Pharmacology in Pregnancy and Breast Feeding Flashcards
What percentage of pregnancy women will take a drug during pregnancy? What percentage of these will be prescribed vs OTC?
50-90%
60% prescribed, 90% OTC
What percentage of women of child-bearing age take medication?
Approx 80%
When should you consider the effect of pregnancy when prescribing?
When prescribing for any woman of child-bearing age, whether pregnant or not
Why might medicines be used in pregnancy and breast feeding?
Hypertension Asthma Epilepsy Migraine Mental health disorders Conditions requiring long-term anticoagulation therapy e.g. AF
What are the processes of pharmacokinetics in pregnancy?
Administration
Distribution
Metabolism
Excretion
How might pregnancy affect the pharmacodynamics of a drug?
Pregnancy may affect the site of action and receptor response to drugs
Concentration of drug, metabolites at site of biological action (changes in blood flow), mechanism of action (changes in receptor)
Efficacy and adverse effects may be different
What are the four basic kinetic processes?
Absorption
Distribution
Metabolism and elimination
Excretion
What absorption changes might there be with medication given via oral route?
May be more difficult due to morning sickness, increase in gastric emptying and gut motility
Unlikely to be a problem with regular dosing but may affect single doses
What absorption changes might there be with medication given via intramuscular route?
Blood flow may be increased so absorption may also increase
What absorption changes might there be with medication given via inhalation?
Increased cardiac output and decreased tidal volume may cause increased absorption of inhaled drugs
Normally only a problem with high dose inhaled steroids
What distribution changes might occur due to pregnancy?
Increase in plasma volume and fat will change distribution of drugs -> increase Vd
Greater dilution of plasma will decrease relative amount of plasma proteins -> increasing fraction of free drugs
What metabolism changes might occur due to pregnancy?
Oestrogen and progestogens are naturally increased in pregnancy and can induce or inhibit liver P450 enzymes, increasing or reducing metabolism
Phenytoin levels reduced due to induction of metabolism
Theophylline levels increased due to inhibition of metabolism
By how much is GFR increased in pregnancy?
50%
What effect does the increased GFR have?
Leads to increased excretion of many drugs
This can reduce the plasma concentration and can necessitate an increase in dose of renally cleared drugs
What are the functions of the placenta?
Attach foetus to uterine wall
Provide nutrients to the foetus
Allow foetus to transfer waste products to the mother’s blood
Why is drug therapy more risky in pregnancy?
Most drugs can cross the placenta
What are the factors that affect placental drug transfer and drug effects on the foetus?
Drug physiochemical properties
Rate at which drugs cross the placenta and amount reaching the foetus
Duration of drug exposure
Distribution in different foetal tissues
What is exchanged across the placenta from mother to foetus?
Oxygen Glucose Amino acids Lipids, fatty acids and glycerol Vitamins Ions Alcohol, nicotine and other drugs Viruses Antibodies
What is exchanged across the placenta from foetus to mother?
CO2
Urea
Other waste products
What does placental transfer depend on?
- Size
- Electrical charge
- Protein binding
- Lipophilicity
Molecular weight - smaller sizes will cross more easily
Polarity - non-polar cross more readily
Lipid solubility - lipid soluble drugs will cross
Placenta may also metabolise some drugs
Safest to assume all drugs will cross the placenta
What are the differences in distribution in foetal pharmacokinetics?
Circulation different - umbilical vein to liver
Less protein binding than adults so more free drug available
Little fat so different distribution
Relatively more blood flow to the brain - blood-brain barrier not fully formed, more porous
What are the differences in metabolism in foetal pharmacokinetics?
Generally have lower metabolic rates
Less enzyme activity though this increases with gestation
Different isoenzymes to adults
What are the differences in excretion in foetal pharmacokinetics?
Excretion is into the amniotic fluid - this is swallowed so recirculation of an excreted drug can occur
Drugs and metabolites can accumulate in the amniotic fluid
Placenta not functioning at delivery so there can be issues with the excretory function
What needs to be considered in terms of the safety of drugs in pregnancy?
Teratogenicity - generally occurs in first trimester, neurological teratogenicity may occur later
Fetotoxicity - second and third trimesters
Management of chronic illness - under-treatment due to fear of using drugs during pregnancy may cause a greater foetal risk and a maternal risk
What percentage of foetal abnormalities are drugs responsible for?
2%
When is the biggest risk of foetal abnormalities caused by drugs?
During organogenesis (3-8 weeks)
What are the mechanisms of teratogenicity?
Folate antagonism Neural crest cell disruption Oxidative stress Vascular disruption Specific receptor or enzyme-mediated teratogenesis
Why is folic acid recommended to all women before and during pregnancy?
To reduce risk of spina bifida
Folate antagonism is a key process in DNA formation and new cell production
What drugs affect folate antagonism?
Two groups of drugs affect folate antagonism - those that block the conversion of folate to THF by binding irreversibly to the enzyme (e.g. methotrexate, trimethoprim) or that block other enzymes in the pathway (e.g. phenytoin, carbamazepine, valproate)
Tend to result in neural tube, pro-facial or limb defects
What drugs cause neural crest cell disruption?
Retinoid drugs e.g. Isotretinoin
What problems might be caused by retinoids due to neural crest cell disruption?
Aortic arch anomalies Ventricular septal defects Craniofacial malformations Oesophageal atresia Pharyngeal gland abnormalities
How might enzyme-mediated teratogenesis occur?
Drugs which inhibit or stimulate an enzyme to produce a therapeutic effect may also interact with specific receptors and enzymes, damaging foetal development e.g. NSAIDs causing orofacial clefts and cardiac septal defects
What are possible issues associated with fetotoxicity?
Growth retardation Structural malformations Foetal death Functional impairment Carcinogenesis
e.g. ACEIs/ARBs cause renal dysfunction and growth retardation
What is the teratogenic effect of anticonvulsants?
Valproate is associated with neural tube defects, as are carbamazepine and phenytoin
What is the teratogenic effect of anticoagulants?
Warfarin is associated with haemorrhage in the foetus as well as multiple malformations of the CNS and skeletal system
What is the teratogenic effect of antihypertensive agents?
ACEIs cause renal damage and may restrict normal growth patterns in the unborn child
What is the teratogenic effect of NSAIDs?
Premature closure of the ductus arteriosus
What is the teratogenic effect of alcohol?
Foetal alcohol syndrome/effects
What is the teratogenic effect of retinoids?
Ear, CSN, cardiovascular and skeletal disorders
What is category A of the toxicity classification?
Controlled human studies show no foetal risks; these drugs are the safest
What is category B of the toxicity classification?
Animal studies show no risk to the foetus but no controlled human studies have been conducted, or animal studies show a risk to the foetus but well-controlled human studies do not
What is category C of the toxicity classification?
No adequate animal or human studies have been conducted, or adverse foetal effects have been shown in animals but no human data are available
What is category D of the toxicity classification?
Evidence of human foetal risk exists, but benefits may outweigh risks in certain situations e.g. life-threatening disorders, serious disorders for which safer drugs cannot be used or are ineffective
What is category X of the toxicity classification?
Proven foetal risks outweigh any possible benefit
Why might there be issues with drugs and breast feeding?
Most drugs will be present at lower doses though breast-feeding than in utero
Almost all drugs the mother takes will be present in breast milk
It is important to know what concentration will be in breast milk
Remember pharmacokinetics are different in the neonate than in the foetus
What drugs should be avoided in breast feeding?
Cytotoxic Immunosuppressants Anti-convulsants Drugs of abuse Amiodarone Lithium Radio-iodine
Where can you find information about risks with specific drugs in pregnancy/breast feeding?
BNF
UK Tetrology Information Service
Schedule of Product Characteristics
Drugs and Lactation Database
What are the main principles of prescribing for women of child-bearing age?
Always consider the possibility of pregnancy - planned or not
Warn women of possible risks
When treating medical conditions, advise women to attend before getting pregnancy if planning to in order to optimise treatment
Discuss contraception
If necessary, do not prescribe without contraception
What are the other principles of prescribing for women of child-bearing age?
If you can, try non-pharmacological treatment first
Use the drug with the best safety record - avoid new drugs unless proven to be 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
Don’t under-treat disease which may be harmful to the foetus
When/why might you face difficult situations in regard to prescribing in pregnancy/women of child-bearing age?
Chronic disease - asthma, epilepsy, cardiac conditions, cancer
Good disease control is important
Drugs are thought to be safe but evidence is often limited
Manufacturers recommend use “only if potential benefit outweighs risk”
Specialist input is vital
What are the principles of prescribing in breast feeding?
Avoid unnecessary drug use
Check up-to-date drug information
May be a lack of information
If licensed and safe in paediatric use (especially 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
