12.2 Adverse drug reactions and side effects

Adverse drug reactions (ADRs) and side effects are crucial concepts in pharmacology. ADRs are unexpected, harmful responses to normal drug doses, while side effects are known, often less severe effects. Understanding these differences is key to safe medication use and patient care.

Classifying ADRs helps predict and manage risks. From mechanism-based types to severity categories, this knowledge guides healthcare providers in assessing potential dangers. Recognizing patient-specific and environmental risk factors is essential for preventing ADRs and ensuring optimal treatment outcomes.

Adverse Drug Reactions: Definition and Distinction

Understanding ADRs and Side Effects

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• Adverse drug reactions (ADRs) manifest as unintended, harmful responses to medications at normal doses for approved indications
• Side effects emerge as known, expected effects of medications that may or may not be harmful
• ADRs typically present more severe and unpredictable outcomes compared to side effects
• World Health Organization (WHO) defines ADRs as noxious and unintended responses to drugs at normal human doses
• ADRs range from mild discomfort to life-threatening conditions (anaphylaxis, Stevens-Johnson syndrome)
• Side effects generally produce less severe and more tolerable outcomes (dry mouth, drowsiness)
• Distinguishing between ADRs and side effects plays a crucial role in medication management and patient safety

Characteristics and Implications

• ADRs often require medical intervention or hospitalization
• Side effects frequently resolve on their own or with minimal intervention
• ADRs may lead to drug discontinuation or dose adjustment
• Side effects commonly managed through patient education and supportive care
• ADRs can significantly impact patient quality of life and treatment adherence
• Side effects usually considered acceptable trade-offs for therapeutic benefits
• Healthcare providers must carefully weigh the risks and benefits when prescribing medications

Classifying Adverse Drug Reactions

Mechanism-Based Classification

• Type A (augmented) reactions stem from dose-dependent, predictable pharmacological actions
  • Examples include bleeding with anticoagulants, hypoglycemia with insulin
• Type B (bizarre) reactions arise from dose-independent, unpredictable immune-mediated responses
  • Examples include anaphylaxis to penicillin, Stevens-Johnson syndrome with certain antibiotics
• Type C reactions result from cumulative dose effects over time
  • Examples include osteoporosis with long-term corticosteroid use, tardive dyskinesia with antipsychotics
• Type D reactions involve delayed onset effects
  • Examples include carcinogenesis, teratogenicity
• Type E reactions occur upon drug withdrawal
  • Examples include rebound hypertension after stopping beta-blockers, benzodiazepine withdrawal syndrome

Severity and Predictability Classification

• Severity categories include mild, moderate, severe, and lethal based on impact on patient health
• Mild ADRs cause minimal discomfort and do not interfere with daily activities (mild nausea)
• Moderate ADRs interfere with daily activities but do not require hospitalization (persistent vomiting)
• Severe ADRs result in hospitalization or prolonged hospital stay (severe allergic reactions)
• Lethal ADRs directly or indirectly lead to patient death (fatal arrhythmias)
• Predictability assessment considers known drug interactions, patient characteristics, and previous reports
• Naranjo Algorithm evaluates the probability of an ADR being caused by a specific drug
• Time-to-onset classification divides ADRs into acute (within 60 minutes), subacute (1-24 hours), and latent (>24 hours) reactions

Risk Factors for Adverse Drug Reactions

Patient-Specific Factors

• Age influences ADR susceptibility (elderly patients more prone due to altered pharmacokinetics)
• Gender affects ADR risk (women more susceptible to certain ADRs due to hormonal differences)
• Genetic variations impact drug metabolism and response (CYP2D6 polymorphisms affecting codeine metabolism)
• Comorbidities increase ADR risk (renal impairment altering drug clearance)
• Polypharmacy elevates drug interaction potential (concurrent use of multiple medications)
• Body weight and composition affect drug distribution and metabolism
• Nutritional status impacts drug absorption and metabolism (malnutrition altering drug protein binding)

Pharmacological and Environmental Factors

• Pharmacokinetic factors alter drug disposition (reduced hepatic clearance in liver disease)
• Pharmacogenetic variations influence individual drug responses (HLA-B*5701 allele associated with abacavir hypersensitivity)
• Specific medical conditions predispose to ADRs (G6PD deficiency increasing risk of hemolysis with certain drugs)
• Drug-drug interactions amplify ADR risk (CYP3A4 inhibitors increasing statin levels)
• Environmental factors interact with medications (grapefruit juice inhibiting CYP3A4 enzymes)
• Alcohol consumption affects drug metabolism and increases ADR risk
• Dietary factors influence drug absorption and efficacy (high-fat meals affecting absorption of certain antibiotics)

Management and Reporting of Adverse Drug Reactions

ADR Management Strategies

• Prompt recognition of ADRs through careful patient monitoring and assessment
• Discontinuation or dose adjustment of offending drugs when appropriate
• Supportive care provision addressing symptoms and complications of ADRs
• Specific antidotes or reversal agents for certain ADRs (naloxone for opioid overdose)
• Alternative medication selection considering patient-specific factors and ADR history
• Patient education on recognizing and reporting potential ADRs
• Follow-up monitoring to assess ADR resolution and prevent recurrence

Pharmacovigilance and Reporting Systems

• FDA's MedWatch program collects and analyzes ADR reports in the United States
• World Health Organization's Uppsala Monitoring Centre maintains VigiBase, the global ADR database
• Healthcare professionals encouraged to report suspected ADRs to national regulatory agencies
• Post-marketing surveillance studies contribute to ongoing drug safety assessment
• Causality assessment tools (WHO-UMC system) evaluate drug-ADR relationships
• Signal detection methods identify potential new safety concerns from ADR reports
• Regulatory decisions regarding medication use informed by pharmacovigilance data
• Risk minimization strategies implemented based on ADR reporting and analysis