L5 - PK Physical implications - Pregnancy & Obesity

Question 1

Distribution – 2

Answer 1

1. Increase in Vd (increased plasma volume, changes in protein binding) could result in decrease in C0 & Cmax
2. If Cl decreased or unchanged: increase in Vd result in increased terminal elimination half-life

Question 2

Protein binding - 3

Answer 2

1. [Albumin] decrease throughout pregnancy, 70–80% [normal] at delivery
2. Low extraction ratio drugs: doses monitored using total Cp (underestimates active Cp phenytoin & valproic acid)
3. High extraction ratio drugs: Narrow therapeutic window, non-oral routes amount unbound increased when albumin decreased, so greater pharmacological effect

Question 3

Metabolism – 3

Answer 3

1. Alters Hepatic Clearance (Clh): protein binding, metabolic enzymes & liver blood flow.
2. Increase activity of several CYP450 & N-acetyltransferase, so must increase in dose in order to avoid loss of efficacy
3. Decrease activity of some CYP450, so dosage reductions to minimise potential toxicity

Question 4

Renal excretion - 2

Answer 4

1. Increased Renal excretion of unchanged drugs
2. Increased Tubular secretion due to saturated reabsorption membrane transport proteins

Question 5

Limits on pregnancy drugs - 3

Answer 5

1. drugs eliminated by CYP or UGT or multiple pathways: require evaluation.
2. limited clinical, evidence-based studies to elucidate effects of pregnancy on PK
3. ethical issues

Question 6

Altered pathophysiology of the obese body - 3

Answer 6

1. Affect drug distribution – higher fat %, lower lean tissue & body water &
2. Affect metabolism – higher cardiac output & liver blood flow, enlarged liver
3. Affects drug elimination - higher renal blood flow & GFR

Question 7

Obese Distribution – 3

Answer 7

1. Distribution between fat & lean tissues: influences PK
2. Obesity: lipophilic compounds> hydrophilic compounds. Better Vd
3. weak or moderate lipophilicity (lithium, vecuronium): limited distribution in excess body fat

Question 8

Obese metabolism - 3

Answer 8

1. liver fatty infiltration (non-alcoholic steatohepatitis), influence metabolic activity of liver
2. Utilise markers to assess enzyme activities e.g. CYP 450 isoforms altered
3. increased glucuronidation & changes for antioxidant systems (glutathione & catalase)

Question 9

Obese Renal function

Answer 9

vancomycin, ciprofloxacin, lithium & gentamicin: significant difference in creatinine clearance (CLcr) between obese & ideal bodyweight