Prescribing for Older Patients: an evidencebased approach

1
Prescribing for Older Patients an evidence-based
approach

• Better Living Through Chemistry?

2
Prescribing for Older Adults
Benefits
Risks Burdens
3
Stroke incidence can be reduced by treatment
of ISH
Stroke/4.5 yrs

• RRR 36
• ARR 3
• NNT Treat 33 people with ISH for 4.5 years to
  prevent 1 stroke

SHEP Cooperative Research Group. JAMA 1991 265
3255-3264
4
CHF incidence can be reduced by treatment
of ISH
CHF /4.5 yrs

• RRR 49
• ARR 2.1
• NNT 48

Kostis JB et al. JAMA 1997278212-216.
5
Atrial Fibrillation-associated Stroke can be
reduced with Anticoagulation
Stroke

• A Fib stroke
• fatal
• recurrent
• severe deficits
• RRR 66
• ARR 3
• NNT/1 yr 33

Arch Int Med 1994 1431449-57 Stroke
1996271760-1764.
6
Calcium and Vit D can reduce nonvertebral
fractures in elders without osteoporosis
with fractures/3 yrs

• RRR 54
• ARR 7
• NNT/ 3 yrs 14

Dawson-Hughes et al N Engl J Med 1997337670-6
7
Effective Therapies are Underutilized in Older
Adults

• Thrombolysis for Acute MI
• Beta-blockers postinfarction
• Coumadin for Atrial Fibrillation
• Anything for osteoporosis
• Opioids for cancer pain

8
Thrombolysis and Acute MIOld vs Young
deaths day 0-35

• lt55 years old
• RRR 26
• ARR 1.2
• NNT 83
• 65-74 years old
• RRR 16
• ARR 2.6
• NNT 38

lt55
65-74
FTT Collaborative Group. Lancet 1994 343 311-22
9
What are the data for those gt75 yo?

• No RCTs
• Fewer older adults with acute MI will meet
  criteria for thrombolysis
• present without chest pain
• present gt3 hours after initial symptoms
• Concern about intracranial hemorrhage
• Observational studies
• Prospective Cohort
• Medicare databases

10
Do benefits outweigh risks for those gt75 yo?

• Medicare database no angioplasty
• gt75 healthier
• a larger proportion of Killip class I and II MIs
• lower rates of anterior MI.
• 30 day hazard ratio
• gt75 years 1.38 (95 CI 1.12-1.71).
• Exclude transfusions/ strokes 1.31, 95CI
  1.04-1.64)
• 65-75 years 0.88 (95CI 0.69-1.12)
• same rate of bleeds, strokes
• more severe consequences??

Thiemann DR, Circulation. 2000 101 2239-2246
11
Effective Therapies are Underutilized in Older
Adults

• Thrombolysis for Acute MI
• Beta-blockers and ACEIs postinfarction
• Coumadin for Atrial Fibrillation
• Anything for osteoporosis
• Opioids for cancer pain

12
Coumadin for Atrial Fibrillation Whats the
evidence trail?

• Efficacy
• Primary prevention
• Secondary prevention

13
Anticoagulation in AF Primary Prevention
Control
AC
ARR
NNT/H
Stroke
4.5
1.5
3.0
33
Major Bleed
1.0
1.3
0.3
NS (333)
2 strokes avoided
0 major bleeds
66 patients anticoagulated (?? years)
1 strokes occur
63 - no effect
Arch Int Med 1994 1431449-57
14
Anticoagulation in AF Secondary Prevention (CSR)
Control
AC
ARR
NNT/H
Stroke
22.6
8.9
13.7
7
Major Bleed
1.4
5.8
4.4
23
3 strokes avoided
1 major bleed
23 patients anticoagulated (2.3 years)
2 strokes occur
17 - no effect
15
Coumadin for Atrial Fibrillation Whats the
evidence trail?

• Minimizing Adverse Effects
• Target INR 4.5 vs 2-3
• Who is at risk of bleeding?
• How to dose to maximize efficacy and minimize
  bleeding?
• What can interfere with INR?
• Improved benefit to risk!

16
Prescribing for Older Adults
Benefits
Risks Burdens
17
Is therapy likely to be effective for this
patient?
YES

• Minimize
• Adverse Events
• Therapeutic Failure

18
Adverse Drug Events in older adults

• Common
• May present differently than in younger adults
• May precipitate or mimic common geriatric
  disorders

• Underrecognition
• Increased morbidity
• ?Additional prescriptions

19
Digoxin Toxicity in the Elderly

• Arrhythmias with normal digoxin levels
• Anorexia, nausea and vomiting
• Lethargy, depression, confusion
• Hazy or muddy vision
• Photopsia innumerable points of light in the
  peripheral visual fields
• Impaired ADLs

20
Adverse Drug Events can mimic or precipitate
geriatric syndromes

• Falls psychotropics
• Urinary incontinence
• Diuretics, caffeine, alcohol
• Anticholinergic agents, including psychotropics
• Sedative/hypnotics
• Narcotic analgesics
• Cardiovascular agents
• Alpha-adrenergic blockers and agonists
• Beta-adrenergic agonists
• Calcium channel blockers

21
Dementia due to medications

• Psychotropics
• Benzodiazepines, Antidepressants, Neuroleptics
• Analgesics
• Meperidine, Indomethacin
• Antihypertensives
• Methyldopa, HCTZ, propranolol
• Others
• H2 Blockers, Amantadine, Insulin

Larson et al, Ann Int Med 1987107169-173
22
ADES Produce Unneccesary Additional
Prescriptions?

• Pharmaco-epidemiological Evidence
• Excess antidepressants are prescribed to patients
  taking beta blockers.
• Excess SinemetTM to patients taking
  neuroleptics.
• Excess antihypertensives to patients taking
  NSAIDs.

23
Better LivingThrough Chemistry?
Benefits
Risks Burdens
24
Individualize Therapy

• All elders are not alike
• Significant heterogeneity
• greater among older individuals than younger

25
Individualization of Therapy

• What is the patients potential for
• An adverse drug event?
• An altered dose response?
• A drug interaction?
• drug-drug
• drug-disease
• drug-nutrient
• Treatment non-adherence?

26
Adverse Drug Reactions
Dose Related
Idiosyncratic
Predictable
Unpredictable
Stevens-Johnson

• G6PD Deficiency
• ACEI Renal Insufficiency
• ?? Falls

27
ADEs Aging or Age-related?
Patients with ADEs
AGE
Hutchinson et al J Chronic Dis 198639533-42
28
ADEs Aging or Age-related?
ADEs per individual drug course
AGE
Hutchinson et al J Chronic Dis 198639533-42
29
Risk Factors for ADEs in the Elderly

• Polypharmacy
• Multiple medical disorders
• Low therapeutic index medications
• Altered pharmacokinetics
• Altered pharmacodynamics
• History of previous ADEs
• ?Problems with treatment adherence

30
Pharmacokinetics Distribution

• Lean body mass decreases.
• Percentage body fat increases
• Males from 18 to 33
• Females from 33 to 45
• Binding proteins not significantly changed.

31
Distribution Clinical Correlates

• Decrease loading dose of
• water soluble drugs
• drugs distributed to skeletal muscles
• Do not increase loading dose of fat soluble
  drugs!
• Weight-adjust dose for small adults

32
Non-Opioid Analgesic Doses weight adjusted
AHCPR Cancer pain guidelines
33
Hepatic Metabolism Inter-individual Variability

• Age
• Genotypes
• slow vs fast acetylation rapid vs poor oxidizers
• Lifestyle habits
• smoking drinking grapefruit juice
• Cardiac output
• Disease and drug interactions
• Gender

34
Metabolism Hepatic Biotransformation

• No age-related change
• Acetylation
• Conjugation
• Age-related decline
• Oxidation the Cytochrome P-450s
• Reduction in liver mass (and metabolizing
  capacity)
• warfarin, diazepam, naproxen, phenytoin
• Reduction in liver blood flow
• propranolol, morphine, verapamil, desipramine

35
Cytochrome P-450s

• Several isozymes
• Different inducers
• Different inhibitors
• Some drugs metabolized by gt1 isozyme

36
Cytochrome P450 CYP3A

• Metabolizes
• Fentanyl, methadone,
• Acetaminophen
• Erythro, Clarithromycin
• Itra- and ketoconazole,
• Amiodarone, lidocaine, quinidine,
• Calcium channel blockers
• Cisapride
• Sertraline, nefazadone
• Alprazolam, zolpidem, triazolam
• Astemizole, loratadine, terfenadine
• Cyclosporine
• Sex hormones, cortisol
• Carbamazepine

• Induced by
• Barbiturates
• Carbamazepine
• Glucocorticoids
• Phenytoin
• Inhibited by
• Cimetidine
• Erythro, clarithromycin
• Diltiazem, nicardipine, verapamil
• Itra-, ketoconozole
• Fluoxetine, methylphenidate

37
Cytochrome P-450 Inducers

• Barbiturates
• Glucocorticoids
• Carbamazepine
• Chronic EtOH

• Cigarette smoke
• Rifampin
• Phenytoin

38
Cytochrome P-450 Inhibitors

• Flu-, itra-, ketoconozole
• Cimetidine
• Erythro, clarithromycin
• Propoxyphene
• Quinidine, propafenone

• Thioridazine, perphenazine
• Fluoxetine, paroxetine
• Chloroquine
• Diltiazem, verapamil, nicardipine
• Methylphenidate

39
Renal Excretion

• GFR decreases in 2/3 of adults
• No formula accurate for community-dwelling
  elderly
• Most common underestimate ClCr
• Cockcroft-Gault -12.1 ml/min sd 26.2
• ClCr (140 - age) Wt (kg)
• 72 Serum Creatinine

40
Normal Serum Creatinine Normal GFR
Serum Creatinine
Creatinine
Creatinine
produced
excreted
41
Adjust Dose GFR lt 50 ml/min

• Antimicrobials
• Acyclovir
• Amantidine
• Aminoglycosides
• Amphotericin
• Aztreonam
• Cephalosporins (many)
• Imipenem
• Penicillins (most)
• Quinolones (most)
• Sulbactans
• Sulfonamides
• Tetracycline
• Vancomycin

• Cardiovascular
• Methyldopa
• Most ACE Inhibitors
• Atenolol, Nadolol, Sotalol
• Digoxin
• Procainamide
• Others
• Lithium
• Meperidine
• Acetaminophen
• H2 Blockers (most)
• Albuterol
• Glyburide
• Insulin

42
PK changes So What?

• Decreased clearance
• Cl organ Organ Blood Flow x Extraction Ratio
• Drug clearance is additive
• Total clearance Cl renal Cl hepatic Cl
  other
• Increased steady-state concentration
• Need to decrease dose

43
So What? continued
Prolonged half life (T1/2) is common T1/2
0.693 x Vd Cl

• Longer dosing interval
• Longer
• to steady state
• until body is drug-free

44
Pharmacodynamic Changes

• Receptors or post-receptor events
• Tissue or end-organ changes
• Compensatory or homeostatic mechanisms

45
Fentanyl Response and Age
Fentanyl dose to produce EEG delta waves
AGE
Scott and Stanski J Pharm Exp Ther 1987240159-66
46
Major Toxicity after Chronic Theophylline
Intoxication
plt0.05
Probability
plt0.05
AGE
Shannon M. Ann Intern Med 19931191161-1167
47
For some drugs, may be able to get same effect in
older adults with lower dose

• Historical examples Captopril, HCTZ?
• Lower doses but same blood levels
• Beta-blockers (Rochon study)
• ATLAS Lisinopril
• lower dose same effect on mortality
• higher dose fewer hospitalizations for any
  reason as well as for CHF

48
Individualization of Therapy

• What is the patients potential for
• An adverse drug event?
• An altered dose response?
• A drug interaction?
• drug-drug
• drug-disease
• drug-nutrient
• Treatment non-adherence?

49
Drug-Disease Interactions

• CHF NSAIDs
• Claudication Beta blockers
• Stress incontinence Alpha1blockers
• Constipation
• CCB, anticholinergics, Betablockers, narcotics
• BPH
• Decongestants, anticholinergics, calcium channel
  blockers
• Parkinsons or Dementia Anticholinergic delirium
  

50
Drug-Nutrient Interactions

• Protein-bound B12 omeprazole
• Folate and Vit D diphenylhydantoin
• Thiamine furosemide
• Coumadin effect Vitamin K
• Calcium channel blocker bioavailability
  grapefruit juice

51
Unproven Medical Therapies

• 1984 report
• 60 of those who try these therapies are gt65
• 10 billion estimate
• Eisenberg (1993)
• More than 70 who use these therapies never
  mention them to their MDs.

52
Unproven Inert

• Vitamin toxicities (even water-soluble)
• C oxalate kidney stones
• B6 neurotoxicity
• Gingko increases bleeding with warfarin or
  aspirin
• Ginseng decreases warfarin effect may increase
  BP
• Garlic increases bleeding with warfarin or
  aspirin

53
Drugs to Avoid in Older Adults

• Analgesics
• Narcotics Propoxyphene (DarvonTM), Meperidine
  (DemerolTM), pentazocine (Talwin TM),
• NSAIDs Indomethacin, Phenylbutazone
• Muscle Relaxants
• RobaxinTM, SomaTM, DitropanTM, ParaflexTM,
  SkelaxinTM, FlexerilTM
• GI Antispasmodics
• BentylTM, LevsinTM, Pro-BanthineTM, DonnatolTM,
  LibraxTM

Beers M Arch Intern Med 19971571531-1536
54
Drugs to Avoid in Older Adults

• TiganTM
• Psychotropics
• Antidepressants Amitriptyline, doxepin
• Sedatives Meprobamate, chlordiazepoxide,
  diazepam, flurazepam, barbiturates
• H1 Blockers (lipid soluble)
• Chlorpheniramine, diphenhydramine, hydroxyzine,
  cyproheptadine, promethazine, dexchlorpheniramine,
  tripelennamine

Beers M Arch Intern Med 19971571531-1536
55
Drugs to Avoid in Older Adults

• Cardio- or Cerebrovascular Drugs
• Disopyramide (NorpaceTM)
• Dipyridamole (PersantineTM)
• Methyldopa, Reserpine
• Ticlopidine (??)
• Hydergine, cyclospasmol
• Chlorpropamide (DiabenaseTM)

Beers M Arch Intern Med 19971571531-1536
56
Suggested Maximum Daily Dosages for Older Adults

• Benzodiazepines/ Hypnotics
• Lorazepam, 3 mg --Temazepam, 15 mg
• Oxazepam, 60 mg -- Zolpidem, 5 mg
• Alprazolam, 2 mg -- Triazolam, 0.25 mg
• Iron Supplements, 325 mg
• Digoxin, 0.125 mg

Beers M Arch Intern Med 19971571531-1536
57
BUT Remember---

• Prescribing is dynamic, not static.
• Patients are dynamic, not static.

58
Were you ever taught

• High systolic blood pressures are normal aging
  and should not be treated?
• For treatment of hypertension
• Captopril 50-75 mg tid
• HCTZ 50-100 mg qd
• Digoxin
• slows the ventricular rate for PAF?
• is a life-long medication?

59
Drug Prescribing for Older Adults
INDIVIDUALIZE THERAPY!
Benefits
Risks Burdens
60
(No Transcript)
61
Appropriate Prescribing for Older Adults

• Whats the patients medication history?
• Allergies, ADEs, tobacco, alcohol, caffeine,
  recreational drugs, diet, weight
• What drugs is your patient taking?
• Other prescribers
• Over the counter drugs
• Dietary supplements, Alternative or complementary
  meds
• Generics

• Bring all medications to appointments
• Ask if other health care providers seen
• since last appointment

62
Appropriate Prescribing for Older Adults

• Match the patients pharmacology, psychology, and
  pathophysiology to your prescription.
• Individualize
• Agent
• Dose and Regimen
• Formulation
• Monitoring criteria
• Therapeutic effect
• Adverse effects

63
Appropriate Prescribingfor Older Adults

• Re-evaluate indications for continued medication
  use.
• Consider drug taper if current benefit unclear
• Old drugs can cause new ADEs
• Cognitive decline
• Functional decline
• Re-evaluate dosage regimens for long-term
  medications.
• Consider closely monitored drug taper.

64
Minimize dose andtotal number of drugs

• Use no drug before its time
• Treat adequately do not withhold therapy for
  treatable disease.
• Start low, go slow.
• initiation of therapy
• restarting therapy
• withdrawing therapy
• Use blood levels wisely to detect
• decreased clearance
• drug or disease interactions

65
Appropriate Prescribing for Older Adults

• Recognize that any new symptom may be an ADE.
• Know the drugs you and your patients use.
• Use new agents with caution.
• Encourage treatment adherence.

66
Individualize Therapy

• What is the patients potential for
• An adverse drug event?
• An altered dose response?
• A drug interaction?
• drug-drug
• drug-disease
• drug-nutrient
• Treatment non-adherence?

67
Appropriate Prescribing for Older Adults

• Know your patients medications and medication
  history.
• Individualize therapy.
• Reevaluate indications for continued drug use.
• Minimize dose and total number of drugs
• Start low, go slow. Use blood levels
  judiciously.
• Treat adequately. Do not withhold therapy for
  treatable diseases.
• Consider the possibility that any new symptom is
  an ADE.
• Know the drugs you and your patients use.
• Use new agents with caution.
• Encourage treatment adherence.

68
Therapeutic Drug Monitoring

• Detect clinically significant PK differences
• drugs with low therapeutic index
• drugs with large variability in dose response
• there is no direct measure of desired effect
• patient at high risk of ADE or ineffective Rx

69
Drug Binding Proteins

• Albumin
• acidic drugs
• eg, phenytoin, warfarin, naproxen
• decreases in
• malnutrition
• cirrosis
• burns
• nephrotic syndrome
• end-stage renal disease

• Alpha-1-acid glycoprotein
• basic drugs
• eg, tcas, quinidine, lidocaine
• increases in
• trauma
• surgery
• acute MI
• infections
• inflammatory diseases
• cancer

70
Therapeutic Drug Monitoring
Drug Measured Free Drug Bound Drug
71
Phenytoin levels hypoalbuminemia

• C calcn C obs
• (K) ALB 1
• Hospitalized patients1, K 0.2
• Nursing home patients2, K 0.25

Albumin
Target Range
4.0 g/dl
10 - 20 ug/ml
2.5 g/dl
Hosp 6.7 - 13.4 ug/ml NH pt 6.1 - 12.3 ug/ml
1Dager et al. Ann Pharmacother 199529667-70 2An
derson et al. Ann Pharmacother 199731279-84.
72
Homeostenosis

• Critical narrowing of homeostatic reserve in
  elders
• Decreased ability to offset drug effects

73
Early Acute MI mortalitycan be reduced with
thrombolysis ages 65-74
deaths day 0-35

• ARR 2.6
• RRR 16
• NNT Treat 38 people post MI to prevent 1 death
  (35 days)

FTT Collaborative Group. Lancet 1994 343 311-22
74
Better Living Through Chemistry?

• People are living longer.
• Living longer living better
• Independent
• Functional
• Contributing
• Mortality is not the most important endpoint.
• 40 rated a hypothetical major stroke to be a
  worse outcome than death

75
Drug level monitoring Caveats

• Cant rule out toxicity
• Within therapeutic range nontoxic
• pharmacodynamics
• toxic effect not considered when range set
• Interpret in light of binding protein levels

76
Cytochrome P450 CYP2D6

• Metabolizes
• Codeine,
• Hydro- and oxy-codone
• Tramadol,
• most oxidized psychotropic drugs (TCAs, SSRIs,
  neuroleptics),
• Metoprolol, propranolol, timolol
• Propafenone

• NOT INDUCIBLE
• Inhibited by
• Cimetidine
• Fluoxetine, paroxetine,
• Propoxyphene,
• Quinidine,
• Perphenazine, thioridazine, methylphenidate,
• Chloroquine,
• Propafenone

77
Pharmacokinetics Bioavailability

• Usually unchanged in aging.
• Increases with
• Labetolol
• Levodopa
• Nifedipine
• Omeprazole
• Ondansetron

78
CHF incidence can be reduced by treatment
of ISH
CHF /4.5 yrs

• NNT 48

Kostis JB et al. JAMA 1997278212-216.
79
Atrial Fibrillation-associated Stroke can be
reduced with Anticoagulation
Stroke

• A Fib stroke
• fatal
• recurrent
• severe deficits
• NNT/1 yr 33

Arch Int Med 1994 1431449-57 Stroke
1996271760-1764.
80
Clinical fractures can bereduced in women with
existing vertebral fractures
with fractures/3 yrs

• NNT/ 3 yrs 22

Black et al. Lancet 19963481535-41
81
Calcium and Vit D can reduce nonvertebral
fractures in elders without osteoporosis
with fractures/3 yrs

• NNT/ 3 yrs 14

Dawson-Hughes et al N Engl J Med 1997337670-6
82
Is it Aging or Age-Related?
Disease
Aging
Lifestyle
83
Drug-induced Orthostatic Hypotension

• Volume loss
• Diuretics, lithium DI
• Vasodilitation
• Centrally acting sympatholytics
• methyldopa, clonidine
• Nifedipine
• Alpha-1-adrenergic antagonists
• TCAs, neuroleptics, prazosin-like drugs

84
Drug-induced Orthostatic Hypotension

• Inability to compensate for hypovolemia
• Impaired thirst response
• Impaired ADH secretion
• Impaired renal concentrating ability
• Impaired heart rate response
• Other risk factors for falls

85
Antihypertensive treatmentNNT for 5 years to
prevent 1 event
Older Younger Mortality
(gt 60 y.o.) Total 72 167
Cardiovascular 58 205 Cerebrovascular 193
365 Coronary Heart Disease
88 NS Morbidity and Mortality
Cerebrovascular 46 168 Coronary Heart
Disease 68 184 Cardiovascular 21 -----
Ref Mulrow, et al. JAMA 19942721932-1938.
86
Pop Quiz
Cost of one months supply

• Digoxin, 0.125 mg qd
• Paroxetine, 20 mg qd
• Enalapril, 5.0 mg qd
• L-thyroxine, 0.1 mg qd
• Pravastatin, 40 mg qd
• Furosemide, 40 mg qd
• Alendronate, 10 mg qd

87
Cost of 1 month supply

• Digoxin 0.125 mg qd 12.95 3.00
• Paroxetine 20 mg qd 74.95 58.50
• Enalapril 5.0 mg qd 39.95 28.55
• L-thyroxine 0.1 mg qd 15.95 3.60
• Pravastatin 40 mg qd 112.95 89.00
• Furosemide 40 mg qd 9.95 3.30
• Alendronate 10 mg qd 59.95 50.10

88
Medication Expenditures

• Cost of previous list
• Monthly 233 - 327
• Yearly 2797 - 3920
• Median income about 11,000.
• Who pays for medications?
• For people gt65 taking prescription meds
• Out-of-pocket drug costs 3.1 house-hold income

89
Drug Therapy Risks and Burdens

• Financial
• Psychological
• Patient accentuate infirmities
• directly reason for treatment
• indirectly difficulty obtaining, remembering,
  administering
• Care partner potential area of conflict
• Adverse Drug Events
• Any injury resulting from medical intervention
  related to a drug

90
Clinical fractures can bereduced in women with
existing vertebral fractures
with fractures/3 yrs

• RRR 25
• ARR 4.6
• NNT/ 3 yrs 22

Black et al. Lancet 19963481535-41