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  1. 1. Geriatric Pharmacotherapy Linda Farho, Pharm.D. University of Nebraska Medical Center College of Pharmacy
  2. 2. Objectives <ul><li>Understand key issues in geriatric pharmacotherapy </li></ul><ul><li>Understand the effect age on pharmacokinetics and pharmacodynamics </li></ul><ul><li>Discuss risk factors for adverse drug events and ways to mitigate them </li></ul><ul><li>Understand the principles of drug prescribing for older patients </li></ul>
  3. 3. The Aging Imperative <ul><li>Persons aged 65y and older constitute 13% of the population and purchase 33% of all prescription medications </li></ul><ul><li>By 2040, 25% of the population will purchase 50% of all prescription drugs </li></ul>
  4. 4. Challenges of Geriatric Pharmacotherapy <ul><li>New drugs available each year </li></ul><ul><li>FDA approved and off-label indications are expanding </li></ul><ul><li>Changing managed-care formularies </li></ul><ul><li>Advanced understanding of drug-drug interactions </li></ul><ul><li>Increasing popularity of “nutriceuticals” </li></ul><ul><li>Multiple co-morbid states </li></ul><ul><li>Polypharmacy </li></ul><ul><li>Medication compliance </li></ul><ul><li>Effects of aging physiology on drug therapy </li></ul><ul><li>Medication cost </li></ul>
  5. 5. Pharmacokinetics (PK) <ul><li>Absorption </li></ul><ul><ul><li>bioavailability : the fraction of a drug dose reaching the systemic circulation </li></ul></ul><ul><li>Distribution </li></ul><ul><ul><li>locations in the body a drug penetrates expressed as volume per weight (e.g. L/kg) </li></ul></ul><ul><li>Metabolism </li></ul><ul><ul><li>drug conversion to alternate compounds which may be pharmacologically active or inactive </li></ul></ul><ul><li>Elimination </li></ul><ul><ul><li>a drug’s final route(s) of exit from the body expressed in terms of half-life or clearance </li></ul></ul>
  6. 6. Effects of Aging on Absorption <ul><li>Rate of absorption may be delayed </li></ul><ul><ul><li>Lower peak concentration </li></ul></ul><ul><ul><li>Delayed time to peak concentration </li></ul></ul><ul><li>Overall amount absorbed (bioavailability) is unchanged </li></ul>
  7. 7. Hepatic First-Pass Metabolism <ul><li>For drugs with extensive first-pass metabolism, bioavailability may increase because less drug is extracted by the liver </li></ul><ul><ul><li>Decreased liver mass </li></ul></ul><ul><ul><li>Decreased liver blood flow </li></ul></ul>
  8. 8. Factors Affecting Absorption <ul><li>Route of administration </li></ul><ul><li>What it taken with the drug </li></ul><ul><ul><li>Divalent cations (Ca, Mg, Fe) </li></ul></ul><ul><ul><li>Food, enteral feedings </li></ul></ul><ul><ul><li>Drugs that influence gastric pH </li></ul></ul><ul><ul><li>Drugs that promote or delay GI motility </li></ul></ul><ul><li>Comorbid conditions </li></ul><ul><li>Increased GI pH </li></ul><ul><li>Decreased gastric emptying </li></ul><ul><li>Dysphagia </li></ul>
  9. 9. Effects of Aging on Volume of Distribution (Vd) diazepam, valproic acid, phenytoin, warfarin  % of unbound or free drug (active)  plasma protein (albumin) quinidine, propranolol, erythromycin, amitriptyline  % of unbound or free drug (active)  plasma protein (  1 -acid glycoprotein) diazepam, trazodone  Vd for lipophilic drugs  fat stores digoxin  Vd for for drugs that bind to muscle  lean body mass ethanol, lithium  Vd for hydrophilic drugs  body water Examples Vd Effect Aging Effect
  10. 10. Aging Effects on Hepatic Metabolism <ul><li>Metabolic clearance of drugs by the liver may be reduced due to: </li></ul><ul><ul><li>decreased hepatic blood flow </li></ul></ul><ul><ul><li>decreased liver size and mass </li></ul></ul><ul><li>Examples : morphine, meperidine, metoprolol, propranolol, verapamil, amitryptyline, nortriptyline </li></ul>
  11. 11. Metabolic Pathways ** NOTE: Medications undergoing Phase II hepatic metabolism are generally preferred in the elderly due to inactive metabolites (no accumulation) lorazepam, oxazepam, temazepam Conversion to inactive metabolites Phase II : glucuronidation, conjugation, or acetylation diazepam, quinidine, piroxicam, theophylline Conversion to metabolites of lesser, equal, or greater Phase I : oxidation, hydroxylation, dealkylation, reduction Examples Effect Pathway
  12. 12. Other Factors Affecting Drug Metabolism <ul><li>Gender </li></ul><ul><li>Comorbid conditions </li></ul><ul><li>Smoking </li></ul><ul><li>Diet </li></ul><ul><li>Drug interactions </li></ul><ul><li>Race </li></ul><ul><li>Frailty </li></ul>
  13. 13. Concepts in Drug Elimination <ul><li>Half-life </li></ul><ul><ul><li>time for serum concentration of drug to decline by 50% (expressed in hours) </li></ul></ul><ul><li>Clearance </li></ul><ul><ul><li>volume of serum from which the drug is removed per unit of time (mL/min or L/hr) </li></ul></ul><ul><li>Reduced elimination  drug accumulation and toxicity </li></ul>
  14. 14. Effects of Aging on the Kidney <ul><li>Decreased kidney size </li></ul><ul><li>Decreased renal blood flow </li></ul><ul><li>Decreased number of functional nephrons </li></ul><ul><li>Decreased tubular secretion </li></ul><ul><li>Result:  glomerular filtration rate (GFR) </li></ul><ul><li>Decreased drug clearance : atenolol, gabapentin, H2 blockers, digoxin, allopurinol, quinolones </li></ul>
  15. 15. Estimating GFR in the Elderly <ul><li>Creatinine clearance (CrCl) is used to estimate glomerular rate </li></ul><ul><li>Serum creatinine alone not accurate in the elderly </li></ul><ul><ul><li> lean body mass  lower creatinine production </li></ul></ul><ul><ul><li> glomerular filtration rate </li></ul></ul><ul><li>Serum creatinine stays in normal range, masking change in creatinine clearance </li></ul>
  16. 16. Determining Creatinine Clearance <ul><li>Measure </li></ul><ul><ul><li>Time consuming </li></ul></ul><ul><ul><li>Requires 24 hr urine collection </li></ul></ul><ul><li>Estimate </li></ul><ul><ul><li>Cockroft Gault equation </li></ul></ul><ul><ul><li>(IBW in kg) x (140-age) </li></ul></ul><ul><ul><li>------------------------------ x (0.85 for females) </li></ul></ul><ul><ul><li>72 x (Scr in mg/dL) </li></ul></ul>
  17. 17. Example: Creatinine Clearance vs. Age in a 5’5”, 55 kg Woman 30 1.1 90 41 1.1 70 53 1.1 50 65 1.1 30 CrCl Scr Age
  18. 18. Limitations in Estimating CrCl <ul><li>Not all persons experience significant age-related decline in renal function </li></ul><ul><li>Some patient’s muscle mass is reduced beyond that of normal aging </li></ul><ul><ul><li>Suggest using 1 mg/dL if serum creatinine is less than normal (<0.7 mg/dL) </li></ul></ul><ul><ul><li>Not precise, may underestimate actual CrCl </li></ul></ul>
  19. 19. Pharmacodynamics (PD) <ul><li>Definition: the time course and intensity of pharmacologic effect of a drug </li></ul><ul><li>Age-related changes: </li></ul><ul><ul><li> sensitivity to sedation and psychomotor impairment with benzodiazepines </li></ul></ul><ul><ul><li> level and duration of pain relief with narcotic agents </li></ul></ul><ul><ul><li> drowsiness and lateral sway with alcohol </li></ul></ul><ul><ul><li> HR response to beta-blockers </li></ul></ul><ul><ul><li> sensitivity to anti-cholinergic agents </li></ul></ul><ul><ul><li> cardiac sensitivity to digoxin </li></ul></ul>
  20. 20. PK and PD Summary <ul><li>PK and PD changes generally result in decreased clearance and increased sensitivity to medications in older adults </li></ul><ul><li>Use of lower doses, longer intervals, slower titration are helpful in decreasing the risk of drug intolerance and toxicity </li></ul><ul><li>Careful monitoring is necessary to ensure successful outcomes </li></ul>
  21. 21. Optimal Pharmacotherapy <ul><li>Balance between overprescribing and underprescribing </li></ul><ul><ul><li>Correct drug </li></ul></ul><ul><ul><li>Correct dose </li></ul></ul><ul><ul><li>Targets appropriate condition </li></ul></ul><ul><ul><li>Is appropriate for the patient </li></ul></ul><ul><ul><li>Avoid “a pill for every ill” </li></ul></ul><ul><ul><li>Always consider non-pharmacologic therapy </li></ul></ul>
  22. 22. Consequences of Overprescribing <ul><li>Adverse drug events (ADEs) </li></ul><ul><li>Drug interactions </li></ul><ul><li>Duplication of drug therapy </li></ul><ul><li>Decreased quality of life </li></ul><ul><li>Unnecessary cost </li></ul><ul><li>Medication non-adherence </li></ul>
  23. 23. Adverse Drug Events (ADEs) <ul><li>Responsible for 5-28% of acute geriatric hospital admissions </li></ul><ul><li>Greater than 95% of ADEs in the elderly are considered predictable and approximately 50% are considered preventable </li></ul><ul><li>Most errors occur at the ordering and monitoring stages </li></ul>
  24. 24. Most Common Medications Associated with ADEs in the Elderly <ul><li>Opioid analgesics </li></ul><ul><li>NSAIDs </li></ul><ul><li>Anticholinergics </li></ul><ul><li>Benzodiazepines </li></ul><ul><li>Also : cardiovascular agents, CNS agents, and musculoskeletal agents </li></ul><ul><li>Adverse Drug Reaction Risk Factors in Older Outpatients. Am J Ger Pharmacotherapy 2003;1(2):82-89. </li></ul>
  25. 25. The Beers Criteria antihistamines diphenhydramine dipyridamole ergot mesyloids indomethacin muscle relaxants amitriptyline chlorpropamide digoxin >0.125mg/d disopyramide GI antispasmodics meperidine methyldopa pentazocine ticlopidine High Potential for Less Severe ADE High Potential for Severe ADE
  26. 26. Patient Risk Factors for ADEs <ul><li>Polypharmacy </li></ul><ul><li>Multiple co-morbid conditions </li></ul><ul><li>Prior adverse drug event </li></ul><ul><li>Low body weight or body mass index </li></ul><ul><li>Age > 85 years </li></ul><ul><li>Estimated CrCl <50 mL/min </li></ul>
  27. 27. Prescribing Cascade <ul><li>ADE interpreted as new medical condition </li></ul>Drug 1 Drug 2 ADE interpreted as new medical condition Drug 3 Rochon PA, Gurwitz JH. Optimizing drug treatment in elderly people: the prescribing cascase. BMJ 1997;315:1097.
  28. 28. Drug-Drug Interactions (DDIs) <ul><li>May lead to adverse drug events </li></ul><ul><li>Likelihood  as number of medications  </li></ul><ul><li>Most common DDIs: </li></ul><ul><ul><li>cardiovascular drugs </li></ul></ul><ul><ul><li>psychotropic drugs </li></ul></ul><ul><li>Most common drug interaction effects: </li></ul><ul><ul><li>confusion </li></ul></ul><ul><ul><li>cognitive impairment </li></ul></ul><ul><ul><li>hypotension </li></ul></ul><ul><ul><li>acute renal failure </li></ul></ul>
  29. 29. Concepts in Drug-Drug Interactions <ul><li>Absorption may be  or  </li></ul><ul><li>Drugs with similar effects can result additive effects </li></ul><ul><li>Drugs with opposite effects can antagonize each other </li></ul><ul><li>Drug metabolism may be inhibited or induced </li></ul>
  30. 30. Common Drug-Drug Interactions Doucet J, Chassagne P, Trivalle C, et al. Drug-drug interactions related to hospital admissions in older adults: a prospective study of 1000 patients. J Am Geriatr Soc 1996;44(9):944-948. Sedation; confusion; falls Benzodiazepine + antidepressant Benzodiazepine + antipsychotic Electrolyte imbalance; dehydration Diuretic + diuretic Bradycardia, arrhythmia Digoxin + antiarrhythmic Hypotension CCB/nitrate/vasodilator/diuretic Electrolyte imbalance; arrhythmia Digoxin + diuretic Antiarrhythmic + diuretic Hyperkalemia, hypotension ACE inhibitor + K sparing diuretic Hyperkalemia ACE inhibitor + potassium Risk Combination
  31. 31. Drug-Disease Interactions <ul><li>Obesity alters Vd of lipophilic drugs </li></ul><ul><li>Ascites alters Vd of hydrophilic drugs </li></ul><ul><li>Dementia may  sensitivity, induce paradoxical reactions to drugs with CNS or anticholinergic activity </li></ul><ul><li>Renal or hepatic impairment may impair metabolism and excretions of drugs </li></ul><ul><li>Drugs may exacerbate a medical condition </li></ul>
  32. 32. Common Drug-Disease Interactions Fluid retention; decreased effectiveness of diuretics NSAIDs + HTN Increased ulcer and bleeding risk NSAIDs + gastropathy Hypoxia; increased risk of lactic acidosis Metformin + CHF Exacerbation of constipation CCB + constipation Narcotics + constipation Anticholinergics + constipation Urinary retention BPH + anticholinergics Fluid retention; CHF exacerbation NSAIDs + CHF Thiazolidinediones + CHF Risk Combination
  33. 33. Principles of Prescribing in the Elderly <ul><li>Avoid prescribing prior to diagnosis </li></ul><ul><li>Start with a low dose and titrate slowly </li></ul><ul><li>Avoid starting 2 agents at the same time </li></ul><ul><li>Reach therapeutic dose before switching or adding agents </li></ul><ul><li>Consider non-pharmacologic agents </li></ul>
  34. 34. Prescribing Appropriately <ul><li>Determine therapeutic endpoints and plan for assessment </li></ul><ul><li>Consider risk vs. benefit </li></ul><ul><li>Avoid prescribing to treat side effect of another drug </li></ul><ul><li>Use 1 medication to treat 2 conditions </li></ul><ul><li>Consider drug-drug and drug-disease interactions </li></ul><ul><li>Use simplest regimen possible </li></ul><ul><li>Adjust doses for renal and hepatic impairment </li></ul><ul><li>Avoid therapeutic duplication </li></ul><ul><li>Use least expensive alternative </li></ul>
  35. 35. Preventing Polypharmacy <ul><li>Review medications regularly and each time a new medication started or dose is changed </li></ul><ul><li>Maintain accurate medication records (include vitamins, OTCs, and herbals) </li></ul><ul><li>“Brown-bag” </li></ul>
  36. 36. Non-Adherence <ul><li>Rate may be as high as 50% in the elderly </li></ul><ul><li>Factors in non-adherence </li></ul><ul><ul><li>Financial, cognitive, or functional status </li></ul></ul><ul><ul><li>Beliefs and understanding about disease and medications </li></ul></ul>
  37. 37. Enhancing Medication Adherence <ul><li>Avoid newer, more expensive medications that are not shown to be superior to less expensive generic alternatives </li></ul><ul><li>Simplify the regimen </li></ul><ul><li>Utilize pill organizers or drug calendars </li></ul><ul><li>Educate patient on medication purpose, benefits, safety, and potential ADEs </li></ul>
  38. 38. Summary <ul><li>Successful pharmacotherapy means using the correct drug at the correct dose for the correct indication in an individual patient </li></ul><ul><li>Age alters PK and PD </li></ul><ul><li>ADEs are common among the elderly </li></ul><ul><li>Risk of ADEs can be minimized by appropriate prescribing </li></ul>
  39. 39. Questions
  40. 40. Case 1 <ul><li>A 73 y/o woman is seen for a routine visit: </li></ul><ul><li>Blood pressure is 134/84 mmHg and HgbA1c is 8.1% </li></ul><ul><li>Metformin is increased to 500mg bid and other daily medications are continued: amlodipine 5mg qd, timolol ophthalmic 1 drop ou bid, aspirin 81mg qd, and calcium citrate 500mg qd </li></ul><ul><li>At 6 month follow-up, blood pressure is 130/82 mmHg, finger stick BS is 93 mg/dL, and HgbA1c is 9.2% </li></ul>
  41. 41. Case 1 <ul><li>Which of the following is the most likely explanation for the increase in HgA1c? </li></ul><ul><li>Incorrect choice of antidiabetic medication </li></ul><ul><li>Inadequate dose of antidiabetic medication </li></ul><ul><li>Long-term non-adherence with medication </li></ul><ul><li>Altered pharmacokinetics </li></ul><ul><li>Altered drug absorption </li></ul>
  42. 42. Case 1 <ul><li>Which of the following is the most likely explanation for the increase in HgA1c? </li></ul><ul><li>Incorrect choice of antidiabetic medication </li></ul><ul><li>Inadequate dose of antidiabetic medication </li></ul><ul><li>Long-term non-adherence with medication </li></ul><ul><li>Altered pharmacokinetics </li></ul><ul><li>Altered drug absorption </li></ul>
  43. 43. Case 2 <ul><li>A 68 y/o woman has a hx of Parkinson’s disease, hypertension, and osteoarthritis </li></ul><ul><li>Daily medications are carbidopa 25mg/levodopa 100mg tid, selegiline 5mg bid, losartan 50mg, celecoxib 200mg qd, and MVI qd </li></ul><ul><li>In the past 3 weeks, she has taken diphenhydramine at bedtime for insomnia </li></ul><ul><li>The patient now reports the onset of urinary incontinence </li></ul>
  44. 44. Case 2 <ul><li>Which of the following is the most appropriate intervention? </li></ul><ul><li>Discontinue celecoxib </li></ul><ul><li>Discontinue diphenhydramine </li></ul><ul><li>Discontinue losartan </li></ul><ul><li>Substitute fosinopril for losartan </li></ul><ul><li>Begin tolterodine </li></ul>
  45. 45. Case 2 <ul><li>Which of the following is the most appropriate intervention? </li></ul><ul><li>Discontinue celecoxib </li></ul><ul><li>Discontinue diphenhydramine </li></ul><ul><li>Discontinue losartan </li></ul><ul><li>Substitute fosinopril for losartan </li></ul><ul><li>Begin tolterodine </li></ul>
  46. 46. Case 3 <ul><li>An 83 y/o woman is brought to the ER because of dizziness on standing, followed by brief LOC; the patient now feels well </li></ul><ul><li>She has hypertension but is otherwise healthy </li></ul><ul><li>Daily medications: metoprolol 50mg/d, captopril 25 mg/d, and nitroglycerin 0.4mg SL prn </li></ul><ul><li>BP is 130/70 mmHg sitting and 100/60 standing; PE is otherwise normal; CBC, BUN, ECG, CMP are all normal </li></ul>
  47. 47. Case 3 <ul><li>Which of the following is the most likely cause of this syncopal episode? </li></ul><ul><li>Sepsis </li></ul><ul><li>Drug-related event </li></ul><ul><li>Hypovolemic hypotensive episode </li></ul><ul><li>Cardiogenic shock </li></ul><ul><li>Unidentifiable cause </li></ul>
  48. 48. Case 3 <ul><li>Which of the following is the most likely cause of this syncopal episode? </li></ul><ul><li>Sepsis </li></ul><ul><li>Drug-related event </li></ul><ul><li>Hypovolemic hypotensive episode </li></ul><ul><li>Cardiogenic shock </li></ul><ul><li>Unidentifiable cause </li></ul>