Chapter 1 · Module 4
Section 1
Types of Adverse Drug Reactions
Dose-Dependent — Predictable
Extension of drug’s pharmacological action. Common. Managed by dose reduction. Examples: warfarin bleeding, insulin hypoglycemia, beta-blocker bradycardia.
Idiosyncratic — Unpredictable
Unrelated to drug mechanism. Rare. Often requires permanent discontinuation. Examples: isoniazid hepatotoxicity, chloramphenicol aplastic anemia, Stevens-Johnson syndrome.
Minutes — IgE-Mediated
Urticaria, angioedema, anaphylaxis. Treat with epinephrine. Permanent avoidance. Classic example: penicillin anaphylaxis.
Hours to Days — Cell-Mediated
Rash, contact dermatitis. Stevens-Johnson syndrome and toxic epidermal necrolysis are severe. Implicated drugs: allopurinol, sulfonamides, antiepileptics.
Section 2
Drug Interactions
Cytochrome P450 Inhibition → Raises Drug Levels → Toxicity Risk
Azole antifungals, macrolides, amiodarone, ritonavir, grapefruit juice inhibit hepatic enzymes. Object drug accumulates. Warfarin bleeding, statin myopathy, QT prolongation result.
Cytochrome P450 Induction → Lowers Drug Levels → Failure Risk
Rifampin, phenytoin, carbamazepine, phenobarbital, St. John’s wort accelerate metabolism. Oral contraceptive failure, antiretroviral failure, transplant rejection result.
Pharmacodynamic — Combined Effect Equals Sum
Exploited therapeutically (combination antihypertensives). Can generate additive toxicity (two QT-prolonging drugs causing torsades de pointes).
Pharmacodynamic — Combined Effect Exceeds Sum
Trimethoprim + sulfamethoxazole: each blocks a different step in bacterial folate synthesis. Together far more effective than either alone.
Pharmacodynamic — Combined Effect Less Than Sum
Exploited in reversal: naloxone reverses opioids, flumazenil reverses benzodiazepines, protamine reverses heparin.
Section 3
Dangerous Combinations
Serotonin Syndrome
Monoamine oxidase inhibitors + selective serotonin reuptake inhibitors / tramadol / meperidine / linezolid
Excess synaptic serotonin → neuromuscular excitability (clonus, hyperreflexia), autonomic instability (hyperthermia, tachycardia), altered mental status. Potentially fatal. Two-week washout required between monoamine oxidase inhibitor and serotonergic drug.
Hypertensive Crisis
Monoamine oxidase inhibitors + tyramine-rich foods (aged cheese, cured meats, fermented foods)
Dietary tyramine normally degraded in gut by monoamine oxidase. When enzyme is blocked, tyramine absorbed intact → massive norepinephrine release → severe hypertension → risk of intracerebral hemorrhage. Dietary counseling is mandatory.
Torsades de Pointes
Two or more QT-prolonging drugs (antiarrhythmics + macrolides / fluoroquinolones / antipsychotics)
Additive QT interval prolongation → risk of fatal ventricular arrhythmia. Electrolyte abnormalities (low potassium, low magnesium) compound risk. Baseline electrocardiogram required before adding second QT-prolonging drug.
Respiratory Depression
Opioids + benzodiazepines (also: alcohol, non-benzodiazepine sedative-hypnotics)
Additive central nervous system and respiratory depression. Major contributor to drug overdose deaths. Avoid combination when possible. If necessary: lowest effective doses, explicit patient counseling, co-prescribe naloxone.
Section 4
Drug-Disease Contraindications
| Drug | Avoid in | Mechanism of Harm |
|---|---|---|
| Beta-blockers | Decompensated heart failure, high-degree atrioventricular block, severe asthma | Reduce contractility; block atrioventricular conduction; beta-2 blockade causes bronchoconstriction |
| Non-steroidal anti-inflammatory drugs | Heart failure, chronic kidney disease, volume depletion, active peptic ulcer disease | Block prostaglandins maintaining renal perfusion; cause sodium retention worsening heart failure; damage gastric mucosa |
| Angiotensin-converting enzyme inhibitors | Pregnancy, bilateral renal artery stenosis, history of angioedema | Fetal renal toxicity; precipitate renal failure in stenotic kidneys; bradykinin accumulation causes angioedema |
| Metformin | Severe renal impairment, tissue hypoxia states | Accumulates when renal clearance reduced; inhibits lactate metabolism → lactic acidosis |
| Anticholinergics | Narrow-angle glaucoma, urinary retention, benign prostatic hyperplasia | Block aqueous humor drainage (acute glaucoma); relax detrusor, contract bladder neck (urinary retention) |
| Statins | Pregnancy, active liver disease | Cholesterol essential for fetal development (teratogenic); may worsen active hepatic disease |