7.1 Geriatric Pharmacotherapy and Deprescribing

Physiological Aging and Clinical Pharmacokinetics

Aging is characterized by progressive physiological changes across all organ systems, altering drug handling and pharmacodynamic sensitivity. Older adults (defined generally as individuals aged $\ge 65$ years, with advanced frailty often appearing at $\ge 75-80$ years) exhibit increased vulnerability to adverse drug reactions (ADRs), drug-drug interactions, and medication-related hospital admissions.

Pharmacokinetic Alterations in Older Adults

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|             AGE-RELATED PHARMACOKINETIC (PK) ALTERATIONS                |
+-------------------------------------------------------------------------+
|  ABSORPTION:                                                            |
|  - Elevated gastric pH (reduced acid secretion) -> decreased solubility |
|    of basic salts (calcium carbonate; use calcium citrate instead)      |
|  - Delayed gastric emptying & decreased splanchnic blood flow           |
|  - Skin atrophy -> variable transdermal absorption                      |
|                                                                         |
|  DISTRIBUTION:                                                          |
|  - Decreased Total Body Water (15-20% reduction) -> reduced Vd and      |
|    higher peak concentrations for hydrophilic drugs (digoxin, lithium)  |
|  - Increased Body Fat (20-40% expansion) -> expanded Vd and prolonged  |
|    elimination half-life for lipophilic drugs (diazepam, amiodarone)    |
|  - Decreased Serum Albumin -> elevated free (unbound) active fraction   |
|    of highly protein-bound acidic drugs (phenytoin, warfarin)           |
|  - Increased Alpha-1-Acid Glycoprotein -> altered basic drug binding    |
|                                                                         |
|  METABOLISM:                                                            |
|  - Decreased hepatic mass and hepatic blood flow (20-40% reduction)     |
|  - Impaired Phase I CYP450 oxidation/reduction/hydrolysis               |
|  - Relatively PRESERVED Phase II conjugation (glucuronidation, sulfation|
|    acetylation) -> 'LOT' agents (Lorazepam, Oxazepam, Temazepam)        |
|                                                                         |
|  EXCRETION:                                                             |
|  - Progressive decline in renal mass, renal blood flow, and GFR         |
|  - Sarcopenia lowers creatinine generation; serum creatinine ALONE is   |
|    unreliable and masks significant renal impairment                   |
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Absorption

Although passive intestinal absorption remains largely intact with age, age-associated achlorhydria and decreased gastric acid secretion elevate gastric pH. This impairs the dissolution and absorption of medications requiring an acidic milieu, such as ketoconazole, itraconazole, oral iron formulations, and calcium carbonate (which requires acid for ionization; calcium citrate is preferred in older adults because its absorption is acid-independent). Splanchnic blood flow declines by $20-30%$, potentially slowing the rate of absorption ($C_{\max}$ delayed, though total bioavailability / AUC is often preserved). Thinning of the epidermal layer and decreased subcutaneous fat alter transdermal drug delivery kinetics (e.g., fentanyl or nitroglycerin patches).

Distribution

Age-associated body composition shifts produce two critical distribution changes:

1. Decreased Total Body Water (TBW) and Lean Muscle Mass: TBW declines by $15-20%$. Hydrophilic drugs (e.g., digoxin, lithium, aminoglycosides, ethanol) distribute into a smaller volume of distribution ($V_d$), generating significantly higher initial peak serum concentrations ($C_{\max}$) at standard doses, escalating toxicity risks.
2. Increased Proportion of Total Body Fat: Body fat increases by $20-40%$. Lipophilic drugs (e.g., diazepam, flurazepam, oxazepam, amiodarone, lidocaine) distribute into an expanded $V_d$, resulting in prolonged elimination half-lives ($t_{1/2} = \frac{0.693 \times V_d}{CL}$) and sustained tissue accumulation upon repeated dosing.
3. Plasma Protein Binding: Hepatic synthesis of albumin decreases (especially in frail, malnourished, or chronically ill seniors), lowering serum albumin. Highly albumin-bound acidic drugs (e.g., phenytoin, warfarin, valproic acid, methotrexate) exhibit an increased free (unbound, pharmacologically active) fraction. Total serum concentration assays may appear normal or low despite elevated, potentially toxic free drug levels.

Metabolism

Hepatic volume declines by $20-30%$ and hepatic portal blood flow decreases by $20-40%$ between ages 30 and 80. Consequently, medications with a high hepatic extraction ratio (first-pass metabolism, such as propranolol, morphine, verapamil, lidocaine, labetalol) exhibit significantly reduced first-pass clearance and elevated systemic bioavailability.

• Phase I Metabolism (Oxidation, Reduction, Hydrolysis via CYP450): Substantially decreased in older adults due to reduced enzyme content and liver perfusion. Drugs metabolized predominantly by CYP1A2, CYP2C9, CYP2C19, and CYP3A4 have reduced clearance and prolonged half-lives.
• Phase II Metabolism (Conjugation: Glucuronidation, Sulfation, Acetylation): Remarkably preserved in healthy aging. For this reason, benzodiazepines that bypass Phase I oxidation and undergo direct Phase II glucuronidation—the 'LOT' agents: Lorazepam, Oxazepam, and Temazepam—are preferred over long-acting agents with active Phase I metabolites (such as diazepam, chlordiazepoxide, and flurazepam) when sedative therapy is unavoidable.

Excretion

Renal function progressively declines with age: renal cortical mass shrinks, glomeruli undergo sclerosis, and renal plasma flow diminishes. Glomerular filtration rate (GFR) declines by approximately $0.75-1.0\text{ mL/min}/1.73\text{ m}^2\text{ per year}$ after age 40. Concurrently, sarcopenia (loss of skeletal muscle mass) decreases the daily generation of endogenous creatinine. Consequently, serum creatinine (SCr) often remains within normal laboratory limits (e.g., $60-90\text{ }\mu\text{mol/L}$) despite a marked drop in true GFR. Clinicians must always calculate estimated Creatinine Clearance (CrCl) using the Cockcroft-Gault equation rather than relying on SCr alone for medication dosage adjustments in older adults.

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Pharmacodynamic Alterations in Aging

Pharmacodynamics (the physiological response to a given drug concentration) undergoes substantial alterations in the elderly, characterized by enhanced target organ sensitivity, receptor density shifts, and blunted homeostatic counter-regulatory mechanisms.

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Inappropriate Prescribing: Beers and STOPP/START Criteria

Potentially Inappropriate Medications (PIMs) are drugs whose adverse risk profiles outweigh their expected clinical benefit in older adults, particularly when safer evidence-based alternatives exist.

American Geriatrics Society (AGS) Beers Criteria (2023 Update)

The AGS Beers Criteria categorizes medications to avoid or use with caution in older adults across several distinct domains:

1. Anticholinergic Agents: (e.g., first-generation antihistamines like diphenhydramine, hydroxyzine, chlorpheniramine; tricyclic antidepressants like amitriptyline, imipramine; antispasmodics like oxybutynin, tolterodine; muscle relaxants like cyclobenzaprine). Highly anticholinergic medications cause acute confusion, delirium, cognitive decline, blurred vision, severe constipation, and acute urinary retention.
2. Sedative-Hypnotics (Benzodiazepines & Z-Drugs): (e.g., lorazepam, diazepam, temazepam, zopiclone, zolpidem). Increase the risk of motor vehicle collisions, cognitive impairment, delirium, falls, and hip fractures by greater than $50%$. Avoid all benzodiazepines and non-benzodiazepine receptor agonists for insomnia; first-line therapy is Cognitive Behavioral Therapy for Insomnia (CBT-I).
3. Sulfonylureas (Long-Acting): Glyburide and chlorpropamide are strongly avoided due to active metabolites that accumulate in renal impairment, causing severe, prolonged, and potentially fatal hypoglycemia. If a sulfonylurea is required, gliclazide (or glimepiride) is preferred due to shorter half-life and inactive metabolites.
4. Non-Selective NSAIDs & COX-2 Inhibitors: (e.g., indomethacin, ketorolac, naproxen, ibuprofen, celecoxib). Chronic oral use is avoided due to risks of GI ulceration/bleeding, acute kidney injury, worsening hypertension, and heart failure decompensation. Indomethacin carries the highest CNS toxicity and ketorolac carries the highest GI bleeding risk.
5. Central Alpha-2 Agonists: (e.g., clonidine, methyldopa). High risk of severe adverse CNS effects, bradycardia, and profound orthostatic hypotension; not recommended as routine antihypertensives.
6. Digoxin: Avoid as first-line therapy for atrial fibrillation or heart failure. In heart failure, doses $> 0.125\text{ mg/day}$ confer no additional benefit and markedly increase mortality and toxicity risks (therapeutic serum target: $0.5-0.9\text{ ng/mL}$ or $0.6-1.2\text{ nmol/L}$).
7. Antipsychotics (Typical and Atypical): (e.g., haloperidol, risperidone, olanzapine, quetiapine). Carry a Health Canada and FDA Black Box Warning for increased risk of stroke and all-cause mortality in older adults with dementia-related psychosis. Avoid unless non-pharmacological interventions have failed and the patient's behaviors pose severe harm to self or others.
8. Proton Pump Inhibitors (PPIs): Scheduled use beyond 8 weeks is avoided without compelling indications (e.g., erosive esophagitis, Barrett's esophagus, chronic NSAID co-prescription, severe GERD) due to increased risks of Clostridioides difficile infection, bone loss, hip fractures, hypomagnesemia, and vitamin B12 deficiency.

STOPP / START Criteria

• STOPP (Screening Tool of Older Persons' Prescriptions): Identifies clinically significant PIMs categorized by organ system (e.g., stopping loop diuretics for dependent ankle edema without heart failure, stopping TCAs in dementia or cardiac conduction disease).
• START (Screening Tool to Alert to Right Treatment): Identifies potential prescribing omissions (PPOs) where evidence-based therapies are inappropriately withheld (e.g., starting an ACE inhibitor/ARB in heart failure, starting a statin in secondary cardiovascular prevention, starting an anticoagulant in atrial fibrillation with high stroke risk).

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Prescribing Cascades and Polypharmacy

Polypharmacy is broadly defined as the routine use of $\ge 5$ medications, while hyperpolypharmacy refers to $\ge 10$ concurrent medications. Polypharmacy exponentially increases the risk of drug-drug interactions, non-adherence, prescribing cascades, falls, hospitalization, and mortality.

+-------------------------------------------------------------------------+
|                   CLASSIC PRESCRIBING CASCADES IN GERIATRICS            |
+-------------------------------------------------------------------------+
|                                                                         |
|  1. INITIAL DRUG: Dihydropyridine CCB (Amlodipine)                     |
|     --> ADVERSE EFFECT: Peripheral vasodilation & dependent edema       |
|     --> MISDIAGNOSIS: Congestive heart failure or venous insufficiency  |
|     --> CASCADE DRUG: Loop Diuretic (Furosemide) added                  |
|     --> RESULT: Hypokalemia, incontinence, orthostatic falls, gout      |
|                                                                         |
|  2. INITIAL DRUG: Cholinesterase Inhibitor (Donepezil / Rivastigmine)   |
|     --> ADVERSE EFFECT: Peripheral cholinergic stimulation (bladder)   |
|     --> MISDIAGNOSIS: Overactive bladder / urge incontinence            |
|     --> CASCADE DRUG: Anticholinergic (Oxybutynin / Tolterodine) added  |
|     --> RESULT: Antagonizes donepezil, worsening dementia & delirium    |
|                                                                         |
|  3. INITIAL DRUG: NSAID (Naproxen / Ibuprofen)                          |
|     --> ADVERSE EFFECT: Renal prostaglandin inhibition & Na retention   |
|     --> MISDIAGNOSIS: Essential hypertension worsening                  |
|     --> CASCADE DRUG: Antihypertensive (ACEi / CCB) added or dose hiked |
|                                                                         |
|  4. INITIAL DRUG: Metoclopramide or Antipsychotic (Prochlorperazine)    |
|     --> ADVERSE EFFECT: Central dopamine-2 receptor antagonism          |
|     --> MISDIAGNOSIS: Newly developed Parkinson's disease               |
|     --> CASCADE DRUG: Levodopa / Carbidopa or Benztropine added         |
|                                                                         |
|  5. INITIAL DRUG: Thiazide Diuretic (Hydrochlorothiazide)              |
|     --> ADVERSE EFFECT: Hyperuricemia via competitive renal excretion   |
|     --> MISDIAGNOSIS: Primary acute gout                                |
|     --> CASCADE DRUG: Allopurinol / Colchicine added                    |
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Deprescribing Principles and Evidence-Based Protocols

Deprescribing is the planned and supervised process of dose reduction or medication discontinuation when a drug may be causing harm, is no longer providing clinical benefit, or no longer aligns with the patient's goals of care.

The 5-Step Deprescribing Process

1. Comprehensive Medication Reconciliation: Compile an accurate list of all prescribed, over-the-counter (OTC), and natural health products.
2. Identify Potentially Inappropriate Medications (PIMs): Screen against Beers/STOPP criteria, assessing current indications, remaining life expectancy, and time-to-benefit (e.g., statins for primary prevention require 3-5 years to demonstrate benefit; tight glycemic control in frail elders offers minimal short-term benefit with immediate hypoglycemia risk).
3. Assess Risks versus Benefits: Evaluate if the drug is contributing to active geriatric syndromes (falls, confusion, anorexia, incontinence, constipation).
4. Formulate a Deprescribing and Tapering Plan: Prioritize one medication at a time. Design a gradual dose reduction schedule to avoid withdrawal syndromes (e.g., rebound hypertension with clonidine/beta-blockers, rebound hyperacidity with PPIs, insomnia/seizures with benzodiazepines).
5. Monitor, Support, and Document: Establish clear clinical monitoring parameters, educate the patient and caregivers on potential withdrawal symptoms, and provide non-pharmacological support.

Canadian Deprescribing Network (CaDeN / deprescribing.org) Algorithms

• Proton Pump Inhibitors (PPIs): For adults with no active indication (e.g., uncomplicated GERD treated for $> 8\text{ weeks}$): reduce daily dose by $50%$ for 1-2 weeks, transition to on-demand dosing or an $H_2$-receptor antagonist (famotidine), and reassure the patient that mild rebound acid hypersecretion resolves within 1-2 weeks.
• Benzodiazepines and Z-Drugs: Reduce dose by approximately $25%$ every 1 to 2 weeks (or slower, e.g., $10-25%$ monthly for long-term users). Implement CBT-I strategies (sleep hygiene, stimulus control, sleep restriction) concurrently.
• Antihyperglycemic Agents: In frail seniors with dementia, history of severe falls, or limited life expectancy, relax the $\text{HbA1c}$ target to $7.1-8.5%$. Deprescribe or switch sulfonylureas (especially glyburide) and reduce complex insulin regimens to basal-only to eliminate severe hypoglycemia risks.