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Thalidomide 1957
Chloramphenicol 1959
Resources
Body composition
Organ function
Drug metabolizing enzymes
Renal function
Receptor response
Unique disorders
Extremely small margin of error for the most fragile
patients
Gastric emptying
GI motility
Percutanous absorption
Intramuscular
Rectal
Breast milk
Transplacental
Neonatal
< 1 mo.
Early
infant
Mid-Infant
35 mo.
Late infanttoddler
6 24 mo.
Older child
Dermal
Lung
PK
Pathway
Absorption
Oral
Plasma proteins
100
80
60
40
20
0
0
3 mo.
6 mo.
9 mo.
1 yr
5 yr
10 yr
20 yr
40 yr
Development of Drug-Metabolizing
Enzymes - Phases of Drug Metabolism
Phase I
Oxidation
Reduction
Hydrolysis
Phase II
Conjugation
JPET Vol. 300, Issue 2, 355-360, February 2002 The Ontogeny of Human Drug-Metabolizing Enzymes: Phase I Oxidative Enzymes
Ginsbergetal.Pediatrics2004;113:973.
Premature
Neonates
Neonatal
< 1 mo.
Early
infant
Mid-Infant
35 mo.
Late infanttoddler
6 24 mo.
Older child
CYP1A2
Scale BW3/4
Scale BW3/4
CYP2E1
Scale BW3/4
Scale BW3/4
CYP A
Scale BW3/4
Scale BW3/4
CYP3A7
Other CYPs
Scale BW3/4
Scale BW3/4
ADH
Scale BW3/4
Scale BW3/4
Metabolism:
Phase I
Premature
Neonates
Neonatal
< 1 mo.
Early
infant
Mid-Infant
35 mo.
Late infanttoddler
6 24 mo.
Older child
Glucuonidation
N-acetylation
Metabolism:
Phase Ii
40
20
0
1-2
days
2-4 wk
2 mo
6 mo
1 yr
2 yr
6 yr
12 yr
Therapeutic implications
Ex betamethsone, indomethacin
Warfarin
Cyclosporine
Midazolam
Erythromycin (intestinal motilin receptors)
Body composition
CNS
ANS
Cardiovascular
Endocrine
Atrophy of thyroid
incidence of diabetes mellitus
Menopause, andropause
Digestive tract
Hepatic
Renal
Pulmonary
Gastric/intestinal motility
Surface area and blood flow
Net negligible change in absorption
Note on syllabus.
Antipyrine Clearance
Renal Elimination
Cl and t1/2 for renally cleared drugs and metabolites.
The age-related change in renal clearance is the
most consistent and predictable change in
pharmacokinetics.
The dose of most drugs that are renally cleared should
be adjusted for renal function.
The adjustment method most frequently used is the
Cockroft-Gault equation to estimate renal clearance.
This method is not without problems, but is simple and
readily applicable in most situations.
CLCr (ml/min) =
0.693 X Vd
t 1/2 =
Clearance
Vd is smaller for water soluble drugs
Clearance is usually diminished with age
Geriatric Pharmacodynamics
Geriatric dictum:
Start low and go slow
Drug Information
Secialized information
Johns Hopkins: The Harriet Lane Handbook: A Manual for Pediatric House
Officers, 16th ed 2002 Mosby, Inc.
Geriatrics At Your Fingertips, 2005 by D Reuben, and Others. The American
Geriatrics Society (AGS)
Exceptions
Investigational drugs
NME (New Molecular Entity)
Indication not labeled
Literature, FDA, Sponsors
Unusual patients (age, disease, indications)
International patients (online resources, Pharmaceutical regulatory
agencies)
Case Study - 1
Case 1
OPI
Description
Clinical Pharmacology
Pharmacokinetics
Absorption, Distribution, Metabolism, Excretion
Special populations: Geriatric, pediatric, gender, renal
insufficiency, hepatic insufficiency
Drug-drug interactions
Special: Antibiotics|Microbiology
Labeling, contd.
Interactions
Drug-drug
Drug-laboratory
Pediatric, geriatric
Carcinogenesis, mutagenesis, impairment of fertility
Pregnancy; teratogenesis, lactation
Other pharmacology
Animal studies
Labeling, contd.
Adverse Reactions
Case 1. Contd.
Approved labeling
Official guidelines (www.guidelines.gov)
Some compendia will list sources
Medline or other primary literature resources
Case 1, contd
Official compendia
Secondary sources
Primary literature (animal studies are not reliable for most
metabolic data)
Metabolism
Metabolism
Pediatric kinetics
Elderly NO
Case 1, contd
Questions?
Email: bholbein@hcin.net
Website: http://phdres.caregate.net
Annotated bibliography
Slides
April 29 :
Age and Pharmacokinetics: Pediatric and Geriatric
Considerations
May 2:
Drug Interactions