Pharmacology in Pregnancy and Breast Feeding Flashcards
What are the four basic pharmacokinetic processes?
- absorption
- distribution
- metabolism and elimination
- excretion
Absorption changes during pregnancy
- Oral route
- May be more difficult “morning sickness” nausea/vomiting
- Decrease in gastric emptying and gut motility
- This is unlikely to be a problem with regular dosing, but may affect single doses
- Intramuscular route
- Blood flow may be increased, so absorption may also increase using this route
- Inhalation
- Increased cardiac output and increased tidal volume may cause increased absorption of inhaled drugs
Distribution changes during pregnancy
- Increase in plasma volume and fat will change distribution of drugs
- Greater dilution of plasma will decrease relative amount of plasma proteins
- Increased Fraction of Free Drug
Metabolism changes during pregnancy
Oestrogen and progestogens can induce or inhibit liver P450 enzymes, increasing or reducing metabolism.
Excretion changes during pregnancy
- GFR is increased in pregnancy by 50% leading to increased excretion of many drugs.
- This can reduce the plasma concentration, and can necessitate an increase in dose of renally cleared drugs.
Pharmacodynamic changes during pregnancy
- Pregnancy may affect site of action & receptor response to drugs
- Concentration of drug and metabolites at sites of biological action (changes in blood flow)
- Mechanism of action (changes in receptors)
- Efficacy may be different
- Adverse effects may be different
What does 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)
Foetal pharmacokinetics distribution
- Circulation different (e.g. Umbilical vein to liver)
- Less protein binding than adults therefore more “free” drug available
- Little fat, so distribution different
- Relatively more blood flow to brain
Foetal pharmacokinetics metabolism
- Less enzyme activity, though increases with gestation
- Different isoenzymes to adults
Foetal pharmacokinetics excretion
- NB excretion is into amniotic fluid - this is swallowed and can allow recirculation
- Drugs and metabolites can accumulate in amniotic fluid
What causes drugs to be unsafe during pregnancy?
- Teratogenicity (first trimester)
- Fetotoxicity (second and third trimester)
- NB Under treatment of chronic illnesses due to fear of using drugs during pregnancy may cause greater fetal risk!
When is the biggest risk of teratogenicity?
During organogenesis - weeks 3-8
What are some mechanisms of teratogenicity?
- Folate Antagonism
- Neural Crest Cell Disruption
- Specific Receptor or Enzyme-mediated Teratogenesis
Folate antagonism result
- Key process in DNA formation and new cell production
- Tend to result in neural tube, oro-facial or limb defects
Which groups of drugs cause folate antagonism?
Two groups of drugs
- Block the conversion of folate to THF by binding irreversibly to the enzyme (eg methotrexate, trimethoprim)
- Block other enzymes in the pathway (eg phenytoin, carbamazepine, valproate)
Neural crest cell disruption - problems
- aortic arch anomalies
- ventricular septal defects
- craniofacial malformations
- oesophageal atresia
- pharyngeal gland abnormalities
Neural crest cell disruption - causes
Retinoid drugs (eg isotretinoin)
Enzyme-mediated teratogenesis
Drugs which cause inhibition or stimulation of enzymes to produce therapeutic effects may also interact with specific receptors and enzymes damaging foetal development.
Fetotoxicity
- Toxic effect on the fetus later in pregnancy
- Possible issues
- Growth retardation
- Structural malformations
- Foetal death
- Functional impairment
- Carcinogenesis
- Example ACE inhibitors/ARBs – renal dysfunction and growth retardation
Drugs to avoid in breast feeding
- Cytotoxics
- Immunosuppressants
- Anti-convulsants (not all)
- Drugs of abuse
- Amiodarone
- Lithium
- Radio-iodine
Principles of prescribing for women of child-bearing age
- Always consider possibility of pregnancy
- Warn women of possible risks
- When treating medical conditions, advise women to attend before getting pregnant if planning to (optimise treatment)
- 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 (avoid new drugs unless proven safe
- 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
- Avoid unnecessary drug use
- Check on up to date drug 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 (eg highly protein bound)
