GI Pharmacology · Module 6 of 8

Liver Part 1: Viral Hepatitis and Acute Liver Failure

Nucleos(t)ide analogues for hepatitis B · Direct-acting antivirals for hepatitis C · Hepatitis D management · N-acetylcysteine and acute liver failure

HBV NAs act as chain terminators incorporated by viral reverse transcriptase/DNA polymerase; first-line agents are entecavir and tenofovir disoproxil fumarate (TDF); entecavir has a high resistance barrier in treatment-naive patients (requires 3 simultaneous mutations) but loses efficacy in lamivudine-experienced patients; TDF has no documented resistance and is preferred after lamivudine failure; tenofovir alafenamide (TAF) delivers higher intrahepatic drug at lower plasma dose → less nephrotoxicity and bone density loss → preferred in renal impairment or osteoporosis risk; older agents (lamivudine, adefovir) not first-line due to low resistance barriers; goal of therapy: HBV DNA below limit of detection; functional cure (HBsAg loss) is rare with NAs.
HCV direct-acting antivirals target three viral enzymes: NS3/4A protease inhibitors (-previr suffix: glecaprevir, voxilaprevir, grazoprevir) cleave polyprotein; NS5B polymerase inhibitor sofosbuvir (prodrug → triphosphate chain terminator) replicates genome; NS5A inhibitors (-asvir suffix: velpatasvir, pibrentasvir, ledipasvir) block replication complex assembly; pan-genotypic regimens: sofosbuvir + velpatasvir (12 weeks) or glecaprevir + pibrentasvir (8 weeks in treatment-naive without cirrhosis) → SVR12 >95% across all genotypes; NS3/4A inhibitors contraindicated in decompensated cirrhosis (worsen hepatic function); sofosbuvir + velpatasvir is drug of choice for decompensated cirrhosis.
HCV drug interactions: NS3/4A protease inhibitors are CYP3A4/P-gp substrates and inhibitors — strong CYP3A4 inducers (rifampin, carbamazepine, phenytoin, St. John's wort) cause treatment failure; sofosbuvir is a P-gp substrate (P-gp inducers reduce absorption); amiodarone + sofosbuvir → fatal bradycardia including complete heart block (absolute contraindication); ledipasvir requires acid environment — PPIs reduce absorption (avoid or use lowest PPI dose).
HDV is a defective RNA virus requiring HBsAg for assembly and entry; only infects HBV-co-infected patients; accelerates fibrosis faster than HBV alone; NAs suppress HBV DNA but not HDV replication (HDV uses surface antigen regardless of HBV DNA level); bulevirtide (NTCP entry inhibitor) is the first approved HDV-specific drug (EU approved; SC dosing); raises bile acids pharmacologically (not hepatotoxicity); pegylated interferon achieves SVR in ~25–30% at 48 weeks but cannot be used in decompensated cirrhosis.
Acetaminophen hepatotoxicity: therapeutic doses → glucuronidation/sulfation (safe) + small fraction CYP2E1/3A4 → NAPQI (neutralized by glutathione); in overdose → phase II pathways saturated → NAPQI accumulates → centrilobular necrosis; CYP2E1 induced by chronic alcohol and fasting → increased NAPQI at lower acetaminophen doses in these groups; N-acetylcysteine (cysteine precursor) replenishes glutathione; IV 21-hour infusion protocol; Rumack-Matthew nomogram guides treatment decision; start within 8 hours to virtually eliminate hepatotoxicity; still beneficial after 24 hours in established ALF; King's College Criteria identify patients unlikely to survive without transplant.

ALF = acute liver failure · ALT = alanine aminotransferase · CYP2E1 = cytochrome P450 2E1 · CYP3A4 = cytochrome P450 3A4 · DAA = direct-acting antiviral · HBsAg = hepatitis B surface antigen · HBV = hepatitis B virus · HCV = hepatitis C virus · HDV = hepatitis D virus · NA = nucleos(t)ide analogue · NAC = N-acetylcysteine · NAPQI = N-acetyl-para-benzoquinoneimine · NTCP = sodium-taurocholate co-transporting polypeptide · P-gp = P-glycoprotein · PPI = proton pump inhibitor · SVR12 = sustained virologic response at 12 weeks · TAF = tenofovir alafenamide · TDF = tenofovir disoproxil fumarate

Hepatitis B: Nucleos(t)ide Analogue Comparison

Agent	Resistance Profile	Key Advantage	Key Caution / Note
Entecavir	High barrier: requires 3 concurrent RT mutations in treatment-naive	First-line; once daily oral; suppresses HBV DNA to undetectable in majority	Substantially less effective in lamivudine-experienced patients (lamivudine resistance mutations lower the entecavir resistance barrier); use TDF instead after lamivudine failure
TDF	No documented resistance in clinical practice	Preferred after lamivudine failure; first-line option in treatment-naive	Nephrotoxicity and reduced bone mineral density with prolonged use; monitor renal function and bone density; switch to TAF in renal impairment
TAF	No documented resistance	Higher intrahepatic drug concentration at lower plasma dose → significantly less nephrotoxicity and bone density loss than TDF	Preferred in patients with renal impairment or osteoporosis risk; equivalent antiviral efficacy to TDF
Lamivudine	Low barrier: resistance in ~20% per year of treatment (YMDD mutations)	Historical first-line; inexpensive; still used in resource-limited settings	Not recommended as first-line therapy; resistance compromises response to entecavir; use TDF if lamivudine failure occurs

Hepatitis C: Three Classes of Direct-Acting Antivirals

NS3/4A Protease Inhibitors

“–previr” Agents

Block viral serine protease → polyprotein cannot be cleaved into functional viral proteins
Agents: glecaprevir, voxilaprevir, grazoprevir, elbasvir
CYP3A4 and P-gp substrates and inhibitors
Strong CYP3A4 inducers (rifampin, carbamazepine, phenytoin, St. John's wort) → treatment failure
Contraindicated in decompensated cirrhosis — worsen hepatic function; use sofosbuvir + velpatasvir instead

NS5B Polymerase Inhibitor

Sofosbuvir

Blocks RNA-dependent RNA polymerase → viral genome replication halted
Prodrug activated intracellularly to triphosphate form; acts as chain terminator
P-gp substrate: P-gp inducers reduce absorption
Amiodarone + sofosbuvir → severe and fatal bradycardia including complete heart block; absolute contraindication
Safe in decompensated cirrhosis; backbone of decompensated cirrhosis regimens (sofosbuvir + velpatasvir)

NS5A Inhibitors

“–asvir” Agents

Block NS5A protein → disrupt viral replication complex assembly and virion packaging
Agents: velpatasvir, pibrentasvir, ledipasvir, elbasvir
Pan-genotypic combinations: sofosbuvir + velpatasvir (12 wk) or glecaprevir + pibrentasvir (8 wk in treatment-naive without cirrhosis) → SVR12 >95%
Ledipasvir: requires acidic environment; PPIs significantly reduce absorption — avoid or use lowest effective PPI dose

Acute Liver Failure: N-Acetylcysteine and Transplant Criteria

N-Acetylcysteine

Glutathione Replenishment for Acetaminophen ALF

Mechanism: acetaminophen → saturation of glucuronidation/sulfation in overdose → CYP2E1/3A4 converts excess to NAPQI → depletes glutathione → centrilobular necrosis; CYP2E1 induced by chronic alcohol and fasting → higher NAPQI production at lower doses in these groups
NAC replenishes glutathione by providing cysteine (rate-limiting precursor for glutathione synthesis)
IV 21-hour loading + maintenance infusion; decision to treat guided by Rumack-Matthew nomogram (acetaminophen level vs. time since ingestion)
Start within 8 hours → virtually eliminates severe hepatotoxicity; still beneficial after 24 hours in established ALF (improved microcirculation + antioxidant effects)
Also used in non-acetaminophen ALF (indeterminate etiology); improves transplant-free survival
Anaphylactoid reaction in 10–20% during loading infusion (urticaria, bronchospasm): stop infusion, give antihistamines, restart at slower rate; not a reason to withhold NAC

King's College Criteria

Indications for Urgent Transplant Evaluation

Acetaminophen ALF — list if arterial pH <7.3 after resuscitation, OR all three of:
PT >100 seconds
Creatinine >300 μmol/L
Grade III or IV hepatic encephalopathy
Non-acetaminophen ALF — list if PT >100 seconds alone, OR any 3 of 5:
Unfavorable etiology (non-A non-B hepatitis, drug other than acetaminophen) · Age <10 or >40 years · Jaundice-to-encephalopathy interval >7 days · Bilirubin >300 μmol/L · PT >50 seconds
Supportive care: lactulose + rifaximin for encephalopathy; correct coagulopathy only for active bleeding or procedures (not prophylactically); renal replacement for hepatorenal syndrome

Critical Rule — Sofosbuvir + Amiodarone: Fatal Bradycardia

Co-administration of amiodarone with sofosbuvir-containing direct-acting antiviral regimens has caused serious and fatal symptomatic bradycardia, including complete heart block requiring pacemaker insertion, and cardiac arrest. The interaction can occur even when amiodarone was discontinued weeks before starting sofosbuvir, because amiodarone has an elimination half-life of 40 to 55 days and tissue concentrations remain high long after stopping. Amiodarone is an absolute contraindication to sofosbuvir-based regimens. Always obtain a complete medication history before starting hepatitis C therapy, including recently discontinued drugs. If a patient on amiodarone requires hepatitis C treatment, a sofosbuvir-free regimen must be used, and cardiology consultation is recommended.

Suggested References

Author / Source	Title	Publication
Katzung BG, ed.	Basic and Clinical Pharmacology, 15th ed. — Chapter on Gastrointestinal Pharmacology	McGraw-Hill; 2021
Brunton L, Knollmann B, Hilal-Dandan R, eds.	Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14th ed.	McGraw-Hill; 2023
Terrault NA et al.	AASLD guidelines for treatment of chronic hepatitis B	Hepatology. 2018;67(4):1560–1599
Lok AS et al.	Antiviral therapy for chronic hepatitis B viral infection in adults: a systematic review and meta-analysis	Hepatology. 2016;63(1):284–306
AASLD-IDSA	HCV guidance: recommendations for testing, managing, and treating hepatitis C	Hepatology. 2018;68(2):827–879
Roth A et al.	Bulevirtide monotherapy or with pegylated interferon alfa-2a for chronic hepatitis D (MYR204)	Lancet. 2021;397(10283):1399–1409
Rumack BH, Matthew H	Acetaminophen poisoning and toxicity	Pediatrics. 1975;55(6):871–876
Lee WM et al.	Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure	Gastroenterology. 2009;137(3):856–864
O’Grady JG et al.	Early indicators of prognosis in fulminant hepatic failure (King’s College Criteria)	Gastroenterology. 1989;97(2):439–445