Geriatric Pharmacotherapy



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Geriatric Pharmacotherapy

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

Objectives

  • 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 patients

The 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 drugs

Challenges of Geriatric Pharmacotherapy

  • New drugs available each year
  • FDA approved and off-label indications are expanding
  • Changing managed-care formularies
  • Advanced understanding of drug-drug interactions
  • Increasing popularity of “nutriceuticals”
  • Multiple co-morbid states
  • Polypharmacy
  • Medication compliance
  • Effects of aging physiology on drug therapy
  • Medication cost

Pharmacokinetics (PK)

  • Absorption
    • bioavailability: the fraction of a drug dose reaching the systemic circulation
  • Distribution
    • locations in the body a drug penetrates expressed as volume per weight (e.g. L/kg)
  • Metabolism
    • drug conversion to alternate compounds which may be pharmacologically active or inactive
  • Elimination
    • a drug’s final route(s) of exit from the body expressed in terms of half-life or clearance

Effects of Aging on Absorption

  • Rate of absorption may be delayed
    • Lower peak concentration
    • Delayed time to peak concentration
  • Overall amount absorbed (bioavailability) is unchanged

Hepatic 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
  • Dysphagia

Effects of Aging on Volume of Distribution (Vd)

  • Aging Effect
  • Vd Effect
  • Examples
  •  body water
  •  Vd for hydrophilic drugs
  • ethanol, lithium
  •  lean body mass
  • 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, nortriptyline

Metabolic Pathways

  • Pathway
  • Effect
  • 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
  • Frailty

Concepts in Drug Elimination

  • 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 Kidney

  • Decreased kidney size
  • Decreased renal blood flow
  • Decreased number of functional nephrons
  • Decreased tubular secretion
  • Result:  glomerular filtration rate (GFR)
  • Decreased drug clearance: atenolol, gabapentin, H2 blockers, digoxin, allopurinol, quinolones

Estimating GFR in the Elderly

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

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
  • 1.1
  • 90
  • 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 function
  • Some patient’s muscle mass is reduced beyond that of normal aging
    • Suggest using 1 mg/dL if serum creatinine is less than normal (<0.7 mg/dL)
    • Not precise, may underestimate actual CrCl

Pharmacodynamics (PD)

  • Definition: the time course and intensity of pharmacologic effect of a drug
  • Age-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 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 outcomes

Optimal Pharmacotherapy

  • Balance between overprescribing and underprescribing
    • Correct drug
    • Correct dose
    • Targets appropriate condition
    • Is appropriate for the patient
    • Avoid “a pill for every ill”
    • Always consider non-pharmacologic therapy

Consequences of Overprescribing

  • Adverse drug events (ADEs)
  • Drug interactions
  • Duplication of drug therapy
  • Decreased quality of life
  • Unnecessary cost
  • Medication non-adherence

Adverse 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 stages

Most 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
  • 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/min

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.

Drug-Drug Interactions (DDIs)

  • May lead to adverse drug events
  • Likelihood  as number of medications 
  • Most common DDIs:
    • cardiovascular drugs
    • psychotropic drugs
  • Most common drug interaction effects:
    • confusion
    • cognitive impairment
    • hypotension
    • acute renal failure

Concepts in Drug-Drug Interactions

  • Absorption may be  or 
  • Drugs with similar effects can result additive effects
  • Drugs with opposite effects can antagonize each other
  • Drug metabolism may be inhibited or induced

Common Drug-Drug Interactions

  • Combination
  • Risk
  • ACE inhibitor + potassium
  • Hyperkalemia
  • ACE inhibitor + K sparing diuretic
  • Hyperkalemia, hypotension
  • Digoxin + antiarrhythmic
  • Bradycardia, arrhythmia
  • Digoxin + diuretic
  • Antiarrhythmic + diuretic
  • 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 drugs
  • Ascites alters Vd of hydrophilic drugs
  • Dementia may  sensitivity, induce paradoxical reactions to drugs with CNS or anticholinergic activity
  • Renal or hepatic impairment may impair metabolism and excretions of drugs
  • Drugs may exacerbate a medical condition

Common Drug-Disease Interactions

  • Combination
  • Risk
  • 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 alternative

Preventing Polypharmacy

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

Enhancing 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 ADEs

Summary

  • 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 prescribing

Questions

Case 1

  • A 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 1

  • Which of the following is the most likely explanation for the increase in HgA1c?
  • Incorrect choice of antidiabetic medication
  • Inadequate dose of antidiabetic medication
  • Long-term non-adherence with medication
  • Altered pharmacokinetics
  • Altered drug absorption

Case 1

  • Which of the following is the most likely explanation for the increase in HgA1c?
  • Incorrect choice of antidiabetic medication
  • Inadequate dose of antidiabetic medication
  • Long-term non-adherence with medication
  • Altered pharmacokinetics
  • Altered drug absorption

Case 2

  • A 68 y/o woman has a hx of Parkinson’s 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 2

  • Which of the following is the most appropriate intervention?
  • Discontinue celecoxib
  • Discontinue diphenhydramine
  • Discontinue losartan
  • Substitute fosinopril for losartan
  • Begin tolterodine

Case 2

  • Which of the following is the most appropriate intervention?
  • Discontinue celecoxib
  • Discontinue diphenhydramine
  • Discontinue losartan
  • Substitute fosinopril for losartan
  • Begin tolterodine

Case 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

Case 3

  • Which of the following is the most likely cause of this syncopal episode?
  • Sepsis
  • Drug-related event
  • Hypovolemic hypotensive episode
  • Cardiogenic shock
  • Unidentifiable cause

Case 3

  • Which of the following is the most likely cause of this syncopal episode?
  • Sepsis
  • Drug-related event
  • Hypovolemic hypotensive episode
  • Cardiogenic shock
  • Unidentifiable cause


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