population pharmacotherapeutic issues

Question 1

placenta as a barrier to drug distribution

Answer 1

ST layer is an epithelial layer–cells have fused to provide little intercellular access to anything; apical and basal membrane bilayers are the primary barrier to movement of drugs across placenta

Question 2

what determines drug passage through placenta:

Answer 2

permeability–lipid solubility which is inversely proportional to size (small mlcls pass more readily); drugs that are bound to albumin cannot pass; weak BASES partition better into fetal circulation because fetus is more acidic than mother (hypoxic, acidotic)

Question 3

how do larger drugs pass placental barrier?

Answer 3

some drugs utilize placental transporters/efflux transporters like p glycoprotein (MDR1)

Question 4

what metabolic enzymes are present in placenta?

Answer 4

ST layer has cyp450s and all phase II enzymes; amounts are far less than adult liver and can vary with fetal age

Question 5

gray baby syndrome results from

Answer 5

chloramphenicol dosing, baby has immature UDP-glucuronosyltransferases resulting in accumulation of toxic metabolites

Question 6

gasping syndrome

Answer 6

benzyl alcohol–immature ability to conjugate benzoic acid with glycine, resulting in accumulation of benzoic acid–>gasping, metabolic acidosis, hypotension, death

Question 7

absorption in neonates compared to adults

Answer 7

lower gastric acid secretion/emptying/intestinal mobility/biliary function; thinner skin, increased cutaneous perfusion, greater body surface/weight ratio; inefficient muscular contractions, reduced muscle blood flow, higher density of skeletal muscle capillaries, greater number of high amplitude rectal contractions decrease absorption of solid drugs

Question 8

differences in neonatal distribution

Answer 8

ECF/kg is 125% that of adults–have a lot more water (increased Vd and lower Co); lower serum albumin–increased free drug eg phenytoin; immature BBB, lower % body fat

Question 9

differences in hepatic clearance neonates

Answer 9

Phase I enzymes are not fully developed in first year; CYP2e1 activity surges after birth followed by 2D6; 3A4 and 2C appear during first week; 1A2 is last at 1-3 months
Phase 2 enzymes: UDP transferases don’t mature to adult levels till 4yrs old (gray baby); glycine conjugation (benzyl alcohol); N-acetyltransferase doesn’t mature to adult levels till 1 year

Question 10

differences in renal clearance in neonates

Answer 10

creatinine clearance is quite low and doesn’t climb till 2 years; same with tubular secretion; important for dosing of drugs cleared renally

Question 11

changes in distribution in the elderly

Answer 11

body water decreases; lean body mass decreases; body fat increases; serum albumin decreases; hepatic/renal blood flow decrease

Question 12

metabolic changes in the elderly

Answer 12

hepatic blood flow decreases; phase 1 clearance decreases (perfusion limited for drugs with high extraction ratios); phase 2 clearance is generally unchanged except for elderly/frail

Question 13

excretion changes in the elderly

Answer 13

renal flow decrease 50% btw 25-65; filtration rate decrease; tubular secretion decreases; reabsorptive changes unknown