Pharmacology in preggo Flashcards
What are the 4 basic pharmacokinetic processes which pregnancy can have implications for?
Absorption
Distribution
Metabolism & elimination
Excretion
How does pregnancy affect the absorption of drugs?
Oral:
- Morning sickness, nausea & vomitting - may make oral intake harder
- Decreased gastric emptying & motility - single dose drugs may have decreased absorption
IM:
- Blood flow may increase - so absorption of IM drugs may be increased
Inhaled:
- Increased Cardiac output & decreased tidal volume may cause increased absorption of inhaled drugs
How does pregnancy affect the distribution of drugs?
Increased Volume of distribution - due to higher plasma volume and fat
Increased fraction of free drug - dilution of plasma will decrease relative amount of plasma proteins
How does the metabolism of drugs change in pregnancy?
Oestrogen and progestogens can induce or inhibit liver P450 enzymes - so can either increase or reduce metabolism of drugs
For example - phenytoin levels reduced due to induction of its metabolism
but Theophylline levels increase due to inhibition of its metabolism
How does the excretion of drugs change during pregnancy?
GFR increases by 50% in pregnancy
so there is increased excretion of many drugs
This reduces plasma concentration of these drugs - so this must be accounted for when giving drugs cleared by the kidney
What factors affect the placental transfer of drugs and the effects of drugs on the fetus?
Drug physiochemical properties
Rate at which drug crosses placenta and amount reaching the fetus
Duration of drug exposure
Distribution of different fetal tissues
Stage of placental and fetal development
Effects of drugs when used in combination
What factors affect placental transfer of drugs and how?
Molecular weight (smaller = crosses more easily)
Polarity (unionised = crosses more easily)
Lipid solubility (lipid soluble = crosses more easily)
How is fetal distribution of drugs different?
Circulation is different (eg umbilcal vein to liver)
Less protein binding (so more free drug in bloodstream)
Little fat
Relatively higher bloodflow to brain & less well developed blood-brain barrier
How is metabolism of drugs different in fetus?
Reduced enzyme activity - although this increases with gestation
Different P450 isoenzymes
How is the excretion of drugs different in a fetus?
Excretion is into amniotic fluid - which fetus swallows, meaning recirculation of excreted drugs
Drugs and metabollites can accumulate in amniotic fluid
Placenta doesnt function at delivery - meaning there can be issues with excretion
PK & PD in pregnant women and the fetus is not well researched, so there is uncertainty around dosing
However, what types of drugs do have available information around dosing?
Anti-convulsants
Anti-hypertensives
Anti-bacterials
Analgesics
What are the 2 major risks for the fetus when a pregnant women takes medication?
Teratogenicity (esp 1st trimester)
Fetotoxicity (esp 2nd & 3rd trimester)
When (weeks) is the risk of teratogenicity highest?
Organogenesis (3-8 weeks)
Name the mechanisms through which teratogens may cause harm
Folate antagonism
Neural crest cell disruption
Endocrine disruption (sex hormones)
Oxidative stress
Vascular disruption
Specific receptor - or enzyme-mediated teratogenesis
Describe what folate antagonism means
Folate metabolism is key process in DNA formation & new cell production
2 groups of drugs affect folate metabolism:
- Block conversion of folate to THF through irreversible binding to enzyme - eg trimethoprim, methotrexate
- Block other enzymes in the folate pathway - eg carbamezapine, phenytoin, valproate
Tend to result in neural tube, Oro-facial or limb defects
What drugs are folate antagonists?
Block folate to THF conversion:
- Methotrexate
- Trimethoprim
Block other enzymes in folate pathway:
- Phenytoin
- Carbamazepine
- Valproate
What drugs cause neural crest cell disruption?
What problems do they cause?
Retinoid drugs - eg isotretinoin
Problems:
- aortic arch anomalies
- VSD
- craniofacial defects
- oesophageal atresia
- pharyngeal gland anomalies
What is meant by enzyme mediated teratogenesis?
What is an example of this?
Drugs which inhibit or stimulate the action of enzymes for therapeutic effect may also interact with specific receptors and enzymes damaging fetal development
Example:
- NSAIDs - can cause orofacial clefts and cardiac septal defects
What is fetotoxicity and the issues it can generate?
Give examples of some fetotoxic drugs?
Toxic effect on the fetus later in pregnancy
Can cause:
- Growth retardation
- Structural malformations
- Fetal death
- Functional impairment
- Carcinogenesis
Example:
- ACE inhibitos / ARB’s - causes renal impairment and growth retardation
What anticoagulant medication is teratogenic?
What are its possible effects on fetal development?
Warfarin
Associated with haemorrhage in the fetus, as well as multiple CNS and skeletal defects
What classes of drugs may need to be avoided in breastfeeding?
Cytotoxics
Immunosuppressants
Anti-convulsants (not all)
Drugs of abuse
Amiadarone
Lithium
Radio-iodine
What risks do the following drugs pose in breastfeeding?
Tetracycline - antibiotic
Isoniazid - antibiotic used for TB
Barbiturates - for anxiety/depression
Chloral hydrate - no idea what used for
Tetracycline - permanent tooth staining of infant
Isoniazid - risk of pyridoxine deficiency in infant
Barbiturates - lethargy, sedation, poor suck reflex
Chloral hydrate - drowsiness if infant fed at peak
What risks do the following drugs pose in breastfeeding…
Diazepam (valium)
Methadone
Iodine
Propylthiouracil
Diazepam - drug accumulation and sedation
Methadone - risk of withdrawel if BF stops
Iodine - thyroid suppression and risk of cancer
Propylthiouracil - suppress thyroid function
What 2 herbal galactogogues may pose risks to infants who are breastfeeding?
Fenugreek
Comfrey
In general - breastfeeding mothers should avoid herbal medicines
