Pharmacology in pregnancy and breastfeeding Flashcards
what % of women take a drug during pregnancy? (prescribed and OTC)
50-90%
60% prescribed and 90% OTC
Why may a woman be on medication?
hypertension asthma epilepsy migraine mental health anti-coagulant
4 basic pharmacokinetic processes
absorption
distribution
metabolism
excretion
Absorption changes - oral route
morning sickness, nausea and vomiting
increased gastric emptying and gut motility
absorption changes - intramuscular
increased blood flow so increased absorption
absorption changes - inhalation
increased CO and decreased tidal volume may cause increased absorption of inhaled drugs
2 distribution changes
increase in plasma volume and fat –> increased Vd
Greater dilution of plasma will decrease relative amount of plasma protein –? increased free fraction of drug
What changes can oestrogen and progesterone play in metabolism changes?
can induce or inhibit P450 liver enzymes
2 examples of metabolism changes
phenytoin levels down due to induced metabolism
theophylline levels up due to inhibited metabolism
Excretion changes and the consequences of this
GFR can increase by 50% so increased excretion of many drugs which means plasma conc reduced and need an increase in dose of renally cleared drugs
Pharmacodynamic changes
concentration of drug, metabolites at sites of biological action –> due to blood flow
mechanism of action due to changes in receptors
3 functions of placenta
- attach fetus to uterine wall
- provide nutrients to fetus
- allow fetus to transfer waste products to the mother’s blood
Mother –> fetus
oxygen - glucose - amino acids - vitamins - lipids, FA, glycerol - alcohol, nicotine, drugs - ions eg Na, Cl, Ca, Fe - antibodies - viruses
fetus –> mother
CO2 - urea - other waste products
Placental transfer depends on: -
a - molecular weight (smaller molecules <500Da)
b - polarity (non-polar)
c - lipid solubility (lipid soluble)
d - protein bound drugs can cross
Fetal PK - distribution (4)
circulation different (umbilical vein –> liver)
less protein binding so more free drug
little fat
relatively more blood flow to the brain
fetal PK - metabolism
less fetal enzyme activity - increases with gestation
different isoenzymes
Excretion of fetus is into…
amniotic fluid and is swallowed and recirculated
Can drugs and metabolites accumulate in amniotic fluid?
yes
Teratogenicity - what trimester?
1
fetotoxicity - what trimester?
2 and 3
What % of fetal abnormalities are drugs responsible?
2
When is the biggest risk of drugs in pregnancy?
organogenesis (3-8 weeks)
Mechanism of teratogenicity (6)
- folate antagonism
- neural crest cell disruption
- endocrine disruption - sex hormone
- oxidative stress
- vascular disruption
- specific receptor on enzyme medicated teratogenesis
Importance of folate
key roles in DNA formation and new cell production
2 groups of drugs that antagonise folate and 1 example of each
- block folate –> THF by binding irreversibly to enzyme
- -> methotrexate, trimethoprim - block other enzymes in pathway eg phenytoin, valproate
Folate antagonistic drugs tend to result in what?
neural tube, oro-facial or limb defects
What group of drugs can cause neural crest cell disruption?
retinoid drugs eg isotretinoin
5 problems with drugs causing neural crest cell disruption
- aortic arch anomalies
- ventricular septal defects
- craniofacial malformations
- oesophageal atresia
- pharyngeal gland abnormalities
Explain the basis of enzyme mediated teratogenesis and an example
Drugs inhibit/stimulate enzymes for therapeutic effects may also interact with specific receptors and enzymes damaging fetal development
Eg –> NSAIDS causing oro-facial cleft and cardiac septal defects
Fetotoxicity
toxic effect on fetus later in pregnancy
5 possible issues of fetotoxicity
- growth retardation
- structural malformations
- fetal death
- carcinogenesis
- functional impairment
examples of drugs that can cause fetotoxicity
ACEI/ARBs - renal dysfunction and growth retardation
Category A-X of fetotoxicity and very brief description
A - controlled human studies show no fetal risks - safest
B - animal studies: no risk, human studies do
C : insufficient studies
D : evidence of risk exists but benefits outweigh risks
X: proven fetal risk outweigh any benefit
List some known teratogenic drugs to avoid
valproate - NTD
warfarin - haemorrhage
ACEI, NSAIDS, alcohol, retinoids
7 drugs to avoid in breastfeeding
- cytotoxics 2. immunosuppressants 3. Lithium
- amiodarone 5. Anti-convulsants 6. radio-iodine
- drugs of abuse
Basic principles of prescribing in pregnancy
try non-pharm first
drug with best safety record, lowest effective dose
shortest time/intermittent
avoid first 10 weeks pregnancy is possible
stop or reduce dose before delivery
do not under treat disease which may be harmful to fetus
Basic principles of prescribing in breastfeeding
avoid unnecessary and check up to date info
licensed in paeds - safe
PK that reduce infant exposure eg protein bound
