5. Mum and baby pharmakokinetics

Question 1

What are the maternal changes to drug absorption?

Answer 1

Gastric motility slows (peaks 3rd trimester), meaning Tmax is increased and Cmax slightly reduced. Normal oral availability

N&V and gastric pH changes can also alter this.

Skeletal muscle blood flow increased meaning IM more rapidly removed. Decreases Tmax and increases Cmax

Only effects single doses, not long term which have reached a steady state

Question 2

What are the maternal changes to distribution?

Answer 2

Extra 6-8 L of ECF meaning hydrophilic drugs Vd increased

Extra 4kg fat meaning lipophilic Vd increased

Lower albumin meaning protein bound drugs now free, increasing Vd

Lower alpha acid glycoprotein: receptor for 50% of basic drugs, so increased Vd for them

Question 3

What does lower albumin mean for drug monitoring?

Answer 3

Usually get total drug levels. But if higher proportion unbound, means higher active free drug available, so could be toxic with same levels.

Question 4

What are the maternal changes to drug metabolism?

Answer 4

Increased hepatic flow. Most hepatic enzymes work below max, so more flow = more metabolism.

Altered hepatic P450
Increased CYP’s 3A4 and 2D6, which metabolise 50%of drugs
Lower CYP1A2 which metabolises caffeine

Lower levels of conjugation (phase 2) e.g. morphine and lamotrigine

25% less extra hepatic plasma pseudocholinesterase (33% post birth). Little effect if normal enzymes, but 10-20% have genetically reduced enzyme levels.

Question 5

What are the differences in maternal elimination?

Answer 5

Increased renal flow = increased elimination

Increased alveolar ventilation = increased elimination of volatiles if spont

Oestrogen causes cholestasis so reduced elimination of biliary excreted e.g. rifampicin and roc

Question 6

What are the baby changes to absorption?

Answer 6

Modified through the placenta

Question 7

What are the baby changes to distribution?

Answer 7

Increased TBW in early, 94% at 16w and 76% at term = increased hydrophilic

Fat only accumulates in third tri (baby under 1kg = negligible) = decreased lipophilic Vd

Most CO to brain, so most drug delivery there.
Pulmonary flow small, so decreased
Hepatic shunt: only 60-80% undergoes first pass metabolism, rest to IVC where diluted by leg and splanchnic blood return.
Placental shunt: 50-60% returns to placenta without perfusing foetus. Alters M:F at placenta and reduced maternal diffusion to baby.
Decreased myelin so less lipophilic enters CNS e.g. phenytoin.

Question 8

What are the baby methods of drug elimination?

Answer 8

1. Placenta
2. Renal, intestinal and skin (water permeable)
3. Re circulation: pee, swallow then reabsorb

Question 9

What is a teratogen and when are drugs the most harmful and why?

Answer 9

Any agent, force or factor that alters any part of development.

Depends on stage of organogenesis and metabolism at the time given.

Embryogenesis occurs 3-8w post implantation, so this is the worst time. After this, all organs are developed except brain, eyes and external genitalia.

Question 10

What drugs should always be avoided in pregnancy?

Answer 10

Amiodarone
Ketamine
Fluconazole
Phenytoin
Warfarin
Lisinopril

Question 11

Why are lipid soluble drugs more potent?

How does this relate to ionisation?

Answer 11

They will dissolve in the cell walls, making the concentration gradient between cell wall and intracellular high.

Unionised drugs are more lipid soluble