TERAPI FARMAKOLOGI TERAPI FARMAKOLOGI PADA GERIATRIPADA GERIATRI

TERAPI FARMAKOLOGI TERAPI FARMAKOLOGI PADA GERIATRIPADA GERIATRI

Geriatri ≥ 65 tahun, 75 s/d 85 (Old old), ≥ 85 Geriatri ≥ 65 tahun, 75 s/d 85 (Old old), ≥ 85 tahun( Oldest old), tahun( Oldest old),

Cabang kedokteran yg konsen thd aging Cabang kedokteran yg konsen thd aging proses:proses:

Pencegahan, diagnosis dan terapi.Pencegahan, diagnosis dan terapi. Objektif:Objektif:

Pengaruh usia thd farmakokinetik dan Pengaruh usia thd farmakokinetik dan farmakodinamikfarmakodinamik

Memahami prinsip-prinsip peresepan obat pd orang Memahami prinsip-prinsip peresepan obat pd orang tuatua

Multiple comorbid stateMultiple comorbid state PolifarmasiPolifarmasi Resiko adverse drug eventsResiko adverse drug events Tingkat kepatuhan minum obatTingkat kepatuhan minum obat BiayaBiaya

Fakta berkaitan dgn geriatriFakta berkaitan dgn geriatri

Pasien berumur 65 th atau lebih Pasien berumur 65 th atau lebih mencakup 13% dari populasi dan mencakup 13% dari populasi dan membelanjakan 33% obat-obatan yg membelanjakan 33% obat-obatan yg diresepkan.diresepkan.

Tahun 2040, geriatri mencakup 25% Tahun 2040, geriatri mencakup 25% populasi dan membelanjakan 50% populasi dan membelanjakan 50% obat-obat yg diresepkan.obat-obat yg diresepkan.

Pharmacokinetics (PK)Pharmacokinetics (PK) AbsorptionAbsorption

bioavailabilitybioavailability: the fraction of a drug dose : the fraction of a drug dose reaching the systemic circulationreaching the systemic circulation

DistributionDistribution locations in the body a drug penetrates expressed locations in the body a drug penetrates expressed

as volume per weight (e.g. L/kg)as volume per weight (e.g. L/kg)

MetabolismMetabolism drug conversion to alternate compounds which drug conversion to alternate compounds which

may be pharmacologically active or inactivemay be pharmacologically active or inactive

EliminationElimination a drug’s final route(s) of exit from the body a drug’s final route(s) of exit from the body

expressed in terms of half-life or clearanceexpressed in terms of half-life or clearance

Efek usia thd Efek usia thd AbsorpsiAbsorpsi

Kecepatan absorpsi terlambat:Kecepatan absorpsi terlambat: Konsentrasi puncak obat lebih rendahKonsentrasi puncak obat lebih rendah Waktu mencapai konsentrasi puncak Waktu mencapai konsentrasi puncak

teterrlambatlambat

Jumlah obat yg diabsorpsi Jumlah obat yg diabsorpsi (bioavailability) tidak berubah(bioavailability) tidak berubah

Hepatic First-Pass Hepatic First-Pass MetabolismMetabolism

For drugs with extensive first-For drugs with extensive first-pass metabolism, bioavailability pass metabolism, bioavailability may increase because less drug may increase because less drug is extracted by the liveris extracted by the liver Decreased liver massDecreased liver mass Decreased liver blood flowDecreased liver blood flow

Faktor-faktor yg Faktor-faktor yg mempengaruhi absorpsi mempengaruhi absorpsi

obatobat Route of administrationRoute of administration What it taken with the drugWhat it taken with the drug

Divalent cations (Ca, Mg, Fe)Divalent cations (Ca, Mg, Fe) Food, enteral feedingsFood, enteral feedings Drugs that influence gastric pHDrugs that influence gastric pH

((Increased GI pHIncreased GI pH)) Drugs that promote or delay GI motilityDrugs that promote or delay GI motility

Comorbid conditionsComorbid conditions Decreased gastric emptyingDecreased gastric emptying DysphagiaDysphagia

Effects of Aging on Volume of Effects of Aging on Volume of Distribution (Vd)Distribution (Vd)

Aging EffectAging Effect Vd EffectVd Effect ExamplesExamples body waterbody water Vd for Vd for

hydrophilic hydrophilic drugsdrugs

ethanol, lithiumethanol, lithium

lean body masslean body mass Vd for for Vd for for drugs that bind drugs that bind to muscleto muscle

digoxindigoxin

fat storesfat stores Vd for Vd for lipophilic drugslipophilic drugs

diazepam, diazepam, trazodonetrazodone

plasma protein plasma protein (albumin)(albumin)

% of unbound % of unbound or free drug or free drug (active)(active)

diazepam, valproic diazepam, valproic acid, phenytoin, acid, phenytoin, warfarinwarfarin

plasma protein plasma protein

((11-acid -acid glycoprotein)glycoprotein)

% of unbound % of unbound or free drug or free drug (active)(active)

quinidine, quinidine, propranolol, propranolol, erythromycin, erythromycin, amitriptylineamitriptyline

Aging Effects on Hepatic Aging Effects on Hepatic MetabolismMetabolism

Metabolic clearance of drugs by the Metabolic clearance of drugs by the liver may be reduced due to:liver may be reduced due to: decreased hepatic blood flowdecreased hepatic blood flow decreased liver size and massdecreased liver size and mass

Examples: morphine, meperidine, metoprolol, propanolol, verapamil, amitryptyline, nortriptyline

Metabolic PathwaysMetabolic Pathways

PathwayPathway EffectEffect ExamplesExamples

Phase IPhase I: oxidation, : oxidation, hydroxylation, hydroxylation, dealkylation, dealkylation, reductionreduction

Conversion to Conversion to metabolites of metabolites of lesser, equal, or lesser, equal, or greatergreater

diazepam, diazepam, quinidine, quinidine, piroxicam, piroxicam, theophyllinetheophylline

Phase IIPhase II: : glucuronidation, glucuronidation, conjugation, or conjugation, or acetylationacetylation

Conversion to Conversion to inactive inactive metabolitesmetabolites

lorazepam, lorazepam, oxazepam, oxazepam, temazepamtemazepam

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

Other Factors Affecting Drug Other Factors Affecting Drug MetabolismMetabolism

GenderGender Comorbid conditionsComorbid conditions SmokingSmoking DietDiet Drug interactionsDrug interactions RaceRace FrailtyFrailty

Concepts in Drug Concepts in Drug EliminationElimination

Half-life time for serum concentration of drug

to decline by 50% (expressed in hours) 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

Effects of Aging on the Effects of Aging on the KidneyKidney

Decreased kidney sizeDecreased kidney size Decreased renal blood flowDecreased renal blood flow Decreased number of functional Decreased number of functional

nephronsnephrons Decreased tubular secretionDecreased tubular secretion Result: Result: glomerular filtration rate glomerular filtration rate

(GFR)(GFR) Decreased drug clearanceDecreased drug clearance: atenolol, : atenolol,

gabapentin, H2 blockers, digoxin, gabapentin, H2 blockers, digoxin, allopurinol, quinolones allopurinol, quinolones

Estimating GFR in the Estimating GFR in the ElderlyElderly

Creatinine clearance (CrCl) is used to Creatinine clearance (CrCl) is used to estimate glomerular rateestimate glomerular rate

Serum creatinine alone not accurate in Serum creatinine alone not accurate in the elderlythe elderly lean body mass lean body mass lower creatinine lower creatinine

productionproduction glomerular filtration rateglomerular filtration rate

Serum creatinine stays in normal Serum creatinine stays in normal range, masking change in creatinine range, masking change in creatinine clearanceclearance

Determining Creatinine Determining Creatinine ClearanceClearance

MeasureMeasure Time consumingTime consuming Requires 24 hr urine collectionRequires 24 hr urine collection

EstimateEstimate Cockroft Gault equationCockroft Gault equation

(IBW in kg) x (140-age)(IBW in kg) x (140-age)------------------------------ x (0.85 for ------------------------------ x (0.85 for

females)females) 72 x (Scr in mg/dL)72 x (Scr in mg/dL)

Example: Creatinine Example: Creatinine Clearance vs. Age in a 55 Clearance vs. Age in a 55

kg Womankg Woman

30301.11.19090

41411.11.17070

53531.11.15050

65651.11.13030

CrClCrClScrScrAgeAge

Pharmacodynamics (PD)Pharmacodynamics (PD)

Definition: the time course and intensity of Definition: the time course and intensity of pharmacologic effect of a drugpharmacologic effect of a drug

Age-relatedAge-related changes: changes: sensitivity to sedation and psychomotor sensitivity to sedation and psychomotor

impairment with impairment with benzodiazepinesbenzodiazepines level and duration of pain relief with level and duration of pain relief with narcotic narcotic

agentsagents drowsiness and lateral sway with drowsiness and lateral sway with alcoholalcohol HR response to HR response to beta-blockersbeta-blockers sensitivity to sensitivity to anti-cholinergic agentsanti-cholinergic agents cardiac sensitivity to cardiac sensitivity to digoxindigoxin

PK and PD SummaryPK and PD Summary

PK and PD changes generally result in PK and PD changes generally result in decreased clearance and increased decreased clearance and increased sensitivity to medications in older adultssensitivity to medications in older adults

Use of lower doses, longer intervals, Use of lower doses, longer intervals, slower titration are helpful in decreasing slower titration are helpful in decreasing the risk of drug intolerance and toxicitythe risk of drug intolerance and toxicity

Careful monitoring is necessary to Careful monitoring is necessary to ensure successful outcomesensure successful outcomes

Optimal Optimal PharmacotherapyPharmacotherapy

Balance between overprescribing Balance between overprescribing and underprescribingand underprescribing Correct drugCorrect drug Correct doseCorrect dose Targets appropriate conditionTargets appropriate condition Is appropriate for the patientIs appropriate for the patient

Avoid “a pill for every ill”Avoid “a pill for every ill”Always consider non-pharmacologic Always consider non-pharmacologic

therapytherapy

Consequences of Consequences of OverprescribingOverprescribing

Adverse drug events (ADEs)Adverse drug events (ADEs) Drug interactionsDrug interactions Duplication of drug therapyDuplication of drug therapy Decreased quality of lifeDecreased quality of life Unnecessary costUnnecessary cost Medication non-adherenceMedication non-adherence

Adverse Drug Events Adverse Drug Events (ADEs)(ADEs)

Responsible for 5-28% of Responsible for 5-28% of acute geriatric hospital acute geriatric hospital admissionsadmissions

Greater than 95% of Greater than 95% of ADEs in the elderly are ADEs in the elderly are considered predictable considered predictable and approximately 50% and approximately 50% are considered are considered preventablepreventable

Most errors occur at the Most errors occur at the ordering and monitoring ordering and monitoring stagesstages

Most Common Medications Most Common Medications Associated with ADEs in the Associated with ADEs in the

ElderlyElderly

Opioid analgesicsOpioid analgesics NSAIDsNSAIDs AnticholinergicsAnticholinergics BenzodiazepinesBenzodiazepines AlsoAlso: cardiovascular agents, CNS : cardiovascular agents, CNS

agents, and musculoskeletal agentsagents, and musculoskeletal agents

Adverse Drug Reaction Risk Factors in Older Outpatients. Am J Ger Pharmacotherapy 2003;1(2):82-Adverse Drug Reaction Risk Factors in Older Outpatients. Am J Ger Pharmacotherapy 2003;1(2):82-89.89.

The Beers CriteriaThe Beers Criteria

High Potential for High Potential for

Severe ADESevere ADEHigh Potential for High Potential for

Less Severe ADELess Severe ADE

amitriptylineamitriptyline

chlorpropamidechlorpropamide

digoxin >0.125mg/ddigoxin >0.125mg/d

disopyramidedisopyramide

GI antispasmodicsGI antispasmodics

meperidinemeperidine

methyldopamethyldopa

pentazocinepentazocine

ticlopidineticlopidine

antihistamines antihistamines

diphenhydraminediphenhydramine

dipyridamoledipyridamole

ergot mesyloidsergot mesyloids

indomethacinindomethacin

muscle relaxantsmuscle relaxants

Patient Risk Factors for Patient Risk Factors for ADEsADEs

PolypharmacyPolypharmacy Multiple co-morbid conditionsMultiple co-morbid conditions Prior adverse drug eventPrior adverse drug event Low body weight or body mass indexLow body weight or body mass index Age > 85 yearsAge > 85 years Estimated CrCl <50 mL/minEstimated CrCl <50 mL/min

Drug-Drug Interactions Drug-Drug Interactions (DDIs)(DDIs)

May lead to adverse drug eventsMay lead to adverse drug events Likelihood Likelihood as number of medications as number of medications Most common DDIs:Most common DDIs:

cardiovascular drugscardiovascular drugs psychotropic drugspsychotropic drugs

Most common drug interaction effects:Most common drug interaction effects: confusion confusion cognitive impairmentcognitive impairment hypotensionhypotension acute renal failureacute renal failure

Concepts in Drug-Drug Concepts in Drug-Drug InteractionsInteractions

Absorption may be Absorption may be or or Drugs with similar effects can result Drugs with similar effects can result

additive effectsadditive effects Drugs with opposite effects can Drugs with opposite effects can

antagonize each otherantagonize each other Drug metabolism may be inhibited Drug metabolism may be inhibited

or inducedor induced

Common Drug-Drug Common Drug-Drug InteractionsInteractions

CombinationCombination RiskRiskACE inhibitor + potassiumACE inhibitor + potassium HyperkalemiaHyperkalemia

ACE inhibitor + K sparing ACE inhibitor + K sparing diureticdiuretic

Hyperkalemia, hypotensionHyperkalemia, hypotension

Digoxin + antiarrhythmicDigoxin + antiarrhythmic Bradycardia, arrhythmiaBradycardia, arrhythmia

Digoxin + diureticDigoxin + diuretic

Antiarrhythmic + diureticAntiarrhythmic + diureticElectrolyte imbalance; Electrolyte imbalance; arrhythmiaarrhythmia

Diuretic + diureticDiuretic + diuretic Electrolyte imbalance; Electrolyte imbalance; dehydrationdehydration

Benzodiazepine + Benzodiazepine + antidepressantantidepressant

Benzodiazepine + Benzodiazepine + antipsychoticantipsychotic

Sedation; confusion; fallsSedation; confusion; falls

CCB/nitrate/vasodilator/CCB/nitrate/vasodilator/diureticdiuretic

Hypotension Hypotension 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.

Drug-Disease Drug-Disease InteractionsInteractions

Obesity alters Vd of lipophilic drugsObesity alters Vd of lipophilic drugs Ascites alters Vd of hydrophilic drugsAscites alters Vd of hydrophilic drugs Dementia may Dementia may sensitivity, induce sensitivity, induce

paradoxical reactions to drugs with paradoxical reactions to drugs with CNS or anticholinergic activityCNS or anticholinergic activity

Renal or hepatic impairment may Renal or hepatic impairment may impair metabolism and excretions of impair metabolism and excretions of drugsdrugs

Drugs may exacerbate a medical Drugs may exacerbate a medical conditioncondition

Common Drug-Disease Common Drug-Disease InteractionsInteractions

CombinationCombination RiskRisk

NSAIDs + CHFNSAIDs + CHF

Thiazolidinediones + CHFThiazolidinediones + CHFFluid retention; CHF Fluid retention; CHF exacerbationexacerbation

BPH + anticholinergicsBPH + anticholinergics Urinary retentionUrinary retention

CCB + constipationCCB + constipation

Narcotics + constipationNarcotics + constipation

Anticholinergics + Anticholinergics + constipationconstipation

Exacerbation of Exacerbation of constipationconstipation

Metformin + CHFMetformin + CHF Hypoxia; increased risk of Hypoxia; increased risk of lactic acidosislactic acidosis

NSAIDs + gastropathyNSAIDs + gastropathy Increased ulcer and Increased ulcer and bleeding riskbleeding risk

NSAIDs + HTNNSAIDs + HTN Fluid retention; decreased Fluid retention; decreased effectiveness of diureticseffectiveness of diuretics

Principles of Prescribing in Principles of Prescribing in the Elderlythe Elderly

Avoid prescribing prior to diagnosisAvoid prescribing prior to diagnosis Start with a low dose and titrate Start with a low dose and titrate

slowlyslowly Avoid starting 2 agents at the same Avoid starting 2 agents at the same

timetime Reach therapeutic dose before Reach therapeutic dose before

switching or adding agentsswitching or adding agents Consider non-pharmacologic agentsConsider non-pharmacologic agents

Peu di tuleh nyou.

Prescribing Prescribing AppropriatelyAppropriately

Determine therapeutic endpoints and plan Determine therapeutic endpoints and plan for assessmentfor assessment

Consider risk vs. benefitConsider risk vs. benefit Avoid prescribing to treat side effect of Avoid prescribing to treat side effect of

another druganother drug Use 1 medication to treat 2 conditionsUse 1 medication to treat 2 conditions Consider drug-drug and drug-disease Consider drug-drug and drug-disease

interactionsinteractions Use simplest regimen possibleUse simplest regimen possible Adjust doses for renal and hepatic Adjust doses for renal and hepatic

impairmentimpairment Use least expensive alternativeUse least expensive alternative

Preventing PolypharmacyPreventing Polypharmacy

Review medications regularly Review medications regularly and each time a new medication and each time a new medication started or dose is changedstarted or dose is changed

Maintain accurate medication Maintain accurate medication records (include vitamins, OTCs, records (include vitamins, OTCs, and herbals)and herbals)

Non-AdherenceNon-Adherence

Rate may be as high as 50% in Rate may be as high as 50% in the elderlythe elderly

Factors in non-adherenceFactors in non-adherence Financial, cognitive, or functional Financial, cognitive, or functional

statusstatus Beliefs and understanding about Beliefs and understanding about

disease and medicationsdisease and medications

Enhancing Medication Enhancing Medication AdherenceAdherence

Avoid newer, more expensive Avoid newer, more expensive medications that are not shown to medications that are not shown to be superior to less expensive be superior to less expensive generic alternativesgeneric alternatives

Simplify the regimenSimplify the regimen Utilize drug calendarsUtilize drug calendars Educate patient on medication Educate patient on medication

purpose, benefits, safety, and purpose, benefits, safety, and potential ADEspotential ADEs

SummarySummary

Successful pharmacotherapy Successful pharmacotherapy means using the correct drug at means using the correct drug at the correct dose for the correct the correct dose for the correct indication in an individual patientindication in an individual patient

Age alters PK and PDAge alters PK and PD ADEs are common among the ADEs are common among the

elderlyelderly Risk of ADEs can be minimized by Risk of ADEs can be minimized by

appropriate prescribingappropriate prescribing

Terapi obat membawa potensi efek yg Terapi obat membawa potensi efek yg menguntungkan dan berbahaya pada pasien menguntungkan dan berbahaya pada pasien geriatric.geriatric.

Pertimbangan perlu diberikan obat dalam arahan Pertimbangan perlu diberikan obat dalam arahan yang benar dengan mengikuti prinsip-prinsip yang benar dengan mengikuti prinsip-prinsip berikut:berikut:

1. membuat anamnesis tentang obat yang jelas.1. membuat anamnesis tentang obat yang jelas.

2. resepkan hanya untuk indikasi yang spesifik 2. resepkan hanya untuk indikasi yang spesifik dan rasionaldan rasional

3. tentukan tujuan terapi obat3. tentukan tujuan terapi obat

4. tetap curiga dan awas pada reaksi dan 4. tetap curiga dan awas pada reaksi dan interaksi obat. interaksi obat.

(perlu mengetahui obat lain yang digunakan (perlu mengetahui obat lain yang digunakan pasien)pasien)

5. sederhanakan regimen sebaik mungkin 5. sederhanakan regimen sebaik mungkin