Which patient with elderly age, multiple comorbidities, polypharmacy, impaired renal or hepatic function, and history of previous adverse drug reactions (ADRs) is at higher risk of experiencing ADRs?

Patients at Highest Risk for Adverse Drug Reactions

An elderly patient with multiple comorbidities, polypharmacy (≥5 medications), impaired renal or hepatic function, and a history of previous ADRs represents the highest-risk profile for experiencing adverse drug reactions. 1

Risk Stratification Framework

Age as a Primary Risk Factor

• Elderly patients (≥65 years) face exponentially higher ADR risk due to age-related physiological changes affecting drug metabolism and clearance 1
• Women aged ≥88 years with impaired renal function demonstrate significantly elevated ADR risk compared to younger elderly patients (mean age 88.8 vs 82.5 years, p=0.014) 2
• Age-related decline in hepatic metabolism (20-50% reduction in CYP450-mediated phase I reactions) and decreased liver mass (20-30%) increase drug exposure and half-life 1
• Decreased cardiac output, reduced tissue perfusion, and altered body composition (decreased total body water, increased adipose tissue) fundamentally change drug distribution patterns 1

Polypharmacy: The Dose-Response Relationship

The risk of ADRs increases dramatically with medication number: from 13% with 2 medications, to 58% with 5 medications, and continues rising exponentially beyond this threshold 1

• Polypharmacy (≥5 drugs) was observed in 48% of elderly cancer patients, with 11-18% receiving potentially inappropriate medications 1
• Drug-drug interactions occur in 27-31% of elderly patients on polypharmacy, with risk escalating steeply when ≥5 drugs are co-administered 1, 3
• Patients taking 7 or more drugs face nearly 4-fold increased risk of 30-day unplanned rehospitalization 4
• Fall risk increases 21% with 4+ medications and 50% with 10+ medications in elderly patients 4

Renal Impairment: The Hidden Multiplier

Impaired renal function is among the most critical risk factors for ADRs, yet it is frequently underrecognized because serum creatinine may appear normal despite significantly reduced kidney function 1, 2

• One-third of ADRs in elderly hospitalized patients are directly related to impaired renal function, particularly in very old women 2
• Creatinine-based equations (Cockcroft-Gault, MDRD) misclassify kidney disease by one stage in >30% of elderly participants due to reduced muscle mass 1
• Women with ADRs had significantly lower creatinine clearance (25.5 vs 37.1 mL/min, p=0.035) compared to those without ADRs 2
• Renal impairment increases DDI prevalence to 56.9-89.1% in CKD patients on polypharmacy 5
• Excessive doses or drugs unsuitable for renal insufficiency were present in 32% of patients with ADRs versus only 3% without ADRs (p=0.0001) 2

Hepatic Dysfunction

• Decreased hepatic blood flow and reduced first-pass metabolism increase oral bioavailability of highly metabolized drugs (diltiazem, propranolol, simvastatin, verapamil) 1
• Reduced plasma albumin increases free drug levels of highly protein-bound medications (amiodarone, warfarin, propranolol), amplifying pharmacodynamic effects 1

History of Previous ADRs

Patients with prior ADRs demonstrate established vulnerability to medication-related harm and should be considered at persistently elevated risk 6

• Age-related physiological changes, decline in renal and hepatic function, and chronic comorbidities make older adults particularly susceptible to recurrent ADRs 6
• Over 80% of serious ADRs are type A reactions (dose-dependent, predictable, and potentially avoidable), indicating that prior ADR history signals ongoing risk 1

Multiple Comorbidities: Compounding Complexity

Patients with severe comorbidities face higher risk of neutropenic fever, death from neutropenic infections, and treatment-related toxicity 1

• Over one-fifth of older people with multimorbidity receive medications that adversely affect coexisting conditions 4, 3
• Comorbidities alter pharmacokinetics and pharmacodynamics through disease-specific mechanisms (heart failure reduces cardiac output and drug distribution; diabetes affects renal function) 1
• Cognitive impairment, renal insufficiency, dependence on caregivers, and polypharmacy are the major predictors of drug-related hospital admissions 1

High-Risk Medication Classes

Patients taking medications requiring regular monitoring (antiplatelets, antiarrhythmics, digoxin, glucose-lowering drugs, diuretics, ACEIs, ARBs, warfarin) face increased ADR risk 1

• Cardiovascular drugs associated with ADR-related hospitalization include beta-blockers, anticoagulants, digoxin, ACEIs, calcium channel blockers, and oral glucose-lowering drugs 1
• Cytochrome P450 inhibition contributes to nonhematologic toxicities, while protein binding interactions cause hematologic toxicities 1

Critical Clinical Pitfalls

• Prescribing cascades occur when ADRs are misinterpreted as new medical conditions, leading to additional unnecessary medications (e.g., NSAID-induced hypertension prompting antihypertensive prescription) 1, 3
• Any new symptom in older people should be considered a possible ADR until proven otherwise 1
• Serum creatinine within reference limits does not exclude significant renal impairment in elderly patients due to reduced muscle mass 1
• Only 5% of over-the-counter medications used prior to hospitalization appear in patient charts, creating hidden drug interaction risks 1

Risk Mitigation Strategies

• Use CKD-EPI creatinine-cystatin C equations for accurate renal function assessment before initiating or adjusting renally cleared drugs 1, 4
• Implement systematic medication review at every encounter, particularly before and after dose changes 4
• Start pharmacological treatment at low doses with gradual upward titration based on clinical response and ADRs 1
• Monitor supine and standing blood pressure, renal function, and serum electrolytes regularly 1, 7
• Deprescribe unnecessary medications, prioritizing highest-risk drugs (opioids, benzodiazepines, anticholinergics, antipsychotics) 3