Makindo Medical Notes

💊 Key Point: Ritonavir is both an antiretroviral protease inhibitor (PI) and a powerful CYP3A4 enzyme inhibitor used to “boost” the plasma levels of other PIs. ⚠️ It has a complex interaction profile — always review the BNF and HIV drug interaction databases before prescribing.

🧠 About

• Ritonavir was one of the first HIV protease inhibitors but is now primarily used as a pharmacokinetic enhancer rather than for direct antiviral effect.
• By potently inhibiting hepatic and intestinal cytochrome P450 3A4 (CYP3A4) and P-glycoprotein, it increases exposure to co-administered PIs such as lopinavir, darunavir, and atazanavir.
• It remains essential in many modern ART combinations (e.g. lopinavir/ritonavir [Kaletra®]).

⚙️ Mode of Action

• As a protease inhibitor, ritonavir blocks the HIV-1 protease enzyme, preventing cleavage of Gag-Pol polyproteins into mature, functional viral components. This produces immature, non-infectious viral particles.
• At lower “booster” doses, its principal role is CYP3A4 and CYP2D6 inhibition — slowing metabolism of other drugs and increasing their plasma concentration and half-life.
• This allows reduced dosing frequency and improved therapeutic levels of co-administered protease inhibitors.

💊 Indications & Dosing

• HIV-1 infection: Used primarily as a pharmacokinetic booster for other PIs (e.g. lopinavir, atazanavir, darunavir).
• Dosing varies according to regimen:
  • Boosting dose: typically 100–200 mg once or twice daily.
  • Full antiretroviral dose: 600 mg twice daily (rarely used now due to poor tolerability).
• Take with food to improve absorption and reduce gastrointestinal side effects.

⚠️ Interactions

• Potent inhibitor of CYP3A4, CYP2D6, and P-glycoprotein → can increase plasma concentrations of many drugs (and toxicities).
• Also a mild inducer of CYP1A2 and glucuronidation enzymes, causing variable effects.
• Common drug classes affected: benzodiazepines, statins, antiarrhythmics, corticosteroids, anticonvulsants, and anticoagulants.
• Simvastatin, lovastatin, and amiodarone are contraindicated due to risk of life-threatening toxicity.
• Always check interactions using a specialist database (e.g. Liverpool HIV Drug Interactions).

⚕️ Cautions

• Monitor for metabolic effects (dyslipidaemia, insulin resistance).
• Use with caution in hepatic impairment — metabolism is hepatic, and accumulation may occur.
• Polypharmacy: due to its wide interaction potential, review all concurrent medications carefully (especially in older or co-morbid patients).
• Monitor LFTs and fasting lipids during prolonged use.

🚫 Contraindications

• Severe hepatic impairment.
• Concurrent use with drugs highly dependent on CYP3A4 for clearance and with narrow therapeutic indices (e.g. simvastatin, pimozide, amiodarone, ergot derivatives).
• Known hypersensitivity to ritonavir or formulation components.

💥 Side Effects

• Common: Nausea, vomiting, diarrhoea, abdominal discomfort, fatigue, taste disturbance.
• Metabolic: Hyperlipidaemia, hyperglycaemia, insulin resistance, lipodystrophy.
• Neurological: Paraesthesia (perioral or extremity), headache, dizziness.
• Hepatic: Transaminase elevation or hepatitis (especially with pre-existing liver disease).

📖 Educational Summary

Ritonavir revolutionised HIV therapy not just as an antiviral, but as a pharmacological booster — allowing lower, more effective dosing of other protease inhibitors. Its mechanism illustrates how drug–drug interactions can be harnessed therapeutically rather than avoided. The key teaching principle is that ritonavir’s enzyme inhibition forms the pharmacokinetic basis of most PI-based ART regimens. However, because this same mechanism affects hundreds of non-ART drugs, it remains a major source of clinically significant interactions — a central concept in safe HIV pharmacotherapy.

📚 References

• Ritonavir – British National Formulary
• BHIVA Guidelines for HIV-1 Treatment (2023)
• European AIDS Clinical Society (EACS) Guidelines, 2023
• Harrison’s Principles of Internal Medicine, 21st Edition – HIV Pharmacology