Pharmacology 4350A/B Study Guide - Cyp3A5, Cytochrome P450, Sulfamethoxazole

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Division of childhood
Most rapid growth
Infancy (birth - 1 yo)
1.
Slow body growth but rapid psycho/social growth + fine motor
Todler (1-3)
2.
Development slows
3.
Development slows
School age (6-10)
4.
Sexual maturation
Adolescent (early,middle,late) (11-19)
5.
Physiological changes
Extracellular water decrease + intracellular water increase AS YOU AGE
1.
Liver + kidney largest % body weight in newborn
2.
Lower Total binding protein
a.
Newborn: lower albumin + lower AAG + fetal albumin present + lower globulin
b.
Infant: lower AAG + no fetal albumin + lower globulin
c.
Child: same as adult
d.
Plasma binding proteins
3.
Pharmacokinetic changes
Gastric pH (lower pH infant = increase absorption for drugs degraded by acid)
Decrease in infant = decrease absorption of some drugs
Biliary function
Decrease gastric emptying = increase T1/2 of some drugs
Decrease GI motility = increase absorption
Transit time
Decrease = lower absorption
Surface area
Reduce transporter activity = reduce absorption
Transporters
Different bacteria in stomach = reduce absorption of some drugs
GI tract microbial colonization
Reduce gut activity of phase 1 + phase 2 enzymes
Metabolism
Absorption factors changes COUNTER-balance so absorption effects may/may not change
-
Infants have more water= increase Vd for water-soluble drugs (Sulfamethoxazole)
Water-fat ratio
Decrease for infants = increase clearance for HIGHLYbound drugs
Plasma-binding protein
Acid-base balance
Regional blood flow
Cardiac output
Distribution changes mostly affect HIGHLY bound drugs but overall changes are minimal
-
Result in different therapeutic/toxic effects
Toddlers more active per kilo than adults + Puberty unknown
3A7 increases as a newborn but decreases towards adult
CYP3A7 (utero) matures into CYP3A4
CYP 3A4 + UGT2B7 increase as child ages (UGT2B7 is higher than adult)
CYP2E1 increases as you age
CYP1A2 appears after 3-4 months (Theophylline metabolism increases after 3-4 months into 1-3
dimethyluric acid)
Phase 1 metabolism less active in newborn than adults
Theophylline metabolite 1,3 dimethyluric acid increases after 3-4 months (CYP1A2)
1.
Phenytoin elimination increases as kid ages (increase CYP 3A/2C)
2.
Metabolite low as new born, then increase over DM as age
Dextromethorphan metabolized by CYP3A + CYP2D6 into 3HM
3.
Warfarin clearance is highest in newborn, decrease as you age
4.
Morphine clearance is MUCH less in kids
1.
Metabolism by CYP of acetaminophen into NAP-QI is minimal in kids
-
Acetaminophen clearance by sulfate is high and in adulthood glucuronide
2.
Phase 2 changes are largely unknown
Metabolism much less activity than adults but highly VARIABLE CYP enzymes activity
-
Renal elimination is decreased for newborns (30%), at 3-4 weeks rises to (65%) , a year to reach 100%
Longer interval dosage for infants due to limited elimination
Aminoglycoside antibiotics - longer interval but same dose to reach therapeutic window
1.
Elimination
-
Differences in transporters
Lower MDR1a in newborns than adults (brain + kidney + liver)
-
Medication errors
10-fold errors
-
More common in babies than adults
-
Majority of errors = wrong dose + wrong frequency
-
ADR in kids are different in adults
Cefaclor-associated serum sickness - 1% in kids but 0.01% in adults
1.
Liquid medication
Kids can't swallow pills
-
Accuracy of dose (how much is a teaspoon)
More cost
Storage + transport
Studies conducted to find best taste
Taste worse than solid
Problems with liquid
-
Clinical trials on children
Most tests on North american / African American children
-
Sulfamethoxazole (water soluble) - increase Vd in infants
Lecture6 - Children
April-22-12
9:51 AM
clinical pharm Page 1
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