Drugs in Pregnancy and Lactation

Question 1

Discuss the transfer of high molecular weight drugs across the placenta

Answer 1

e.g. insulin

Negligible transfer

Question 2

Discuss the transfer of lipophilic, un-ionised, polar, and weakly basic drugs across placenta

Answer 2

Lipophilic un-ionised drugs = cross placenta easier than polar drugs

Weakly basic drugs = may be trapped in foetal circulation due to their lower pH compared to mum

Question 3

What factors about a drug should be considered if it was to be used in pregnancy, foetus, or neonate?

Answer 3

Teratogenicity

Pharmacological effect

timing of drug exposure

Pharmacokinetic changes

Question 4

What are tetrataogens?

Answer 4

An agent that interfere with normal growth and development of foetus = some obvious, others take time to develop

Question 5

What are some examples of teratogenic drugs?

Answer 5

ACE inhibitors

Androgens

Carbamazepine

Lithium

Misoprostol

Phenytoin

Tetracycline

Warfarin

Question 6

When are signs of foetal stress due to drug development observed usually?

Answer 6

Generally only at birth

Question 7

Outline some drugs and their pharmacokinetic effect on neonate (ACEi, antidepressants/benzos/opioids, anti-HTN, NSAIDs)

Answer 7

ACEi = renal dysfunction, intrauterine growth retardation

Antidepressants/ Benzos/ Opiods = w/drawal reaction

Anti-HTN = foetal hypoxia

NSAIDs = premature closure of ductus arteriosus

Question 8

Explain the effects of drug exposure during the pre-embryonic stage

Answer 8

(first 17 days)

All-or-nothing response = either death of embryo or complete recovery and normal development

Malformation unlikely

Question 9

Explain the effects of drug exposure during the embryonic stage

Answer 9

(days 18-56)

Organogenesis (except CNS, eyes, teeth, external genitals, ears)

Exposure to drugs = greatest risk of major birth defects by interfere with organ function

Question 10

Explain the effects of drug exposure during the embryonic stage

Answer 10

(Weeks 8-38)

CNS can be damaged by some drugs (e.g. ethanol)

Question 11

How does absorption change in pregnancy?

Answer 11

High circulating progesterone = delay gastric emptying, inc intestinal transit time

Question 12

How does distribution change in pregnancy?

Answer 12

Inc in total body water, 30% inc in plasma volume = Inc Vd of drug

Loading dose may be required

Question 13

How does protein binding change in pregnancy?

Answer 13

Albumin binds acidic drugs

Plasma albumin drops sig in preg = inc fraction of unbound drugs

Question 14

How does metabolism change in pregnancy?

Answer 14

Hepatic drug metabolising enzymes are induced during preg

More hepatic metabolism

Question 15

How does clearance change in pregnancy?

Answer 15

Inc GFR by approx 50% and remains high until after delivery

renally excreted drugs = more excretion, higher maintenance doses are required

Question 16

Explain category A drugs in pregnancy

Answer 16

Taken by large number of preg women + women of child-bearing age

No proven inc in freq of malformation or direct/indirect harmful effect observed on foetus

Question 17

Explain category B drugs in pregnancy

Answer 17

Drugs been taken by limited no. preg women/child-bearing age = no inc in freq of malformation or direct/indirect effect on foetus

B1 = animal studies showed no evidence

B2= studies in animals lacking or inadequate, available data show no effect

B3 = animal studies show evidence of inc occurrence of foetal damage, sig in human uncertain

Question 18

Explain category C drugs in pregnancy

Answer 18

Drugs, due to pharm effect, suspected to/have caused harmful effects in foetus or neonate w/out malformation

Effects may be reversible, consult specialised texts

Question 19

Explain category D drugs in pregnancy

Answer 19

Drugs have caused or suspected to have caused or may be expected to cause inc risk of foetal malformation or irreversible damage

May have ADRs

Consult specialised texts

Question 20

Explain category X drugs in pregnancy

Answer 20

High risk of permanent damage

Should not be used in preg or possibility of preg

Question 21

What questions should be considered when introducing a drug to pregnant mother/neonate/foetus?

Answer 21

Gestational age

How essential is drug

How much will pass to foetus

Safer alternatives?

How severe is illness?

What will happen if not treated?

What is ADEC category for drug?

Question 22

What factors influence extent/rate of passive diffusion into breast milk?

Answer 22

Maternal pharmacokinetics

Physiological nature of blood vs milk

physiochemical properties of drug

Question 23

How does drug pKa influence drug transfer into breast milk?

Answer 23

basic drugs = more ionised at acidic pH –> trap weak bases

Acidic drugs = more ionised at higher pH values –> trapped in maternal plasma

*more acidic drug stays in maternal plasma

Question 24

How does drug protein binding influence drug transfer into breast milk?

Answer 24

*The higher the percentage the better

Highly bound drugs = retain in maternal plasma due to lower protein content in milk

Question 25

How does drug lipophilicity influence drug transfer into breast milk?

Answer 25

highly lipophilic = dissolve into lipid content of milk –> inc extent of transfer into milk from maternal plasma

Question 26

Summarise the characteristics of drugs that minimally transfer into breast milk

Answer 26

Acidic drug that is highly protein bound and has low to moderate lipophilicity

Question 27

What does a high milk:plasma ratio indicate?

Answer 27

> 1.5 = drug may sequester into milk

Question 28

What does a low milk:plasma ratio indicate?

Answer 28

<1 = minimal levels are transferred into milk

Question 29

Highlight the techniques used reduce infant exposure to drugs

Answer 29

Give maternal dose directly after infant has fed = avoid maximal drug exposure

Question 30

What drugs are at high exposure to infant from breast milk?

Answer 30

Amiodarone
carbimazole
isoniazid
lithium
theophylline
metronidazole