EpistemisAntifungals: Terbinafine, Itraconazole and Fluconazole
Common trade names: Lamisil, Terbinafine MK (Terbinafine); Sporanox, Itraconazole Genfar (Itraconazole); Diflucan, Fluconazole Normon (Fluconazole).
Mechanism
Pharmacological Class and Group
Antifungals for systemic and topical use belonging to the class of Allylamines (Terbinafine) and Triazoles (Itraconazole and Fluconazole).
Mechanism of Action
Both classes act by selectively interfering with the biosynthesis pathway of ergosterol, an essential lipid component to maintain the fluidity, integrity and protective function of the fungal cell membrane.
Inhibition of Ergosterol Biosynthesis: Squalene Epoxidase vs. 14-α-Demethylase
1. Mechanism of Allylamines (Terbinafine): Selectively inhibits the transmembrane fungal enzyme Squalene Epoxidase in the initial step of the pathway. This stops the conversion of squalene to lanosterol:
Terbinafine Squalene Epoxidase ↓ Ergosterol and ↑ Intracellular Squalene (Toxic)
The massive intracellular accumulation of free squalene in a non-esterified form generates deposits of abnormal lipid droplets, altering the permeability of the membrane and causing cell rupture of the fungus (rapid fungicidal effect, ideal for dermatophytes).
2. Mechanism of Azoles (Itraconazole, Fluconazole): They competitively inhibit the fungal cytochrome P450 enzyme Lanosterol 14-α-demethylase (fungal CYP51). This stops the demethylation of lanosterol to ergosterol, altering the structural functionality of membrane enzymes and blocking hyphal growth (broad fungistatic effect, ideal for yeast).
Pharmacokinetics
High Resolution Pharmacokinetics
- Absorption: Terbinafine has oral absorption greater than 70%. Itraconazole strictly requires an acidic gastric environment for its optimal dissolution (administration with cola drinks improves its absorption in hypochlorhydric patients). Fluconazole has an excellent absorption of 90% independent of gastric acidity or food intake.
- Distribution and Keratinophilia: Terbinafine and Itraconazole are extremely lipophilic and exhibit an extraordinary affinity for keratin (keratinophilia). They actively concentrate in the stratum corneum of the skin, hair and nail bed in concentrations up to 100 times higher than plasma concentrations, persisting in the nail for more than 6 months after stopping the drug. Fluconazole is more hydrophilic and distributes well into body fluids, including vaginal secretions and saliva.
- Metabolism: Terbinafine is metabolized by mixed hepatic biotransformation mediated (CYP2C9, CYP1A2, CYP3A4, CYP2C19). Itraconazole is a CYP3A4 substrate. Fluconazole is barely metabolized (less than 11%).
- Excretion: Terbinafine and Itraconazole are eliminated through bile and feces in an inactive manner. Fluconazole is predominantly excreted via the kidneys in unchanged form (80%).
Indicators and dose
Clinical Indications and Off-Label Uses
- Dermatophytosis (Tinea Capitis, Tinea Corpus, Tinea Cruris and Tinea Pedis): Systemic treatment of choice (oral Terbinafine) when the extent of the lesions precludes topical control.
- Onychomycosis (Dermatophytic): First-line therapy (Terbinafine orally for 12 weeks for toenails).
- Pityriasis Versicolor and Recurrent Cutaneous Candidiasis: Oral Itraconazole or Fluconazole when shampoo or local cream regimens fail.
- Cutaneous Sporotrichosis (off-label / CDC guideline): Itraconazole is the first therapeutic line of choice for cutaneous or lymphocutaneous forms.
Dosage and Clinical Adjustment
Terbinafine (Onychomycosis):
- Standard Dose: 250 mg orally once a day, with or without food.
- Treatment Duration: 6 weeks for fingernails; 12 continuous weeks for toenails.
Itraconazole (Pulse Scheme for Onychomycosis):
- Pulse Scheme: 200 mg orally twice daily (total 400 mg daily) administered for one full week, followed by a 3-week period of complete rest without medication. One pulse is performed for hands and 3 to 4 consecutive monthly pulses for toenails. Mandatory to eat with fatty foods.
Fluconazole (Ringworms of the body / Candidiasis):
- 150 mg orally once a week for a period of 2 to 4 weeks.
Adjustment in Kidney Failure:
- Terbinafine: Its use is not recommended if creatinine clearance is < 50 mL/min due to lack of robust clinical experience.
- Fluconazole: Reduce the dose by 50% after the initial loading dose if creatinine clearance is below 50 mL/min.
Security
Absolute and Relative Contraindications
Absolute Contraindications
- Hypersensitivity to the active ingredient or related azoles.
- Active liver disease or decompensated liver cirrhosis (for terbinafine and itraconazole).
- Concomitant use of Itraconazole with drugs metabolized by CYP3A4 that prolong the cardiac QTc interval.
- Congestive heart failure with reduced ejection fraction (for Itraconazole, due to demonstrated negative inotropic effect).
Relative Contraindications
- Moderate renal impairment (dose adjustment required for fluconazole).
- Severe renal dysfunction (for terbinafine, avoid if clearance is < 50 mL/min due to lack of studies).
Adverse Effects (ADR) and Specific Toxicity
- Frequent (1%-10%): Gastric dyspepsia, mild nonspecific abdominal pain, watery diarrhea, headache, transient skin rash, asymptomatic elevation of transaminases.
- Uncommon (0.1%-1%): Taste disorders (ageusia or dysgeusia reversible within weeks after the use of terbinafine), moderate hypokalemia due to itraconazole.
- Rare (<0.1%): Fulminant necrotizing hepatitis of idiosyncratic course (associated with the use of systemic terbinafine or itraconazole), severe neutropenia, Stevens-Johnson syndrome induced by azoles.
Critical Toxicity: Liver Monitoring in Onychomycosis Treatment
Although severe hepatotoxicity from oral terbinafine is rare (1 case per 45,000-120,000 exposed patients), prolonged administration for 12 weeks for onychomycosis requires systematic preventive analytical monitoring. The baseline value of liver transaminases (AST and ALT) should be determined before prescribing oral terbinafine and repeat the analytical determination after 4-6 weeks of treatment.
Elevation of Transaminases > 2-3x ULN Immediate suspension of Terbinafine
The patient should be warned that, if he or she presents symptoms suggestive of liver dysfunction (unexplained persistent nausea, extreme asthenia, conjunctival jaundice, tea-colored choluric urine, or oppressive pain in the right upper quadrant), he or she should immediately stop the medication and seek evaluation.
Drug Interactions of Clinical Relevance
- Itraconazole (Potent CYP3A4 inhibitor): Doubles or triples the plasma levels of statins (atorvastatin, simvastatin), benzodiazepines, calcium channel blockers and oral anticoagulants. Its coadministration with quinidine or pimozide can induce lethal ventricular arrhythmias (torsade de pointes).
- Fluconazole (CYP2C9 inhibitor): Dangerously elevates systemic levels of Warfarin (significantly prolonging the INR with risk of bleeding) and Sulfonylureas (causing profound hypoglycemia).
- Antacids and Proton Pump Inhibitors (Omeprazole): They raise gastric pH, almost completely canceling the intestinal absorption of itraconazole.
Safety in Pregnancy and Breastfeeding
- Pregnancy: Not recommended. There is a lack of controlled studies in pregnant women for topical or systemic terbinafine. Continuous high-dose systemic fluconazole use in the first trimester has been associated with specific congenital craniofacial anomalies. Prefer topical antifungals (Ciclopiroxolamine or local Clotrimazole).
- Breastfeeding: Contraindicated. They are actively excreted in breast milk in high concentrations due to their lipophilic nature (terbinafine), which is why it is strongly discouraged.
Epistemis is educational review material. It is not a medical device, does not diagnose or prescribe treatment, and does not replace formal medical training, current clinical guidelines, or professional clinical judgment.
- System
- Dermatology
- Cluster
- Therapeutics in Cutaneous Mycoses and Onychomycosis