Pharmacology in pregnancy and breast feeding Flashcards
Certain physiological changes during pregnancy have implications for drug therapy and may affect any of the four basic kinetic processes namely?
1) Absorption
2) Distribution
3) Metabolism
4) Excretion
Absorption changes during pregnancy - Oral?
- May be more difficult “morning sickness” nausea/vomiting
- Increase in gastric emptying and gut motility
- This is unlikely to be a problem with regular dosing, but may affect single doses
Absorption changes during pregnancy - Intramuscular?
Blood flow may be increased, so absorption may also increase using this route
Absorption changes during pregnancy - Inhalation?
Increased cardiac output and decreased tidal volume may cause increased absorption of inhaled drugs
Distribution changes of drugs within pregnancy?
Increase in plasma volume and fat will change distribution of drugs.
= Increased Vd
Greater dilution of plasma will decrease relative amount of plasma proteins.
= Increased Fraction of Free Drug
Metabolism changes of drugs within pregnancy?
Oestrogen and progestogens can induce or inhibit liver P450 enzymes, increasing or reducing metabolism.
Examples:
- Phenytoin levels reduced (due to induction of metabolism)
- Theophylline levels increased (due to inhibition of metabolism)
Excretion changes of drugs within 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.
Functions of the placenta?
Attach the fetus to the uterine wall
Provide nutrients to the fetus
Allow the fetus to transfer waste products to the mother’s blood
Exchange of materials across the placenta - Mother to foetus?
Oxygen Glucose Amino acids Lipids, fatty acids & glycerol Vitamins Ions; Na, Cl, Ca, Fe Alcohol, nicotine + other drugs Viruses Antibodies
Exchange of materials across the placenta - foetus to mother?
Carbon dioxide
Urea
Other waste products
Concepts of placental transfer?
Depends on:
1) Molecular weight (smaller sizes will cross more easily)
2) Polarity (non-polar cross more readily)
3) Lipid solubility (lipid soluble drugs will cross)
Placenta may also metabolise some drugs
Safest to assume all drugs will cross placenta
What size do most drugs cross the placenta?
Most drugs withMW < 500 Da cross the placenta. MW > 1000 Da do not
Which charge allows most drugs cross the placenta?
Non-ionized drugs cross the placenta more easily than ionized drugs
Effect of lipophilicity on placental transfer?
High lipophilicity will increase placental transfer
Why may drugs and metabolites accumulate within a foetus?
As many drugs and metabolites are excreted within the amniotic fluid which is swallowed again
What is teratogenicity?
First trimester toxic drugs
What is fetotoxicity?
Second and third trimester toxic drugs
How are some drugs teratogenic?
Folate Antagonism
Neural Crest Cell
Disruption
Endocrine Disruption: Sex Hormones
Oxidative Stress
Vascular Disruption
Specific Receptor- or Enzyme-mediated
Teratogenesis
Which drugs can cause flat antagonism? what effect is there?
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)
Key process in DNA formation and new cell production. Tend to result in neural tube, oro-facial or limb defects
How is methotrexate teratogenic, what can it cause?
Folate antagonism - Block the conversion of folate to THF by binding irreversibly to the enzyme
Tend to result in neural tube, oro-facial or limb defects
How is trimethoprim teratogenic, what can it cause?
Folate antagonism - Block the conversion of folate to THF by binding irreversibly to the enzyme
Tend to result in neural tube, oro-facial or limb defects
How is phenytoin teratogenic, what can it cause?
Folate antagonism - Block other enzymes in the pathway
Tend to result in neural tube, oro-facial or limb defects
How is carbamazepine teratogenic, what can it cause?
Folate antagonism - Block other enzymes in the pathway
Tend to result in neural tube, oro-facial or limb defects
How is valproate teratogenic, what can it cause?
Folate antagonism - Block other enzymes in the pathway
Tend to result in neural tube, oro-facial or limb defects
How are retinoids (e.g. istretinoin) teratogenic, what can it cause?
Neural crest cell disruption
Problems
- Aortic arch anomalies
- Ventricular septal defects
- Craniofacial malformations
- Oesophageal atresia
- Pharyngeal gland abnormalities
How are NSAIDs teratogenic, what can it cause?
Enzyme-mediated teratogenesis
NSAIDs causing orofacial clefts and cardiac septal defects
What can fetotoxicity lead to?
Possible issues
- Growth retardation
- Structural malformations
- Fetal death
- Functional impairment
- Carcinogenesis
Examples of fetotoxic drugs?
ACE inhibitors/ARBs – renal dysfunction and growth retardation
Anticonvulsants are teratogenic, what can it cause?
Valproate is associated with neural tube defects, as is carbamazepine and phenytoin
Anticoagulants are teratogenic, what can it cause?
Warfarin is associated with haemorrhage in the fetus, as well as multiple malformations in the central nervous system and skeletal system.
Anti-hypertensives are teratogenic, what can it cause?
ACE inhibitors cause renal damage and may restrict normal growth patterns in the unborn child.
NSAIDs are teratogenic, what can it cause?
Premature closure of the ductus arteriosus.
Alcohol are teratogenic, what can it cause?
Fetal alcohol syndrome/effects
Retinoids are teratogenic, what can it cause?
Ear, CNS, cardiovascular, and skeletal disorders
Drugs to avoid during breast feeding?
Cytotoxics Immunosuppressants Anti-convulsants (not all) Drugs of abuse Amiodarone Lithium Radio-iodine
