pharmacology in pregnancy and breastfeeding Flashcards
what % of pregnant women take medicines
~50-90% will take a medicine
60% prescribed
90% OTC
what is the implication of unplanned pregnancy
many pregnancies are unplanned
80% of women of child bearing age take medication
why may a woman be on medication during pregnancy, birth and lactation
HT asthma epilepsy migraine mental health disorders long term anticoagulation
what 4 processes can the physiological changes during pregnancy effect in relation to medication
absorption
distribution
metabolism and elimination
excretion
oral route absorption changes during pregnancy
may be more difficult - morning sickness, N+V
decrease in gastric emptying and gut motility - unlikely to be a problem with regular dosing but may affect single doses
IM route absorption changes during pregnancy
blood flow may be increased
absorption may also increase using this route
inhalation absorption changes during pregnancy
increased cardiac output
decreased tidal volume
increased absorption of inhaled drugs
distribution changes during pregnancy
increase in plasma volume and fat will change distribution of drugs - increased volume of distribution
greater dilution of plasma will decrease relative amount of plasma proteins 0 increased fraction of free drug
metabolism changes during pregnancy
oestrogen and progestogens can induce/inhibit liver P450 enzymes - increases/decreases metabolism
e.g. phenytoin levels reduced due to induction of metabolism, theophylline levels increased due to inhibition of metabolism
excretion changes during pregnancy
GFR increased by 50% in pregnancy - increased excretion of many drugs
this can reduce the plasma concentration and can require an increased dose of the medicines cleared by the kidney
pharmacodynamic changes during pregnancy
pregnancy may affect the site of drug action and receptor response to drugs
- concentration of drug, metabolites at sites of biological action (changes of blood flow)
- mechanism of action (changes in receptors)
efficacy and adverse effects may be different
what factors affect placental drugs transfer and drug effects on the foetus
drug physiochemical properties
rate at which drug crosses placenta and amount reaching the foetus
duration of drug exposure
distribution in different foetal tissues
stage of placental and foetal development
effects of drugs when used in combination
what does placental transfer depend on
molecular weight - smaller sizes cross more easily
polarity - unionised molecules cross more readily
lipid solubility - lipid soluble drugs will cross
placenta may also metabolise some drugs
safe to assume all drugs will cross placenta
fetal pharmacokinetics - distribution
circulation is different
less protein binding than adults - more free drug available
little fat, distribution different
relatively more blood flow to brain
fetal pharmacokinetics - metabolism
reduced enzyme activity - although this increases with gestation
exhibits different P450 isoenzymes to adults
fetal pharmacokinetics - excretion
excretion is into amniotic fluid - foetus swallows leading to recirculation
drugs and metabolites can accumulate in amniotic fluid
placenta not functioning at delivery - can be issues with excretory function
issues with PK and PD during pregnancy
inadequate data for most drugs so uncertainty around dosing
some information available for some drug groups - anti-convulsants, anti-hypertensives, analgesics, antibacterials
factors of safety of drugs in pregnancy
teratorgenicity - 1st trimester
fetotoxicity - 2nd and 3rd trimester
principles of prescribing for women of child bearing age
always consider possibility of pregnancy
warn re. possible risks
when treating medical conditions advise women to attend before getting pregnant if planning to - optimise treatment
discuss contraception
if necessary, don’t prescribe w/o contraception
principles of prescribing in pregnancy
try non-pharmacological methods first
use the drug with the best safety record, avoid new drugs unless proven safe
check SPC for most up to date info
use lowest effective dose
use the drug for the shortest possible time, intermittently if possible
avoid the first 10wks of pregnancy if possible
consider stopping/reducing dose before delivery
never under treat a disease which may be harmful to the mother/fetus
why is treatment of chronic illness still important during pregnancy
under-treatment of maternal illness due to fear of using medicines during pregnancy may cause greater fetal risk
what % of fetal abnormalities are drugs responsible for
2%
when is the highest risk of drug caused fetal abnormalities
during organogenesis
3-8wks
by what mechanisms can drugs cause fetal abnormalities
folate antagonism neural crest cell disruption endocrine disruption - sex hormones oxidative stress vascular disruption specific receptor/enzyme mediated teratogenesis
what is folate antagonism
key process in DNA formation and new cell production
what groups of drugs affect folate metabolism
2 groups:
- block the conversion of folate –> THF by binding irreversible to the enzyme e.g. methotrexate, trimethoprim
- block other enzymes in the folate pathway e.g. phenytoin, carbamazepine, valproate
what types of defects does folate antagonism tend to result in
neural tube
oro-facial
limb defects
what drugs cause neural crest cell disruption
retinoid drugs e.g. isotretinoin (accutane)
what defects can be caused by neural crest cell disruption
aortic arch anomalies ventricular septal defects craniofacial malformations oesophageal atresia pharyngeal gland abnormalities
describe enzyme mediated teratogenesis
drugs which inhibit/stimulate enzymes to produce therapeutic effects may also interact w/ specific receptors and enzymes damaging fetal development
example of enzyme mediated teratogenesis
NSAIDs causing orofacial clefts and cardiac septal defects
what is fetotoxicity
toxic effect on the fetus later in pregnancy
possible issues related to fetotoxicity
growth retardation structural malformations fetal death functional impairment carcinogenesis
example of fetotoxicity
ACE inhibitors/ARBs - renal dysfunction and growth retardation
category A drugs
controlled human studies - no fetal risks
safest drugs
category B drugs
animal studies - no risk to fetus but no controlled human studies conducted
OR
animal studies show risk to fetus but well controlled human studies dont
category C drugs
no adequate animal/human studies have been conducted
OR
adverse fetal effects have been shown in animals but no human data available
category D drugs
evidence of human fetal risk exists but benefits > risks in certain situations (life threatening disorders, serious disorders for which safer drugs can’t be used/are ineffective)
category X drugs
proven fetal risks»_space; any possible benefit
6 categories of known teratogens to avoid during pregnancy
anticonvulsants anticoagulants antihypertensive agents NSAIDs alcohol retinoids
examples of teratogenic anticonvulsants
valproate, carbamazepine, phenytoin - neural tube defects
examples of teratogenic anticoagulants
warfarin - haemorrhage in fetus, multiple malformations in CNS and skeletal system
examples of teratogenic antihypertensive agents
ACE inhibitors - renal damage, may restrict normal growth patterns in the unborn child
examples of teratogenic effects of NSAIDs
premature closure of ductus arteriosus
examples of teratogenic effects of alcohol
fetal alcohol syndrome/effects
examples of teratogenic effects of retinoids
ear, CNS, CVS and skeletal disorders
ACEI - trimester affected, effects
all
renal damage
TCAs - trimester affected, effects
3rd
neonatal withdrawal syndrome
barbituates - trimester affected, effects
all
chronic use - neonatal dependence
carbamazepine - trimester affected, effects
1st
neural tube defects
cocaine, tamoxifen - trimester affected, effects
all
risk of spontaneous abortion
ethanol - trimester affected, effects
all
fetal alcohol syndrome
iodine - trimester affected, effects
all
congenital goitre
hypothyroidism
lithium - trimester affected, effects
1st
increased ICP
tobacco - trimester affected, effects
all
intrauterine growth retardation
tetracycline - trimester affected, effects
all
discolouration of teeth, altered bone growth
thalidomide - trimester affected, effects
1st limb malformation (DES cancer risk increased)
warfarin - trimester affected, effects
1st - alters resp tract formation
2nd - CNS malformation
3rd - risk of bleeding, IC haemorrhage
issues with drugs and lactation
almost all drugs the mother takes will be present in breast milk
important to know what the concentration will be in the breast milk
PK are different in the neonate to the fetus
minimal exposure during BF - questions to ask
is maternal drug therapy necessary?
if yes, what is the safest option for the infant?
possibility of harm –> monitor infant blood levels of drug
MINIMISE INFANT EXPOSURE
minimising the infant exposure during BF - steps to take
if possible, postpone drug treatment until baby is weaned
use non-pharmacological options where possible
if drug needs to be used, mother should take immediately after feeding baby
avoid BF during peak drug effect
avoid drugs w/ long 1/2 life or active metabolites
drugs that are highly protein bound are preferred
extra caution if baby is severely ill/pre-term
which drugs should be avoided during breast feeding
cytotoxics immunosuppressants anti-convulsants (not all) drugs of abuse amiodarone lithium radio-iodine
tetracycline - effects on infant when used during lactation
risk of permanent tooth staining in infant
isoniazid - effects on infant when used during lactation
risk of pyridoxine deficiency in infant
barbituates - effects on infant when used during lactation
lethargy, sedation, poor suck reflexes
chloral hydrate - effects on infant when used during lactation
drowsiness if infant fed at peak
diazepam - effects on infant when used during lactation
drug accumulation and sedation
methadone - effects on infant when used during lactation
risk of withdrawal if breastfeeding stops
iodine - effects on infant when used during lactation
thyroid suppression
risk of cancer
propylthiouracil - effects on infant when used during lactation
can suppress thyroid function in infant
which 2 popular herbal medicine can pose a risk in breast feeding mothers to their children
marketed as galactagogues to improve milk supply:
fenugreek
comfrey
risk of herbal medicines during pregnancy - when do they occur
almost 1/2 of pregnant women
increases potential of teratogenicity when used during 1st trimester and fetotoxcity in 3rd trimester
examples of herbal medicines which can pose a risk to the child if the mother is breastfeeding
Bladderwrack Buckthorn Chaparral Coltsfoot (Farfarae folium) Dong Quai (Angelica Root) Elecampane Ephedra / Ephedra sinica / Ma Huang Ginseng (Panax ginseng) Indian Snakeroot Kava-kava (piper methysticum) Petasites root Phen-fen, herbal Rhubarb Star anise Tiratricol (TRIAC) Uva Ursi Wormwood
advice for breastfeeding mothers re. herbal medicines
should avoid
lack of info re scientific safety date
contamination of herbal products w/ conventional medicines, pesticides or heavy metals
specific risks of herbal medicines in breastfeeding mothers
herbs containing pyrrolizidine alkaloids (PAs) can be hepatotoxic
some have hormonal effects
some contain constituents with sedative properties
principles of prescribing in breast feeding
avoid unnecessary drug use
check on up to date drug info - may be a lack of info
if licensed and safe in paediatric use (esp <2y/o) a drug is likely to be safe in breast feeding
choose drugs w/ pharmacokinetic properties that reduce infant exposure e.g. highly protein bound
