5.3 Adverse Effects, Side Effects, and Drug Interactions
Key Takeaways
- Type A adverse reactions are dose-dependent and predictable from pharmacology; Type B reactions are idiosyncratic, immunologic, or genetically determined and unrelated to dose.
- Pharmacokinetic interactions alter absorption, distribution, metabolism, or excretion; CYP induction lowers substrate levels and CYP inhibition raises them, often precipitating toxicity.
- Pharmacodynamic interactions produce additive, synergistic, or antagonistic effects at the same or different receptors without changing drug concentrations.
- QT-prolonging drugs share a common ionic mechanism (IKr blockade) and their combination can precipitate torsades de pointes; cumulative QT risk must be reviewed before prescribing.
- Drug-disease, drug-food, and drug-laboratory interactions require explicit review at every transition of care; high-risk combinations include NSAIDs in CKD and heart failure, beta-blockers in asthma, and warfarin with vitamin K intake changes.
Adverse Drug Reaction Classification
Adverse drug reactions (ADRs) are unwanted, sometimes harmful effects occurring at normal therapeutic doses. Rawlins and Thompson classify them into two principal types:
- Type A (Augmented) — dose-dependent, predictable from the drug's pharmacology, common, and rarely fatal. Examples: beta-blocker bradycardia, opioid constipation, insulin hypoglycemia, NSAID gastric erosion.
- Type B (Bizarre) — idiosyncratic, unrelated to dose, uncommon, and often serious. Examples: penicillin anaphylaxis, halothane hepatitis, sulfa Stevens-Johnson syndrome, clozapine agranulocytosis, malignant hyperthermia with volatile anesthetics.
Further subtypes include Type C (chronic/long-term, e.g., glucocorticoid osteoporosis), Type D (delayed, e.g., diethylstilbestrol-related adenocarcinoma), Type E (end-of-treatment withdrawal, e.g., opioid withdrawal), and Type F (failure of therapy, e.g., antimicrobial resistance). The FPGEE emphasis is on recognizing the Type A versus Type B distinction and the dose-dependence question.
Organ-Specific Toxicities
| Organ system | Prototype drugs | Mechanism |
|---|---|---|
| Hepatotoxicity | Acetaminophen, statins, isoniazid, methotrexate, amiodarone | Direct injury, reactive metabolite (NAPQI), idiosyncratic |
| Nephrotoxicity | NSAIDs, aminoglycosides, radiocontrast, cisplatin, vancomycin | Afferent vasoconstriction, proximal tubular injury, interstitial nephritis |
| Cardiotoxicity | Anthracyclines (doxorubicin), trastuzumab, QT-prolonging agents | Oxidative stress myocarditis, HER2-cardiomyocyte signaling, IKr blockade |
| CNS effects | Antipsychotics, SSRIs (SIADH), opioids, benzodiazepines, levodopa | Dopamine/serotonin modulation, sedation, dyskinesia |
| Pulmonary toxicity | Amiodarone, bleomycin, methotrexate, nitrofurantoin | Interstitial pneumonitis, fibrosis |
Drug-Drug Interactions
Drug-drug interactions (DDIs) are divided into pharmacokinetic and pharmacodynamic categories. Pharmacokinetic interactions change concentration at the site of action; pharmacodynamic interactions change the response at a given concentration.
Pharmacokinetic Interactions
The cytochrome P450 (CYP) family in the small intestine and liver is responsible for the majority of clinically important metabolic interactions. Key isoenzymes include CYP3A4 (~50% of marketed drugs), CYP2D6, CYP2C9, CYP2C19, and CYP1A2.
- CYP inhibition is usually rapid (hours to days) and reduces substrate clearance, increasing concentration and toxicity risk. Strong inhibitors include ketoconazole and itraconazole (CYP3A4), fluoxetine and paroxetine (CYP2D6), and fluconazole (CYP2C9).
- CYP induction is slower (days to weeks) and increases substrate clearance, reducing efficacy. Prototypical inducers are rifampin, carbamazepine, phenytoin, and St. John's wort.
Classic pairings:
- Warfarin + fluconazole or fluoroquinolones — inhibition of CYP2C9 raises INR and bleeding risk.
- Simvastatin + clarithromycin or itraconazole — CYP3A4 inhibition raises statin levels, risking rhabdomyolysis.
- Grapefruit juice — irreversibly inhibits intestinal CYP3A4, markedly raising levels of felodipine, simvastatin, cyclosporine, and some DOACs.
P-glycoprotein (P-gp, ABCB1) is an efflux transporter on enterocytes, renal tubules, and the blood-brain barrier. Inhibitors (amiodarone, clarithromycin, verapamil) raise digoxin and dabigatran levels; inducers (rifampin) lower them.
Pharmacodynamic Interactions
Pharmacodynamic interactions do not alter drug concentrations but change the net physiologic effect:
- Additive / synergistic — benzodiazepines plus opioids produce supra-additive respiratory depression; ACE inhibitors plus potassium-sparing diuretics produce hyperkalemia.
- Antagonistic — naloxone blocks opioid receptors; vitamin K opposes warfarin; calcium reverses CCB toxicity.
Drug-Disease, Drug-Food, Drug-Allergy, and Drug-Laboratory Interactions
| Pairing | Risk | Management |
|---|---|---|
| NSAIDs in CKD or heart failure | Reduced GFR, sodium retention, hyperkalemia | Avoid; use acetaminophen or topical NSAIDs |
| Beta-blockers in asthma | Bronchoconstriction via beta-2 blockade | Use cardioselective agents cautiously; avoid in active bronchospasm |
| Metformin in renal impairment (eGFR < 30) | Lactic acidosis | Contraindicated; dose-reduce at eGFR 30-45 |
| ACE inhibitors in bilateral renal artery stenosis | Acute renal failure | Avoid; monitor creatinine after initiation |
| SSRIs with tramadol | Serotonin syndrome | Avoid combination; consider alternative analgesic |
| MAOIs + tyramine-rich foods | Hypertensive crisis | Tyramine-restricted diet |
| Warfarin + fluctuating vitamin K intake | INR instability | Counsel on consistent dietary vitamin K |
| Bisphosphonates + calcium or iron | Chelation; reduced absorption | Separate by at least 30 minutes (alendronate) or 2 hours (iron) |
| Penicillin-cephalosporin cross-reactivity | Allergic reaction (~1-2% with current cephalosporins) | Verify reaction history; consider test dosing |
| Sulfonamide cross-reactivity | Stevens-Johnson in susceptible patients | Avoid all sulfonamide antibiotics; nonantibiotic sulfonamides generally safe |
| PPIs + magnesium (chronic PPI use) | Hypomagnesemia | Monitor magnesium for long-term PPI users |
Laboratory Interactions
Anticoagulants produce expected laboratory signatures rather than interactions per se: heparin prolongs PTT, low-molecular-weight heparin anti-Xa levels correlate with effect, warfarin raises INR, and DOACs affect specific anti-Xa or thrombin assays rather than routine INR. False results occur when assays are applied outside their intended drug — for example, INR does not reliably reflect apixaban anticoagulation.
QT Prolongation and Torsades de Pointes
Many drugs block the delayed rectifier potassium channel IKr (hERG), prolonging the QT interval and risking torsades de pointes (TdP). Classic offenders include class IA and III antiarrhythmics (quinidine, sotalol, amiodarone, dofetilide), macrolides (erythromycin, azithromycin), fluoroquinolones (moxifloxacin), antipsychotics (haloperidol, ziprasidone), methadone, and ondansetron. Additive risk is the rule: combining two QT-prolonging drugs, or adding to a patient with hypokalemia, hypomagnesemia, bradycardia, or structural heart disease dramatically raises TdP risk. Review the cumulative QT burden and the patient's electrolyte status before prescribing.
A patient stabilized on warfarin (INR 2.5) is prescribed oral fluconazole for candidiasis. What is the most likely outcome and the responsible mechanism?
Which combination most directly increases the risk of torsades de pointes through additive IKr blockade?