pharmacology in pregnancy and breastfeeding Flashcards by Becca M

what % of pregnant women take medicines

~50-90% will take a medicine
60% prescribed
90% OTC

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what is the implication of unplanned pregnancy

many pregnancies are unplanned

80% of women of child bearing age take medication

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why may a woman be on medication during pregnancy, birth and lactation

HT
asthma
epilepsy
migraine 
mental health disorders
long term anticoagulation

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what 4 processes can the physiological changes during pregnancy effect in relation to medication

absorption
distribution
metabolism and elimination
excretion

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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

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IM route absorption changes during pregnancy

blood flow may be increased

absorption may also increase using this route

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inhalation absorption changes during pregnancy

increased cardiac output
decreased tidal volume
increased absorption of inhaled drugs

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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

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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

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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

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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

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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

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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

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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

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fetal pharmacokinetics - metabolism

reduced enzyme activity - although this increases with gestation
exhibits different P450 isoenzymes to adults

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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

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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

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factors of safety of drugs in pregnancy

teratorgenicity - 1st trimester

fetotoxicity - 2nd and 3rd trimester

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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

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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

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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

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what % of fetal abnormalities are drugs responsible for

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when is the highest risk of drug caused fetal abnormalities

during organogenesis

3-8wks

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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

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what is folate antagonism

key process in DNA formation and new cell production

what groups of drugs affect folate metabolism

2 groups: 1. block the conversion of folate --> THF by binding irreversible to the enzyme e.g. methotrexate, trimethoprim 2. 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 >> 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