Pharmacology in Pregnancy and Breast Feeding Flashcards
describe drug absorption changes in pregnancy
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.
describe the drug distribution changes in pregnancy
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.
describe the drug metabolism changes in pregnancy
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.
describe the drug excretion changes in pregnancy
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.
describe the pharmacodynamic changes i pregnancy
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.
what does how much placental transfer of drugs depend on?
- Molecular weight – smaller sizes will cross more easily
- Polarity – non-polar cross more readily
- 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
factors affecting drug transfer across the placenta
- Drug physiochemical factors
- Rate and amount of drug
- Duration of drug exposure
- Distribution in foetal tissues
foetal pharmacokinetics: distribution
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.
foetal pharmacokinetics: metabolism
There is less enzyme activity though this increases with gestation. A foetus has different isoenzymes compared to adults.
foetal pharmacokinetics: excretion
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
mechanisms of teratogenicity
- Folate antagonism
- Neural crest cell disruption
- Endocrine disruption – sex hormones
- Oxidative stress
- Vascular disruption
- Specific receptor or enzyme mediated teratogenesis
describe folate antagonism in regards to foetal development
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.
describe neural crest cell disruption in regards to foetal development
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
describe enzyme mediated teratogenesis
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.
what may fetotoxicity result in
- Growth retardation
- Structural malformations
- In utero foetal death
- Functional impairment
- Carcinogenesis
name 2 classes of fetotoxic drugs and their effects
ACEI, ARBS
renal dysfunction and growth retardation
anticonvulsants and pregnancy
Valproate is associated with neural tube defects, as is carbamazepine
and phenytoin
warfarin and pregnancy
Warfarin is associated with haemorrhage in the foetus, as well as
multiple malformations in the CNS and skeletal system
antihypertensives and pregnancy
ACEI renal damage and growth restruction
NSAIDS and pregnancy
premature closure of the ductus arteriosus
alcohol and pregnancy
foetal alcohol syndrome
retinoids and pregnancy
ear, CNS, CV and skeletal disorders
discuss drugs and lactation
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.
drug classes to avoid in breast feeding
- Cytotoxic
- Immunosuppressants
- Anti-convulsant (not all)
- Drugs of abuse
- Amiodarone
- Lithium
- Radio-iodine
tetracycline and breast feeding
tooth staining
isoniazid and breast feeding
convulsions and neuropathy
barbiturates and breast feeding
drowsiness
chloral hydrate and breast feeding
sedation
diazepam and breast feeding
sedation
methadone and breast feeding
withdrawal
iodine and breast feeding
neonatal hypothyroidism or goitre
propylthiouracil and breast feeding
thyroid function
principles of prescribing for women of child bearing age
• 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
principles of prescribing in pregnancy
- 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
principles of prescribing in breast feeding
• 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
