6.1 Geriatric Pharmacotherapy & Beers Criteria

Geriatric Pharmacokinetics and Pharmacodynamics

As patients age, profound physiological changes permanently alter the pharmacokinetics (PK) and pharmacodynamics (PD) of medications. Understanding these alterations is critical for appropriate drug selection and dosing to minimize adverse drug events (ADEs), which disproportionately lead to hospitalizations in the elderly.

Absorption

While the overall extent (bioavailability) of drug absorption is generally unchanged in older adults, the rate of absorption may be substantially delayed. Factors include decreased gastric acid secretion (resulting in achlorhydria and increased gastric pH), delayed gastric emptying, reduced gastrointestinal motility, and a 40-50% reduction in splanchnic blood flow. These changes notably diminish the absorption of medications requiring a highly acidic environment to dissolve. For example, calcium carbonate absorption plummets, prompting the preference for calcium citrate in elderly patients on acid-suppressing therapy. Similarly, iron supplements and azole antifungals (e.g., itraconazole, ketoconazole) exhibit reduced bioavailability.

Distribution

Significant age-related shifts in body composition dramatically impact the volume of distribution (Vd):

• Decreased total body water (by 10-15%): Leads to a significantly smaller Vd for hydrophilic drugs (e.g., lithium, digoxin, ethanol, aminoglycosides). Standard adult doses yield higher peak serum concentrations, increasing toxicity risk.
• Increased total body fat (by 20-40%): Causes a massively increased Vd for lipophilic drugs (e.g., diazepam, amiodarone, haloperidol, fentanyl). The prolonged half-life of these medications leads to significant drug accumulation with repeated dosing. For instance, the half-life of diazepam can exceed 90 hours in older adults.
• Decreased lean muscle mass: Affects endogenous creatinine production, resulting in falsely reassuring serum creatinine levels that mask severe underlying renal impairment.
• Decreased serum albumin: Often exacerbated by malnutrition or chronic illness, reduced albumin (by up to 20%) increases the free (active) fraction of highly protein-bound drugs (e.g., phenytoin, warfarin, valproic acid). This drastically increases the risk of toxicity, even when total drug concentrations appear within the "normal" therapeutic range.

Metabolism

Hepatic metabolism, specifically Phase I (oxidative, hydrolytic, and reductive) metabolism mediated by the cytochrome P450 (CYP) system, declines due to a 40% reduction in hepatic blood flow and decreased liver mass. In contrast, Phase II (conjugation) metabolism (e.g., glucuronidation, acetylation, sulfation) is relatively preserved. Therefore, medications metabolized primarily via Phase II pathways—such as the benzodiazepines lorazepam, oxazepam, and temazepam (the "LOT" drugs)—are strongly preferred in older adults when a benzodiazepine is clinically unavoidable.

Elimination

Renal elimination is the most predictably altered PK parameter. Glomerular filtration rate (GFR) and renal tubular secretion progressively decline, starting around age 30. The Cockcroft-Gault equation remains the gold standard for estimating creatinine clearance (CrCl) for medication dose adjustments. Clinicians must round severely low serum creatinine values (e.g., < 1.0 mg/dL) up to 1.0 mg/dL cautiously in frail, low-muscle-mass elderly patients to avoid overestimating CrCl and overdosing renally cleared drugs like dabigatran, rivaroxaban, or gabapentin.

The AGS Beers Criteria & STOPP/START Criteria

The American Geriatrics Society (AGS) Beers Criteria is a seminal, evidence-based guideline identifying potentially inappropriate medications (PIMs) in adults aged 65 and older. Concurrently, the STOPP/START criteria provide a physiological system-based approach to deprescribing and initiating essential therapies.

1. Medications to Avoid in Most Older Adults

• Anticholinergics: First-generation antihistamines (diphenhydramine, hydroxyzine, chlorpheniramine, promethazine) and antispasmodics (dicyclomine). These drugs precipitate profound confusion, delirium, dry mouth, severe constipation, and urinary retention, particularly in men with BPH.
• Cardiovascular Agents: Peripheral alpha-1 blockers (doxazosin, prazosin, terazosin) used for hypertension risk severe orthostatic hypotension and syncope. Digoxin should not be used as first-line for atrial fibrillation or heart failure; if used, the dosage should not exceed 0.125 mg/day due to decreased renal clearance. Amiodarone is strictly avoided as a first-line agent for atrial fibrillation rate control due to multiorgan toxicities.
• Central Nervous System (CNS) Drugs: Benzodiazepines and Non-benzodiazepine receptor agonist hypnotics/Z-drugs (zolpidem, eszopiclone, zaleplon). Older adults have increased PD sensitivity to these agents, leading to prolonged sedation, cognitive impairment, delirium, and a significantly increased risk of falls, motor vehicle accidents, and hip fractures.
• Endocrine Agents: Sliding-scale insulin regimens and long-acting sulfonylureas (glyburide, glimepiride) carry an unacceptably high risk of severe, prolonged hypoglycemia.
• Gastrointestinal Agents: Metoclopramide strongly increases the risk of extrapyramidal symptoms (EPS) and irreversible tardive dyskinesia. Chronic proton pump inhibitor (PPI) use (without indication such as Barrett's esophagus or hypersecretory conditions) increases the risk of C. difficile infection, pneumonia, and osteoporotic bone loss.
• Pain Medications: Meperidine has a neurotoxic metabolite (normeperidine) causing seizures. Chronic NSAID use increases the risk of upper GI bleeding, worsening heart failure, and acute kidney injury.

2. Medications to Avoid with Specific Diseases

• Heart Failure: Avoid NSAIDs, COX-2 inhibitors, nondihydropyridine CCBs (diltiazem, verapamil), and TZDs (pioglitazone), all of which promote fluid retention or exert negative inotropic effects.
• Dementia/Cognitive Impairment: Avoid all systemic anticholinergics, benzodiazepines, and Z-drugs, which directly antagonize the goals of dementia therapy.

Polypharmacy and Prescribing Cascades

Polypharmacy (often defined as the concurrent use of 5 or more medications) is a predominant driver of drug-drug interactions, non-adherence, ADEs, and increased hospitalizations.

A prescribing cascade occurs when an adverse drug reaction (ADR) is misinterpreted as a new medical condition, prompting the prescription of yet another medication. This vicious cycle exacerbates polypharmacy and compounds side effects. Classic Prescribing Cascades:

• Amlodipine -> Peripheral edema -> Misdiagnosed as volume overload -> Prescribed furosemide (leading to dehydration and AKI).
• NSAIDs -> Increased blood pressure -> Prescribed lisinopril or amlodipine.
• Metoclopramide or Typical Antipsychotics -> Parkinsonian EPS -> Prescribed carbidopa/levodopa or benztropine.
• Cholinesterase inhibitors (donepezil) -> Overactive bladder/Urinary incontinence -> Prescribed oxybutynin (an anticholinergic that crosses the blood-brain barrier and worsens dementia).
• Thiazide diuretics -> Hyperuricemia -> Prescribed allopurinol.

Deprescribing is the deliberate, systematic process of identifying and tapering off medications where the potential harms outweigh the benefits. It requires slow dose reduction to avoid rebound withdrawal syndromes (e.g., rebound hypertension from beta-blockers, severe rebound insomnia from benzodiazepines) and vigilant monitoring for the recurrence of the underlying indication.