Geriatric Pharmacotherapy Linda Farho, Pharm.D. University of Nebraska Medical Center College of Pharmacy

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  • Geriatric Pharmacotherapy Linda Farho, Pharm.D. University of Nebraska Medical Center College of Pharmacy
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  • Objectives 1. Understand key issues in geriatric pharmacotherapy 2. Understand the effect age on pharmacokinetics and pharmacodynamics 3. Discuss risk factors for adverse drug events and ways to mitigate them 4. Understand the principles of drug prescribing for older patients
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  • The Aging Imperative Persons aged 65y and older constitute 13% of the population and purchase 33% of all prescription medications Persons aged 65y and older constitute 13% of the population and purchase 33% of all prescription medications By 2040, 25% of the population will purchase 50% of all prescription drugs By 2040, 25% of the population will purchase 50% of all prescription drugs
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  • Challenges of Geriatric Pharmacotherapy New drugs available each year New drugs available each year FDA approved and off-label indications are expanding FDA approved and off-label indications are expanding Changing managed-care formularies Changing managed-care formularies Advanced understanding of drug-drug interactions Advanced understanding of drug-drug interactions Increasing popularity of nutriceuticals Increasing popularity of nutriceuticals Multiple co-morbid states Multiple co-morbid states Polypharmacy Polypharmacy Medication compliance Medication compliance Effects of aging physiology on drug therapy Effects of aging physiology on drug therapy Medication cost Medication cost
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  • Pharmacokinetics (PK) Absorption Absorption bioavailability: the fraction of a drug dose reaching the systemic circulation Distribution Distribution locations in the body a drug penetrates expressed as volume per weight (e.g. L/kg) Metabolism Metabolism drug conversion to alternate compounds which may be pharmacologically active or inactive Elimination Elimination a drugs final route(s) of exit from the body expressed in terms of half-life or clearance
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  • Effects of Aging on Absorption Rate of absorption may be delayed Rate of absorption may be delayed Lower peak concentration Delayed time to peak concentration Overall amount absorbed (bioavailability) is unchanged Overall amount absorbed (bioavailability) is unchanged
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  • Hepatic First-Pass Metabolism For drugs with extensive first-pass metabolism, bioavailability may increase because less drug is extracted by the liver For drugs with extensive first-pass metabolism, bioavailability may increase because less drug is extracted by the liver Decreased liver mass Decreased liver blood flow
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  • Factors Affecting Absorption Route of administration Route of administration What it taken with the drug What it taken with the drug Divalent cations (Ca, Mg, Fe) Food, enteral feedings Drugs that influence gastric pH Drugs that promote or delay GI motility Comorbid conditions Comorbid conditions Increased GI pH Increased GI pH Decreased gastric emptying Decreased gastric emptying Dysphagia Dysphagia
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  • Effects of Aging on Volume of Distribution (Vd) Aging Effect Vd Effect Examples body water Vd for hydrophilic drugs ethanol, lithium lean body mass Vd for for drugs that bind to muscle digoxin fat stores Vd for lipophilic drugs diazepam, trazodone plasma protein (albumin) % of unbound or free drug (active) diazepam, valproic acid, phenytoin, warfarin plasma protein ( 1 -acid glycoprotein) % of unbound or free drug (active) quinidine, propranolol, erythromycin, amitriptyline
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  • Aging Effects on Hepatic Metabolism Metabolic clearance of drugs by the liver may be reduced due to: Metabolic clearance of drugs by the liver may be reduced due to: decreased hepatic blood flow decreased liver size and mass Examples: morphine, meperidine, metoprolol, propranolol, verapamil, amitryptyline, nortriptyline Examples: morphine, meperidine, metoprolol, propranolol, verapamil, amitryptyline, nortriptyline
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  • Metabolic Pathways PathwayEffectExamples Phase I: oxidation, hydroxylation, dealkylation, reduction Conversion to metabolites of lesser, equal, or greater diazepam, quinidine, piroxicam, theophylline Phase II: glucuronidation, conjugation, or acetylation Conversion to inactive metabolites lorazepam, oxazepam, temazepam ** NOTE: Medications undergoing Phase II hepatic metabolism are generally preferred in the elderly due to inactive metabolites (no accumulation)
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  • Other Factors Affecting Drug Metabolism Gender Gender Comorbid conditions Comorbid conditions Smoking Smoking Diet Diet Drug interactions Drug interactions Race Race Frailty Frailty
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  • Concepts in Drug Elimination Half-life Half-life time for serum concentration of drug to decline by 50% (expressed in hours) Clearance Clearance volume of serum from which the drug is removed per unit of time (mL/min or L/hr) Reduced elimination drug accumulation and toxicity Reduced elimination drug accumulation and toxicity
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  • Effects of Aging on the Kidney Decreased kidney size Decreased kidney size Decreased renal blood flow Decreased renal blood flow Decreased number of functional nephrons Decreased number of functional nephrons Decreased tubular secretion Decreased tubular secretion Result: glomerular filtration rate (GFR) Result: glomerular filtration rate (GFR) Decreased drug clearance: atenolol, gabapentin, H2 blockers, digoxin, allopurinol, quinolones Decreased drug clearance: atenolol, gabapentin, H2 blockers, digoxin, allopurinol, quinolones
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  • Estimating GFR in the Elderly Creatinine clearance (CrCl) is used to estimate glomerular rate Creatinine clearance (CrCl) is used to estimate glomerular rate Serum creatinine alone not accurate in the elderly Serum creatinine alone not accurate in the elderly lean body mass lower creatinine production glomerular filtration rate Serum creatinine stays in normal range, masking change in creatinine clearance Serum creatinine stays in normal range, masking change in creatinine clearance
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  • Determining Creatinine Clearance Measure Measure Time consuming Requires 24 hr urine collection Estimate Estimate Cockroft Gault equation (IBW in kg) x (140-age) ------------------------------ x (0.85 for females) 72 x (Scr in mg/dL) 72 x (Scr in mg/dL)
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  • Example: Creatinine Clearance vs. Age in a 55, 55 kg Woman 301.190 411.170 531.150 651.130CrClScrAge
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  • Limitations in Estimating CrCl Not all persons experience significant age- related decline in renal function Not all persons experience significant age- related decline in renal function Some patients muscle mass is reduced beyond that of normal aging Some patients muscle mass is reduced beyond that of normal aging Suggest using 1 mg/dL if serum creatinine is less than normal (
  • The Beers Criteria High Potential for Severe ADE High Potential for Less Severe ADE amitriptylinechlorpropamide digoxin >0.125mg/d disopyramide GI antispasmodics meperidinemethyldopapentazocineticlopidineantihistaminesdiphenhydraminedipyridamole ergot mesyloids indomethacin muscle relaxants
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  • Patient Risk Factors for ADEs Polypharmacy Polypharmacy Multiple co-morbid conditions Multiple co-morbid conditions Prior adverse drug event Prior adverse drug event Low body weight or body mass index Low body weight or body mass index Age > 85 years Age > 85 years Estimated CrCl
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  • Prescribing Cascade Drug 1 ADE interpreted as new medical condition 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.
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  • Drug-Drug Interactions (DDIs) May lead to adverse drug events May lead to adverse drug events Likelihood as number of medications Likelihood as number of medications Most common DDIs: Most common DDIs: cardiovascular drugs psychotropic drugs Most common drug interaction effects: Most common drug interaction effects: confusion cognitive impairment hypotension acute renal failure
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  • Concepts in Drug-Drug Interactions Absorption may be or Absorption may be or Drugs with similar effects can result additive effects Drugs with similar effects can result additive effects Drugs with opposite effects can antagonize each other Drugs with opposite effects can antagonize each other Drug metabolism may be inhibited or induced Drug metabolism may be inhibited or induced
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  • Common Drug-Drug Interactions CombinationRisk ACE inhibitor + potassium Hyperkalemia ACE inhibitor + K sparing diuretic Hyperkalemia, hypotension Digoxin + antiarrhythmic Bradycardia, arrhythmia Digoxin + diuretic Antiarrhythmic + diuretic Electrolyte imbalance; arrhythmia Diuretic + diuretic Electrolyte imbalance; dehydration Benzodiazepine + antidepressant Benzodiazepine + antipsychotic Sedation; confusion; falls CCB/nitrate/vasodilator/diureticHypotension 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.
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  • Drug-Disease Interactions Obesity alters Vd of lipophilic drugs Obesity alters Vd of lipophilic drugs Ascites alters Vd of hydroph

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