Pharmacotherapy in Older Adults Janet Cho, PharmD, CGP Clinical Pharmacist, Keck Medical Center of USC Bradley R. Williams, PharmD, FASCP, CGP Professor, Clinical Pharmacy & Clinical Gerontology

Prescription Medication Use Gu Q, et al., NCHS Data Brief No. 42, 2010

Why Are We Concerned? Older adults account for 49.8% of hospital admissions due to adverse drug events1 Rate is greatest for age 85+ years 87% due to hypoglycemics, anticonvulsants, warfarin, digoxin, theophylline, lithium Adults age 50+ account for 51.1% of ED admissions for adverse drug events2 CNS drugs (28.8%), blood modifiers (22.6%), cardiovascular meds (18.1%) are most common 1Budnitz, et al, JAMA, 2006; 2The DAWN Report, 2011

Why Are We Concerned? Medicare hospital readmissions1 30 days (19.6%); 60 days (28.2%) Heart failure, pneumonia, COPD, psychosis are most common discharge diagnoses Preventable medication errors2 Renal and hepatic function Drug interactions Lack of individualized therapy 1 Jencks, et al., NEJM, 2009; 2 Kohn, et al. Institute of Medicine, 2000

Age-associated Issues Physiologic changes affect both pharmacokinetics and pharmacodynamics Reduced physiologic reserve narrows the margin for error Polymedicine increases the risk for adverse reactions and drug interactions Multiple providers and self-care both increase the risk for inappropriate medication use

Physiologic Changes Body composition Increase in body fat (% of total body weight) Women: 33% to 48% Men: 18% to 36% Decrease in body water Reduced serum albumin Increased α1-acid glycoprotein Decreased lean body mass

Physiologic Changes Gastrointestinal tract Increased gastric pH Reduced intestinal blood flow Impaired active & passive transport mechanisms Delayed gastric emptying Slowed GI motility

Physiologic Changes Liver Decreased hepatic mass Reduced hepatic blood flow Kidney Loss of functioning nephrons Reduced renal blood flow Decreased tubular secretion Decreased glomerular filtration

Drug Absorption Primarily a passive process that occurs in the small intestine Rate of absorption may be slowed Delayed, lower peak serum levels Increased bioavailability for some hepatically metabolized drugs due to reduced first-pass effect (e.g., verapamil, labetalol, lidocaine) Transdermal absorption is variable

Drug Distribution Factors leading to altered distribution… Increased Decreased Lean body mass Total body water Serum albumin Cardiac output Increased Total body fat α1-acid glycoprotein

Drugs with Decreased Binding Benzodiazepines Diazepam Lorazepam Temazepam Triazolam Desipramine Meperidine NSAIDs Diflunisal* Naproxen* Salicylates* Phenytoin Theophylline Valproate* Warfarin * >50% decrease

Drug Metabolism Factors leading to altered metabolism… Reduced liver mass and volume Decreased hepatic blood flow Altered enzyme activity Sex and genetic differences Age-associated declines Drug interactions Nutrition and health status

Decreased or Unchanged Aging & CYP Activity Decreased Decreased or Unchanged Unchanged CYP 1A2 CYP 2C19 CYP 2A CYP 2C9 CYP 3A4 CYP 2D6 -Cusack. Am J Geriatr Pharmacother 2004;2:274-302

Induction/Inhibition Other Influences Factor Result Smoking Induction Alcohol Drugs Induction/Inhibition Diet Variable Malnutrition Inhibition, if severe Frailty Inhibition -O’Mahoney & Woodhouse. Pharmacol Ther 1994;61:279-287

Drug Renal Excretion Factors leading to altered excretion… Reduced kidney mass, number and size of nephrons Decreased renal blood flow Decreased glomerular filtration Reduced tubular secretory mechanisms Effect of disease

CNS Changes Reduced blood flow and oxygenation Increased MAO levels Decreased norepinephrine, dopamine More sensitive to sedating agents Greater sensitivity to anticholinergic agents Increased permeability of the blood-brain barrier

Cardiovascular Changes Decreased response to catecholamines Primarily affects ß-receptors Increased circulating norepinephrine Reduced cardiac output Increased peripheral resistance Less responsive baroreceptors

Pharmacogenomic Issues No apparent changes across the adult lifespan Possibly some decrease in CYP 3A4 and 2A6 Fast and slow metabolizers N-acetyltransferase activity Slow acetylators (autosomal recessive)

Medication-related Problems Adverse drug reaction Unnecessary medication Duplicate No indication Problem resolved Untreated indication Patient not receiving medication Dose too high Dose too low Improper medication Contraindication Allergy Inappropriate for patient’s age or function Drug interaction

Medication Risk Assessment > 5 medications > 12 daily doses Narrow therapeutic index drugs Multiple prescribers Taking medicines for at least 3 problems Uses multiple pharmacies Someone brings medicines to the home Complex regimen At least 4 direction changes in 1 year Any medicine taken for an unknown reason -Levy HB, Ann Pharmacother, 2003

High-risk Patients Multiple diseases Complex regimens Drug-disease interactions Multiple drugs Adverse effects Drug-drug interactions Frail Risk for overdosage Depressed Multiple somatic complaints Non-adherence Demented Unreliable regarding adherence, adverse effects, etc.

Summary Age-associated changes in pharmacokinetics and pharmacodynamics present therapeutic challenges Interpatient variability makes it difficult to predict clinical effects with certainty Disease, nutrition, adherence, other drugs complicate the picture Patients benefit from a “risk management” approach