Adverse Drug Reactions: GI, Hepatic, Pulmonary & Renal

Hepatotoxicity patterns

Acetaminophen. At therapeutic doses most of the drug is glucuronidated or sulfated, and a small fraction is oxidized by CYP2E1 to NAPQI, a reactive electrophile that glutathione immediately neutralizes. In overdose the conjugation pathways saturate, more drug is shunted to CYP2E1, glutathione is exhausted, and NAPQI binds hepatocyte proteins. Necrosis begins in zone 3 (centrilobular), which has the most CYP2E1 and the lowest oxygen tension; ALT often reaches the thousands. Chronic alcohol use (CYP2E1 induction plus low glutathione) and fasting raise the risk. N-acetylcysteine works by replenishing glutathione.

Zone 1 (periportal) is favored by viral hepatitis and zone 2 by yellow fever; drug-induced dose-dependent necrosis is centrilobular.

TB drugs. Isoniazid, rifampin and pyrazinamide all injure hepatocytes, and the combination is more hepatotoxic than any single agent. Isoniazid hepatitis becomes more likely with age and alcohol use; pyrazinamide toxicity is dose related; rifampin injury is more often cholestatic. Therapy is stopped when ALT exceeds 5× the upper limit of normal, or 3× with symptoms or jaundice.

Statins raise transaminases in about 1% of patients but rarely cause clinical hepatitis; LFTs are checked at baseline and when symptoms appear rather than routinely.

Valproate impairs mitochondrial β-oxidation and depletes carnitine, producing hepatitis with microvesicular steatosis that can become fulminant failure. Risk is highest in children under 2 taking several anticonvulsants and in POLG mitochondrial disease, and LFTs are monitored closely in the first 6 months. Aspirin given to children with viral illness (Reye syndrome), high-dose IV tetracycline and acute fatty liver of pregnancy produce the same microvesicular picture.

Cholestasis follows erythromycin estolate, amoxicillin-clavulanate (often weeks after the course ends), 17α-alkylated anabolic steroids and estrogen-containing oral contraceptives. Halothane causes an immune hepatitis directed at trifluoroacetylated protein adducts, with fever, eosinophilia and massive necrosis, mainly after repeated anesthetic exposures.

Gastrointestinal reactions

Pancreatitis. Classic drug causes are didanosine, valproate, azathioprine and 6-mercaptopurine, glucocorticoids, loop and thiazide diuretics, and GLP-1 receptor agonists (exenatide, liraglutide, semaglutide). Drugs that raise triglycerides, such as estrogens and isotretinoin, act indirectly. Diagnosis rests on epigastric pain radiating to the back with lipase above 3× the upper limit of normal.

Pill esophagitis. Tablets that lodge in the esophagus, often near the aortic arch, release caustic contents and cause odynophagia with discrete ulcers. Bisphosphonates (alendronate), doxycycline and other tetracyclines, potassium chloride, NSAIDs and aspirin, and ferrous sulfate are typical. Alendronate is taken on an empty stomach with a full glass (about 240 mL) of plain water, and the patient stays upright for at least 30 minutes.

C. difficile colitis. Antibiotics that clear competing colonic flora let toxigenic C. difficile flourish; toxins A and B glucosylate and inactivate Rho GTPases, causing watery diarrhea, pseudomembranous colitis and, at worst, toxic megacolon. Clindamycin, fluoroquinolones and 2nd- and 3rd-generation cephalosporins are the classic culprits, and PPIs add risk. Oral vancomycin or fidaxomicin is the treatment; metronidazole was used in the past.

Bowel habit. Metformin's most common adverse effect is diarrhea, reduced by slow titration or extended release. Diarrhea is also an early sign of colchicine toxicity, and misoprostol (a PGE₁ analog) and orlistat (a lipase inhibitor causing oily steatorrhea and fat-soluble vitamin loss) loosen stools. Opioids constipate through μ receptors, and tolerance to this effect never develops; verapamil (Ca²⁺ channel blockade in gut smooth muscle), ondansetron (5-HT₃ antagonist) and vincristine (autonomic neuropathy, sometimes paralytic ileus) also constipate.

Pulmonary reactions

Pulmonary fibrosis. Drug-induced interstitial disease produces a restrictive pattern with reduced DLCO. Bleomycin is the prototype: its injury is dose related because lung and skin contain little bleomycin hydrolase, and high inspired oxygen concentrations worsen it. Busulfan, amiodarone (dose and duration related), methotrexate (often as a hypersensitivity pneumonitis) and long-term nitrofurantoin prophylaxis in older adults complete the list.

ACE-inhibitor cough. ACE is the same enzyme as kininase II, so ACE inhibitors let bradykinin and substance P accumulate and cause a dry cough in roughly 5–20% of patients. Switching to an ARB such as losartan, which spares kinin breakdown, usually resolves it. Angioedema is rarer but shares the bradykinin mechanism, is more common in Black patients, forbids rechallenge, and makes hereditary C1-esterase inhibitor deficiency a contraindication.

Nonselective β-blockers, including propranolol, nadolol and even timolol eye drops, block airway β₂ receptors and can precipitate bronchospasm in asthma or COPD; β₁-selective metoprolol, atenolol or bisoprolol are safer.

Aspirin-exacerbated respiratory disease. Patients with asthma, nasal polyps and chronic rhinosinusitis react to aspirin and other NSAIDs because COX-1 inhibition shunts arachidonic acid toward cysteinyl leukotrienes. COX-2-selective celecoxib is generally tolerated, and leukotriene modifiers such as montelukast help.

Renal and bladder toxicity

Interstitial nephritis is a hypersensitivity reaction that usually appears 1–2 weeks after the drug is started, with rising creatinine, sterile pyuria and WBC casts. NSAID-related cases often lack fever and rash. Removing the drug is essential, and glucocorticoids may speed recovery.

Tubular necrosis from direct toxins is dose related. Aminoglycosides are taken up by proximal tubule cells and cause nonoliguric AKI about 5–10 days into therapy. Amphotericin B wastes potassium and magnesium and causes distal (type 1) RTA. Cisplatin wastes magnesium and is given with vigorous hydration, with amifostine as a protectant. IV contrast combines renal vasoconstriction with tubular injury, and creatinine rises within 24–48 hours; unlike other toxic ATN, FENa is often <1% early.

Crystals and Fanconi syndrome. Rapid IV acyclovir, high-dose methotrexate and indinavir precipitate within tubules. Tenofovir disoproxil, ifosfamide and degraded, outdated tetracycline poison the proximal tubule, wasting glucose, amino acids, phosphate and bicarbonate (type 2 RTA with a normal anion gap acidosis).

Hemorrhagic cystitis. Cyclophosphamide and ifosfamide are prodrugs activated by hepatic CYP enzymes; one metabolite, acrolein, concentrates in urine and damages the urothelium, causing hemorrhagic cystitis and, with cyclophosphamide, a later increase in bladder cancer. Vigorous hydration and mesna, a thiol that binds acrolein within the bladder, prevent it.