Geriatric PharmacotherapyLinda Farho, Pharm.D.University of Nebraska Medical CenterCollege of Pharmacy

ObjectivesUnderstand key issues in geriatric pharmacotherapyUnderstand the effect age on pharmacokinetics and pharmacodynamicsDiscuss risk factors for adverse drug events and ways to mitigate themUnderstand the principles of drug prescribing for older patients

The Aging ImperativePersons 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

Challenges of Geriatric PharmacotherapyNew drugs available each yearFDA approved and off-label indications are expandingChanging managed-care formulariesAdvanced understanding of drug-drug interactionsIncreasing popularity of nutriceuticalsMultiple co-morbid statesPolypharmacyMedication complianceEffects of aging physiology on drug therapyMedication cost

Pharmacokinetics (PK)Absorptionbioavailability: the fraction of a drug dose reaching the systemic circulationDistributionlocations in the body a drug penetrates expressed as volume per weight (e.g. L/kg)Metabolismdrug conversion to alternate compounds which may be pharmacologically active or inactiveEliminationa drugs final route(s) of exit from the body expressed in terms of half-life or clearance

Effects of Aging on AbsorptionRate of absorption may be delayedLower peak concentrationDelayed time to peak concentrationOverall amount absorbed (bioavailability) is unchanged

Hepatic First-Pass MetabolismFor drugs with extensive first-pass metabolism, bioavailability may increase because less drug is extracted by the liverDecreased liver massDecreased liver blood flow

Factors Affecting AbsorptionRoute of administrationWhat it taken with the drugDivalent cations (Ca, Mg, Fe)Food, enteral feedingsDrugs that influence gastric pHDrugs that promote or delay GI motilityComorbid conditionsIncreased GI pHDecreased gastric emptyingDysphagia

Effects of Aging on Volume of Distribution (Vd)

Aging Effects on Hepatic MetabolismMetabolic clearance of drugs by the liver may be reduced due to:decreased hepatic blood flowdecreased liver size and massExamples: morphine, meperidine, metoprolol, propranolol, verapamil, amitryptyline, nortriptyline

Metabolic Pathways** NOTE: Medications undergoing Phase II hepatic metabolism are generally preferred in the elderly due to inactive metabolites (no accumulation)

Other Factors Affecting Drug MetabolismGenderComorbid conditionsSmokingDietDrug interactionsRaceFrailty

Concepts in Drug EliminationHalf-lifetime for serum concentration of drug to decline by 50% (expressed in hours)Clearancevolume of serum from which the drug is removed per unit of time (mL/min or L/hr)Reduced elimination drug accumulation and toxicity

Effects of Aging on the KidneyDecreased kidney sizeDecreased renal blood flowDecreased number of functional nephronsDecreased tubular secretionResult: glomerular filtration rate (GFR)Decreased drug clearance: atenolol, gabapentin, H2 blockers, digoxin, allopurinol, quinolones

Estimating GFR in the ElderlyCreatinine clearance (CrCl) is used to estimate glomerular rateSerum creatinine alone not accurate in the elderly lean body mass lower creatinine production glomerular filtration rateSerum creatinine stays in normal range, masking change in creatinine clearance

Determining Creatinine ClearanceMeasureTime consumingRequires 24 hr urine collection

EstimateCockroft Gault equation

(IBW in kg) x (140-age)------------------------------ x (0.85 for females) 72 x (Scr in mg/dL)

Example: Creatinine Clearance vs. Age in a 55, 55 kg Woman

Limitations in Estimating CrClNot all persons experience significant age-related decline in renal function

Some patients muscle mass is reduced beyond that of normal agingSuggest using 1 mg/dL if serum creatinine is less than normal (

Pharmacodynamics (PD)Definition: the time course and intensity of pharmacologic effect of a drugAge-related changes: sensitivity to sedation and psychomotor impairment with benzodiazepines level and duration of pain relief with narcotic agents drowsiness and lateral sway with alcohol HR response to beta-blockers sensitivity to anti-cholinergic agents cardiac sensitivity to digoxin

PK and PD SummaryPK and PD changes generally result in decreased clearance and increased sensitivity to medications in older adultsUse of lower doses, longer intervals, slower titration are helpful in decreasing the risk of drug intolerance and toxicityCareful monitoring is necessary to ensure successful outcomes

Optimal PharmacotherapyBalance between overprescribing and underprescribingCorrect drugCorrect doseTargets appropriate conditionIs appropriate for the patient

Avoid a pill for every illAlways consider non-pharmacologic therapy

Consequences of OverprescribingAdverse drug events (ADEs)Drug interactionsDuplication of drug therapyDecreased quality of lifeUnnecessary costMedication non-adherence

Adverse Drug Events (ADEs)Responsible for 5-28% of acute geriatric hospital admissionsGreater than 95% of ADEs in the elderly are considered predictable and approximately 50% are considered preventableMost errors occur at the ordering and monitoring stages

Most Common Medications Associated with ADEs in the Elderly

Opioid analgesicsNSAIDsAnticholinergicsBenzodiazepinesAlso: cardiovascular agents, CNS agents, and musculoskeletal agents

Adverse Drug Reaction Risk Factors in Older Outpatients. Am J Ger Pharmacotherapy 2003;1(2):82-89.

The Beers Criteria

Patient Risk Factors for ADEsPolypharmacyMultiple co-morbid conditionsPrior adverse drug eventLow body weight or body mass indexAge > 85 yearsEstimated CrCl

Prescribing CascadeADE interpreted as new medical conditionDrug 1Drug 2ADE interpreted as new medical conditionDrug 3Rochon PA, Gurwitz JH. Optimizing drug treatment in elderly people: the prescribing cascase. BMJ 1997;315:1097.

Drug-Drug Interactions (DDIs)May lead to adverse drug eventsLikelihood as number of medications Most common DDIs:cardiovascular drugspsychotropic drugsMost common drug interaction effects:confusion cognitive impairmenthypotensionacute renal failure

Concepts in Drug-Drug InteractionsAbsorption may be or Drugs with similar effects can result additive effectsDrugs with opposite effects can antagonize each otherDrug metabolism may be inhibited or induced

Common Drug-Drug InteractionsDoucet 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.

Drug-Disease InteractionsObesity alters Vd of lipophilic drugsAscites alters Vd of hydrophilic drugsDementia may sensitivity, induce paradoxical reactions to drugs with CNS or anticholinergic activityRenal or hepatic impairment may impair metabolism and excretions of drugsDrugs may exacerbate a medical condition

Common Drug-Disease Interactions

Principles of Prescribing in the ElderlyAvoid prescribing prior to diagnosisStart with a low dose and titrate slowlyAvoid starting 2 agents at the same timeReach therapeutic dose before switching or adding agentsConsider non-pharmacologic agents

Prescribing AppropriatelyDetermine therapeutic endpoints and plan for assessmentConsider risk vs. benefitAvoid prescribing to treat side effect of another drugUse 1 medication to treat 2 conditionsConsider drug-drug and drug-disease interactionsUse simplest regimen possibleAdjust doses for renal and hepatic impairmentAvoid therapeutic duplicationUse least expensive alternative

Preventing PolypharmacyReview medications regularly and each time a new medication started or dose is changedMaintain accurate medication records (include vitamins, OTCs, and herbals)Brown-bag

Non-AdherenceRate may be as high as 50% in the elderly

Factors in non-adherenceFinancial, cognitive, or functional statusBeliefs and understanding about disease and medications

Enhancing Medication AdherenceAvoid newer, more expensive medications that are not shown to be superior to less expensive generic alternativesSimplify the regimenUtilize pill organizers or drug calendarsEducate patient on medication purpose, benefits, safety, and potential ADEs

SummarySuccessful pharmacotherapy means using the correct drug at the correct dose for the correct indication in an individual patientAge alters PK and PDADEs are common among the elderlyRisk of ADEs can be minimized by appropriate prescribing

Questions

Case 1A 73 y/o woman is seen for a routine visit:

Blood pressure is 134/84 mmHg and HgbA1c is 8.1%

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

At 6 month follow-up, blood pressure is 130/82 mmHg, finger stick BS is 93 mg/dL, and HgbA1c is 9.2%

Case 1Which of the following is the most likely explanation for the increase in HgA1c?

Incorrect choice of antidiabetic medicationInadequate dose of antidiabetic medicationLong-term non-adherence with medicationAltered pharmacokineticsAltered drug absorption

Case 1Which of the following is the most likely explanation for the increase in HgA1c?

Incorrect choice of antidiabetic medicationInadequate dose of antidiabetic medicationLong-term non-adherence with medicationAltered pharmacokineticsAltered drug absorption

Case 2A 68 y/o woman has a hx of Parkinsons disease, hypertension, and osteoarthritis

Daily medications are carbidopa 25mg/levodopa 100mg tid, selegiline 5mg bid, losartan 50mg, celecoxib 200mg qd, and MVI qd

In the past 3 weeks, she has taken diphenhydramine at bedtime for insomnia

The patient now reports the onset of urinary incontinence

Case 2Which of the following is the most appropriate intervention?

Discontinue celecoxibDiscontinue diphenhydramineDiscontinue losartanSubstitute fosinopril for losartanBegin tolterodine

Case 2Which of the following is the most appropriate intervention?

Discontinue celecoxibDiscontinue diphenhydramineDiscontinue losartanSubstitute fosinopril for losartanBegin tolterodine

Case 3An 83 y/o woman is brought to the ER because of dizziness on standing, followed by brief LOC; the patient now feels well

She has hypertension but is otherwise healthy

Daily medications: metoprolol 50mg/d, captopril 25 mg/d, and nitroglycerin 0.4mg SL prn

BP is 130/70 mmHg sitting and 100/60 standing; PE is otherwise normal; CBC, BUN, ECG, CMP are all normal

Case 3Which of the following is the most likely cause of this syncopal episode?

SepsisDrug-related eventHypovolemic hypotensive episodeCardiogenic shockUnidentifiable cause

Case 3Which of the following is the most likely cause of this syncopal episode?

SepsisDrug-related eventHypovolemic hypotensive episodeCardiogenic shockUnidentifiable cause