Age and Pharmacokinetics

Pediatric and Geriatric

Considerations
Pediatric Pharmacology - History
Some of the most disastrous therapeutic misadventures occurred in
pediatrics.
Thalidomide 1957

Thalidomide is well known for its teratogenic effects. Cause

multiple congenital fetal abnormalities (particularly limb
deformities), thalidomide also can cause polyneuritis, nerve
damage, and mental retardation.

Chloramphenicol 1959

Gray baby syndrome was first reported in two neonates who

died after excessive doses of chloramphenicol (100300
mg/kg/day); the serum concentrations of chloramphenicol
immediately before death were 75 and 100 mcg/mL.

Patients with gray baby syndrome usually have abdominal

distension, vomiting, diarrhea, a characteristic gray color,
respiratory distress, hypotension, and progressive shock.

Directly led to the modern era of pharmaceutical regulation with KefauverHarris Drug Amendments of 1962
Requirement for demonstrated efficacy and safety for FDA approval
and USA marketing.
Pediatric pharmacology - Whats unique?
Continuous development from embryo to adolescent
Perpetual pharmacologic moving target
Pharmacodynamics and pharmacokinetics change with time
The most profound differences occur in the first weeks through first year of
life.
Descriptive pharmacology (especially for new drugs) in pediatric patients is
often lacking
Children are not miniature adults

Dosing based on rule (Youngs, Clarks) or scaling (by body

weight or body surface area) not always predictable for a given
drug.

Animal studies not always predictive.

Clinical studies in children fraught with ethical and financial hurdles.
Administration of drug can also be problematic.
The Moving Target - Developmental Changes

Body composition

Organ function

Drug metabolizing enzymes

Unique metabolic pathways

Renal function

Receptor response

Unique disorders

Extremely small margin of error for the most fragile patients

Errors can be devastating
Individual variance unpredictable
Developmental Pharmacology - Absorption - GI
Gastric acid - approaches adult values ~ 3 mo in full-term infants.
Bioavailability increased for acid-labile drugs (some penicillin
derivatives)
Decreased for drugs requiring acid to be absorbed.
Digestive enzymes including pancreatic enzymes are low in newborns.
Colonization of the gut occurs rapidly after birth but is highly variable
and unpredictable.
Developmental Pharmacokinetics of Pediatrics
Gastric emptying
Delayed and unpredictable in newborns - adult values ~ 6 mo.
GI motility

 Slow in newborns; may be increased in children.

Usually affects the rate but not the fraction of drug absorbed.
The absorptive surface area/BSA is > infants and children vs. adults
The impact on absorption is usually minimal but is unpredictable

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

Geriatric Pharmacology - Whats unique?

Physiology
Changes in underlying physiology occurs over time.
Altered, usually diminished, receptor sensitivity and responsiveness
The ability to mount a compensatory physiologic response is
diminished.
Normal homeostatic mechanisms are blunted and sometimes produce
inappropriate responses.

 Even healthy elderly have diminished capacities.

Aging is a continuum and the aged are stratified by degree of age.
Young old is 65 75 years
Old 75 85 years
Old old age > 85 years
As age progresses so do the exceptional considerations.
Geriatric Pharmacology - Whats unique?
Physiology
Body composition

total body water, lean body mass, body fat; serum albumin, -1
acid glycoprotein

CNS

weight and volume of the brain

sensitivity to depressant drugs: ethanol, anticholinergic effects,
antipsychotic agents.

CNS effects and side effects are exaggerated

Delirium and dementia complicate therapy.
ANS
Responsiveness and appropriate reflex effects are diminished.
Orthostatic hypotension - frequent side effect due to diminished
capacity for response to agents with any degree of sympathetic
blockade.
Geriatric Pharmacology - Whats unique?
Physiology
Cardiovascular

-adr receptor activity, baroreceptor activity

Cardiac output is generally fairly well maintained

Cardiac disease and reserve capacity diminish with age.
Adrenergic receptor sensitivity is altered.
Any pro-arrhythmic side effect can be accentuated.

 Endocrine
Atrophy of thyroid
incidence of diabetes mellitus

Menopause, andropause
Geriatric Pharmacology - Whats unique?
Physiology
Digestive tract

gastric emptying time, GI blood flow; gastric pH,

intestinal transit time.

Hepatic

liver size, hepatic blood flow.

Some hepatic functions are better preserved than others.

albumin
Alcohol use, gallstones, cholangitis, fatty liver (NASH), heart
failure, and conditions requiring concomitant drugs can affect
metabolism.

Geriatric Pharmacology - Whats unique?

Physiology
Renal

GFR, renal blood flow, tubular function

Renal function and size diminishes with age.

Pulmonary

respiratory muscle strength, chest wall compliance, total alveolar

surface

Most systems are more affected by disease than age alone.

ALTERED PHYSIOLOGIC VARIABLES IN
OLDER PATIENTS
ALTERED PHYSIOLOGIC VARIABLES IN OLDER PATIENTS
ALTERED PHYSIOLOGIC VARIABLES
IN OLDER PATIENTS

Geriatric Pharmacology - Whats unique?

Polypharmacy
With the accumulation of disease these is an accumulation of treatments
Polypharmacy Multiple medications for multiple chronic diseases
Multiple physicians
Self-medication
Disproportionate use of drugs in the elderly.
12% of population receive 30% of all prescriptions.
2/3 use 1 or more drugs daily.

Ave 5 - 12 drugs daily

< 5% use no drugs.

1/3 use 1 or more psychotropic drugs each year.

It is often difficult to distinguish between disease and adverse drug events.

Geriatric Pharmacology - Whats unique?
Disease
The elderly accumulate diseases.
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
ADE interpreted as new medical condition
Geriatric Pharmacokinetics - Absorption
Age related changes are small.
Gastric/intestinal motility

 Surface area and blood flow

Net negligible change in absorption
Less significant than disease-specific changes.
Effects of age on absorption for delayed and sustained release formulations
have not been well-documented.
A diminished first-pass effect results in an increased bioavailability.
Geriatric Pharmacokinetics - Distribution
Lean body mass and body water
Vd (volume of distribution) for water soluble drugs
Water soluble drug - conc.

Ex. ethanol

Fat soluble drugs conc.

Increased fat serves as a repository for fat soluble drugs
Ex. Amiodarone, desipramine, diazepam, haloperidol, digitoxin
Impact on drug therapy in general is not great.
Protein binding to albumin and -1 acid glycoprotein is more affected by
disease than age.
Decreased albumin can result in increased free fraction of drugs.

Increased delivery to receptor

Increased drug interactions

Estimating Renal Function

Cockcroft Gault estimation
Assumes steady state production of creatinine.
Very limited utility in critically ill, clinically unstable, malnourished or wasted
patients.
Measure creatinine clearance or use extrinsic marker if critically
important.
Other formulas may be more accurate in special populations.
Geriatric Pharmacokinetics - Renal Function

 Drugs with predominantly renal elimination and potentially serious

toxic effects should have dosing adjusted based on renal function.

Geriatric Pharmacodynamics
Receptor alteration with age best documented for adrenergic receptors and
autonomic nervous system.
Increased sensitivity to sedation.
Increased sensitivity to hypotensive (side) effects due to decreased
baroreceptor function.
Diminished adaptive capacity most manifested as increased
occurrence of adverse events with medications.
Treatment of elderly patients can be very complex because of multiple
diseases and drug therapies that can produce adverse drug reactions.

Appropriate Prescribing for Geriatric Patients

Obtain a complete drug history
Avoid prescribing before a diagnosis is made
Review medications regularly and before prescribing a new medication
Know the actions, adverse effects, and toxicity profiles of he medications you
prescribe
Start low dose and titrate dose based on tolerability and response
Appropriate Prescribing for Geriatric Patients
Educate patient and/or caregiver about each medication
Avoid using one drug to treat the side effects of another
Attempt to use one drug to treat two or more conditions
Use combination products cautiously
Communicate with other prescribers
Avoid using drugs from the same class or with similar actions

Summary: Pediatric pharmacology

Children and infants, especially neonates, have different pharmacokinetic
parameters than adults

 Appropriate drug therapy cannot be assumed to identical to adults, even

when adjusted for weight or body surface area.
Each agent is unique and requires adequate clinical studies before a drug can
safely be used in children.

Summary - Geriatric pharmacology

Normal homeostatic mechanisms are blunted and sometimes produce
inappropriate responses.
Metabolism and renal elimination are most often impacted

Phase II drug metabolizing reactions are better preserved than

Phase I.

The dose of most drugs that are renally cleared should be

adjusted for renal function.

Cockroft-Gault equation is frequently used to estimate

renal function.

Summary - Geriatric pharmacology contd

Disease and environmental factors have a greater impact on hepatic drug
metabolism than age.
Therapeutic plan should include only agents with established efficacy.
Most drugs should started at lower doses and titrated more slowly.
Frequent review of the complete therapeutic plan to minimize interactions
and side effects.
Adverse drug effects can mimic disease and should be included in the
evaluation of a patient.
Drugs are the great imitator of disease