure of its heterocycle, the drug belongs to triazoles (contains a five-membered ring with three nitrogen atoms).
The mechanism of action is based on high selectivity for the fungal enzyme 14$\alpha$-demethylase. The key pharmacodynamic advantage of fluconazole over imidazole derivatives (e.g., ketoconazole) is its selectivity: the drug practically does not block human 17,20-desmolase. Due to this, it does not disrupt the synthesis of endogenous sex hormones and glucocorticoids.
Pharmacokinetics
Fluconazole is a hydrophilic compound. It is administered orally and intravenously.
- Absorption: When taken orally, it is absorbed excellently, with bioavailability reaching approximately 100%. A critical difference from ketoconazole and itraconazole is that fluconazole absorption does not depend on gastric juice pH.
- Distribution: The drug freely penetrates all body fluids. It is detected in therapeutic concentrations in sputum, urine, saliva, and, most importantly clinically, in cerebrospinal fluid (CSF).
- Elimination: Excreted primarily by the kidneys.
Indications for use
Fluconazole is used to treat systemic mycoses and dermatophytoses. It is the drug of choice for:
- Systemic candidiasis;
- Cryptococcal meningitis;
- Coccidioidal meningitis.
Note: The use of fluconazole in meningitis avoids intrathecal administration of amphotericin B, which is associated with severe complications.
Also, the drug is used as part of the etiotropic therapy for dysbiosis. Broad-spectrum antibiotics kill the beneficial microflora of the mucous membranes, local immunity decreases, and opportunistic fungi of the genus Candida begin to proliferate actively. Fluconazole is prescribed to suppress this process.
Spectrum limitations:
- Absolutely ineffective against aspergillosis.
- Less effective than itraconazole in treating blastomycosis, histoplasmosis, and sporotrichosis.
Side effects and interactions
The drug has a low toxicity profile, which accounts for its widespread use (despite the cost).
- Common reactions (about 10%): gastrointestinal disorders (nausea, vomiting, abdominal pain, diarrhea).
- With prolonged therapy: reversible alopecia (hair loss) is possible.
- Rare but severe complications: Stevens-Johnson syndrome, liver failure.
Drug interactions: It should be noted that simultaneous intake of barbiturates decreases fluconazole concentration in the blood.
Dosage forms and prescription
According to the prescription reference guide, the drug is available in the following forms:
- Capsules 0.05, 0.1, 0.15, and 0.2 g;
- 0.5% syrup;
- 0.2% intravenous solution.
Dosage for oral and intravenous administration ranges from 0.05 to 0.4 g.
Prescription example (150 mg capsules for candidiasis): Rp.: Caps. Fluconazoli 0.15 D.t.d. N. 1 S. Take orally 1 capsule once.
Briefly: answers to topical questions
What drugs does fluconazole have clinically significant interactions with?
Fluconazole interacts with a number of medications.
- Amitriptyline, cyclosporine, phenytoin, warfarin — fluconazole increases their concentration.
- Barbiturates, carbamazepine, isoniazid — decrease fluconazole concentration.
How does fluconazole affect human cytochrome P450 enzymes?
Fluconazole has a lesser effect on similar human cytochrome P450 enzymes compared to other azoles. Triazoles have higher selectivity for fungal 14α-demethylase and practically do not block human 17,20-desmolase, therefore they do not disrupt the synthesis of sex hormones and glucocorticoids.
What are the contraindications for fluconazole use?
Fluconazole is contraindicated during pregnancy, especially in the 1st trimester, due to the risk of teratogenic effects. In early pregnancy, there is evidence of a risk of limb defects in the fetus.
Fluconazole — "Fluorine, Triazole, Liquor". Three letters remind us of the structure (2 fluorine atoms, 3 nitrogen atoms in the ring) and the main clinical advantage: free penetration into the cerebrospinal fluid.
Class and exam questions
Why is fluconazole safer for the endocrine system than ketoconazole?
Fluconazole has high selectivity for fungal 14α-demethylase and practically does not block human 17,20-desmolase. Therefore, it does not suppress the synthesis of steroid hormones (sex hormones and glucocorticoids).
Does fluconazole bioavailability depend on stomach acidity?
No. Unlike itraconazole and ketoconazole, fluconazole absorption does not depend on gastric juice pH, making its uptake more predictable.
Can fluconazole be used to treat aspergillosis?
No, the drug is ineffective against fungi of the genus Aspergillus. In such cases, other antimycotics are required (e.g., itraconazole).
What is the role of fluconazole in the treatment of fungal meningitis?
Due to its hydrophilicity and ability to freely penetrate the CSF, it is the drug of choice in cryptococcal and coccidioidal meningitis, replacing the difficult intrathecal administration of amphotericin B.
What else to study on this topic
- Comparative characteristics of triazole and imidazole derivatives
- Itraconazole pharmacokinetics: lipophilicity and pH dependence
- Pathogenesis of dysbiosis during antibiotic therapy and methods of its correction
- Lipid formulations of amphotericin B: mechanism of nephrotoxicity reduction
- Mechanism of action of flucytosine (conversion to 5-fluorouracil)
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