Pharmacology Flashcards
What is the biggest risk period for teratogenic drugs?
Organogenesis or weeks 3-8
What are the major mechanisms of teratogenesis?
Folate Antagonism (prevents DNA/cell formation)
Neural Crest Cell Disruption
Specific recepotr or enzyme/mediated teratogensis
Sex Hormone disruption
Oxidative Stress
Vascular Disruption
What drugs can disrupt the production of DNA and new cells by antagonizing folate?
MTX
Trimethoprim
Anti-convulsants:
- Phenytoin
- Carbamazepine
- Valproate
What defects does folate antagonism cause?
- Neural Tube
- Oro-facial
- Limb
What drugs can disrupt neural crest cells?
Notably Retinoids like isotretinoin
What defects does Neural Crest Cell disruption cause?
- Aortic Arch anomalies
- Ventricular Septal Defects
- Craniofacial malformation
- Oesophageal atresia
- Pharyngeal Gland Abnormalities
How does specific receptor/enzyme-mediated teratogenesis work?
Drugs designed to inhibit/stimulate an enzyme or receptor can have -ve effects on the developing foetus
E.g. NSAIDS lead to Orofacial clefts and septal defects
Some drugs are dangerous to the foetus in the 2nd/3rd trimester, i,e. fetotoxic instead of teratogenic. What issues can they cause?
Growth retardation
Structural malformation
Foetal death
Functional impairment
Carcinogenesis
Example of a fetotoxic drug?
Any ACEI or ARB is fetotoxic
Causing Renal Dysfunction and growth retardation
How do we categorize the danger of a drug to a foetus?
A, B. C. D & X.
With A being good and X being bad
What does a drug of risk A mean?
Human studies show no foetal risk
What does a drug of Risk B mean?
Either:
- Animal studies safe & no human studies
- Animal studies risky but human studies safe
What does a drug of Risk C mean?
Either:
- No adequate studies
- Animal studies risky & no human studies
What does a drug of risk D mean?
Proven foetal risk in humans but sometimes outweighed by benefit
What does a drug of risk X mean?
Proven foetal risk is never outweighed by benefit
What about a drug promotes placental transfer?
Assume all will transfer to some extent but certain drugs are more easily absorbed into the foetal circulation:
- Smaller molecular weight
- Non-polar
- Lipid soluble
In what way are foetal Pharmacokinetics different to adults?
Distribution:
- Less protein –> more free drug
- Less fat –> more free drug
- More blood flow to brain
Metabolism:
- Less activity and different isoenzymes
Excretion:
- Excreted into amniotic fluid –> Swallowed –> Can be re-circulated
How does pregnancy affect the mothers Absorption of drugs?
Oral can be difficult with morning sickness
Gastric emptying and decreased gut motility can affect absorbed dose
Increased CO & increased tidal volume can increase absorption of inhaled drugs
How does pregnancy affect a woman’s distribution of drugs?
Increased Plasma & fat –> Increased Volume of Distribution (requires higher dose)
Increased plasma –> Lower proportion of proteins –> More free drug fraction
How does pregnancy affect a woman’s metabolism of drugs?
Oestrogen/progestogens affect P450 enzymes in the liver:
- Induces enzymes –> drop in phenytoin levels
- Inhibits others –> Rise in theophylline levels
How does pregnancy affect a woman’s Excretion of drugs?
GFR increases by 50% so renally cleared drugs are excreted faster
Name some major drug classes that should be avoided in pregnancy?
- Some anticonvulsants (phenytoin, carbamazepine & valproate)
- Warfarin
- ACEI/ARBs
- NSAIDs
- Alcohol
- Retinoids
Whats the major danger of NSAIDs in pregnancy?
Premature closure of the Ductus Arteriosus
Whats the major danger of warfarin in pregnancy?
Foetal or maternal Haemorrhage
Also teratogenic –> CNS/Skeletal malformations
