PHARMACOLOGY II - DRUG DISPOSITION IN PERINATAL, PEDIATRIC AND GERIATRIC PATIENTS

DRUG THERAPY IN PREGNANCY

DISCLAIMER:
This note is intended only as a guide in pharmacology. This note is INCOMPLETE thus must not be used as reference for whatever reason other than stated. In case of conflict, Dr. Layugs ppt.,
Katzung and Craigs Pharmacology Textbooks will remain the standard reference and will prevail over this note.
PHARMA II- MODULE 1 l Lecture Date: July 10, 2012 l DRUG DISPOSITION IN PERINATAL, PEDIATRIC AND GERIATRIC PATIENTS 1
 1. Physiochemical properties of Drug:
Induces fetal hepaticenzymes of
The bigger / heavier , the harder to be passed or Bilirubin
reabsorbed less incidences of jaundice, not
Solubility: lipid soluble---placenta practiced anymore
Ionization: membranes/placenta---non-ionized ANTI-ARRHYTMICS
form readily transferred DIGOXIN
2. Rate at which drug crosses the placenta VERAPAMIL
3. Duration of exposure PROCAINAMIDE
4. Distribution
5. Placental and Fetal Developmental Stage at time of Fetal arrhythmiaDopplerFHTEchocardiogramgive
exposure anti-arrythmics

LIPID SOLUBILITY ANTIRETROVIRAL

THIOPENTAL ZIDOVUDINE/ AZT
anesthetic during pregnancy MAGNESIUM SULFATE
if markedly INCREASED can cause Tocolytic
APNEA in NEWBORN (-) uterine contractions
lipid solubility= greater absorption >6 mg/dl - HYPOTONIA/LETHARGY
Ionized= less absorption
TERBUTALINE
MOLECULAR SIZE Beta-adrenergic
Lower molecular weight readily cross the Anti-asthmatic
placenta
UTERINE ATONY---SHOCK
Molecular size = more time to cross
Induce fetal tachycardia and transient
ANTI-COAGULANT:
hyperglycemia in NEWBORN
HEPARIN- relatively safe
WARFARIN- more teratogenic, avoided NOTE: Study autonomic effects in neonate
(Beta-adrenergics)!!!

PLACENTAL TRANSPORTERS
MDR gene OPIOIDS
P-Glycoprotein Transporter- drug efflux/out MORPHINE
PHENTANYL
PROTEIN BINDING NALBUPHINE
More protein bound = in absorption/distribution Antidote: NARCAN/NALOXONE
Bound albumin = less free drug Naloxone CANNOT be given in neonates, can cause
Not readily absorbable convulsions

Drug- protein complex- big enough to be

confined in one site DRUG EFFECTS IN THE FETUS

PENTOBARBITAL LITHIUM
actively absorbed Anti-manic/ mood stabilizing agents
EBSTEIN ANOMALY displacement of TRICUSPID
Drug needs to pass to UMBILICAL VEIN ---to VALCE towards RIGHT VENTRICLE allows blood
PLACENTA back to RIGHT ATRIUM
Drug should be NON-POLAR to pass the
memberane VALPROIC ACID
Anti-seizure
FETAL THERAPEUTICS
Bipolars/ mood stabilizers
CORTICOSTEROIDS
Can cause NTDs esp. SPINA BIFIDA
Enable fetal lung maturation
Betamethasone OPIOIDS
Neonatal Withdrawal Syndrome
PHENOBARBITAL
Physiological and Behavioral Syndromes
Anticonvulsant
*** STUDY!!!
 ACE INHIBITORS 1 mo.- 2 yrs
FETUS: irreversible renal damage - Most system function at adult level
2- 12 years
DES (Diethylstilbestrol ) - Clearance greatly increases and exceeds adult
level
Induces VAGINAL ADENOCARCINOMA/ADENOSIS
t - shortening
STUDY: Table in KATZUNG!!!
o Drug therapy in Perinatal/Pediatric/Geriatric TRIMETHOPRIM
o Drug Disposition Chapter Folate antagonist
Co-trimoxazole

PRETERM INFANTS AGE t

NB 10.8
1. GFR: 1/10 of a term NB, rate of excretion 1-3 3.7
2. Urinary loss of filtered substances 8-10 5.4
3. Phase II Hepatic metabolism (Glucorination) Young adult 11.2
pathways, appear after 20 weeks AOG
Dec./Less t = Increase frequency of dosage
AGE- REL. MATURATION OF SELECTED SYSTEMS

Phase I (5 mos-5 years) DIFFERENCES IN SEX

Oxidation/ Reduction/Hydrolization d/t Estrogen
Prepare drug to enter to phase II Female VS Male
Phase II (3-6mos.) Dec. GASTRIC ACIDITY = Inc. GASTRIC
Attachment of conjugation---water solube EMPTYING TIME
Inc. CYT P450
GASTRIC EMPTYING = ABSORPTION (small
intestine) = faster gastric transit
ABSORPTION
GASTRIC EMPTYING = ABSORPTION (small Gastric acid initially secreted within 1st few
intestine) = slower gastric transit hours of life
Peak levels within first 10 days of life
2 FACTORS IN DEGREE OF ABSORPTION AND Dec. in first 20 days of life
ELIMINATION OF DRUG:
Gastric emptying time and peristalsis SLOW
1. pH
a. pH = drug absorption
Long fatty acids- Dec. gastric emptying time
(milk formulas)
b. pH = drug absorption
2-12 years- gastric emptying time INC. together
2. Degree of ionization ( pKa ) with SPLANCHNIC BLOOD FLOW

a. Ionization= pH = absorption
b. Ionization= pH = absorption INC Splanchnic BF =
INC absorption/faster drug absorption

FACTORS AFFECTING NB DRUG DISPOSITION LOW BLOOD FLOW through the muscles
1. Inc. Body Water Distribution among neonates
2. Dec. Body Fat
3. Dec. Exocrine pancreatic function
PERCUTANEOUS DRUG
4. Dec. albumin concentration and binding
PRETERM
5. Dec .total plasma protein
Does not have the same protective capacity
until 2-3 weeks of life
May have excessive toxicity in young infants
EARLY & LATE CHILDHOOD
PHISOHEX
Most systems work in adult level
 Quartenary ammonium compound ADULTS (PARACETAMOL)
Can cause BRAIN DAMAGE in infants Leads to INC formation of
GLUTHATHIONE
Leading to reactive intermittent
ANALINE DYES
LIVER TOXOCITY
Can cause CYANOSIS secondary to NEWBORN
METHEMOGLOBINEMIA INC ability to sulfate
ACETAMINOPHEN
EMLA DEC heaptotoxicity
Topical anesthetic PHASE II enzyme system reach ADULT level
Can cause METHEMOGLOBINEMIA in between 3-6 months of age
NEWBORN
EXCRETION
1. GFR
2. Tubular Secretion
3. Tubular Reabsorption
Renal Blood flow, GFR and tubular functions are
DISTRIBUTION REDUCED in BOTH PRETERM and TERM NEONATES.
1. TBW is significantly greater
GENTAMYCIN, AMIKACIN, STREPTOMYCIN

FETUS - 100% Have different dosing interval

Baby at BIRTH- 80% ADULT Q8

Normal ADULT- 70% NB Q12

ELDERLY Person- 50% PRETERM OD

LOADING DOSE= Vd X Target Concentration DRUG ACTION

LD= steady state plasma/peak dose APNEA OF PREMATURITY

Vd= Volume of distribution Cessation if breathing <15seconds

NB need LOADING DOSE d/t INC TBW THEOPHYLLINE can be used as tx

CAFFEINE used to tx APNEA OF
2. NB have DEC fat PREMATURITY
3. NB have DEC Plasma albumin and Total
Plasma Protein concentration PDA
a. INC drug toxicity Induced PROSTAGLANDIN E1
b. KERNICTERUS accumulation of Tx to close: INDOMETACIN (NSAID)
BILIRUBIN in BRAIN
PARADOXICAL EFFECTS
METABOLISM adults (+) effects, NB (-) effect
CYT P 450 enzyme system function more slowly
in in infants than in adults PHENOBARBITAL
OXIDATION, DEMETHYLATION DEC. Adult- sedation
NB- metabolize 30% of THEOPHYLLINE Children- paradoxical hyperactivity
PHASE II synthetic enzyme reactions involving
Glucorinadation are immature in the newborn RITALIN (METHYLPHENIDATE)
tx hyperactivity/ ADHD
GRAY BABY SYNDROME
d/t CHLORAMPHENICOL
aplastic anemia DRUGS USE DURING LACTATION
CV collapse
Most drugs used to lactating women are
D/t INC blood concentration of detectable in breastmilk BUT
UNCONJUGATED blood
Optimal dose/time on LACTATING MOTHER take
SULFATION (PHASE I) medications:
o BEFORE NURSING: 30-60mins
ACETAMINOPHEN o 3-4 hours to next feeding period
 o REASON?! BOOK-STUDY!!! 3. RED tubular secretory activity
STUDY TABLE OF DRUGS LACTATION 4. RED number of functioning nephrons

DRUGS USED DURING LACTATION PHARMACODYNAMICS EFFECTS (PLS READ!!!)

CNS drugs
TETRACYCLINE- Teeth staining, impede Calcium Cardiovascular drugs
Antimicrobial drugs
Anti-inflammatory drugs
ISONIAZID Opioids
VITAMIN B PYRIDOXINE DEFICIENCY
SIDEROBLASTIC ANEMIA ?! EXAMPLE OF DRUG EFFECTS
PHOCOMELIA ?! Thalidomide
VAGINAL ADENOCARCINOMA- DES
OPIOIDS GRAY BABY SYNDROME- Chloramphenicol
Neonatal Narcotic Dependence/Syndrome
Withdrawal syndrome GUIDE QUESTIONS (ppt)
Please refer to PPT.
Mother subjected to RADIATION/ IODINE THERAPY-
INC risk of infants having CANCER by 10x fold.

THAT IN ALL THINGS, GOD MAY BE

GLORIFIED!
DISPOSITION TO ELDERLY/GERIATRIC POPULATION

1. DEC GFR
2. DEC cardiac index
3. DEC maximal breathing capacity

ABSORPTION
1. DEC splanchnic blood flow
2. DELAYED gastric emptying time
a. Absorption depending on pH and state of
ionization
b. Non-ionized in LOW pH = DEC absoption of
drug
DISTRIBUTION
1. HYPOALBUMINEMIA
a. DEC 20% plasma albumin cincerntration in
human d/t HEAPTIC SYNTHESIS OF
ALBUMIN
2. Qualitative changes in drug binding sites
3. DEC muscle mass
4. INC in proportion of fat
5. DEC TBW

METABOLISM
1. RED hepatic enzyme activity
2. RED hepatic mass, volume and blood volume
UPTAKE- OXIDATION-CONJUGATION-EXPORT

INC t1/2 in ELDERLY

Ex: DIAZEPAM
Young 20 hours
Elderly 4x fold 80 hours
DEC drug metabolism
DEC drug clearance

EXCRETION
1. RED renal blood flow
2. RED GFR