Title: PERINATAL AND PEDIATRIC PHARMACOLOGY
1PERINATAL AND PEDIATRIC PHARMACOLOGY
- Dr. Manuel E. Valdez
- Department of Pediatrics UPHRMC
2Aspects of Drug Therapy During Pregnancy
- access of the drugs to the fetus
- pharmacodynamic aspects of drug action in the
fetus -
- Recent WHO survey showed that 89 of women take
prescription drugs during pregnancy (avg 3
prescription each) not including OTC preparation
and alternative therapies
3Access of the Drug to the Fetus
- Lipid solubility
- Molecular size
- Protein binding
- Placental and Fetal metabolism
4Lipid solubility
- Lipid soluble drugs readily cross the placental
barrier ionized drugs do not - Example a) thiopental given as anesthetic for
C/S. Readily crosses the placenta and can produce
sedation and apnea in newborn - b) salicylates ionized at blood
PH. However, small amount that is not ionized
crosses the placenta and can be trapped there
5Molecular size
- Placenta excludes drugs of high MW
- MW 250-500 drugs are readily permeable
- MW 500-1000- greater difficulty in crossing the
placenta - MWgt1000- excluded or diffuse very poorly
- Exception-maternal antibody globulins cross
placenta through poorly characterized carrier
mechanism - Therapeutic implications Most important clinical
implication of this is that Heparin (large MW) is
the anticoagulant of choice in pregnant women
6Protein binding
- Plasma protein binding of a drug will inhibit
placental transfer. Tighter binding inhibits more
than weak binding - Highly lipid soluble drugs may transfer anyway
despite avid protein binding - Plasma protein affinity may be different in fetal
circulation vs. maternal . Thus free fetal plasma
concentration may be higher than free maternal
plasma concentration of drug at equilibrium
(sulfonamides, barbiturates, phenytoin and local
anesthetics)
7Placental/Fetal drug metabolism
- Placenta important site of drug metabolism
especially aromatic oxidation reactions
(hydroxylation, N-dealkylation, demethylation)
Ex. Phenobarbital oxidized by placenta - Fetal drug metabolism 40-50 of umbilical
venous blood enters fetal liver
8Pharmacodynamic aspects of drug action on the
fetus
- Maternal drug action
- Therapeutic action on the fetus
- Toxic action on the fetus
- Teratogenic action of specific agents
9Maternal drug action
- Mother may need to take drugs for conditions that
arise during pregnancy. These drugs may affect
the fetus or fetal drug metabolism - Ex. Pregnancy induced heart failure (digitalis
and diuretics) pregnancy induced diabetes
(insulin)
10Therapeutic action on the fetus
- Drugs are given for fetal condition in utero
- Ex. Corticosteroids-used to stimulate fetal lung
maturation in expected premature birth - Phenobarbital used to induce fetal hepatic
enzymes which glucorunidate bilirubin
11Toxic action on the fetus
- Ex. Opiates can cause dependency in newborn
leading to neonatal withdrawal syndrome - ACE inhibitors produce renal toxicity in the
developing kidney
12Teratogenic action of specific agents
- Teratogens result in characteristic malformation
indicating selectivity of action of the drug - Act predominantly at a defined stage of fetal
development - Dose dependency
- Lists of specific teratogens
13Teratogenic drug effects
- Category Drug Teratogenic
effect - Antibiotics Amonoglycosides
Deafness,vestibular damage - Tetracyclines
Anomalies of teeth bone - Quinolones
Arthropathies (Animal studies) - Sulfonamides
Hyperbilirubinemia/kernicterus - Anticholinergics
Meconium ileus - Anticoagulants Warfarin
Skeletal CNS defects (DWS) - Anticovulsants Carbamazepine Neural tube
defects - Phenytoin
Growth retardation,CNS defects - Valproic acid
Neural tube defects - Trimethadione
CNS and facial defects -
14Teratogenic drug effects
- Antidepressant Lithium
Ebstein anomaly, hypotonia -
reduced sucking,hyporeflexia - Antihypertensives ACE inhibitors Renal
failure, decreased skull -
ossification, renal tubular -
dysgenesis - B-blockers
Growth restriction, neonatal -
bradycardia/hypoglycemia - Antithyroid drugs PTU
Fetal/neonatal goiter/hypo- -
thyroidism - Methimazole
Aplasia cutis, fetal/neonatal -
goiter/hypothyroidism
15Teratogenic drug effects
- Cytotoxic drugs Amonopterin/
CNS/limb malformations - methotrexate
- Cyclophosphamide
CNS malformations, -
secondary cancer - Diuretics Furosemide
? uterine blood flow, -
hyperbilirubinemia - Thiazides
Neonatal -
thrombocytopenia - Hypoglycemics Chlorpropamide,
Neonatal hypoglycemia - glibenciamide
-
16Teratogenic drug effects
- NSAIDS Indomethacin Premature
closure of PDA, NEC, -
neonatal PHN - Salicylates
Hemorrhage - PG analogues Misoprostol Moebius
sequence - Recreational Ethanol
Fetal alcohol syndrome - drugs Cocaine
Growth retardation - Sex hormones DES
Genitourinary defects in male/ -
female offspring - Danazol
Masculinization of female fetus -
17Teratogenic drug effects
- Sedatives Thalidomide Limb
shortening(phocomelia) -
hearing defect - Psychoactive drugs Barbiturates Neonatal
withdrawal syndromes - benzodiazepines
- opioids
- Phenothiazines
Neonatal effects of impaired -
thermoregulation, extra- -
pyramidal effects - Miscellaneous Vit.A
Congenital anomalies, cleft -
palate,eye damage,syndactyly - Vit K
Hyperbilirubinemia/kernicterus
18Effect of drug administration to lactating mother
- Drugs affecting lactation
- Drug concentration in breastmilk
- Pharmacodynamics of drug ingested in breastmilk
-
19Drugs affecting lactation
- Bromocriptine,ergotamine,cabergoline,lisuride,terg
uride, and metergoline- inhibit prolactin - OCP -risk of ?milk supply, N2 protein content
of milk - estrogen-antagonizes the milk producing effect of
prolactin and inhibit lactation - clonidine- inhibit milk ejection ?maternal
prolactin levels - Thiazides- suppress lactation
20Drug concentration in breastmilk
- Most drugs are excreted into breastmilk by
passive diffusion making the drug concentration
in milk directly proportional to maternal plasma
concentration - Human milk is more acidic than plasma, drugs that
pass into milk are weak bases,water soluble,
lipid soluble and poorly bound to proteins - Milkplasma (MP) ratio serves as an index of
extent of drug excretion in the milk
21Drug excretion in human breastmilk
- DRUG
- Amoxicillin
- Atenolol
- Carbamazepine
- Cefotoxime
- Diazepam
- Digoxin
- Lithium
- Penicillin
- Phenytoin
- Propranolol
- Theophylline
- Warfarin
- MP RATIO
- 0.014-0.043
- 1.5-6.8
- 0.6-0.7
- 0.029-0.16
- 0.08-0.13
- 0.6-0.8
- 0.25-0.77
- 0.02-0.2
- 0.12-0.24
- 0.5
- 0.57
- lt0.01
22Principles that can guide management of cases of
drug exposure in a breastfed infant
- Human milk drug concentration usually do not
exceed the maternal plasma concentration - Even when the MP ratio for a given drug
approaches or exceeds 1.0, the amount of drug
ingested by the infant rarely is sufficient to
attain therapeutic concentration - Short exposure to a drug is usually of less
concern than given for long period of time - Amount of drug ingested can be minimized by
feeding the infant just before or at the time of
maternal administration
23Drug concentration in breastmilk
- Drug concentration in breastmilk difficult to
predict and usually measured empirically. However
effect on infant is usually lower than in mother
since dose comes from free plasma concentration
of the mother - If nursing mother must take drugs, optimal
time is 30-60 minutes after feeding and 3-4 hrs
before next feeding or before the next dose is
due, when the concentration of drug in milk is
low.
24Pharmacodynamics of drug ingested in breast milk
- Drugs that eventually reach the infants systemic
circulation in any appreciable amount (gt10)
should be avoided.
25Pharmacodynamics of drugs ingested in breastmilk
Examples
- Tetracyclines-70 of maternal serum
concentration-- permanent tooth staining in
infants - Diazepam( many other sedative hypnotics)--
sedation in infants and can accumulate in infant
due to long half life - Cancer chemotherapy- immunosuppresion/neutropenia
- I tracers - thyroid cancer in infant
- Lithium(same concentration in breastmilk as in
plasma)- tremor and involuntary movements - Amiodarone- thyroid disturbance because of high
Iodine content - ASA- Reye syndrome
26Pharmacodynamics of drug ingested in
breastmilk-Examples
- Chloramphenicol- grey baby syndrome
- Sulphonamides- jaundice because of competition
for bilirubin for binding to albumin - Quinolones- adverse effect on cartilage
development - Tinidazole- risk of carcinogenicity and
mutagenicity - Laxatives containing phenolpthalein- risk of
carcinogenicity - Antithyroid (carbimazole,methimazole) - thyroid
suppression - H2 antagonist (cemitidine )-because of their
accumulation in breastmilk (6mg/L of milk could
mean an average dose of 18mg /day for a newborn)-
effect on gastric acidity and inhibition of cP450 - Ergotamine- risk of ergotism in infants
27Epidemiology
- Ave. of 0.9 medication/patient contact is
prescribed in pediatric practice vs 1.1
drugs/patient contact for all the disciplines
together. - 1st 5 years of life- 95 of children have been
prescribed medications w/ ave. of 8.5 courses of
prescriptions and 5.5 different medications - Greatest number of prescriptions is given to
children between 7 and 12 months
28Therapeutic use of drugs in infants and children
- Unique aspects of
- Drug absorption
- Drug distribution
- Drug metabolism
- Drug excretion
29Unique aspects of drug absorption in infants and
children
- Absorption from I.M. injection sites
- - Blood supply and flow, Muscle mass
- - Drug related factors
- Absorption from GIT
- - gastric PH
- - peristaltic rate and gastric
emptying time - - diarrhea
- - bacterial flora
- Absorption from the rectum
30Drug absorption at IM injection sites-Local
factors
- a) Blood supply and flow
- - Conditions like low CO, RDS or shock may
compromise blood supply to muscles severely
leading to decreased absorption from the injected
site. - - Immobility slows absorption rate
- - Exercise enhances absorption Ex. After
IM insulin- exercise-induced hypoglycemia - Ex. Injected IM digoxin improves regional
blood flow therefore drug absorption/toxicity - b) Muscle mass - Ex. Infants, malnourished
children has small muscle mass, Obesity -
-
31Drug Absorption from IM injection sites- Drug
-related factors
- Muscle is more acidic than blood
- Ex. Phenytoin after IM injection is converted
into acid form. The sodium salt of Phenytoin
precipitates at site of injection which leads to
erratic and slower absorption
32Drug absorption from GIT
- a) Gastric PH slowly rises in premature infants
- b) Gastric emptying time is prolonged in
neonates. May increase absorption if drug is
absorbed in stomach or delay if absorbed in
intestines - c) Peristalsis slower in neonates, could increase
intestinal absorption - d) diarrhea interfere with drug absorption from
GIT, effect is exaggerated in neonates - e)Bacterial flora affects hydrolysis of drug
conjugates that are excreted in bile Ex Vit K
other fat soluble vitamins
33Oral drug absorption in neonates vs older children
- DRUG Oral Absorption
- Acetomenophen Dec
- Ampicillin Inc
- Diazepam N
- Digoxin N
- Penicillin Inc
- Phenobarbital Dec
- Phenytoin Dec
- Sulfonamides N
34Rectal administration of drugs
- Useful in conditions such as nausea,vomiting,
status epilepticus,for induction of anesthesia
and for administration of drugs that have a large
first-pass effect - Ex. Diazepam solutions- well absorbed from the
rectum compared with suppositories for which
absorption is erratic and slow - Other drugs- lorazepam,midazolam,atropine,
- barbiturates have been administered rectally
with great success
35Unique aspects of drug distribution in infants
and children
- Total body water content
- Fat content
- Protein binding
36Drug distribution-Total body water content
- Neonate 70-75 (premature can be up to 85) vs
50-60 in adults) - ECW 40 in neonates, 20 in adults
- Neonates undergo diuresis in 1st 48 hrs
- Thus neonates have a larger relative plasma
volume which affects distribution of water
soluble drugs(Ex aminoglycosides,ampicillin) - Water soluble drugs are distributed throughout
ECW, therefore the volume of ECW compartment
determines drug concentration
37Drug distribution-Fat content
- Varies in neonates. Prematures can be 1, full
term 15 - This affects distribution of lipid soluble drugs
- Ex. Digoxin which may accumulate in smaller
amounts in immature infants
38Drug distribution-Protein binding
- Neonates esp preterm are at risk of altered
drug protein intercation - - ? concentration of albumin and protein lead
to decreased drug protein binding. Ex Higher
cord/adult free drug ratios for salicylates,
sulfonamides, morphine, phenobarbital and
phenytoin-greater drug effects/toxicity. - - Changing affinity of albumin for different
drugs at different stage of maturation (e.g
acidic drug affinities for serum albumin increase
dramatically over the first few weeks of life)
39Drug distribution-Protein binding
- ?concentration of FFA and B 1 affect protein
binding. FFA and B1 have high affinity for
albumin which can result in competition or even
displacement of drugs from albumin binding sites
Ex sulfonamides,phenytoin - CNS distribution of drugs- tighter junctions in
the brain endothelial capillaries and the close
approximation of glial connective tissues to the
capillary endothelium limit drug distribution to
brain tissues. Ex. Water soluble antibiotics
(aminoglycosides)are less likely to cross blood
brain barrier
40Protein binding affect free drug
concentration-Example
- Diazepam - 98 protein bound in older children,
plasma drug concentration of 300 ug/ml yields a
free concentration of 6 ug/ml - In neonates 90 protein
bound and yields a free concentration of 30 ug/ml -
41Unique aspects of Drug Metabolism in infants and
neonates
- Liver- major organ of drug metabolism
- Other organs like lungs,GIT or blood are
capable of metabolizing drugs - Drug metabolism can result in either generation
of weaker or inactive metabolites or
transformation of a parent compound or prodrug
into the active compound (theophylline to
caffeine codeine to morphine)or an even more
active metabolite - Generally slower drug metabolism in infants and
neonates
42Drug metabolism in infants and neonates-2 major
steps
- Phase 1 reactions (oxidation, reduction,methylatio
n) - reach maximal maturity by 6 months of age.
- Ex. Theophylline- 10 is methylated to
caffeine, with 50 excreted unchanged in urine.
W/ maturation of hydroxylation and acetylation of
hepatic enzymes, the rate of clearance increases
resulting in short half life (3-5 hrs in infants
and children vs 8 hrs in adult)
43Drug metabolism in infants and children
- Hepatic Phase II reactions (glucorunidation,
sulfation, acetylation) - CP450 and conjugating enzymes are reduced in
activity in the neonates (50-70 adult values)
- Glucorunide formation- reach adult levels in
3rd-4rth year of life - Sulfation pathway-reach adult levels just days
after birth - Decreased ability of neonates to metabolize drugs
result in prolonged elimination half lives
leading to ADR or toxicity from overdose - Variation in enzyme activity make it difficult to
predict plasma values of drugs Ex. Phenytoin - Infants more susceptible to drug toxicity vs
adults when drug must undergo hepatic elimination
44Half life of Phenytoin in neonates
- Days after birth T 1/2
- 0-2 80
hrs - 3-14 18 hrs
- 14- 50 6 hrs
- Compared with carbamazepine which has identical
plasma half lives in neonates and adults
45Unique aspects of drug excretion in infants and
children
- i) GFR lower in neonates and children
- a) Week 1 GFR -30-40 of adult values (even
lower in prematures) - Week 3 - 50-60 of adult values
- By 6-12 months -reaches adult values (per
unit surface area)
46Drug excretion
- b) elimination is thus lower in children for
most drugs vs adults - c) conditions that reduce GFR (heart failure)
also further reduce elimination - ii) Tubular secretion rate is about 25-50 lower
in newborn reaching adult levels at age 1- 3
years
47Drug excretion
- Renally eliminated agents- aminoglycosides,penici
llins, digoxin - Ex- Dose of gentamycin younger than 7days old
neonate- 5mg/k x 2 Older than 7 days old- 7.5
mg/k x 3 - Digoxin- renal clearance increases from 33
mL/min/BSA in neonates to 98 mL/min/BSA at 3
months and 144 mL/min/BSA at 1.5 years
48Drug interactions
- Defined as clinically measurable modifications in
either magnitude or duration of action of one
drug caused by prior or concomittant
administration of another substance - 2 types 1) Desirable -such as seen in treatment
of HPN by using multiple drugs with different
mechanisms of action - 2) Adverse- serious or life
threatening (3 of hospitalized patient with 7
of these caused by drug interaction. - Mechanism pharmacokinetic and pharmacodynamic
49Drug interactions affecting oral bioavailability
- GIT- Ex Tetracycline can chelate
calcium,magnesium or iron leading to decrease
absorption - Oral neomycin or antineoplastic
agents can damage the intestinal absorptive
surface - Metoclopramide,domperidone- can
enhance gastric emtying which affects rate of
absorption - Morphine,anticholinergics,antacids-can
delay gastric emptying which affects rate of
absorption - Relevance- when a rapid onset of drug effect is
desired such as sedation or pain relief -
-
50Interactions affecting oral bioavailability
- Drugs that have an extensive first-pass
effect(i.e. those that are extracted or
metabolized during transit across the intestinal
epithelium or during the first pass through the
liver) such as beta blockers,Ca channel blockers, - tricyclic antidepressants, morphine), the
primary factor affecting clearance is hepatic
blood flow - Coadministration of drugs that decrease hepatic
blood flow such as cimetidine would increase free
concentration of these drugs
51Protein binding drug interactions
- Serum concentration of a measured drug refers to
the total drug concentration in the plasma (free
protein bound). - Only the free drug exerts its pharmacologic
effect - Drugs that are highly bound to protein are
subject to displacement by other drugs that have
high affinity for the same protein binding sites
resulting to increase in the free concentration
of the index drug Ex- salycylates, sulfonamides
52Drug interactions affecting biotransformation
- Many of the prescribed drugs in children may
inhibit or enhance the metabolism of other drugs - Drugs that have an inhibitory effects on hepatic
drug metabolism resulting in a functionally
impaired or inactive enzyme that cannot oxidize,
reduce or hydrolyze drugs (cimetidine,
erythromycin, ciprofloxacin, omeprazole) - Coadministration of these drugs with
theophylline may result in increased plasma
concentration and toxicity of theophylline
53Drug interactions affecting biotransformation
- Enzyme induction can enhance the clearance of
index drugs which can lead to decreased or even
loss of efficacy. Drug enzyme inducers are the
following - a) Rifampicin - Coadministration with
cyclosporine or prednisone leads to graft
rejection or with oral contaceptives leads to
failure because of increased metabolism - b) Phenytoin- Coadministration with methadone
leads to withdrawal symptoms - c)Phenobarbital
- If an induction interaction is established,
?the dose of index drug. If the inducing drug is
stopped, ?the index drug dose to avoid toxicity
54Drug interactions due to altered renal function
- Drugs excreted by GFR are unlikely to be affected
by other drugs - Drugs that are actively transformed into the
tubular lumen can be inhibited by other drugs Ex-
Methotrexate toxicity can be induced by
inhibition of its tubular secretion by
salicylates - Renal clearance of lithium is reduced in the
presence of thiazides - Probenecid enhances the tubular secretion of
penicillin
55Pharmacodynamic features of the neonate
- PDA - kept open by PGE
- - closed by Indomethacin
- PDA-vessels connecting LPA with aorta
- PGE infusion can be used to keep ductus
arteriosus patent in infants with TOF or TGA
56Drug dosage in infants and children
- Special dosage forms for infants
- Patient compliance
- Calculation of pediatric drug dosage
- FDA approval and safety assurance
57Special dosage forms
- Elixir - alcoholic solution in which drug is
dissolved ( No shaking is needed) - Suspensions- undissolved particles of drug
floating in thich vehicle ( Must shake, at first
dose will contain less drug than last dose), can
reduce efficacy in early treatment and enhance
toxicity late in treatment (ex. Phenytoin) - Chewable tablets-usually drug is to be chewed not
swallowed for optimal absorption
58Patient compliance
- 21 of adolescents noncompliant with AED therapy
- 28 of asthmatic children noncompliant with
theophylline - 30-40 of thalssemia major patients noncompliant
with nightly subcutaneous infusions of
desferrioxamine - To improve compliance a) take time to explain the
nature of the illness b) provide precise
instructions for treatment (including the names
and purposes of the drug or drugs prescribed) and
c) give specific instructions about dosage
59Patient compliance
- teaspoon- should be 5 ml but can vary from 2.5
to 7.8 ml in common household spoons. Get a
measuring syringe - dosing often spilled, spit out, forgotten (Be
clear in patient direction-e.g wake them to give
drug or cant wait till morning etc) - left over drugs- Give full dose especially
antibiotics which are often discontinued upon
cessation of symptoms (antibiotic resistance)
60Calculation of pediatric drug dosage
- Youngs rule
- dose adult dose x (age in yrs)/ (age
12) - Clarks rule (more precise than Youngs rule)
- dose adult dose x wt (kg)/ 70
- dose adult dose x wt (lbs)/ 150
- BSA (Body Surface Area)
- Neonate BSA/Adult BSA x 100 of adult dose
needed - Often labeling info for manufactures contain no
dosages for children lt 12. When using such a drug
the dose must be started based on conversion
factor
61Determination of drug dosage from surface area
- Wt Approx age SA of adult
dose - 3 kg (6.6 lbs) NB 0.2
12 - 6 kg (13.2lbs) 3 mos 0.3
18 - 10 kg (22 lbs) 1 year 0.45
28 - 20 kg (44 lbs) 5.5 years 0.8
48 - 30 kg(66lbs) 9 years 1.0
60 - 40 kg (88 lbs) 12 years 1.3
78 - 50 kg (110 lbs) 14 years 1.5
90 - 60 kg (132 lbs) adult 1.7
102 - 70 kg (154lbs) adult 1.76
103
62Therapeutic Drug monitoring
- Measurement of drug concentrations and the use of
pharmacokinetic principles to individualize drug
dosing in an attempt to maximize therapeutic
efficacy while minimizing potential toxicity - Applicable for medications that possess narrow
therapeutic indices and for agents that
demonstrate a good correlation between serum
concentrations and pharmacologic effect - Trough levels- provide accurate interpretation of
drug concentration - Peak levels- less accurate because they are
subject to significant variability due to
differences in absorption and distribution rates. - Reserved for medications with short
half-lives in which peak levels are associated
with efficacy or toxicity -
63Therapeutic drug monitoring-Examples
- Theophylline serum concentrations
- 10-20 mcg/mL- clinical bronchodilation in
asthmatic children - 5-10 mcg/ml- diaphragmatic stimulation
- gt20 mcg/mL -toxicity
- Aminoglycosides
- Peak levels of 12-14 mcg/mL or trough levels
gt2 mcg/mL- ototoxicity/nephrotoxicity - Chloramphenicol- 25 mcg/mL or higher- risk of
reversible bone marrow suppression - Vancomycin- trough levels gt 30 mg/L-
nephrotoxicity -
80-100 mg/L - ototoxicity -
64FDA approval and safety assurance
- New drugs need to have studies in pediatric
patient for safety and efficacy if they are
likely beneficial in children - Certain existing classes of drugs need to be
studied and labeled for use in children. Criteria - - drug would represent an improvement in
standard therapy for children - - drug currently prescribed gt50,000
times/year - - drug is in a class or for use where
additional option for children are needed