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
What drugs should be avoided during breastfeeding?
Immunosuppressants Some Anti-convulsants Amiodarone Lithium Radio-iodine
What should you consider when prescribing to a woman of childbearing age?
- Are they pregnant?
- Warn of risks and advise re-attending should they decide to get pregnant
- Contraception?
- Can you treat non-pharmacologically?
- Use lowest effective dose
- Use shortest treatment possible
- If possible avoid 1st 10 wks of pregnancy
- If possible stop or reduce before delivery
Don’t under treat a disease that could damage the foetus
What else should you think about when prescribing to a breast feeding woman?
If its licensed and safe for paeds (particularly <2yrs) its probably fine for breastfeeding
Pick something that reduces infant exposure e.g. a highly protein-bound drug
Case - 35yr old overweight woman presents with new diagnosis of hypertension but wants to get pregnant in the next year, what do you do?
Normally you’d give an ACEI but they can cause renal dysfunction and growth retardation.
Start with non-pharmacological treatments such as weight loss
Then discuss an alternative anti-hypertensive
Case - 17yr old girl with severe acne is offered Isotretinoin, what else should you think about?
Ensure shes on atleast 1 form of contraception and undergoes monthly pregnancy checks to avoid Neural crest Cell Disruption.
Actually demanded in the BNF
