Clinical Pharmacokinetics and Physiologic Considerations in Geriatric Patients

Introduction and Epidemiology of Geriatric Care

    Demographic Trends:     * Milestone Year (2034): Predicted that the older adult population will outnumber those under age $18$ for the first time in U.S. history.     * Global Trend: Worldwide populations are aging due to increased longevity and decreased birth rates.     * Proportion of Population: In 2018, older adults comprised $16\%$ of the population; by 2060, this is expected to reach nearly $25\%$

• Life Expectancy (2023 Data):     *

• Men: $75.8\,years$.     * Women: $81.1\,years$.     *

• Fluctuations: Declined during the COVID-19 pandemic but is currently rebounding.

• Prevalence of Chronic Conditions:     * Nearly $80\%$ of older adults have two or more chronic medical conditions.     * Common Conditions:         *

• Hypertension (High blood pressure): Top of the list; often requires multiple drug classes for control.         *

• Dyslipidemia: High prevalence of statin use.         * Arthritis.         *

• Heart Disease: Leading cause of death.

• Age related changes in our bodies contribute to the onset of disease.

Risks of Polypharmacy and Medication-Related Problems

• Polypharmacy Definition: The use of multiple medications to treat multiple conditions.

• Adverse Clinical Outcomes:     *

  • Postural/orthostatic hypotension.     *

  • Hypoglycemic events (extremely low blood sugar).     *

  • Constipation and urinary retention.     * Delirium and cognitive decline.     *

  • Bleeds (e.g., GI or intracranial).     *

  • Functional decline.

  • Drug-Drug interactions

  • Drug-disease interactions

• The Significance of Falls:     *

• Falls are a primary focus in geriatric care due to high morbidity and mortality risk.     *

• Anecdote: The lecturer shared a story of falling while carrying laundry at age $50$ with no injury. Conversely, a fall for an older patient (e.g., her mother on Eliquis for A-fib) could result in a brain bleed, hip fracture, rehabilitation, or permanent loss of independent living.     * Complications: Falls lead to high healthcare expenditures and decreased quality of life.

• Interactions:     * Drug-Drug Interactions (DDI): Risk increases exponentially with the number of agents.     * Drug-Disease Interactions: Medications for one condition may exacerbate another.

Physiologic Changes of Aging

• Body Composition (High-Yield Topic):     *

  • Decrease in total body water.     *

  • Decrease in lean body mass and muscle mass.     *

  • Increase in total body fat (distributed centrally; thinning of subcutaneous fat on extremities).     *

  • Stable or decreased serum albumin levels.

• Cardiovascular System:     *

• Decreased response to stress and decreased baroreceptor activity.     *

• Decreased exercise tolerance and cardiac output.     *

• Increased systemic vascular resistance (leads to increased systolic blood pressure). Much more pressure likely in vasculature. Decreased resting and maximal heart rate.    *

• Increased risk for arrhythmias (e.g., Atrial Fibrillation).     * Heart Rate Equation: $\text{Max Heart Rate} = 220 - \text{age}$.     * Decrease in coronary perfusion.

• Neurological System:     *

  • Decreased size of the hippocampus, frontal, and temporal lobes.     *

    • Decreased number of receptors but an increase in receptor sensitivity.     *

      • Decreased short-term memory coding, retrieval, and executive function.     *

        • Increased Blood-Brain Barrier (BBB) permeability (leads to higher sensitivity to CNS-active drugs). Correlates to focus on CNS meds so sensitivity is higher.

• Endocrine System:     *

•     Decreased hormone levels: Estrogen, testosterone, growth hormone, and thyroid hormone.     *

  • Altered insulin signaling.     *

    • Decreased basal metabolic rate (metabolism slows, making weight loss difficult).

• Gastrointestinal (GI) System:     *

  • Slowed gastric motility.     *

  • Decreased splanchnic blood flow and small bowel surface area.

• Genitourinary (GU) System:     *

  • Vaginal atrophy (due to decreased estrogen).     * Prostatic hypertrophy (BPH is common in older males).     *

  • Detrusor hyperactivity (predisposes to urinary incontinence).

• Hepatic System:     *

  • Decrease in hepatic size and blood flow.     *

  • Decrease in Phase I metabolism (oxidation, reduction, and hydrolysis).

• Renal System:     *

  • Predictable decline in function: Decreased Glomerular Filtration Rate (GFR) and renal blood flow.     *

  • Decrease in the number of functioning nephrons, tubular secretory function, and renal mass.

• Immune System:

  • Decrease in antibody production in response to an antigen

  • Increase in autoimmunity

• Pulmonary System:     *

  • Decreased respiratory muscle strength and chest wall compliance.     *

  • Decreased lung tissue elasticity and impaired $CO_2$ elimination.

• Sensory and Musculoskeletal:     *

  • Presbyopia (necessity for reading glasses) and decreased night vision.     *

  • Hearing loss, specifically high-pitch frequencies.     * Decreased skeletal bone mass: Osteopenia (T-score $-1.5$ to $-2.5$) and Osteoporosis (T-score below $-2.5$).     * Joint stiffening due to reduced water content in tendons and ligaments.     * Altered gait and posture (shorter steps, hunched posture).

  • Decreased sensitivity of smell and taste

• Oral:

  • Altered dentition

• Integumentary System:     *

  • Thinning of the skin and decreased melanocytes.     *

  • Atrophy of sweat glands (impairs thermoregulation).  

  • Decrease melanocytes

  • Decrease of depth and extent of the SUBQ fat layer.

  • Hair thinning and graying.

Clinical Pharmacokinetics in Geriatrics: ADME

• General Principle: Physiologic status is a better predictor of PK changes than chronological age alone.

• Absorption:     *

  • Passive Diffusion: Generally remains unchanged.     *

  • Bioavailability ($F$): Unchanged for most drugs; however, first-pass extraction may decrease, increasing $F$ for drugs like Verapamil and Labetalol.     *

  • Pro-drugs: Decreased bioavailability for agents requiring activation, such as Enalapril and Codeine.     *

  • Active Transport: Decreased for key vitamins and minerals (B12, Calcium, Iron, Magnesium).         * Requirement for splits: Calcium doses above $500\,mg$ should be divided for optimal absorption. Metformin can cause vitamin B12 deficiency. Iron, Vitamin C and D best taken together for absorption.         *

  • pH sensitivity: Iron is better absorbed in acidic environments (often taken with Vitamin C).         *

  • Drug-induced deficiencies: Proton Pump Inhibitors (PPIs) can cause Magnesium deficiency; Metformin can cause Vitamin B12 deficiency.

  • Decreased or variable rates of transdermal, SQ, IM absorption, atrophy of the epidermic and dermis, tissue blood perfusion is reduced.

  • Buccal absorption occurs at a slower rate due to decreased saliva production.

• Distribution:     *

  • Water-Soluble Drugs (e.g., Digoxin): Decreased Volume of Distribution ($V_d$) resulting in increased plasma concentration.     *

•     Lipid-Soluble Drugs (e.g., Benzodiazepines): Increased $V_d$ resulting in an increased terminal disposition half-life ($t_{1/2}$).  

• Depends on blood flow, plasma protein binding, body comp.

• Decreased Vd, and increase plasma concentration of water soluble drugs like ethanol, digoxin, lithium, theophylline.

  • Maintained or decreased serum albumin level which is important to consider for highly protein bound drugs with a narrow therapeutic window like phenytoin or warfarin. Rapid decreases in albumin increase the effects of the drug.

  • Phenytoin example: Free drug is 10% when albumin 4.4, when albumin 2.0, the free drug is 20%.

•  Increased Vd, and increased terminal half life for lipid soluble drugs like diazepam, amiodraone, verapamil.  *

• Protein Binding Concentration Example: For a highly protein-bound drug like Phenytoin, if serum albumin drops from $4.4\,mg/dL$ to $2.0\,mg/dL$, the amount of free (active) drug doubles (e.g., from $10\%$ to $20\%$), significantly increasing pharmacologic activity.

• Metabolism:     *

  • Flow-Limited Metabolism: Depends on blood flow; hepatic blood flow may decline by $40\%$ to $60\%$. Reduced clearance for Amitriptyline, Fentanyl, Metoprolol, and Morphine. Clearance decreases and half life increases if drug has high hepatic intrinsic clearance.    *

  • Capacity-Limited Metabolism: Depends on enzyme activity. Phase I metabolism is more affected by age than Phase II.  Clearance increased or unchanged.   *

  • Frailty Syndrome: Characterized by unintentional weight loss, malnourishment, and inflammation, which down-regulates drug metabolism. Fraility is a risk factor associated with declining health and disability, also associated with inflammation, which may downregulate the drug metabolism.

  • Relies of perfusion, capacity and activity of drug metabolizing enzymes, transfer of drug into the hepatocyte form the blood, and protein binding.

• Elimination:     *

  • Renal Clearance: The most predictable age-related PK change. Kidney declines with age, person specific.    *

  • Cockcroft-Gault Equation: The current standard for estimating creatinine clearance ($CrCl$) for renal dosing.     * Serum Creatinine ($SCr$) Fallacy: $SCr$ alone is an unreliable measure of renal function in the elderly. Due to decreased muscle mass, an older patient may have a "normal" $SCr$ (e.g., $0.8\,mg/dL$) but still have significantly reduced renal clearance.

  • Many medications using GFR rather than CCG now.

  • As we age, we have less Cr due to decrease in muscle mass. We can have normal Cr but decrease in renal clearance. Can have an obese patient, Cr is normal, but kidneys may not be functioning normally.

  • CKD is in stages, uses GFR range.

Geriatric Pharmacodynamics (PD)

• General Sensitivity: Older adults generally show an increased response/sensitivity to medications.

  • Mechanisms: Changes in drug concentation at the receptor, changes in receptor numbers, receptor affinity, post-receptor alterations, and age-related impairment of homeostatic mechanisms. CNS and cardio.

• CNS Sensitivity: Increased sensitivity to Benzodiazepines, Barbiturates, Opioids, Muscle relaxants, Gabapentinoids, and Anesthetic agents, anti-psychotics, z-drugs.

• Anticholinergic Burden:     *

  • Side Effects: "Can't see (blurred vision), can't spit (dry mouth), can't pee (urinary retention), can't shit (constipation)."     *

    • Serious Risks: Delirium, mental confusion, and falls.     *

    • Clinical Advice: Avoid medications with anticholinergic properties (e.g., certain Tricyclic Antidepressants) whenever possible.

    • Can cause dry mouth, eyes, falls, urinary retention, delirium, impairment, confusion.

• Cardiovascular Sensitivity:     *

  • Calcium Channel Blockers: Increased risk of hypotension and bradycardia.     *

  • Warfarin: Increased risk of bleeding.     *

  • Beta-Blockers and Diuretics: Decreased response/efficacy.     *

    • Preferred Agents: ACE inhibitors and ARBs typically maintain efficacy and provide renal/cardiovascular protection.

Clinical Strategy: Shared Decision-Making

• Dosing Mantra: "Start low and go slow."

• Patient-Centered Care: Decisions should incorporate overall condition, life expectancy, frailty status, and individual patient choices.

• Avoid anticholinergics, antipsychotics, benzos, and sedative hypnotics.

• Pharmacist Role: Educate and empower patients to understand the risks and benefits of therapy to improve medication adherence.