Pharmacology in Pregnancy and Breast Feeding

Question 1

describe drug absorption changes in pregnancy

Answer 1

The oral route may become more difficult due to nausea and vomiting. During pregnancy there is an increase in gastric emptying and gut motility. This is unlikely to be a problem with regular dosing but may affect single doses. Blood flow is increases so absorption by the intramuscular route may be increased. For inhaled drugs, there is an increased cardiac output and decreased tidal volume (especially as the lungs become more compressed) which may cause increased absorption of inhaled drugs.

Question 2

describe the drug distribution changes in pregnancy

Answer 2

An increase in plasma volume and fat will cause the volume of distribution to increase. Greater dilution of plasma will decrease relative to the amount of plasma proteins therefore increasing the free fraction of the drug.

Question 3

describe the drug metabolism changes in pregnancy

Answer 3

Oestrogen and progestogens can induce or inhibit liver P450 enzymes, thereby either increasing or reducing metabolism. Phenytoin levels are reduced as there is an induction of metabolism. Theophylline levels are increased as metabolism is inhibited.

Question 4

describe the drug excretion changes in pregnancy

Answer 4

GFR is increased in pregnancy by 50% leading to increased excretion of many drugs. This can and can necessitate an increase in dose of renally cleared drugs.

Question 5

describe the pharmacodynamic changes i pregnancy

Answer 5

These are less well understood. Pregnancy may affect site of action and receptor response to drugs:
1. Concentration of drug, metabolites at sites of biological action (changes in blood flow)
2. Mechanism of action (changes in receptors)
Efficacy of drugs may be different as well as the adverse effects.

Question 6

what does how much placental transfer of drugs depend on?

Answer 6

1. Molecular weight – smaller sizes will cross more easily
2. Polarity – non-polar cross more readily
3. Lipid solubility – lipid soluble drugs will cross
   a. Breast milk, brain, liver
   The placenta may also metabolise drugs but evidence to support this is limited

Question 7

factors affecting drug transfer across the placenta

Answer 7

• Drug physiochemical factors
• Rate and amount of drug
• Duration of drug exposure
• Distribution in foetal tissues

Question 8

foetal pharmacokinetics: distribution

Answer 8

It is important to remember that circulation is different e.g. the umbilical vein to liver. Less protein binding than adults therefore more free drug available. The foetus has little fat and so distribution is different. There is relatively more blood flow to brain and BBB is not fully formed.

Question 9

foetal pharmacokinetics: metabolism

Answer 9

There is less enzyme activity though this increases with gestation. A foetus has different isoenzymes compared to adults.

Question 10

foetal pharmacokinetics: excretion

Answer 10

Excretion is into amniotic fluid which is then swallowed and can allow recirculation. Drugs and metabolites can accumulate in amniotic fluid. Placenta is not functioning at delivery so there can be issues with excretory function

Question 11

mechanisms of teratogenicity

Answer 11

1. Folate antagonism
2. Neural crest cell disruption
3. Endocrine disruption – sex hormones
4. Oxidative stress
5. Vascular disruption
6. Specific receptor or enzyme mediated teratogenesis

Question 12

describe folate antagonism in regards to foetal development

Answer 12

The key process in DNA formation and new cell production requires folate. Two groups of drugs antagonise folate:
1. Block the conversion of folate to THF by binding irreversibly to the enzyme (e.g. methotrexate, trimethoprim)
2. Block other enzymes in the pathway (e.g. phenytoin, carbamazepine, valproate)
These tend to result in neural tube, oro-facial or limb defects.

Question 13

describe neural crest cell disruption in regards to foetal development

Answer 13

One class of drugs that can cause this are the retinoids eg isotretinoin used for severe acne. They
cause problems resulting in:
1. Aortic arch anomalies
2. Ventricular septal defects
3. Craniofacial malformations
4. Oesophageal atresia
5. Pharyngeal gland abnormalities

Question 14

describe enzyme mediated teratogenesis

Answer 14

Drugs which inhibit or stimulate enzymes to produce therapeutic effects may also interact with specific receptors and enzymes damaging foetal development. NSAIDs, if taken chronically esp. during early pregnancy, can cause orofacial cleft and cardiac septal defects.

Question 15

what may fetotoxicity result in

Answer 15

1. Growth retardation
2. Structural malformations
3. In utero foetal death
4. Functional impairment
5. Carcinogenesis

Question 16

name 2 classes of fetotoxic drugs and their effects

Answer 16

ACEI, ARBS

renal dysfunction and growth retardation

Question 17

anticonvulsants and pregnancy

Answer 17

Valproate is associated with neural tube defects, as is carbamazepine
and phenytoin

Question 18

warfarin and pregnancy

Answer 18

Warfarin is associated with haemorrhage in the foetus, as well as
multiple malformations in the CNS and skeletal system

Question 19

antihypertensives and pregnancy

Answer 19

ACEI renal damage and growth restruction

Question 20

NSAIDS and pregnancy

Answer 20

premature closure of the ductus arteriosus

Question 21

alcohol and pregnancy

Answer 21

foetal alcohol syndrome

Question 22

retinoids and pregnancy

Answer 22

ear, CNS, CV and skeletal disorders

Question 23

discuss drugs and lactation

Answer 23

Most drugs will be present at lower doses through breast feeding than in utero. It is important to know what concentration will be present in breast milk. Concentrations are generally negligible but may be increased in low MW and highly lipophilic drugs. Pharmacokinetics are different in the neonate from the foetus.

Question 24

drug classes to avoid in breast feeding

Answer 24

• Cytotoxic
• Immunosuppressants
• Anti-convulsant (not all)
• Drugs of abuse
• Amiodarone
• Lithium
• Radio-iodine

Question 25

tetracycline and breast feeding

Answer 25

tooth staining

Question 26

isoniazid and breast feeding

Answer 26

convulsions and neuropathy

Question 27

barbiturates and breast feeding

Answer 27

drowsiness

Question 28

chloral hydrate and breast feeding

Answer 28

sedation

Question 29

diazepam and breast feeding

Answer 29

sedation

Question 30

methadone and breast feeding

Answer 30

withdrawal

Question 31

iodine and breast feeding

Answer 31

neonatal hypothyroidism or goitre

Question 32

propylthiouracil and breast feeding

Answer 32

thyroid function

Question 33

principles of prescribing for women of child bearing age

Answer 33

• Always consider possibility of pregnancy (planned or not)
• Warn women of possible risks
• When treating medical conditions, advise women to attend before getting pregnant if
planning to
• Discuss contraception
• If necessary, do not prescribe without contraception

Question 34

principles of prescribing in pregnancy

Answer 34

• If possible, try non-pharmacological treatment first
• Use the drug with the best safety record and avoid new drugs unless proven safe
• Check the SPC for the most up to date information
• Use the lowest effective dose
• Use the drug for the shortest possible time, intermittently if possible
• Avoid the first 10 weeks of pregnancy if possible
• Consider stopping or reducing dose before delivery
• Don’t under treat disease which may be harmful to the foetus

Question 35

principles of prescribing in breast feeding

Answer 35

• Again, avoid unnecessary drug use
• Check on up to date drug information
• May be a lack of information
• If licensed and safe in paediatric use (esp. under 2 years), a drug is likely to be safe in breast
feeding
• Choose drugs with pharmacokinetic properties that reduce infant exposure
o Highly protein bound, highly polarised, low lipophilicity