Pharmacology in Pregnancy and Breast Feeding Flashcards
Why might a woman be on medication at the start of a pregnancy?
- Hypertension
- Asthma
- Epilepsy
- Migraines
- Mental health disorder
- Long-term anticoagulant therapy e.g. for AF
What are the 4 basic kinetic drug processes?
- Absorption
- Distribution
- Metabolism and elimination
- Excretion
What are the changes in the oral route of absorption in pregnancy?
- May be more difficult due to morning sickness
* Decrease in gastric emptying and gut motility - more likely to affect single dose rather than multiple dosing
What are the changes in the intramuscular route of absorption in pregnancy?
Blood flow may be increased, so absorption may also increase using this route
What are the changes in the inhalation route of absorption in pregnancy?
Increased cardiac output and decreased tidal volume may cause increased absorption of inhaled drugs
Why is distribution different in pregnancy?
- Increase in plasma volume and fat will change distribution of drugs - increased volume distribution (Vd)
- Greater dilution of plasma will decrease relative amount of plasma proteins - increases fraction of free drug
What metabolism changes occur in pregnancy?
- Oestrogen and progesterone can induce or inhibit liver P450 enzymes
- This leads to an increase or reduction in metabolism
What are some examples of liver enzyme changes?
- Phenytoin levels reduced - due to induction of metabolism
* Theophylline levels increased - due to inhibition of metabolism
How does excretion change in 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 medicines cleared by the kidney
How well are pregnancy pharmacodynamics understood?
Less well understood
How does pregnancy affect pharmacodynamics?
- Pregnancy may affect the site if drug action and the receptor response to drugs
- Concentration of drug change metabolites at sites of biological action (changes in blood flow)
- Mechanism of action (changes in receptors)
How does pregnancy affect pharmacodynamics?
- Pregnancy may affect the site of drug action and the receptor response to drugs
- Concentration of drug change 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 are the material exchanged from mother to foetus across the placenta?
- Oxygen
- Glucose
- Amino acids
- Lipids, fatty acids & glycerol
- Vitamins
- Ions; Na, Cl, Ca, Fe
- Alcohol, nicotine + other drugs
- Viruses
- Antibodies
What are the material exchanged from foetus to mother across the placenta?
- Carbon dioxide
- Urea
- Other waste products
Can drugs pass the placenta during pregnancy?
Yes, most do
What are the factors affecting placental drug transfer and drug effects on the foetes inside?
- Drug physiochemical properties
- Rate at which drug crosses placenta and amount reaching the fetus
- Duration of drug exposure
- Distribution in different fetal tissues
- Stage of placental and fetal development
- Effects of drugs when used in combination
What does placental transfer depend on?
- Molecular weight (smaller sizes will cross more easily)
- Polarity (unionised molecules cross more readily)
- Lipid solubility (lipid soluble drugs will cross)
- Placenta may also metabolise some drugs
- Safest to assume all drugs will cross placenta
What molecular weight (size) of drugs can pas the placenta?
- Most drugs withMW < 500 Da cross the placenta
* MW > 1000 Da do not
How easily do ionised drugs cross the placenta?
•Non-ionized drugs cross the placenta more easily than ionized drugs
How does protein-binding affect drugs crossing the placenta?
Previously it was believed that protein-bound drugs did not cross the placenta, however as these medications exist in equilibrium with non-bound versions this is not true
How does lipophilicity affect drugs crossing the placenta?
High lipophilicity will increase placental transfer
How is distribution different in foetal pharmacokinetics?
- Circulation is 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
How is metabolism different in foetal pharmacokinetics?
- Reduced enzyme activity, although this increases with gestation
- Fetus exhibits different P450 isoenzymes to adults
How is excretion different in foetal pharmacokinetics?
- Excretion is into amniotic fluid – which the fetus swallows leading to recirculation
- Drugs and metabolites can accumulate in amniotic fluid
- Placenta not functioning at delivery so can be issues with excretory function
In which drug groups is there actually information available on pregnancy and PK and PD?
- Anti-convulsants
- Anti-hypertensives
- Analgesics
- Antibacterials
When does teratogenicity occur?
The first trimester
When does fetotoxicity occur?
Second and third trimester
N.B. Under treatment due to fear of using drugs during pregnancy may cause greater foetal risk
What are the principles of prescribing for women of a 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
What are the principles when prescribing in pregnancy?
- If you can, try non-pharmacological treatment first
- Use the drug with the best safety record (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
- Never under a treat disease which may be harmful to the mother or fetus
Drugs are responsible for what percentage of foetal abnormalities?
2%
When is the highest risk of teratogenesis?
3-8 weeks
What mechanisms can cause teratogenicity?
- Folate Antagonism
- Neural Crest Cell Disruption
- Endocrine Disruption: Sex Hormones
- Oxidative Stress
- Vascular Disruption
- Specific Receptor- or Enzyme-mediated teratogenesis
What is folate antagonism?
A key process in DNA formation and new cell production
Why is folate essential in pregnancy?
Key in DNA formation and new cell production
What are the mechanisms of the two groups of drugs that affect folate metabolism?
- Block the conversion of folate to THF by binding irreversibly to the enzyme (eg methotrexate, trimethoprim)
- Block other enzymes in the folate pathway (e.g. phenytoin, carbamazepine, valproate)
What happens if folate requirements are not met?
Tends to result in neural tube, oro-facial or limb defects
Which drugs cause neural crest cell disruption?
Retinoid drugs e.g. isotretinoin (Accutane)
What are the effects of neural crest cell disruption?
- Aortic arch anomalies
- Ventricular septal defects
- Craniofacial malformations
- Oesophageal atresia
- Pharyngeal gland
- Abnormalities
How does enzyme-mediated teratogenesis occur?
- Drugs which inhibit or stimulate enzymes to produce therapeutic effects may also interact with specific receptors and enzymes damaging fetal development
- E.g. NSAIDs causing orofacial clefts and cardiac septal defects
What is feototoxicity?
Toxic effect on the fetus later in pregnancy
What are the possible issues caused by foetotoxicity?
- Growth retardation
- Structural malformations
- Fetal death
- Functional impairment
- Carcinogenesis
•E.g. ACE inhibitors/ARBs – renal dysfunction and growth retardation
How does the FDA categorise teratogenic drugs?
From A-X
Describe each category of teratogenic drug
TERATOGENIC DRUG CLASSIFICATION
What is the effect of anticonvulsants in pregnancy?
Valproate is associated with neural tube defects, as is carbamazepine and phenytoin
(all anti-seizure)
What is the effect of anticoagulants in pregnancy?
Warfarin is associated with haemorrhage in the fetus, as well as multiple malformations in the central nervous system and skeletal system
What is the effect of antihypertensive agents in pregnancy?
ACE inhibitors cause renal damage and may restrict normal growth patterns in the unborn child
What is the effect of NSAIDs in pregnancy?
Premature closure of the ductus arteriosus
What is the effect of alcohol in pregnancy?
Fetal alcohol syndrome/effects
What is the effect of retinoids in pregnancy?
Ear, CNS, cardiovascular, and skeletal disorders
What issues do drugs pose to breast feeding?
- Almost all drugs the mother takes will be present in breast milk
- Important to know what concentration will be in breast milk
- Remember pharmacokinetics are different in the neonate compared to the fetus
How should a possibility of harm to the infant through breast feeding be monitored?
Monitor infant blood levels of the drug
How else might the issues surrounding drugs and breast feeding be tackled?
- If possible postpone drug treatment until the baby is weaned
- Use non-pharmacological strategies when possible.
- If a drug needs to be used, then the mother should take the medication immediately after feeding the baby
- Avoid breast-feeding during peak drug effect
- Avoid drugs with long half-life or active metabolites
- Drugs that are highly protein-bound are preferred
- Extra caution if baby is severely ill or preterm
How else might the issues surrounding drugs and breast feeding be tackled?
- If possible postpone drug treatment until the baby is weaned
- Use non-pharmacological strategies when possible.
- If a drug needs to be used, then the mother should take the medication immediately after feeding the baby
- Avoid breast-feeding during peak drug effect
- Avoid drugs with long half-life or active metabolites
- Drugs that are highly protein-bound are preferred
- Extra caution if baby is severely ill or preterm
What are some drugs to avoid when breast-feeding?
- Cytotoxics (chemotherapy)
- Immunosuppressants
- Anti-convulsants (not all)
- Drugs of abuse
- Amiodarone (anti-arrhythmic)
- Lithium
- Radio-iodine
What effect does tetracycline have on the infant during lactation?
Risk of permanent tooth staining in infant
What effect does isoniazid have on the infant during lactation?
Risk of pyridoxine (vit B6) deficiency in the infant
TB antibiotic
What effect do barbiturates have on the infant during lactation?
Lethargy, sedation and poor suck reflexes
What effect does chloral hydrate have on the infant during lactation?
Drowsiness if infant fed at peak
Sedative
What effect does diazepam have on the infant during lactation?
Drug accumulation and sedation
What effect does methadone have on the infant during lactation?
Risk of withdrawal if breast feeding stops
What effect does iodine have on the infant during lactation?
Thyroid suppression and risk of cancer
What effect does propylthiouracil have on the infant during lactation?
Can suppress thyroid function in infant
for hyperthyroidism
What are the two most popular galactagogues for nursing mothers?
- Fenugreek
* Comfrey
Why should breast-feeding mothers avoid herbal remedies?
- This is is due to the lack of information of scientific safety data
- Contamination of herbal products with conventional medicines, pesticides or heavy metals
- Herbs containing pyrrolizidine alkaloids (PAs) can be hepatotoxic
- Some herbal medicines have hormonal effects.
- Some herbal medicines contain constituents with sedative properties
What are the 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 (e.g. highly protein bound)
