Geriatric Pharmacotherapy

ObjectivesUnderstand key issues in geriatric pharmacotherapyUnderstand the effect age on pharmacokinetics and pharmacodynamicsDiscuss risk factors for adverse drug events and ways to diminish 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 expandingAdvanced understanding of drug-drug interactionsIncreasing popularity of nutriceuticalsPolypharmacyMedication 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

Age-related changes which affect pharmacokinetics

decreased lean body massaffects drug distributiondecreased levels of serum albuminaffects drug distributiondecreased liver functionaffects drug metabolism/biotransformationdecreased renal functionaffects drug elimination

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 motilityIncreased GI pHDecreased gastric emptyingDysphagia

Effects of Aging on Volume of Distribution (Vd)

Aging EffectVd EffectExamples body water Vd for hydrophilic drugsethanol, lithium lean body mass Vd for for drugs that bind to muscledigoxin fat stores Vd for lipophilic drugsdiazepam, 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

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)

PathwayEffectExamplesPhase I: oxidation, hydroxylation, dealkylation, reductionConversion to metabolites of lesser, equal, or greaterdiazepam, quinidine, piroxicam, theophyllinePhase II: glucuronidation, conjugation, or acetylationConversion to inactive metaboliteslorazepam, oxazepam, temazepam

enzymatic reactions preparing drugs for elimination Phase I reactions:oxidation: catalyzed by cytochrome P450 enzymesPhase II reactions:conjugation: addition of small chemical groups which increase solubility to facilitate elimination

decrease in hepatic blood flow often associated with decreased First Pass EffectPhase I metabolism decreasedPhase II metabolism generally preserved

Other Factors Affecting Drug MetabolismGenderSmokingDietDrug interactionsRaceWeakness

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)

Drug elimination changes in the elderlydecrease in renal functionsdecreased blood flow to the kidneysdecreased glomerular filtrationdecreased tubular secretiondecline in creatinine clearance

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

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

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 cost

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 Criteria

High Potential for Severe ADEHigh Potential for Less Severe ADEamitriptylinechlorpropamidedigoxin >0.125mg/ddisopyramideGI antispasmodicsmeperidinemethyldopapentazocineticlopidineantihistamines diphenhydraminedipyridamoleergot mesyloidsindomethacinmuscle relaxants

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

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.

CombinationRiskACE inhibitor + potassiumHyperkalemiaACE inhibitor + K sparing diureticHyperkalemia, hypotensionDigoxin + antiarrhythmicBradycardia, arrhythmiaDigoxin + diureticAntiarrhythmic + diureticElectrolyte imbalance; arrhythmiaDiuretic + diureticElectrolyte imbalance; dehydrationBenzodiazepine + antidepressantBenzodiazepine + antipsychoticSedation; confusion; fallsNitrate/vasodilator/diureticHypotension

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 worsen a medical condition

Common Drug-Disease Interactions

CombinationRiskNSAIDs + CHFThiazolidinediones + CHFFluid retention; CHF exacerbationBPH + anticholinergicsUrinary retentionNarcotics + constipationAnticholinergics + constipationExacerbation of constipationMetformin + CHFHypoxia; increased risk of lactic acidosisNSAIDs + gastropathyIncreased ulcer and bleeding riskNSAIDs + HTNFluid retention; decreased effectiveness of diuretics

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

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