Pharmacotherapeutic Considerations in the Elderly

1. Pharmacotherapeutic Considerations in the Elderly Melanie A. Dodd, Pharm.D., Ph.C., BCPS Assistant Professor of Pharmacy in Geriatrics College of Pharmacy The University of New Mexico

2. OBJECTIVES • At the conclusion of the lecture the student shall be able to: • Describe the effects of aging on pharmacokinetic and pharmacodynamic parameters • Discuss the principles of prescribing for older patients • Given an elderly patient with multiple medical problems, recommend appropriate pharmacotherapeutic changes

3. Why are geriatric pharmacokinetics important? • Persons aged 65 and older are prescribed the highest proportion of medications in relation to their percentage of the U.S. population • Now, 13% of total population buy 33% of all prescription drugs • By 2040, 25% of total population will buy 50% of all prescription drugs

4. Why are geriatric pharmacokinetics important? • Increased risk of adverse drug reactions • Multiple medications • >20% of elderly use 5 or more medications • Increased frequency of drug-drug interactions • Decreased medication adherence • Multiple comorbidities • Age-related changes in drug pharmacokinetics • Age-related changes in drug pharmacodynamics

5. The Burden of Injuries from Medications • ADEs are responsible for 5% to 28% of acute geriatric hospital admissions • ADEs occur in 35% of community-dwelling elderly persons • ADEs incidence: 26/1000 hospital beds • In nursing homes, $1.33 spent on ADEs for every $1.00 spent on medications

6. RISK FACTORS FOR ADEs • 6 or more concurrent chronic conditions • 12 or more doses of drugs / day • 9 or more medications • Prior adverse drug reaction • Low body weight or body mass index • Age 85 or older • Estimated CrCl < 50 mL / min

7. ADE PRESCRIBING CASCADE DRUG 1 Adverse drug effect- misinterpreted as a new medical condition - DRUG 2 • Source Note: Rochon PA, Gurwitz JH. Optimising drug treatment for elderly people: the prescribing cascade. BMJ. 1997;315(7115):1097. Reprinted with permission. Adverse drug effect- misinterpreted as a new medical condition

8. Principles of prescribing for older patients: The Basics • Start with a low dose • Titrate upward slowly, as tolerated by the patient • Avoid starting 2 drugs at the same time

9. Before Starting a New Medication, Ask: • Is this medication necessary? • What are the therapeutic end points? • Do the benefits outweigh the risks? • Is it used to treat effects of another drug? • Could 1 drug be used to treat 2 conditions? • Could it interact with diseases, other drugs? • Does patient know what it’s for, how to take it, and what ADEs to look for?

10. PHARMACOKINETICS Absorption Distribution Metabolism Elimination

11. Aging and Absorption • Clinical significance is not well characterized • Most drugs absorbed through passive diffusion in the proximal small bowel • Exception: levodopa • Threefold increase in bioavailability due to reduced activity dopa-decarboxylase in the stomach wall

12. Absorption • Alterations in GI function • Decreased gastric parietal cell function • Decrease in secretion of hydrochloric acid • Increase in gastric pH • Ex: tetracycline, Fe, ketoconazole • Decreased rate of gastric emptying • Ex: anticholinergics, opiates, Fe, anticonvulsants • Drug-drug interactions • Divalent cations (calcium, magnesium, iron) and fluoroquinolones (e.g., ciprofloxacin)

13. Absorption • Topical absorption (patches, creams, ointments, etc.) • Thinning and reduction of absorptive surface • Skin atrophy and decreased fat content • Reduction in vascular network and risk of contact dermatitis

14. Effects of aging on volume of distribution (Vd) • Depends mostly on physiochemical properties of individual medications t½ = (0.693 x Vd)/Cl

15. Distribution •  body water (10-15%)  lower Vd for hydrophilic drugs • Ex: warfarin, digoxin, lithium, cimetidine, APAP, ETOH •  lean body mass  lower Vd for drugs that bind to muscle •  fat stores  higher Vd for lipophilic drugs • Ex: diazepam, lidocaine, TCAs, propranolol

16. DistributionProtein Binding • Decreased serum albumin • 10 to 20% in hospitalized or poorly nourished pt. • Increase in unbound fraction of highly protein bound acidic drugs • Monitor drug levels—free phenytoin level with low albumin • Ex: warfarin, phenytoin, naproxen • Increased -1 acid glycoprotein • Decrease in unbound fraction of highly protein bound basic drugs • Ex: lidocaine, propranolol, imipramine

17. Aging and Metabolism • The liver is the most common site of drug metabolism • Metabolic clearance of a drug by the liver may be reduced because … • Decrease in liver blood flow • 40 to 45% with aging, related to cardiac function • Increase in bioavailability • Decreased 1st pass effect = more parent drug • Reduce initial dose, then titrate • Decrease in liver size • 20 to 50% decrease in absolute weight up to age 80 • Reduction of total amount of metabolizing enzymes • Leads to decrease in Cl and increase in t½ • Start with lower dosage • Caution with toxic metabolites • Ex: meperidine and propoxyphene

18. Other Factors that Affect Drug Metabolism • Gender • Hepatic congestion from heart failure • Smoking

19. Elimination • Most drugs exit body via kidney • Reduced elimination  drug accumulation and toxicity • Aging and common geriatric disorders can impair kidney function

20. The Effects of Aging on the Kidney •  kidney size •  renal blood flow • ~1%/year after age 50 •  number of functioning nephrons •  renal tubular secretion • Result: Lower glomerular filtration rate • ~35% in healthy individuals between ages 20 and 90 • Accumulation increased risk of toxicity • Ex: lithium, aminoglycosides, captopril, NSAIDs

21. Serum Creatinine does NOT reflect Creatinine Clearance •  lean body mass  lower creatinine production and •  glomerular filtration rate (GFR) Result: In older persons, serum creatinine stays in normal range, masking change in creatinine clearance (CrCl)

22. Two Ways to Calculate Creatinine Clearance • Measure: • Time-consuming to be accurate • Requires 24-h urine collection • 8-h collection may be accurate but not widely accepted • Estimate: • Cockroft and Gault equation (see next slide)

23. Cockroft and Gault Equation (Ideal weight in kg) (140 - age) _________________________ x (0.85 if female) (72) (serum creatinine in mg/dL)

24. Pharmacodynamics Definition • Time course and intensity of pharmacologic effect of a drug • Impairment varies considerably from person to person • All organ systems are affected • Kidneys, liver, GI, CNS, CV, GU

25. Altered Pharmacodynamic Mechanisms • Change in receptor numbers • Change in receptor affinity • Postreceptor alterations • Age-related impairment of homeostatic mechanisms

26. CNS • Changes are significant, yet idiosyncratic • Decrease in weight and volume of brain • Alterations in cognition • Increased sensitivity to medications • Ex: benzodiazepines, opioids, anticholinergics, NSAIDs

27. CNS • Cholinergic blockade results in • Sedation, confusion, and reduced ability to recall • Ex: TCAs, diphenhydramine, antispasmodics, antipsychotics • Benzodiazepines can cause severe CNS depression • Leads to falls and hip fractures • Use caution and small dosages

28. Cardiovascular • Decreased baroreceptor responsiveness • Results in orthostatic hypotension • Ex: Antihypertensives—use caution and counseling

29. GU • Urinary incontinence • 15 to 30% of community-dwellers • 50% of nursing home residents • Enlarged prostate, urine retention • Ex: anticholinergics

30. Inappropriate Medication Use in Older Adults (Beers Criteria update) • Fick DM, et al.Arch Intern Med 2003;163:2716-2724. • 48 medications or classes to avoid in older adults • 20 diseases/conditions and medications to avoid in older adults with these diseases

31. Inappropriate Drug Therapy based on Beers’ Criteria

32. Beers’ Criteria: Independent of DiagnosisAnalgesics • Meperidine (long t1/2 metabolite, CNS) • Non-steroidal anti-inflammatory drugs • Indomethacin (CNS) • Ketorolac-immediate and long-term use (GI bleeds)* • Non-COX selective NSAIDs, longer t1/2-long-term use (GI bleeds, renal failure)* • Propoxyphene • Pentazocine (CNS)

33. Beers’ Criteria: Independent of DiagnosisPsychiatric • Antidepressants • Amitriptyline/doxepin (anticholinergic) • Daily fluoxetine (CNS)* • Anxiolytics • Long-acting benzodiazepines-chlordiazepoxide, flurazepam (sedation/fractures) • Doses of short-acting benzodiazepines • Meprobamate (addiction/sedation) • Antipsychotics • Thioridazine (CNS/EPS)* • Mesoridazine (CNS/EPS)*

34. Beers’ Criteria: Independent of DiagnosisCardiovascular • Ticlopidine (no better than aspirin) • Disopyramide (negative inotrope/anticholinergic) • Amiodarone (QT interval/torsades de pointes)* • Methyldopa (bradycardia/depression) • Clonidine (CNS/orthostatic hypotension)* • Doxazosin (hypotension/dry mouth)* • Short-acting nifedipine (hypotension/constipation)* • Ethacrynic acid (HTN, fluid imbalances)*

35. Beers’ Criteria: Independent of Diagnosis • Antihistamines (anticholinergic) • Diphenhydramine (confusion/sedation) • Chlorpheniramine • Promethazine • Hydroxyzine • Stimulant laxatives, long term use: e.g., bisacodyl (bowel dysfunction) • Cimetidine (CNS, confusion)* • Chlorpropamide (hypoglycemia/SIADH)

36. Beers Criteria Considering Diagnosis • Heart failure-disopyramide (negative inotropic effect) • Gastric or duodenal ulcers-NSAIDs and aspirin >325 mg (exacerbate existing ulcers or produce new ulcers) • Epilepsy-clozapine, chlorpromazine (may lower seizure threshold) • Insomnia-decongestants, theophylline, methylphenidate (CNS stimulants)

37. Beers Criteria Considering Diagnosis • Depression-long-term benzodiazepines (exacerbate depression)* • Syncope or falls-TCAs and short to intermed acting benzodiazepines (may produce syncope/additional falls)* • Chronic constipation-CCBs, anticholinergics, TCAs

38. Conclusions • Age alters pharmacokinetics (drug absorption, distribution, metabolism, and elimination) • Age alters pharmacodynamics • ADEs are common among older patients • Successful drug therapy means: • Choosing the correct dosage of the correct drug for the condition and individual patient • Monitoring the therapy

39. CVA X 6 Carotid stenosis Right endarterectomy in 6/05 Osteoarthritis Chronic constipation Diabetes Peripheral neuropathy Coronary artery disease Hypertension Hypothyroidism Hypercholesterolemia Osteopenia Urinary incontinence Recurrent pyelonephritis Atrophic vaginitis Reactive airway disease Case: AB 81 year-old femaleProblem List

40. levothyroxine 75 mcg daily lovastatin 10 mg, 2 tablets at bedtime clopidogrel 75 mg daily nitroglycerin SL tabs 0.4mg prn amlodipine 10 mg daily furosemide 20 mg daily potassium 10 mEq, 2 tablets twice daily clonidine 0.2 mg, 2 tablets twice daily metoprolol 50 mg twice daily Novolin 70/30, 25 units qam, 15 units qpm glipizide extended release 10 mg twice daily conjugated estrogen vaginal cream twice weekly gabapentin 300 mg tid for neuropathy in feet nortriptyline 10 mg at bedtime hydrocodone/ acetaminophen 5/325 mg, 1 tab every 4-6 hours prn pain (uses 3-4 tabs/day) alendronate 70 mg weekly tolterodine (Detrol LA) 4 mg qhs albuterol MDI with chamber once weekly Medications

41. docusate 100 mg bid mineral oil prn constipation glycerin suppositories prn constipation (uses about 2x/week) aspirin 81 mg daily diphenhydramine 25 mg at bedtime for sleep (uses 3-4 x/week) calcium 500 mg with vitamin D bid glucosamine 2 caps qd Medications(continued)

42. Vital Signs: BP 168/63 HR 79 RR 24 Temp. 97.8˚F Weight 177.9 lbs. Pain 1/10 Lab Values: Na 140 K 4.8 Cl 104 BUN 25 Scr 1.3 HbA1c 6.8% Mean blood glucose 164.8 TSH 5.680 Lipids TC 144 TG 258 HDL 39 LDL 53 Objective

43. References • Golden AG, et al. J Am Geriatr Soc 1999;47(8):948-53. • Goulding MR. Arch Intern Med 2004 164(3):305-12. • Simon SR, et al. J Am Geriatr Soc 2005;53(2):227-32. • Zhan C, et al. JAMA 2001;286(22):2823-9. • Cusack BJ. Pharmacokinetics in older persons. Am J Geriatr Pharmacother. 2004;2:274-302.