Drug Toxicity and Adverse Effects

• Occur in majority of adverse drug reactions
• Related to drug concentration and pharmacokinetic variability
• Example: Hypoglycemia from excessive insulin, bleeding from warfarin overdose
• Reversible upon dose reduction or discontinuation

• Immune-mediated mechanisms: Drug acts as hapten, combines with carrier protein → immune response (e.g., penicillin anaphylaxis, drug fever, Stevens-Johnson syndrome)
• Genetic/metabolic abnormalities: Pharmacogenomic variations in drug metabolism (e.g., G6PD deficiency with sulfonamides, pseudocholinesterase deficiency with succinylcholine, slow acetylators with INH)
• Incidence independent of dose; often severe and unpredictable
• High mortality rate if severe (anaphylaxis, toxic epidermal necrolysis)

• Organ accumulation: Heavy metals (lead, mercury), digoxin, amiodarone (hepatotoxicity)
• Teratogenicity: Drug effects on fetal development during critical periods
• Carcinogenicity: Long-term malignant transformation (alkylating agents, estrogens, tobacco)
• Example: Cisplatin nephrotoxicity, methotrexate hepatic cirrhosis

• Carcinogenesis: Years to decades (thalidomide, DES, tobacco)
• Teratogenesis: Fetal malformations (ACE inhibitors in 2nd/3rd trimester)
• Organ fibrosis: Bleomycin pulmonary toxicity

• Occur when therapeutic effect wanes between doses
• Beta-blocker rebound hypertension/tachycardia when abruptly discontinued
• Benzodiazepine seizures upon sudden withdrawal
• Clonidine hypertensive crisis if stopped abruptly

Metabolic and Genetic Factors Affecting Toxicity

• Hepatic dysfunction: Impaired Phase I (oxidation) and Phase II (conjugation) metabolism → drug accumulation
• Renal impairment: Reduced glomerular filtration and active secretion → nephrotoxic drug accumulation
• Genetic polymorphisms: Cytochrome P450 variants (CYP2D6, CYP2C19) affecting drug metabolism rates
• Drug-drug interactions: Enzyme induction (rifampin, phenytoin) or inhibition (ketoconazole, cimetidine)
• Age extremes: Neonates (immature liver) and elderly (reduced clearance) at high risk

Common Organ-System Presentations

• Gastrointestinal toxicity: Nausea, vomiting, diarrhea (NSAIDs, antibiotics), GI bleeding (warfarin), hepatotoxicity (acetaminophen, isoniazid). Clinical pearl: "Idiosyncratic" hepatotoxicity is unpredictable; "dose-dependent" hepatotoxicity (acetaminophen) follows predictable kinetics.

• Hematologic toxicity: Bone marrow suppression (chemotherapy, phenothiazines, sulfonamides), agranulocytosis (clozapine, carbimazole), thrombocytopenia (heparin, NSAIDs), hemolytic anemia (penicillin, methyldopa, G6PD-triggering drugs like sulfonamides)

• Renal toxicity: Acute kidney injury from NSAIDs (prerenal via afferent arteriole vasoconstriction), aminoglycosides (acute tubular necrosis), cisplatin; chronic interstitial nephritis from lithium, NSAIDs

• Pulmonary toxicity: Pulmonary fibrosis (bleomycin, amiodarone, methotrexate), acute respiratory distress syndrome (chemotherapy), aspiration risk (anticholinergics reducing swallowing)

• Cardiovascular toxicity: Myocarditis (anthracycline chemotherapy, clozapine), arrhythmias (QT prolongation with macrolides, antipsychotics), hypertension (NSAIDs, decongestants, oral contraceptives), hypotension (ACE inhibitors, nitrates)

• Neurologic toxicity: Peripheral neuropathy (chemotherapy—taxanes, vinca alkaloids), seizures (withdrawn benzodiazepines), tremor (lithium), cerebellar ataxia (phenytoin, alcohol)

• Hypersensitivity reactions: Spectrum from mild rash → Stevens-Johnson syndrome/Toxic Epidermal Necrolysis (SJS/TEN) with allopurinol, sulfonamides, anticonvulsants; Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) with carbamazepine, allopurinol

• Anaphylaxis: Penicillin (most common drug cause), other beta-lactams, NSAIDs in aspirin-sensitive patients. Classic presentation: urticaria, angioedema, bronchospasm, hypotension within minutes.

• Teratogenicity: ACE inhibitors (2nd/3rd trimester → renal dysgenesis), thalidomide (limb defects), methotrexate (neural tube defects), isotretinoin (CNS/cardiac malformations)

Clinical Assessment

• Temporal relationship: Drug start → symptom onset (typically within 1-2 weeks, but variable). Dechallenge/rechallenge if safe helps confirm causation.
• History of prior reactions to same/structurally similar drugs
• Known risk factors: Renal/hepatic dysfunction, genetic polymorphisms, polypharmacy (drug interactions)
• Rule out alternative etiologies before attributing to drug (infections, malignancy, underlying disease)

Laboratory and Diagnostic Testing

• CBC with differential: Detect bone marrow suppression, eosinophilia (DRESS syndrome)
• Liver function tests (AST, ALT, bilirubin, ALP): Hepatotoxicity patterns distinguish cholestasis (↑↑ALP, ↑bilirubin) vs. hepatocellular injury (↑↑AST/ALT)
• Renal function (BUN, creatinine, urinalysis): Acute kidney injury, proteinuria, hematuria in drug nephrotoxicity
• Therapeutic drug levels: For drugs with narrow therapeutic index (digoxin, lithium, aminoglycosides, phenytoin). Essential in toxicity assessment.
• Skin biopsy: If SJS/TEN suspected (shows full-thickness epidermal necrosis)
• Patch testing: Delayed hypersensitivity confirmation (contact dermatitis from topicals)
• Imaging: CXR for pulmonary toxicity, echocardiogram for cardiotoxicity assessment

Diagnostic Criteria

• Naranjo Probability Scale: Quantifies likelihood drug caused adverse event (scores: definite, probable, possible, unlikely)
• **WHO-Uppsala

Hepatotoxicity

• Acetaminophen: saturation of glucuronidation/sulfation shunts drug to CYP2E1, generating NAPQI, which depletes glutathione and covalently binds hepatocyte proteins → centrilobular (zone 3) necrosis. Chronic alcohol use and fasting potentiate injury by inducing CYP2E1 and depleting glutathione. Antidote: N-acetylcysteine, a glutathione precursor; ACG and AASLD guidance supports giving NAC early in suspected acetaminophen-induced acute liver failure, using the Rumack–Matthew nomogram for a single acute ingestion with a known time.
• Isoniazid, valproate, methotrexate, amiodarone: idiosyncratic or cumulative hepatocellular injury; pyridoxine prevents INH neurotoxicity and treats INH-induced seizures but does not prevent hepatitis.

Nephrotoxicity and ototoxicity

• Aminoglycosides: cationic drug accumulates in proximal tubular cells (megalin-mediated uptake) → non-oliguric ATN, and in cochlear hair cells → irreversible sensorineural hearing loss; risk is amplified by the mitochondrial MT-RNR1 variant. Monitor renal function and levels; avoid combining with loop diuretics or vancomycin when possible.
• Vancomycin: per the 2020 IDSA/ASHP/PIDS/SIDP consensus, dose to a 24-hour AUC/MIC of 400–600; trough-only targets of 15–20 mcg/mL have been retired.
• NSAIDs: prostaglandin blockade removes afferent arteriolar vasodilation → hemodynamic AKI; also interstitial nephritis with eosinophiluria. Avoid in volume depletion, CKD, and with ACEI/ARB plus diuretic (triple whammy).
• Cisplatin: proximal tubular injury plus magnesium wasting; amifostine and saline hydration are mitigations.

• Acetaminophen is the leading cause of acute liver failure in the US: expect AST/ALT in the thousands with a disproportionately modest bilirubin early on. The single best next step in a plausible overdose is N-acetylcysteine — do not wait for a level or for the nomogram if timing is unknown or the ingestion was staggered.
• Flumazenil is the classic distractor. In a chronic benzodiazepine user or a mixed overdose it can precipitate refractory seizures; supportive airway management is the answer. Naloxone, by contrast, is given freely for opioid-induced respiratory depression.
• Widened QRS after an overdose = TCA (fast sodium-channel blockade) → sodium bicarbonate, which both alkalinizes and provides a sodium load. Rightward terminal QRS axis in aVR is the buzzword.
• P450 mnemonic pairs: inducers (rifampin, phenytoin, carbamazepine, phenobarbital, St. John's wort, chronic alcohol) cause oral contraceptive failure and warfarin under-anticoagulation; inhibitors (azoles, macrolides other than azithromycin, protease inhibitors, grapefruit juice, amiodarone, cimetidine) cause statin myopathy and bleeding on warfarin.
• Aminoglycoside ototoxicity is irreversible; nephrotoxicity usually is not. Loop diuretics add ototoxicity, cisplatin adds both — the stem's clue is a combination, not a single agent.
• Do not repeat the 10% penicillin–cephalosporin cross-reactivity figure. True cross-reactivity is roughly 1–3% and tracks with shared R1 side chains rather than the beta-lactam ring, so most penicillin-allergic patients can receive a structurally dissimilar cephalosporin.
• The one association examiners love: allopurinol plus azathioprine/6-MP → xanthine oxidase inhibition → profound myelosuppression; reduce the thiopurine dose or avoid the combination. Similarly, HLA-B*57:01 and abacavir hypersensitivity requires pretreatment testing.
• Suspect drug-induced when the timing fits and nothing else does: eosinophilia plus rash plus transaminitis two to six weeks after carbamazepine or allopurinol is DRESS — stop the drug first; steroids are secondary.