Download Aging - Pharmacology of. Geriatric Therapy

GERIATRIC THERAPY
Marian G. Suarez, M.D.
Diplomate, American Board of
Internal Medicine and Geriatrics
The Pharmacology of Aging
The world population is
aging.
Data from US Bureau of
Census showing some
projected
population
growth number.
World Demographics
(US Bureau of Census, International Database,
1996)Merck Manual,Geriatrics,1999
1. Growth of 65+
increase dramatically 1996-2025
% of ≥60 years old expected to
increase from 17% to 82% in
Europe
(about
200%
in
developing countries)
2. China and India
Has the largest total population
Will have the largest absolute
numbers of elderly
World Demographics
(US Bureau of Census, International database, 1996)
Merck Manual,Geriatrics,1999
3. 2020: Expected to have >1 billion persons
≥60 yrs old
4. 85 yrs old and over: “Oldest old” will
increase to 18 million by 2050
5. Centenarians will increase from 57,000
persons (1996) to 447,000 (2040)
Epidemiology of Medication
Use in the Elderly
1.
2.
65 + comprise 13% US population
consume 30% of all prescription
drugs
consume 40% of all non-prescription
drugs
2004: Health care cost for >65 +
~50% of National Health Care Bill
(substantial
portion
spent
on
medications)
Epidemiology of Medication
Use in the Elderly
3. On average-older adult uses 2-4 different
prescription drugs at the same time
4. Community dwellers (65-84) – 61% >3
drugs/year
37% receive ≥ 5
19% receive >7
5. Elderly NH patient- receive 6-8 meds daily
33%- 9-14 drugs daily
Epidemiology of Medication
Use in the Elderly
6. Women more likely than men
use
prescription
medication
7. Several studies show at least
90% of elderly use 1 + over
the counter drugs (OTC)
8. Most common OTC drugs:
Analgesics,Vitamins,Nutritio
nal supplements,Laxatives,
Antacids,Antihistamines
Epidemiology of Medication
Use in the Elderly
9. Polypharmacy associated with
increase
incidence
of
adverse
drug
reactions
(ADRs)
10. ADR responsible for 10-17%
of hospital admissions of
elderly outpatients
(other studies: ADR→35%
of all hospital admission in
the high risk elderly ≥ 5
drugs daily
Major Responsibility of the Pharmacist
Prevention
Rapid identification
And resolution of
drug-related
problems
Categories of Drug-Related Problems
1. Untreated medical problem (patient with
medication problem require prescription
drug but does not receive the drug)
2. Improper drug selection (taking the wrong
drug)
3. Underdosage (too little of correct drug)
4. Failure to receive drug
Categories of Drug-Related Problems
5. Overdosage
6. Adverse Drug Reaction
7. Drug Interaction (drugdrug
;drug-food;
drug-disease
interaction)
8. Drug use with no
indication
WHO Definition of ADR
(Adverse Drug Interaction)
Noxious, unintended & undesired effect of a drug,
which occurs at doses used in humans for
prophylaxis, diagnosis or therapy
Excludes:
o therapeutic failures
o intentional/ accidental overdoses
o drug abuse
o “adverse events” due to error in drug
administration or noncompliance
History of ADR
1960-1970’s – data suggested age as a
risk factor for development of ADR
1980 – spontaneous ADR reports to FDA
indicating rate of ADR in 65+ y/o, nearly
double of younger individuals (problem
of inappropriate Rx to older individuals
was acknowledged & publicized by
medical & advocacy groups for this
elderly
History of ADR
1980-1990 – gov’t regulatory &
legislative occurred to improve policy
making; and to decrease ADR in geriatric
patients
1987 – Omnibus Budget Reconciliation
Act (OBRA) established regulations for
use
of
sedative-hypnotics
&
antipsychotics in Medicare-certified NH
History of ADR (continued…)
1990 – OBRA required all states to conduct DUR
(Daily Utilization Reviews) of Medicaid Rx drug
claims
1995 – Report on “Prescription Drugs and the
Elderly” concluded inappropriate use of Rx drugs =
significant health problems in the elderly
2001 – FDA released a guidance for industry to
submit revised labeling for drugs already in the
market
Prescribers, Dispensers and Monitors of
medication must understand age-related
changes affecting the dispositon of drugs.
Age-Related Changes in
Pharmacokinetics
Pharmacokinetics
study of the absorption, distribution,
metabolism, and excretion of drug
“what the body does to the drug”
Pharmacodynamics
“what the drug does to the body”
Drug Administration
(route: oral, intravenous, intravascular,
inhalational, intranasal, topical)
Absorption
Bioavailability
(ie. Fraction of drug availablevariable)
Metabolism
(liver, kidney, others)
Distribution
Depot drug:
Lipid
Water
Circulating drug:
Protein-bound
Free
Excretion
Drug Effect
Renal
(glomerular
filtration, tubular
secretion)
Benefit
(efficacy)
Adverse Effect
(side effect or toxicity)
Hepatic
Other
(skin, lung,
gastrointestinal)
Schematic Representation of
Drug Pathway
Pharmacokinetic Principles in the Elderly
1.
Drug Absorption
Age-related
physiologic
changes can include:
Decreased
acid
production
Decreased absorptive
surface
(mucosal
atrophy)
Decreased splanchnic
perfusion
Decreased GI motility
Generally no significant
age-related ABSORPTION
for most drugs
BIOAVAILABILITY
BIOAVAILABILITY – refers to the fraction of
an administered drug that reaches the
circulation
- variable
IV med – 100%
Oral drug usually later
Pharmacokinetic Principles
in the Elderly
2. Drug distribution
Age-related physiologic changes include:
Decreased total body water- water-soluble
drugs (lithium, digoxin, aminoglycosides:
lower maintenance dose to avoid ADR)
Decreased lean body mass
Decreased serum albumin (binds acid
i,e.warfarin, phenytoin)
Pharmacokinetic Principles
in the Elderly
Increased a1- acid glycoprotein (AAG)- binds
basic drugs (lidocaine, propranolol)
 Protein-bound [inactive drug]
 Free drug [active drug]
ie. Warfarin 99% protein-bound, has
increased anticoagulant activity & toxicity in
patients w/ decreased albumin levels
• Increased total body fat
 Lipid-soluble drugs
(eg benzodiazepines)
increase volume of distribution in elderly;
remain in fat depots for prolonged period
exerting their effect long after drug has been
withdrawn
Pharmacokinetic Principles
in the Elderly
Drug Metabolism
Age-related physiologic changes include:
Decreased hepatic mass
Decreased hepatic blood flow (40%)
Age-related decrease in liver blood flow
directly influence the rate of drug
extraction from the blood
Pharmacokinetic Principles
in the Elderly
Drugs are metabolized in the liver by Phase I or
Phase II metabolism
Phase I metabolism (e.g. oxidation,
reduction, hydrolysis) declines in the elderly
due to decreased hepatic blood flow ( to
nearly half by 85y/o)
– Diazepam/ Flurazepam w/ prolonged
duration of activity
Phase II metabolism- primarily conjugation
(e.g. glucoronidation, sulfation) less affected
by aging
Pharmacokinetic Principles
in the Elderly
Cytochrome P450 (CYP) system- family of enzymes
involved in oxidative metabolism
Comprises 3 major groups:
CYP1
CYP 2
CYP 3A – accounts for metabolism of ~ 50%
of drugs
CYP minimally altered by age alone
Many drugs/ other substances alter effects of
CYP enzymes
Multiple drugs may induce or inhibit CYP450
enzymes
Common Inhibitors & Inducers
of CP 450 Enzymes
Inhibitors
Cimetidine
Ciprofloxacin
Diltiazem
Erythromycin
Fluconazole
Grapefruit juice
Haloperidol
Theophylline
Verapamil
Inducers
Carbamazepine
Charbroiled meat
Morphine
Omeprazole
Phenobarbital
Phenytoin
Prednisone
Rifampicin
Tobacco smoking
Pharmacokinetic Principles
in the Elderly
Drug excretion
Age-related physiologic changes include:
Decreased renal blood flow (
creatinine clearance)
Decreased GFR (~ 50% bet. ages 2090) – “unbound drugs”
Decreased tubular secretion (protein
bound drugs)
Pharmacokinetic Principles
in the Elderly
Drugs potentially toxic in the elderly due to
predominant renal elimination:
Aminoglycosides, amantadine, lithium,
digoxin, procainamide, cimetidine, NSAIDS
Pharmacokinetic Principles
in the Elderly
Glomerular
Filtration
Rate
(GFR)
is
approximated by calculating creatinine
clearance. The formula, Cockroft & Gault
Equation, is used to adjust drug dosage:
Creatinine clearance= 140-age x wt (kg)
72 x serum creatinine
In females, the result is multiplied by 0.85
Age-related Changes in
Pharmacodynamics
“what drug does to the body”- may be due to
changes in:
Drug receptors- blunted homeostatic mechanism
predisposes to respiratory depression, sedation &
constipation
Drug-receptor
interactionless
active
baroreceptor reflexes predispose elderly on
antihypertensives to postural hypotension
Altered adaptive homeostatic responses or
organopathology- impaired thermoregulatory
response to cooling predispose them on
barbiturates or phenothiazines in hypothermia
Primary Approaches to Determine
Appropriateness of medication
Prescribing in the Elderly
Drug Lists- most familiar “BEERS CRITERIA”
Published 1991- identified inappropriate meds
use in NH residents
(19 meds to be avoided, 11 criteria re: doses,
frequencies, duration of med Rx that should not
be exceeded in frail NH residents)
Updated 1997- to apply to older people in all
care settings
(28 medications to be avoided, doses &
frequencies of administration not to be exceeded
& 35 meds to be avoided in elderly known to
have any of several common conditions (drugdisease criteria)
Drug Utilization Review (DUR)
Evaluation of drug use in
a given health
environment against predetermined criteria to
assess appropriateness of drug therapy
Implicit Method
Focus on appropriateness of a patients’ entire
medication regimen rather than on a single drug
or drug class & combines medical history and the
clinician’s judgment & knowledge
6 Domains to Measure
Inappropriate Prescribing
1.
2.
3.
4.
5.
6.
Lack of indication
Improper schedule
Inadequate dosage
Potential drug interaction
Therapeutic duplication
Allergy
Suboptimal Prescribing
1. Overuse or Polypharmacy
Prescribing w/o proper indication
According to patient expectation for a prescription
Polypharmacy can lead to ADRs
Contributes to development of several “geriatric
syndromes” ie. cognitive impairment, delirium, falls,
urinary incontinence & increases health care costs
2. Inappropriate Use
Rx of a med w/ more potential risk than benefit
Rx that does not agree w/ accepted medicine
standards
Improper drug selection
Appropriate drug but wrong dose (too low/too high)
Suboptimal Prescribing
3. Underutilization
Omission of a drug indicated for Rx or
prevention of a disease condition
Underprescribing [ie. Use of warfarin for
atrial fibrillation; Rx of cancer pain]
Appropriate Rx for the Elderly
1. Dosage determination
“start slow & go slow”
2. Compliance
Unintentional
noncompliancedue
to
forgetfulness, confusion, decreased vision
Intentional noncompliance- due to side effects;
financial barriers
3. Role of Pharmacist
Provide services in DUR
Improve compliance
Simplify drug regimens
Increase patient education
General Principles for Improved
Geriatric Prescribing
1. Obtain thorough history of a drug use from all
physicians & sources
2. Evaluate the need for drug therapy
3. Periodically review medication regimen/ avoid
polypharmacy
4. Know pharmacology of drug(s) prescribed
5. Check renal function & adjust drug doses
accordingly
6. Simplify drug regimen/ help ensure compliance
7. Develop awareness of the COST of medications
1997 Beers criteria
Table 1. Potentially Inappropriate Medications for Use in the Elderly
Propoxyphene
Indomethacin
Phenybutazone
Pentazocine
Trimethobenzamine
Methocarbamol, cansoprodol,
Oxybutynin, chloroxazone,
metaxalone, cyclobenzapine
Amitriptyline, chlordiazepoxide-
amytriptyline, perphenazineamitriptyline
Doxepin
Flurazepam
Meprobamate
Lorazepam, 3mg; oxazepam, 60mg;
alprazolam, 2mg; temazepam,
15mg; zolpidem, 5mg; traizolam,
0.25mg
Disopyramide
Methyldopa; methyldopa + HCTZ
Reserpine
Dicyclomine; hyoscyamine; propantheline
Reserpine; reserpine + HCTZ
Chlorpheniramine, diphenhydramine,
Hydroxyzine, cyproheptadine,
promethazine
Ergot mesylate
Iron supplements > 325mg
All barbiturates except phenobarbital
Meperidine
Ticlopidine
Comparisons of Initial Doses Recommended in FDA- approved Product labeling
versusLower Effective Doses Reported in the Medical Literature
Drug
Recommended Initial Dose (mg)
Effective Lower Dose (mg)
400
200
50-75
10-25
Amlodipine besylate
5
2.5
Atenolol
50
25
Atorvastatin Ca
10
2.5 & 5
Bisoprolol fumarate
5
2.5
Bupropion HCl
100 BID
50 BID
Celecoxib
100 BID
50 BID
Cerivastatin Na
0.4
0.2 or 0.3
Chlorthalidone
15
12.5
Cimetidine HCl
800 HS
400 HS
0.625
0.3
50 BID-QID
25 TID
Doxepin HCl
75
10, 25 or 50
Ethacrynic acid
50
25
20 BID or 40 QD or BID
10 BID or 20 QD
Acebutolol HCl
Amitriptyline
Estrogens, conjugated
Diclofenac Na
Famotidine
Comparisons of Initial Doses Recommended in FDA- approved Product labeling
versusLower Effective Doses Reported in the Medical Literature
Drug
Recommended Initial Dose (mg)
Effective Lower Dose (mg)
5
2.5
60 BID
20 TID or 40 BID
Fluoxetine HCl
20
2.5, 5 or 10
Flurazepam HCl
30 QHS
15 QHS
Furosemide
80
40
Hydrochlorothiazide
25
12.5
400 TID-QID
200 TID
Imipramine HCl
75
10-25
Lisinopril
10
5
Losartan potassium
50
25
Lovastatin
20
10
Metorpolol tartrate
50-100
50
Misoprostol
200ug
50 or 100ug QID
100 BID
50 QD or BID
150 BID or 300 HS
25 BID or 100 HS
50-75
10 or 25
Felodipine
Fexofenadine HCl
Ibuprofen
Nefazodone HCl
Nizatidine
Nortriptyline HCl
Comparisons of Initial Doses Recommended in FDA- approved Product labeling
versusLower Effective Doses Reported in the Medical Literature
Drug
Recommended Initial Dose (mg)
Effective Lower Dose (mg)
20
10
Ondansetron HCl
8 BID
1-4 TID
Penbutolol sulfate
20
10
Pravastatin Na
10-20
5-10
Propranolol HCl
80
40
Ramipril
2.5
1.25
Ranitidine HCl
150 BID or 300 HS
100 BID
Sertraline HCl
50
25 once daily
Simvastatin
10-20
2.5, 5 or 10
Spironolactone
50-100
25
Torsemide
10
5
Trazodone HCl
150
25-100
100 BID
25-100 QD
75
37.5 or 50 (in divided doses)
120-180
90
10mg vs 5mg
7.5 HS
Omeprazole
Triamterene
Venlafaxine HCl
Verapamil HCl
Zolpidem tartrate