Past papers questions on pregnancy

briefly discuss the metabolism of acetaminophen in neonates and what factors will contribute to toxicity?

1. Metabolism of Acetaminophen in Neonates:

In adults, acetaminophen is metabolized mainly by glucuronidation (40-67%), sulfation (20-46%), and a small percentage by cytochrome P450 (CYP2E1) into NAPQI, a toxic metabolite detoxified by glutathione.

In neonates, glucuronidation is immature, so metabolism shifts to sulfation, which is relatively preserved. However:

If high doses are given, more drug is shunted to CYP2E1 → NAPQI production increases.

Neonates have reduced glutathione reserves, making it harder to detoxify NAPQI.

Therefore, even therapeutic doses can accumulate, especially if dosing is incorrect.

Toxicity risk factors in neonates:

• Immature liver enzymes → decreased clearance.

• Reduced renal elimination.

• Higher body water and altered volume of distribution.

• Inadequate dosing adjustments (failure to use mg/kg basis).
  

a highly lipid soluble drug A with a molecular weight of 350 daltons and a pKa of 9; could this drug be transferred across the placenta membrane?give the reasons why or why not. what would determine the excretion of this drug? 

2. Placental Transfer of Drug A (Lipid Soluble, MW 350 Da, pKa 9):

Molecular weight (MW): <500 Da → generally can cross the placenta.

Lipid solubility: Facilitates passive diffusion through lipid bilayers of the placenta.

pKa of 9: Indicates the drug is a weak base. At physiological pH (~7.4), most of the drug will be ionized.

Ionized drugs have lower membrane permeability, slowing transfer.

-Despite some ionization, because it is lipophilic and low MW, it will likely cross, though less efficiently than non-ionized forms.

Excretion is influenced by:

• Fetal renal function, which is immature (↓ GFR, tubular function) → slower elimination.

• Drug half-life in neonates is longer → risk of accumulation.

• Hepatic metabolism in fetus is limited → drugs with active metabolites or requiring metabolism for clearance may persist longer.

• Placental clearance (drug may be transferred back to mother).
  

explain 4 important considerations when prescribing for a newborn infant.

1. Immature renal and hepatic function:

• ↓ metabolism (especially glucuronidation, oxidation).

• ↓ renal clearance (GFR, secretion, reabsorption).

2. Altered body composition:

• Neonates have ~70–80% total body water vs adults ~60%.

• Water-soluble drugs (e.g., gentamicin) have larger Vd → may require higher loading doses.

3. Immature blood-brain barrier (BBB):

• More permeable → increased CNS penetration → increased risk of neurotoxicity (e.g., opioids, sedatives).

4. Dosing should be individualized:

• Use weight (kg) and gestational/postnatal age for accurate dosing.

• Neonatal dosing guidelines should be used (e.g., Neofax).
  

apart from the physiochemical properties of the drug what critical factors affects the drug transfer across the placenta?

1. Placental blood flow:

Adequate perfusion is necessary for transfer.

Conditions like preeclampsia can reduce flow and limit drug transfer.

2. Gestational age:

Early in pregnancy, the placenta is less permeable.

As pregnancy progresses, permeability increases.

3. Placental transporter proteins:

e.g., P-glycoprotein efflux pumps limit fetal exposure by pushing drugs back into maternal circulation.

4. Maternal and fetal protein binding:

Only unbound (free) drug crosses.

If a drug binds extensively to maternal proteins, less is available to cross.

Fetal albumin may have different affinity, influencing distribution.

the loading dose of indomethacin is a neonate is 0.2mg/kg of body weight by infusion. 

a. what would be the dose for a neonate weighing 6lbs 4 oz.

b. how many milliters of an injection containing 1mg  of indomethacin per 5mls should be administer to get this dose?

Indomethacin Neonatal Dose Calculation:

a. Convert weight:

6 lbs 4 oz = 6.25 lbs

6.25 lbs × 0.454 = 2.84 kg

Dose = 0.2 mg/kg × 2.84 kg = 0.568 mg

b. If 1 mg = 5 mL, then:

0.568 mg × 5 mL / 1 mg = 2.84 mL

Answer: Administer 2.84 mL of the solution.

discuss the mode of delivery of drug to the fetus. What control mechanisms are in place to reduce the amount of drug that reaches the fetus?(6marks)

Mode of Delivery of Drugs to Fetus & Control Mechanisms (6 Marks):

Drugs reach the fetus primarily through passive diffusion from the maternal blood to placental circulation, and then into the fetal capillaries.

Control mechanisms to reduce fetal drug exposure:

1. Placental metabolism:

Enzymes (e.g., CYP1A1, UGTs) metabolize drugs before reaching the fetus.

2. Efflux transporters:

P-glycoprotein, BCRP on placental membrane push drugs back into maternal circulation.

3. Protein binding:

Only free (unbound) drugs can cross the placenta.

4. Placental barrier:

Structurally limits some drug passage.

5. Ion trapping:

Weak bases (higher pKa) may become ionized in fetal circulation (more acidic), limiting further movement.

6. Short maternal drug half-life:

Less exposure time reduces fetal accumulation.