Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
27 Cards in this Set
- Front
- Back
challenges in conducting any type of drug research in children |
-ethics of experimentation -issues of consent -small percentage of market (recruitment, "bang for buck") |
|
challenges in conducting pharmacokinetic research studies in children |
-limitations using animal models -constraint in the number of blood samples that can be collected (newborn baby has ~250mL of blood) -age categories are not perfect... constantly changing |
|
gastric pH changes |
-greatest changes in the neonatal period term birth: 6-8 (higher relative pH from reduced acid output and reduced gastric secretions) day 1-2: 1-3 day ~10: 6-8 then slowly decreases to ~2 by 3 yrs of age |
|
oral absorption |
-drugs must cross GIT membranes to get absorbed -most drugs are weak acids or weak bases so they are ionized or unionized -ionized molecules are charged and attract water molecules to form large complexes that cannot easily cross the membranes (therefore drugs are better absorbed if unionized) -the H-H eqn helps determine the extent to which a drug is ionized at a given pH acidic env: weak acid unionized: weak base ionized basic env: weak acid is ionized; weak base unionized |
|
gastric emptying |
-neonates have weaker peristalsis (less muscle) -prolonged gastric emptying and intestinal transit time in neonates and young infants (adult levels at ~6m) -differences between formula vs breastfed babies (breast-fed tend to move things through GIT faster) |
|
intestinal microflora |
-in utero, the GIT is sterile but within hrs of birth, microbial colonization begins -the types of bacteria that will colonize the GIT differ in breastfed vs formula fed babies -the bioavailability of certain drugs can be influenced by the hydrolysis and the reduction of the drug molecule by microflora (eg clindamycin must be hydrolyzed to active form) |
|
IM absorption |
-decreased muscle mass, erratic blood flow to muscles in neonates -may have compromised peripheral perfusion (premature neonates) -variable, unpredictable, unreliable, painful |
|
rectal absorption |
-very vascular area -can achieve fast systemic concentrations (and effect) -can be erratic (does not necessarily equal absorption by po route) -but useful when po not available |
|
topical absorption |
neonates have: -poorly developed epidermis (especially if premature) -thinner stratum corneum (esp if premature) -more hydrated skin than older children/adults -less hairy -larger SA can have significant drug penetration (skin permeability 100-1000x greater in premature neonates than adults; 3-4x greater in full term neonates than adults) |
|
BBB |
immature and more permeable in neonate, especially premature neonates -increased potential for CNS drug penetration -increased potential for CNS toxicity useful in treating meningitis -abx cross into BBB well eg: therapy in neonate w meningitis is ampicillin + gentamycin (gent is not used in adults w meningitis b/c does not cross BBB) |
|
key determinants of drug distribution |
water, fat, protein binding neonate: ECF < ICF < fat adults: ICF < fat < ECF eg: gentamycin (hydrophilic) -will distribute mainly to the ECF -therefore larger Vd in neonate Concentration = dose/Vd the dose required for a neonate to achieve the same concentration as adult is larger (on a mg/kg basis) |
|
protein binding |
albumin (and alpha-1 acid glycoprotein) -less albumin around (until age 1yr) -less ability to bind to drugs eg: phenytoin ~70% bound in neonate, ~90% in adults -neonates have increased RBC volume and increased RBC breakdown, less albumin, decreased ability to glucuronidate (form water-soluble conjugated bilirubin) competition w bilirubin for binding to albumin |
|
why do we avoid cotrimoxazole in infants < 2mos |
-competes for binding to albumin -> displaces bilirubin -> increases levels of bilirubin -> can lead to "kernicterus" (can result in severe CNS dysfunction -seizures, death) |
|
prothrombin |
a plasma glycoprotein that gets converted into thrombin during the blood clotting process |
|
warfarin |
-plasma conc. of warfarin, vit K, vit K-dependent proteins, and INR were measured in pre-pubertal, pubertal, and adult pts on warfarin -similar plasma conc in all groups -BUT, pre-pubertal pts had significantly lower concentrations of Vitamin K-dependent factors (proteins C and prothrombin 1&2) -higher INRs than the adults studied (more risk of bleeding) -must consider this increased response to warfarin when estimating warfarin doses in pre-pubertal children |
|
antithrombin III |
a small protein molecule that inactivates enzymes of the coagulation system (ie acts like a "blood thinner") |
|
enoxaparin |
-activates antithrombin III and inhibits anti-Xa so that less thrombin is produced -the dose for a 1 month old infant is higher than that for a 6 year old child -partly explained by differences in metabolism/elimination but also antithormbin III levels at birth are less (30-40% of adult levels at birth; 60% of adult levels at 1m) |
|
drug metabolism at birth |
-reduced activity of most metabolizing enzymes: CYP, glucuronidation, conjugation -liver is big but not very "active" at 2-4y of age: increased enzyme activity -doses of many drugs are increased during this time |
|
codeine in neonates & young infants |
-up to 15% metabolized to morphine (active meatbolite) by: CYP2D6, CYP3A4, UGT2B7 -codeine less effective in neonates & young children due to lower metabolism to morphine -respiratory depression, apnea, and death have occured w the use of codeine as an antitussive in < 1y olds (ability to "deactivate" codeine not fully developed; immature, more permeable BBB leads to higher rates of resp depression w morphine in young infants) -if mother is prescribed codeine for post-partum pain relief... codeine gets excreted into breastmilk... reaches neonate |
|
phase II rxns developed in neonates |
sulfation: develops in-utero methylation: well developed in neonates |
|
acetaminophen |
sulfation -> sulfate metabolte glucuronidation -> glucuronide metabolite CYP2E1 -> toxic intermediate (NAPQI) -> mercapturic acid (via glutathione) infants unable to form glucuronidation and CYP2E1 does not develop until ~1y -therefore infant would need relatively higher dose to get toxicity |
|
theophylline |
baby: used in premature babies w apnea -methylation to caffeine ++ unchanged in urine child: rarely used for asthma -practically no caffeine -some unchanged in the urine adult: -practically no caffeine -little unchanged in the urine |
|
first pass metabolism |
-liver metabolism after po administration, before reaching systemic circ -high first-pass = reduced bioavailability eg: morphine, midazolam, propranolol ability to metabolize via first-pass is reduced at birth and increases w age -increased bioavailability of drugs like midazolam eg. rifampin undergoes first-pass, therefore give less dose to infant |
|
renal elimination |
renal blood flow: -at birth, < 10% of CO -by 2-4y, 25% of CO all renal processes are immature at birth significant changes in urine output and SCr each renal process matures at a different stage -GFR first, then tubular secretion, lastly tubular re-absorption |
|
GFR changes |
at birth GFR is 30-50% of adult levels -increased by 50% after the 1st week of life due to increased renal blood flow (dosing guidelines may be different between a 4 day old and 9 day old infant) -reaches adult levels (90-140 mL/min) at ~1y |
|
development of renal processes |
at birth, tubular secretion is 20% of adult levels -generally, neonates have slower clearance of renally eliminated drugs and require less frequent dosing -but between 2-24mos of age, GFR and tubular secretion are more mature than tubular re-absorption (for some drugs, this can cause an increase in renal clearance eg. digoxin) |
|
Schwartz Eqn |
to estimate renal fxn (GFR) GFR (mL/min/1.73m^2) = (height (cm) x "K")/SCr (umol/L) x 88.4 K = constant based on age and gender -low birth weight infants (< 2500g) = 0.33 -term neonates & infants = 0.45 -children > 2yrs = 0.41 ("modified schwartz") |