Usage
Itraconazole is prescribed for the treatment of various fungal infections. These include:
- Systemic mycoses: Such as aspergillosis, blastomycosis, histoplasmosis, sporotrichosis, and onychomycosis.
- Superficial mycoses: Like dermatophytosis, oral and vaginal candidiasis.
Pharmacological Classification: Antifungal agent (Triazole)
Mechanism of Action: Itraconazole inhibits the synthesis of ergosterol, a crucial component of fungal cell membranes, by inhibiting the enzyme lanosterol 14α-demethylase, a cytochrome P450 enzyme. This disruption in ergosterol synthesis leads to altered membrane permeability and ultimately fungal cell death.
Alternate Names
Itraconazole is the generic name.
Brand Names: Sporanox®, Onmel™, Tolsura®
How It Works
Pharmacodynamics: Itraconazole exerts its antifungal effect by inhibiting ergosterol synthesis, which is essential for maintaining the integrity of the fungal cell membrane. This leads to increased membrane permeability and ultimately fungal cell death.
Pharmacokinetics:
- Absorption: Oral absorption is enhanced by an acidic environment and is improved when taken with food. The oral solution has better bioavailability than the capsule formulation.
- Distribution: Itraconazole is highly lipophilic and distributes widely throughout the body, reaching high concentrations in tissues such as the skin, nails, and lungs. It penetrates poorly into the cerebrospinal fluid.
- Metabolism: Extensive hepatic metabolism via the cytochrome P450 3A4 (CYP3A4) enzyme system. Itraconazole and its major metabolite, hydroxyitraconazole, both contribute to the antifungal activity.
- Elimination: Primarily eliminated via the biliary route in feces, with a small amount excreted in the urine. The elimination half-life varies depending on the dose and duration of therapy.
Mode of Action: Itraconazole binds to the fungal cytochrome P450 enzyme lanosterol 14α-demethylase, inhibiting the conversion of lanosterol to ergosterol. This ultimately leads to fungal cell death.
Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Itraconazole inhibits the fungal enzyme lanosterol 14α-demethylase.
Elimination Pathways: Predominantly hepatic metabolism and biliary excretion with a small portion renally excreted.
Dosage
Standard Dosage
Adults:
The dosage and duration of treatment vary based on the indication. Common regimens include:
- 200 mg once or twice daily.
- For some infections, a loading dose of 200 mg three times daily for three days may be given.
- The maximum dose is generally 400 mg daily.
Children:
Dosing in children is typically based on body weight (3-5 mg/kg/day divided into two doses) and tailored to the specific fungal infection being treated. The oral solution is often preferred in pediatric patients.
Special Cases:
- Elderly Patients: Dose adjustments are usually not necessary, but close monitoring for adverse events is advisable.
- Patients with Renal Impairment: Dose reductions are generally not required, but monitoring is recommended.
- Patients with Hepatic Dysfunction: Dose adjustments may be required and close monitoring is essential.
- Patients with Comorbid Conditions: Careful assessment and potential dose adjustments are necessary for patients with conditions such as congestive heart failure and other relevant conditions.
Clinical Use Cases
The dosage of itraconazole does not vary with intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. However, patients in these settings might require closer monitoring for drug interactions and adverse events.
Dosage Adjustments
Dose adjustments may be required in individuals with hepatic or renal impairment, or those taking medications that interact with itraconazole.
Side Effects
Common Side Effects:
- Nausea, vomiting, diarrhea, constipation
- Headache, dizziness
- Rash, pruritus
- Elevated liver enzymes
- Edema
- Hypokalemia
Rare but Serious Side Effects:
- Severe hepatotoxicity
- Congestive heart failure
- Stevens-Johnson syndrome
- Toxic epidermal necrolysis
- QT prolongation
- Ventricular tachyarrhythmias
Long-Term Effects: Prolonged use can lead to chronic liver disease.
Adverse Drug Reactions (ADR): The most serious ADRs include hepatotoxicity, heart failure and QT interval prolongation.
Contraindications
- Hypersensitivity to itraconazole
- Concurrent use with certain drugs metabolized by CYP3A4 (e.g., cisapride, terfenadine, pimozide)
- Congestive heart failure (for onychomycosis treatment)
- Pregnancy (except in life-threatening situations)
Drug Interactions
Itraconazole is primarily metabolized by CYP3A4 and can interact with numerous medications, including:
- CYP3A4 inhibitors: These drugs increase the plasma concentration of itraconazole, potentially leading to toxicity. Examples include erythromycin, clarithromycin, ketoconazole, and ritonavir.
- CYP3A4 inducers: These drugs decrease the plasma concentration of itraconazole, potentially reducing its efficacy. Examples include rifampin, phenytoin, and carbamazepine.
- Other interactions: Itraconazole can also interact with drugs like warfarin, digoxin, calcium channel blockers, statins, and certain antacids.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: C (Risk cannot be ruled out. Animal studies have shown adverse effects on the fetus.)
- Fetal Risks: Potential for teratogenic effects, especially in the first trimester.
- Breastfeeding: Itraconazole is excreted in breast milk. Breastfeeding is generally not recommended while taking itraconazole.
Drug Profile Summary
- Mechanism of Action: Inhibits fungal ergosterol synthesis.
- Side Effects: Nausea, vomiting, headache, rash, hepatotoxicity, heart failure (rare).
- Contraindications: Hypersensitivity, concurrent use of certain CYP3A4 substrates, congestive heart failure (in onychomycosis), pregnancy.
- Drug Interactions: Numerous drug interactions, particularly with CYP3A4 inhibitors and inducers.
- Pregnancy & Breastfeeding: Avoid during pregnancy unless benefits outweigh risks; not recommended during breastfeeding.
- Dosage: Varies depending on indication; typically 200-400 mg daily for adults.
- Monitoring Parameters: Liver function tests, potassium levels, ECG (in patients at risk for QT prolongation).
Popular Combinations
Itraconazole is not typically used in combination with other antifungals for the same infection. However, it may be used in combination with other medications for different conditions.
Precautions
- General Precautions: Monitor for hepatotoxicity and cardiac events.
- Specific Populations: Use with caution in patients with hepatic or renal impairment, pregnancy, and breastfeeding.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Itraconazole?
A: The dosage varies depending on the indication. For adults, the usual dose is 200 mg once or twice daily. For children, it’s 3-5 mg/kg/day, divided into two doses. Higher doses or loading doses may be necessary for some infections.
Q2: What are the common side effects of Itraconazole?
A: Common side effects include nausea, vomiting, diarrhea, headache, and rash.
Q3: Is Itraconazole safe during pregnancy?
A: Itraconazole should be avoided during pregnancy unless the potential benefits outweigh the risks to the fetus.
Q4: Can Itraconazole be used in patients with liver disease?
A: Itraconazole should be used with caution in patients with liver disease, and dose adjustments or close monitoring may be necessary.
Q5: What are the serious side effects of Itraconazole?
A: Rare but serious side effects can include severe liver damage, heart failure, and severe allergic reactions.
Q6: Does Itraconazole interact with other medications?
A: Yes, Itraconazole can interact with many other medications, particularly those metabolized by the CYP3A4 enzyme system.
Q7: What should I monitor in patients taking Itraconazole?
A: Liver function tests, potassium levels, and ECG (in patients at risk for QT prolongation) should be monitored periodically.
Q8: What is the difference between Itraconazole capsules and oral solution?
A: The oral solution generally has better bioavailability than the capsules. The oral solution is also preferred in pediatric patients.
Q9: How long does it take for Itraconazole to reach steady state?
A: It generally takes about 7 to 14 days to reach steady-state concentrations.
