Download Seminar On Altered kinetics in pediatrics

SEMINAR
ON
ALTERED KINETICS IN PEDIATRICS
By
RAJANI THOUTREDDY
(M. Pharm I- Sem)
DEPARTMENT OF PHARMACEUTICS
BLUE BIRDS COLLEGE OF PHARMACY
(Affiliated to Kakatiya University)
WARANGAL
2009
CONTENTS
1.
2.
3.
4.
5.
6.
7.
8.
9.
INTRODUCTION
CALCULATION OF CHILD DOSE
DRUG ABSORPTION
DRUG DISTRIBUTION
DRUG METABOLISM
DRUG ELIMINATION
THERAPEUTIC DRUG MONITORING
DOSING CONSIDERATIONS
CONCLUSION
REFERENCES
1. INTRODUCTION
Pediatric population comprises 20-25% of total world
population.
Table. 1. PEDIATRIC AGE GROUPS TERMINOLOGY
TERMS
DEFINITION
Gestational Age
Time from the mother’s last menstrual period to the time
the baby is born
Postnatal age
Age since birth
Neonate
First 1 month of life
Pre mature
neonates
Born at less than 37 weeks gestation
Full term
neonates
Born between 37 and 42 weeks gestation
Infant
1 month to 1 year of age
Child
1-12 years of age
Adolescent
12-18 years of age
2. CALCULATION OF CHILD DOSE
 Dose for child from adult dose can be calculated by any of
the following formulaeClark’s Formulae: (For infants and Children)
(Weight in pounds) x (adult dose)
50
Fried’s Formulae: (For infants and children up to 1 to 2
years)
(Age in months) x (adult dose)
150
Young’s Formulae: (For children of 1 to 12 years)
(Age in years) x (adult dose)
Age + 12
Based of Surface area
% of Adult dose =
Surface area of child x 100
Surface area of adult
Table. 2
Age
% of Adult dose
1 Month
10
2 Months
15
4 Months
20
1 Year
25
3 Years
35
5 Years
40
10 Years
60
12 Years
75
16 Years
90
3. DRUG ABSORPTION
3.1
3.2
3.3
3.4
3.5
Oral absorption
Intravenous absorption
Intramuscular absorption
Percutaneous /Transdermal absorption
Rectal absorption
3.1. Oral Absorption






Effected by –
Gastric pH
Gastric emptying and GI motility
Absorptive surface area
Pancreatic enzyme activity
Bile Salt production
Underlying disease state
3.2. Intravenous Absorption
Effected by –
 Site of injection
 IV flow rate
 Dose volume
3.3. Intramuscular Absorption
Used when child is unable to take medication
orally or when drug is unavailable for oral use.
Effected by –
 Surface area available
 Blood flow to site of injection
 Muscle activity
Less desirable because of pain, irritation
and decreased drug delivery compared to I.V.
administration
Pain can be over come by applying topical
anesthetic such as lidocaine.
3.4. Percutaneous /Transdermal Absorption
Effected by –




Patient age
Skin hydration
Stratum corneum thickness and intactness
Application site
Drug diffusion by percutaneous absorption is explained by
the equation –
J = Km x Dm x Cs
l
J – Flux
Km – Partition Co-efficient
Dm – Diffusion constant under specific conditions such as
temperature and hydration
Cs – Concentration gradient
l – Length /thickness of stratum corneum
3.5. Rectal Absorption
 Used as an alternative to oral, I.V and I.M
routes of absorption
 Absorption is more in solution from than in the
form of suppositories
 Not generally preferred due to –
 Delay in onset of action
 Failure to reach minimum effective
concentrations in the plasma.
4. DRUG DISTRIBUTION
4.1. Volume of distribution
Total body water as a percentage of total body
weight
 85% in premature infants
 78% in full term neonates
Percentage of extra cellular water –
 65% of total body weight premature infants
 35-44% in full term neonates
 20% in adults
Percentage of intra cellular water –
 25% in premature neonates
 33% in full term neonates
 40% in adults
• Amino glycosides such as gentamycin have extra
cellular volume of 0.5 -1.2 L/Kg for a neonate but
only 0.2 – 0.3 L/Kg for an older child /adult
• Vd is decreased for lipid soluble drugs such as diazepam
in neonates. Neonates exhibit apparent Vd of 1.4 – 1.8
L/Kg compared to 2.2 -2.6 L/Kg in adults
4.2. Protein binding
Acidic Drugs – Albumin
Basic Drugs – Alpha1– acid glycoprotein (AGP)
These proteins are less efficient in neonates in
binding drugs such as phenytoin, phenobarbital,
chloramphenicol, penicillin, propranolol, lidocaine etc
Adult levels of albumin and AGP occur at
approximately 10-12 months of age
4.3. Presence of endogenous substances
Free fatty acids
Unconjugated bilirubin
Drugs like sulfonamides or ceftriaxome bind to
plasma proteins, may displace bilirubin and
contribute to high levels of bilirubin in neonate and
infants.
Displaced bilirubin can cross the blood brain
barrier and deposit in the brain causing an
encephalopathy termed “Kernicterus”.
Unconjugated bilirubin normally binds noncovalently to plasma albumin, but binding affinity is
reduced in neonates, not approaching adult values
until 6 months of age.
5. DRUG METABOLISM
 Drug Metabolism occurs primarily in the liver with
additional biotransformation occurring in the
intestine, lung, adrenal gland and skin.
 In liver, metabolism involves –
1) Phase – I reactions (Non Synthetic reactions)
2) Phase – II reactions (Synthetic Reactions)
1) Phase – I reactions:

Oxidation, reduction, hydrolysis, hydroxylation
etc

Cytochrome P450 mono-oxygenase enzymes
which are responsible for Phase –I oxidation
reactions are 50% of the activity of the adults.
Table. 3. Age dependent differences in activity of important
drug metabolising phase – I enzymes and drug metabolism
Enzyme
Neonate
Infant
Child
Adolescent
Pharmacokinetic
Consequences
O-demethylation of codeine
to morphine ↓ in
neonate/infants resulting in
lack of efficacy and poor
pain control.
CYP2D6
Reduced
(20% adult
activity)
Reduced
Adult pattern (by Adult pattern
age 3-5 yr)
CYP2C19
Reduced
Adult pattern
(reached by
age 6 months)
Increased (peak
activity at age 34 years)
Adult pattern
(decreases to
adult value at
puberty)
Diazepam half-life ↑ in
neonates/infants (25-100hrs)
compared to children (737hrs) and adults (20-50 hrs)
due to ↓oxidative activity
CYP2C9
Reduced
Adult pattern
( reached by
age 1-6
months)
Increased (peak
activity at age 310 years)
Adult pattern
(decreases to
adult value at
puberty)
Phenytoin half life ↓from 80
hrs at 0-2 days, to 15 hrs at
3-14 days, to 6 hrs at 14-150
days of life due to slow
maturation
CYP3A4
Reduced (3040% of adult
activity)
Adult
pattern(by age
6 months)
Increased
Adult pattern
(between age 1-4 (at puberty)
years then
progressively ↓)
↑ Metabolism of
carbamazepine to its 10,11
epoxide in infants/children
with ↑CYP3A4 activity
compared to neonates, and
adults
2) Phase –II reactions:
 Glucuronidation, sulfation, acetylation, glutathione
conjugation etc.
 Involve the conjugation of active drugs with
endogenous molecules to form metabolites that are
more water soluble.
 Glucoronidation in children reaches adult levels by the
age of 2 years.
 Sulfate conjugation is fully developed immediately prior
to or at the time of birth.
 Theophylline is example of drug that is readily
metabolized in neonates by N-Methylation to caffeine.
 Drugs like cimetidine, erythromycin and ketoconazole
inhibit metabolism of other medications in children.
Table. 4. Age dependent differences in activity of important
drug metabolising Phase – II enzymes and drug metabolism
Enzyme
Neonate
Infant
Child
Adolescent
N-acetyl –
transferase – 2
Reduced
(up to 2
months)
Methyltransferase
Increased
Adult pattern Adult pattern Adult
(50% higher
pattern
than adults)
Reduced
Adult pattern Adult pattern Adult
pattern
Glucuronosyl
transferase
Sulfotranferase
Reduced
(10-20% of
adult
activity)
Reduced (by Adult pattern Adult
age 4-5
(present age pattern
months)
1-3 yrs)
Increased (for Increased
specific
(for specific
substances)
substrates)
Adult
pattern
Pharmacokinetic
Consequences
↓ Acetylation of (sulfa pyridine
metabolite) results in ↑ side
effects– nausea, headache,
abdominal pain in neonates and
infants
Specific example not available
↑ Ratio of glucuronide to sulfate
of acetaminophen with age;
newborn 0.34; child (3-10 yrs)
0.8; adolescent 1.61 and adult
1.8 -2.3 sulfation compensates
for glucuronide so no major
consequences
for
dosage
adjustments in pediatric patients
Specific example not available
6. DRUG ELIMINATION
 Kidney is the major route of drug elimination for
both water soluble drugs and water soluble
metabolites of lipid soluble drugs.
The basic processes in renal elimination –
1) Glomerular filtration
 30% - 50% of adult value in full term neonates
 85% adult values by 3-5 months of age
 Premature infants have reduced filtration rates
due to incomplete nephrogenesis.
2) Tubular function
 In infants tubular secretion rates are approximately 20% of adult
values and do not achieve adult rates until 6-7 months of age.
 Some drugs like penicillin stimulate their own secretion, before
secretion is fully mature leading to decreased efficacy.
 In neonates tubular reabsorption is decreased, unlike tubular
secretion, its development remains poorly understood.
 Elimination of amino glycosides (gentamicin, tobramycin,
amikacin) and digoxin are effected by renal maturation.
 Dosage adjustment for digoxin is necessary as renal function
matures in neonates and young infants.
 Older infants and children require higher mg/kg doses of digoxin
than adults due to decreased digoxin absorption or increased
renal elimination.
 Glomerular filtration rates can be estimated by
assessing creatinine clearance.
 Estimated by using nomograms or mathematical
formulae.
 Creatinine clearance (CrCL) in pediatric
population can be calculated by using Schwartz
formulae.
CrCL = KL/SCr
CrCL is estimated in ml/min/1.73m2, where
L- Body length in Cm
SCr – Serum creatinine in mg/dL
K- constant of proportionality
Table.5. Values of K for estimating clearance
with the Schwartz formulae
Age Group
k (Mean Value)
0.33
Low birth weight infants  1 year
0.45
Full term  1 year
Children 2-12 years
0.55
Females 13-21 years
0.55
Males 13-21 years
0.70
Table.6. Age dependent differences in physiologic
functions and drug disposition
Physiologic
Variability
Absorption
Gastric pH
Neonate
Increased
(>5)
Infant
Child
Increased
(2-4)
Normal
(2-3)
Gastric
and Reduced
intestinal
and
emptying time Irregular
Increased
Increased
Biliary
function
Immature
Near adult Adult
pattern
pattern
Pancreatic
function
Immature
Near adult Adult
pattern
pattern
Pharmacokinetic Consequences
Increase in bioavailability of acid labile
drugs e.g. penicillin G, ampicillin,
nafcillin in neonates and infants
compared to children and adults,
decreased bio-availability of weak
organic acids e.g. Phenobarbital
Increased time to achieve peak plasma
acetaminophen concentration when
administered with meperidine due to
decreased gastrointestinal motility
Increased absorption of fat and fat
soluble vitamins D and E in infants and
children.
Increased hydrolysis and bio-availability
of oral liquid ester formulations of
dindamycin and chloramphenicol in
infants and children
Gut
microbial
colonization
Reduced
Near Adult Adult
pattern
pattern
Intramuscula Variable
r absorption
Increased
Skin
Increased
permeability
and
percutaneous
absorption
Increased
Rectal
absorption
Increased
Increased
Increased bio availability of digoxin
in infants compared to adults due to
lack of microbial gut colonization
with a oral digoxin reducing
anaerobic bacteria.
Increased Benzathine penicillin G more rapidly
to near absorbed in children compared to
adult
adults since no measurable activity
pattern
was detected in children 18 days after
the injection
Near
EMLA (Eutectic mixture of local
adult
anesthetics lignocaine and prilocaine)
pattern
contraindicated in patients less than 3
months of age due to risk of
methemoglobinemia due to increased
percutaneous absorption of prilocaine
and
decreased
methemoglobin
reductase.
Near
Increased rate and extent of diazepam
Adult
absorption from rectal solution
pattern
compound to suppositories, used to
prevent and treat febrile seizures in
infants and children.
Physiologic
Neonate Infant Child Pharmacokinetic Consequences
Variability
Distribution
Increase in mean apparent volume
Total Body Increase Increased Near of distribution (Vd) for hydrophilic
water (Extra d
Adult drugs. E.g. gentamicin. Vd<34WK
pattern 0.67 ± 0.13 l/kg; Vd34-48WK 0.52 ±
cellular)
0.10 l/Kgs;Vd1-4.9yrs 0.38±0.16 l/Kgs,
Vd5-9.9yrs 0.33±0.14 l/Kgs, Vd10-16yrs,
0.31 ± 0.12 l/Kgs, Vdadult < 0.30
l/Kgs
Total body Reduced Reduced Increa Increase in mean apparent Vd for
fat
sed
lipophillic drugs e.g. diazepam 1.6 –
(age
3.2 l/Kg in adults vs 1.3 – 2.6 l/Kg
5-10 in infants
yrs)
Total plasma Reduced Reduced Adult Increase in Vd and free phenytoin
proteins
to
near pattern concentration in neonates and
adult
children
and
adults
with
pattern
physiologic/pathologic conditions
leading
to
altered
protein
concentration
Renal
Reduced Adult
Elimination pattern Pattern
Glomerular
Filtration
Adult
Famotidine – 80% excreted
unchanged in the urine in older
children and adults; renal
clearance equivalent to adults by
1 year of age
Tubular
secretion
Reduced Near
Adult
pattern
Adult
pattern
Penicillins
–
increased
elimination half life due to
decreased excretion both by
glomerular filtration and tubular
secretion, therefore increase
dosing interval in neonates and
infants compared to children and
adolescent.
Tubular
Reduced Near
reabsorption
Adult
pattern
Adult
Pattern
Specific example not available
7. THERAPEUTIC DRUG MONITORING
Correlation of serum drug concentrations and
therapeutic effects.
Technical problems
Adverse drug reaction
8. DOSING CONSIDERATIONS
Dosing intervals
Disease states
Error in dosage calculations/drug preparation
9. CONCLUSION
Poorly developed organ functions
High risk of toxicity
Suboptimal dosage regimen due to altered
kinetics
Dosage requirements
Role of pharmacist in immunization
Education and Training
REFERENCES
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clinical pharmacokinetics, (3): 52-68 (2008)
Begg, E. J, “ Dosing in children”, Instant clinical Pharmacology,
34-36 (2003)
Danish, M & Kottke, M. K, “ Pediatric and Geriatric Aspects of
Pharmaceutics”, Modern Pharmaceutics, Banker, G.S &
Rhodes, C. T, (4): 1-18 (2002)
Fox, E & Balis, F. M, “ Drug therapy in Neonates and Pediatric
patients”, Principles of Clinical Pharmacology, (2): 359-373
(2007)
Perucca, E, “ Drug metabolism in infancy and childhood”,
Journal of Pharmacology and Therapeutics, 34(1): 129-143
(1987)
Reed, M. D, “ The ontogeny of drug disposition : Focus on
drug absorption, distribution and execution”, Journal of
Drug Information, 30: 1129-1134 (1996)
Sorenson, M. K, Phillips, B. B & Mutnick, A. H, “ Drug Use
in special patient populations : Pediatric, Pregnant,
Geriatric”, Comprehensive pharmacy review, Shargel, L,
Mutnick, A. H, Souney, P. F & Swanson, L. N, 5: 673-677
(2004)
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4(3): 2629-2648 (2000)