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 receptor or enzyme/mediated teratogensis
- Sex Hormone disruption
- Oxidative Stress
- Vascular Disruption
In what two groups of drugs can disrupt the production of DNA and new cells by ANTAGONISING folate?
- Block the conversion of folate to THF by binding irreversibly to the enzyme (eg methotrexate, trimethoprim)
- Block other enzymes in the pathway (eg phenytoin, carbamazepine, valproate)
What defects does folate antagonism cause?
Defects in:
- Neural Tube
- Oro-facial
- Limb
What drugs can disrupt neural crest cells?
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 which inhibit or stimulate enzymes to produce therapeutic effects may also interact with specific receptors and enzymes damaging fetal development.
I.e. NSAIDs causing orofacial clefts and cardiac 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 categorise the danger of a drug to a foetus?
A, B. C. D and X - with A being good and X being bad
What does a drug of risk A mean?
Human studies show no foetal risk (these are safest drugs)
What does a drug of Risk B mean?
Animal studies safe and no human studies - animal studies show risk to foetus but human studies safe
What does a drug of Risk C mean?
No adequate studies or animal studies she risk and no human studies
What does a drug of risk D mean?
Proven foetal risk in humans but sometimes the benefit outweighs risk
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 enzyme 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 and increased tidal volume can increase absorption of inhaled drugs
- Blood flow increased, so absorption may also increase (intramuscular route)
How does pregnancy affect a woman’s distribution of drugs?
Increased plasma and fat –> increased Volume of Distribution (requires higher dose)
Increased plasma –> lower proportion of proteins due to dilutions –> increase fraction of free drug
How does pregnancy affect a woman’s metabolism of drugs?
Oestrogen and progestogens can induceor inhibit liver P450 enzymes, increasingor reducing metabolism.
- Phenytoin levels reduced (due to induction of metabolism)
- Theophylline levels increased (due to inhibition of metabolism)
How does pregnancy affect a woman’s Excretion of drugs?
GFR increases by 50% so renally cleared drugs are excreted faster
This can reduce the plasma concentration, and can necessitate an increase in dose of renally cleared drugs.
Name some major drug classes that should be avoided in pregnancy?
- Anticonvulsants (phenytoin, carbamazepine and valproate)
- Anticoagulants (warfarin)
- Antihypertensives (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 haemorrhage and multiple malformations in the CNS and skeletal system
What drugs should be avoided during breastfeeding?
- Cytotoxics
- Immunosuppressants
- Anti-convulsants (not all)
- Drugs of abuse
- 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?
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
- Choose drugs which reduce 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
What should you be thinking about when prescribing in Pregnancy?
- 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
