Itraconazole
Mechanism of Action
Generic Name
Mechanism of Action
Mechanism
* Inhibits ergosterol synthesis – competitively blocks the lanosterol 14‑α‑demethylase (CYP51) enzyme.
* Accumulates toxic sterol intermediates → disruption of fungal cell‑membrane integrity.
* Broad‑spectrum activity against dermatophytes, yeasts (e.g., *Candida* spp.), molds (e.g., *Aspergillus* spp.), and *Blastomyces*.
Pharmacokinetics
* Formulations: capsules (standard, oral solution), topical cream, transdermal patch.
* Absorption: highly variable; food (especially high‑fat meals) enhances uptake by 4‑fold.
* Bioavailability: ~60 % with food; poor when taken on an empty stomach.
* Distribution: extensive lymphatic spread; high protein binding (~96 %) → rich skin and lung tissue levels.
* Metabolism: primarily CYP3A4 → first‑pass hepatic metabolism.
* Excretion: mainly fecal (biliary), minor renal elimination (~8 %).
* Half‑life: 10–40 h (depends on formulation and food effects).
* Drug interactions: potent CYP3A4 inhibitor → ↑ serum levels of many agents (e.g., opioids, benzodiazepines); concurrent use with strong CYP3A4 inducers (rifampin, carbamazepine) reduces plasma concentration.
* Special populations:
* Pregnancy Category D – avoid unless benefits outweigh risks.
* Breast‑feeding: detected in milk → caution.
Indications
| Condition | Typical regimen |
| *Aspergillus* (e.g., invasive aspergillosis) | 200 mg PO BID for 2 weeks, then 200 mg PO QD |
| *Blastomycosis* | 200 mg QD for 6–12 weeks |
| *Histoplasmosis* | 200 mg QD; 14–16 weeks (intracavitary disease) |
| *Dermatophyte* infections (tinea corporis, cruris, etc.) | 200 mg PO QD, 3–6 weeks |
| *Cryptococcosis* (complications) | Adjunct with amphotericin B in refractory cases |
| *Onychomycosis* (onychomycosis) | 200 mg daily, 3–6 months |
| *Vulvovaginal candidiasis* (topical) | 200 mg topical cream QD x4 weeks |
Contraindications
* Hay fever (allergic to triazole) → severe hypersensitivity.
* Severe hepatic impairment (Child‑Pugh C); monitor liver enzymes.
* Conduction disorders (QRS >120 ms, prolonged PR, QTc >500 ms) → risk of ventricular arrhythmia.
* Concurrent use of >3 mg of oral corticosteroids → steroid-induced complications.
* Pregnancy & lactation → Category D – avoid if possible.
* Drug‑drug interactions: Avoid with strong CYP3A4 inducers; begin dose‑adjusted therapy with strong CYP3A4 inhibitors; caution with antiarrhythmics, warfarin, and non‑steroidal anti‑inflammatory drugs.
Dosing
* Capsule – give with a full meal; avoid grapefruit juice or other CYP3A4 inhibitors.
* Oral solution – same as capsules; can be given on an empty stomach but with a low‑fat snack.
* Transdermal patch – for adjunctive therapy in refractory onychomycosis; apply to clean, skin‑dry area, change weekly.
* Duration: 2–6 weeks; extend for systemic fungal infections ‑ 3–12 months, per guidelines.
Adverse Effects
| Category | Examples |
| Gastrointestinal | Nausea, vomiting, abdominal pain, dyspepsia, diarrhea |
| Hepatic | Elevated ALT/AST, cholestatic jaundice; monitoring every 2–3 weeks |
| Cardiac | QT prolongation, torsades de pointes (rare) → monitor ECG in high‑risk patients |
| Allergic | Rash, pruritus, urticaria; severe hypersensitivity reactions (rare) |
| Dermatologic | Phototoxicity – avoid excessive sun exposure when on oral solution |
| Other | Hyperbilirubinemia, taste disturbances, hair loss (rare) |
Monitoring
* Baseline: CBC, CMP (LFTs), renal panel, fasting lipid panel.
* LFTs: Every 2–3 weeks during first 3 months; thereafter every 3 months.
* ECG: Prior to initiation if QRS >120 ms or QTc >500 ms; repeat if arrhythmia suspected.
* Drug levels: Optional if therapeutic failure or toxicity; trough >1 µg/mL considered adequate for systemic infections.
* Pregnancy status: Confirm pregnancy before starting; double‑check at each visit.
Clinical Pearls
* Food is your friend – give *Itraconazole* with a high‑fat meal or molasses‑based drink to push absorption up to 4‑fold.
* Avoid grapefruit – strong CYP3A4 inhibitor that can dramatically raise levels, predisposing to hepatotoxicity and arrhythmias.
* Patch‑work therapy – the transdermal patch is a useful adjunct for recalcitrant onychomycosis; absorption bypasses the GI tract, reducing systemic exposure.
* QTc rule – any patient with a pre‑existing QTc >450 ms should get an ECG before starting; consider dose reduction or alternative if >500 ms.
* Drug‑drug dance – never pair *Itraconazole* with strong CYP3A4 inducers (rifampin, carbamazepine) unless doses are drastically reduced; monitor trough levels if unavoidable.
* Liver‑watch – children and patients with mild liver disease tolerate *Itraconazole* well; for severe hepatic disease, consider oral 5‑azacytidine or others.
* Oral solution convenience – for patients with dysphagia or vomiting, the liquid formulation offers improved compliance but may require carbonation-free drinks; the “dry‑spray” formulation mitigates dosage errors.
> _Tip for students_: Remember that *Itraconazole* is the only triazole with a *transdermal patch* and *oral solution* that have unique pharmacokinetics – leverage this knowledge when designing multi‑drug regimens in fungal infections.