Geriatric Pharmacology

Lisa Rosenberg, MD
Touro University Nevada
April 6, 2011
Basic Principles of Geriatrics
Emory University Division of Geriatric Medicine and Gerontology

Aging

Is not a disease
Does not cause symptoms
Occurs at different rates among individuals and
among organs/organ systems
Increases susceptibility to disease and other
bad events (homeostenosis)
Basic Principles of Geriatrics

Medical Conditions in Older Adults

Chronic
Multiple
Multifactorial
Acute conditions superimposed on chronic
Treatment of one condition can affect other
conditions
Basic Principles of Geriatrics

Reversible or Treatable Conditions are

Under-detected

Conditions attributed to age

Atypical presentations
Geriatric syndromes
Systematic screening can identify a deficiency
Basic Principles of Geriatrics

Importance of Functional Ability and Quality of

Life (QoL)

Unclear mortality benefit of medications

Small changes can greatly affect function and
QoL
Function and QoL can both be measured and
followed
Basic Principles of Geriatrics

Cognitive/Affective Disorders

Prevalent
Under-diagnosed
Affect treatment plans, compliance
Basic Principles of Geriatrics

Iatrogenesis - Common and Treatable

Adverse drug events

Polypharmacy and the prescribing cascade
Drug-disease interactions
Complications of hospitalization
Two Parts of Geriatric Pharmacology
Pharmacokinetics
“what the body does to the drug”
absorption, distribution,
metabolism, clearance

Pharmacodynamics
“what the drug does to the body”
transmitters, receptors,
second messengers
Physiologic Changes With
Aging - Pharmacokinetics
Absorption
Distribution
Metabolism
Clearance/Elimination
ABSORPTION

No significant change with age, per se

Affected by
Achlorhydria
Prolonged transit time in gut
Competing compounds, especially OTC’s
DISTRIBUTION
Body Composition

Decreased water and lean muscle mass as %

of body weight
Decreases Vd of hydrophilic drugs

Increased fat as % of body weight

Increases Vd of lipophilic drugs
DISTRIBUTION
Body Composition
Changes in transport proteins – clinically
relevant mainly in chronic disease or severe
undernutrition
Mainly affects loading dose of drugs like
digoxin, warfarin
Albumin – binds many drugs, especially weakly
acidic drugs
Orosomucoid (α-acid glycoprotein) – binds
mainly basic drugs
METABOLISM
Variable decline in liver’s ability to metabolize, among
individuals, among enzymatic processes and among drugs,
mainly related to change in liver size and blood flow
 Acetylation, conjugation do not change appreciably with age

 Oxidative metabolism (cytochrome P450 system) does decline

with aging, resulting in variably decreased clearance of drugs

*Age-related decline in liver’s ability to recover from injury
Types of Usual Change
Processes products with Age
Phase I Oxidation Active Greater
Hydroxylation metabolites
Reduction
Phase II Conjugation Inactive Lesser
metabolites
METABOLISM
Genetics, nutrition, environmental exposure, disease
(e.g. congestive heart failure) and other drugs all
have a greater effect on drug metabolism than
does age alone.

Ideal drug for an older adult undergoes phase II

metabolism and does not compete for, induce or
suppress its own metabolism.
ELIMINATION
Kidney is main organ of elimination
One third of older adults have truly preserved
creatinine clearance (means 2/3 of older adults do
not)
Serum creatinine tends NOT to change with age…
falsely reassuring

Cockcroft-Gault formula* (ages 40-80)

(Ideal weight in kg) (140 - age)
(72) (serum Cr in mg/dL)
*multiply by 0.85 if female
ELIMINATION
Lungs important in elimination of volatile
drugs

Volatile drugs tend not to be used in elderly

due to age-associated changes in lung
function as well as greater prevalence of
active pulmonary disease
Pharmacodynamics
Pharmacodynamics

Homeostatic mechanisms that diminish with

aging:
Postural blood pressure control
Posture control
Extrapyramidal functions
Cognitive function
Thermoregulation
Pharmacodynamic Changes with
Aging
Limitations in our understanding of this:
1. Difficulty in accounting for baseline differences
2. Dependence on cultural/educational differences (when
assessing drug effects on cognition or other subjective
symptoms)
3. Dependence on cultural differences when assessing
subjective responses

Cross-sectional Studies – Limitations

4. Assume mean changes between age groups reflect changes
in the individual over time
5. Birth cohort effects confound those of age
6. Selective mortality effects
Pharmacodynamics
CNS-active drugs
-reasons for altered dynamics
1. Altered neurotransmitters/receptors
2. Hormonal changes (sex and growth
hormones)
3. Impaired cerebral glucose metabolism
4. Decreased oxygen with cerebrovascular
changes
5. Better CNS penetration with age (reduced p-
glycoprotein activity)
Pharmacodynamics
Benzodiazepines
Changes especially important because of
association with falls, hip fractures
Demonstrated by EC50 of midazolam decreased
by 50% in older adults
PD differences documented variably for
benzodiazepines
Likely mechanism is change in distribution of
drug to the brain in older adults
-N.B. EC50 reflects relationship between serum
concentration and drug effect
Pharmacodynamics
Anesthetics, NMB, Opioids
Anesthetics – increased sensitivity
Neuromuscular blockers – no change in
sensitivity but decreased dosing
requirements due to changes in
pharmacokinetics
Opioids – increased sensitivity and changed
kinetics
Pharmacodynamics
Cardiovascular Drugs
ACE-inhibitors
 No change with age per se
 Decrease in sensitivity after repeated dosing

(seen in both age groups, enzyme induction)

 Only age-related difference was that younger

group more likely to have headaches, older

group more likely to be orthostatic,
lightheaded
Pharmacodynamics
Cardiovascular Drugs
Dihydropyridines – greater response observed
in treatment-naïve elderly, diminishes in as
little as three months
Non-dihydropyridines
1. Decrease in sensitivity of PR response
(which is prolonged in the young)
2. Enhanced HR and BP responses
Pharmacodynamics
Autonomic Agents
β-sensitivity decreases with age
- prevalence of high-affinity receptors ↓ with
age; does not explain diminished response to β
antagonists
- may be related to Gs proteins
-adrenoceptors couple with G proteins
-Gs proteins demonstrate ↓ with age
exception: activity of β-blockers in elderly with
very high blood pressure
α-sensitivity has shown varied responses
Pharmacodynamics
Diuretics
Traditional approach to looking at drug effect
does not apply
Action is at luminal surface in nephron
No change in drug sensitivity with age
GFR is greatest predictor of diuretic response
*diuretics further ↓ GFR
*HCTZ not an effective antihypertensive if
CrCl < 30 mL/min
Appear due to pharmacokinetic changes
Pharmacodynamics
Anticoagulants
Increased risk of pathologic bleeding
Warfarin – no PK effect but greater decrease in
K-dependent clotting factor synthesis
Sensitivity difficult to quantify
Serum levels of warfarin don’t apply

AGE IS ONE OF GREATEST PREDICTORS OF

ANTICOAGULANT REPSONSE
Interacting Drugs
Warfarin, NSAIDs
Warfarin, sulfa
Warfarin, macrolide
(highly probably, often delayed)
Warfarin, quinolones
Warfarin, phenytoin
ACE-inhibitors, K+ supplements
ACE-inhibitors, aldactone/
spironolactone
Digoxin, amiodarone
Digoxin, verapamil
Theophylline, quinolones
Impact Mechanism Prevention
Increased risk of NSAIDs irritate gastric lining & Monitor weekly INR and for
bleeding impair platelet function s/s of bleeding
Increased warfarin Change in gut flora responsible for Dec. warfarin dose by 50%
activity K production during and 1 wk after abx
Increased effect of E-mycin inhibits warfarin metab. If macrolide necessary,
warfarin and clearance; change in gut flora monitor INR qod. ID pathogen
to confirm need.
Increased effect of Change in gut flora; ? change in Monitor INR qod if quinolone
warfarin warfarin metab. and clearance is necessary
Increased effects of Keep INR at lower end of thx
both drugs range. Monitor INR and PTN
lvl.
Elevated serum K+ Decreased aldosterone/K+ Monitor K+; are both drugs
secretion necessary?
Elevated serum K+ Probably additive effect Monitor K+; are both drugs
necessary?
Digoxin toxicity ? amio ↓ clearance of digoxin; ? Dig lvl prior to amiodarone;
additive effect at sinus note decrease dig dose and
monitor weekly
Digoxin toxicity, Synergistic effect of slowed Monitor HR and EKG (PR
bradycardia, heart block impulse conduction and reduced interval)
contractility
Theophylline toxicity Quinolones inhibit hepatic Monitor theophylline lvl AND
metabolism of theophylline watch for s/s
Drug Errors/Adverse Drug Events

Drug error: inappropriate/incorrect omission,

administration (timing or route), dose; included
administration to the wrong patient
Adverse Drug Event: any drug-related incident that results
in harm to a patient; does not necessarily mean that an
error was made
What is the difference between an adverse drug event and
an adverse drug reaction?
An adverse drug reaction implies/requires a causal (and
temporal) link between drug and event.
Adverse Events: Risk Factors
Advanced age
Gender (female)
Frailty (physiologically advanced age)
Polypharmacy
Multiple prescribers
Prior adverse drug reactions
Cognitive impairment
Serotonin Syndrome
Caused by elevated
levels of serotonin
-too high a dose of
some medications
-medication
combinations
-some illicit drugs
and herbal
supplements
Signs/Symptoms:
agitation, confusion,
tachycardia, HA,
diaphoresis, diarrhea
Serotonin Syndrome - Treatment

 Stop medication
 Hydrate patient
 Cool to counteract hyperpyrexia
 Benzodiazepines for agitation

 Primary prevention: avoid multidrug regimens

Neuroleptic Malignant Syndrome
 Usually develops within first two weeks of
treatment
 Most serious adverse effect of neuroleptics
 Features:

◦ Muscle rigidity – “lead pipe”

◦ Autonomic dysregulation
◦ Hyperthermia (hours to days after exposure)
◦ Altered mental status (even coma)
Neuroleptic Malignant Syndrome
 Treatment
◦ Stopping culprit medication
◦ Cool patient
◦ Support vital functions (normalize VS)
◦ Mild: benzodiazepine
◦ Moderate: ?dopaminergic agonist (bromocriptine)
◦ Severe: dantrolene to address muscle rigidity
 Use atypical antipsychotics in future (eg.
quetiaptine/Seroquel)
Tousi 2008
Disorders Related to Parkinson’s
Disease
 Parkinsonism-hyperpyrexia syndrome
◦ Withdrawal/decrease of dopaminergic medications
 Also: amantadine and anticholinergics
◦ Fever, rigidity, autonomic instability, risk of
aspiration pneumonia
◦ Rx: dopaminergics, supportive care +/-
methylprednisolone
◦ Important that patients going into surgery still
receive their Parkinson’s Disease medications
Disorders Related to Parkinson’s
Disease
 Parkinsonian dyskinesia
◦ Levodopa-induced
◦ Related to disease severity and dose
◦ Use of dopamine agonist as initial therapy can delay
◦ Exhausting if prolonged, risk of rhabdomyolysis
◦ Treatment: lower dose of dopaminergics, mild
benzodiazepine for dyskinesia; ? amantadine
Dystonic Reactions
 Acute dystonic reaction
◦ Usually occurs ≤ 24 hrs after medication
◦ Neuroleptics/antiemetics
 DDx includes meningitis, CVA, electrolyte abnormalities,
drug toxicity
◦ Rx: Stop ppt’ing medication, anticholinergics
 Benztropine, IV diphenhydramine
 Laryngeal dystonia with multiple system atrophy
 Myoclonus – from opiate toxicity or withdrawal
 Baclofen withdrawal – life-threatening syndrome
◦ Rigidity, fever, change in mental status, worsening
dystonic symptoms
One Final Message

The only way to find the mistakes

in a patient’s medication regimen
is to look at the list as if the
previous prescriber made a mistake

…even if the previous prescriber

was you.
Prescribing Cascade
The tendency to prescribe a
medication to address a sign or
symptom caused by another
medication

Usually not appreciated

Anticholinergic Side Effects
Medications with
Anticholinergic Effects
Rational Prescribing for Older Adults
Careful drug history
Look for drug reactions and interactions
Prescribe for a specific indication
Make goals and endpoints of therapy clear
Simplify regimen as much as possible
Start with conservative dose and dose intervals
– explain to patient that achieving an
effective dose may take time
“start low and go slow”
Acknowledgements
Emory University Geriatric Educational
Resources
http://medicine.emory.edu/ger/edu_resources/
Rosemary D. Laird, MD, University of Kansas
Multidisciplinary Medication Management
Project
UCSF Primary Care Lecture Series