Geriatric Pharmacotherapy
Dr. Esra Tariq AnwerObjectives
Understand key issues in geriatric pharmacotherapy Understand the effect age on pharmacokinetics and pharmacodynamics Discuss risk factors for adverse drug events and ways to mitigate them Understand the principles of drug prescribing for older patientsThe Aging Imperative
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 drugsChallenges of Geriatric Pharmacotherapy
New drugs available each yearFDA approved and off-label indications are expandingChanging managed-care formulariesAdvanced understanding of drug-drug interactionsIncreasing popularity of “nutriceuticals”Multiple co-morbid statesPolypharmacyMedication complianceEffects of aging physiology on drug therapyMedication costPharmacokinetics (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 drug’s final route(s) of exit from the body expressed in terms of half-life or clearanceEffects of Aging on Absorption
Rate of absorption may be delayed Lower peak concentration Delayed time to peak concentration Overall amount absorbed (bioavailability) is unchangedHepatic First-Pass Metabolism
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
Factors Affecting Absorption
Route of administration 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 Increased GI pH Decreased gastric emptying DysphagiaEffects of Aging on Volume of Distribution (Vd)
Aging EffectVd 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
Aging Effects on Hepatic Metabolism
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, nortriptylineMetabolic Pathways
PathwayEffect
Examples
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)
Other Factors Affecting Drug Metabolism
Gender Comorbid conditions Smoking Diet Drug interactions Race FrailtyConcepts in Drug Elimination
Half-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 toxicityEffects of Aging on the Kidney
Decreased kidney sizeDecreased renal blood flowDecreased number of functional nephronsDecreased tubular secretionResult: glomerular filtration rate (GFR)Decreased drug clearance: atenolol, gabapentin, H2 blockers, digoxin, allopurinol, quinolonesEstimating GFR in the Elderly
Creatinine 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 Clearance
Measure Time consuming Requires 24 hr urine collection Estimate Cockroft 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 5’5”, 55 kg Woman 30
1.190
41
1.1
70
53
1.1
50
65
1.1
30
CrCl
Scr
Age
Limitations in Estimating CrCl
Not all persons experience significant age-related decline in renal functionSome patient’s muscle mass is reduced beyond that of normal agingSuggest using 1 mg/dL if serum creatinine is less than normal (<0.7 mg/dL)Not precise, may underestimate actual CrClPharmacodynamics (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 digoxinPK and PD Summary
PK and PD changes generally result in decreased clearance and increased sensitivity to medications in older adults Use of lower doses, longer intervals, slower titration are helpful in decreasing the risk of drug intolerance and toxicity Careful monitoring is necessary to ensure successful outcomesOptimal Pharmacotherapy
Balance between overprescribing and underprescribingCorrect drugCorrect doseTargets appropriate conditionIs appropriate for the patientAvoid “a pill for every ill”Always consider non-pharmacologic therapyConsequences of Overprescribing
Adverse drug events (ADEs) Drug interactions Duplication of drug therapy Decreased quality of life Unnecessary cost Medication non-adherenceAdverse Drug Events (ADEs)
Responsible for 5-28% of acute geriatric hospital admissions Greater than 95% of ADEs in the elderly are considered predictable and approximately 50% are considered preventable Most errors occur at the ordering and monitoring stagesMost Common Medications Associated with ADEs in the Elderly
Opioid analgesics NSAIDs Anticholinergics Benzodiazepines Also: 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
High Potential for Severe ADEHigh Potential for Less Severe ADE
amitriptyline chlorpropamide digoxin >0.125mg/d disopyramide GI antispasmodics meperidine methyldopa pentazocine ticlopidine
antihistamines diphenhydramine dipyridamole ergot mesyloids indomethacin muscle relaxants
Patient Risk Factors for ADEs
Polypharmacy Multiple co-morbid conditions Prior adverse drug event Low body weight or body mass index Age > 85 years Estimated CrCl <50 mL/minPrescribing Cascade
Drug 1ADE 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.
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 failureConcepts in Drug-Drug Interactions
Absorption may be or Drugs with similar effects can result additive effectsDrugs with opposite effects can antagonize each otherDrug metabolism may be inhibited or inducedCommon 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/diuretic
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 Interactions
Obesity 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 conditionCommon Drug-Disease Interactions
CombinationRisk
NSAIDs + CHF Thiazolidinediones + CHF
Fluid retention; CHF exacerbation
BPH + anticholinergics
Urinary retention
CCB + constipation Narcotics + constipation Anticholinergics + constipation
Exacerbation of constipation
Metformin + CHF
Hypoxia; increased risk of lactic acidosis
NSAIDs + gastropathy
Increased ulcer and bleeding risk
NSAIDs + HTN
Fluid retention; decreased effectiveness of diuretics
Principles of Prescribing in the Elderly
Avoid prescribing prior to diagnosis Start with a low dose and titrate slowly Avoid starting 2 agents at the same time Reach therapeutic dose before switching or adding agents Consider non-pharmacologic agents
Prescribing Appropriately
Determine therapeutic endpoints and plan for assessment Consider risk vs. benefit Avoid prescribing to treat side effect of another drug Use 1 medication to treat 2 conditions Consider drug-drug and drug-disease interactions Use simplest regimen possible Adjust doses for renal and hepatic impairment Avoid therapeutic duplication Use least expensive alternativePreventing Polypharmacy
Review medications regularly and each time a new medication started or dose is changedMaintain accurate medication records (include vitamins, OTCs, and herbals)“Brown-bag”Non-Adherence
Rate may be as high as 50% in the elderly Factors in non-adherence Financial, cognitive, or functional status Beliefs and understanding about disease and medicationsEnhancing Medication Adherence
Avoid newer, more expensive medications that are not shown to be superior to less expensive generic alternatives Simplify the regimen Utilize pill organizers or drug calendars Educate patient on medication purpose, benefits, safety, and potential ADEsSummary
Successful pharmacotherapy means using the correct drug at the correct dose for the correct indication in an individual patient Age alters PK and PD ADEs are common among the elderly Risk of ADEs can be minimized by appropriate prescribingQuestions
Case 1
A 73 y/o woman is seen for a routine visit: Blood pressure is 134/84 mmHg and HbA1c 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 1
Which of the following is the most likely explanation for the increase in HbA1c? Incorrect choice of antidiabetic medication Inadequate dose of antidiabetic medication Long-term non-adherence with medication Altered pharmacokinetics Altered drug absorptionCase 1
Which of the following is the most likely explanation for the increase in HbA1c? Incorrect choice of antidiabetic medication Inadequate dose of antidiabetic medication Long-term non-adherence with medication Altered pharmacokinetics Altered drug absorptionCase 2
A 68 y/o woman has a hx of Parkinson’s disease, hypertension, and osteoarthritisDaily medications are carbidopa 25mg/levodopa 100mg tid, selegiline 5mg bid, losartan 50mg, celecoxib 200mg qd, and MVI qdIn the past 3 weeks, she has taken diphenhydramine at bedtime for insomniaThe patient now reports the onset of urinary incontinenceCase 2
Which of the following is the most appropriate intervention? Discontinue celecoxib Discontinue diphenhydramine Discontinue losartan Substitute fosinopril for losartan Begin tolterodineCase 2
Which of the following is the most appropriate intervention? Discontinue celecoxib Discontinue diphenhydramine Discontinue losartan Substitute fosinopril for losartan Begin tolterodineCase 3
An 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