Pharmacology Flashcards
What is the biggest risk period for teratogenic drugs? [1]
Organogenesis -weeks 3-8
What are the major mechanisms of teratogenesis? [6]
Folate Antagonism (prevents DNA/cell formation)
Neural Crest Cell Disruption
Specific receptor or enzyme/mediated teratogenesis
Sex Hormone disruption
Oxidative Stress
Vascular Disruption
What drugs can disrupt the production of DNA and new cells by antagonizing folate? [4]
What defects does folate antagonism cause? [3]
MTX
Trimethoprim
Anti-convulsants:
- Phenytoin
- Carbamazepine
- Valproate
- Neural Tube
- Oro-facial
- Limb
What drugs can disrupt neural crest cells? [2]
Notably Retinoids like isotretinoin
What defects does Neural Crest Cell disruption cause? [5]
- Aortic Arch anomalies
- Ventricular Septal Defects
- Craniofacial malformation
- Oesophageal atresia
- Pharyngeal Gland Abnormalities
How does specific receptor/enzyme-mediated teratogenesis work? Give one example of a drug and its teratogenic effects
Drugs designed to inhibit/stimulate an enzyme or receptor can have negative 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? [5]
Functional impairment Growth retardation Structural malformation Carcinogenesis Foetal death
Example of a fetotoxic drug [2] and what problems do they cause [2]
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 and 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 and 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 and 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
Assume all will transfer to some extent but certain drugs are more easily absorbed into the foetal circulation. Name 3 factors
- 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?
2 problems with oral route
1 difference to be considered with intramuscular route
1 difference with inhalation drugs
Oral can be difficult with morning sickness
Gastric emptying and increased gut motility can affect absorbed single > regular doses
Intramuscular route: increased blood flow so increased absorption
Inhalation - Increased CO and decreased tidal volume can increase absorption of inhaled drugs
How does pregnancy affect a woman’s Distribution of drugs? [2]
Increased Plasma and fat –> Increased Volume of Distribution > Requires higher dose)
Increased plasma –> Lower proportion of proteins –> free drug fraction increased
How does pregnancy affect a woman’s metabolism of drugs? What 2 groups of drugs can this affect?
Oestrogen/progestogens affect P450 enzymes in the liver:
- Induces enzymes –> drop in phenytoin levels
- Inhibits others –> Rise in theophylline levels (COPD, asthma)
How does pregnancy affect a woman’s Excretion of drugs? [1]
GFR increases so renally cleared drugs are excreted faster
Name 6 major drug classes that should be avoided in pregnancy? Give one example and its associated teratogenic effect.
- Anticonvulsants (phenytoin, carbamazepine, valproate > NTDs)
- Anticoagulants eg warfarin - hemorrhage + malformations
- Antihypertensives -ACEI/ARBs - renal damage, growth restriction
- NSAIDs - premature closure of ductus arteriosus
- Alcohol - FAS
- Retinoids - ear, CNS, CVS and skeletal malformations
Whats the major danger of warfarin in pregnancy?
Foetal or maternal Haemorrhage
Also teratogenic –> CNS/Skeletal malformations
What drugs should be avoided during breastfeeding? [5]
Immunosuppressants Some Anti-convulsants Amiodarone Lithium Radio-iodine
What should you consider when prescribing to a woman of childbearing age? [4]
- Are they pregnant?
- Warn of risks and advise re-attending should they decide to get pregnant
- Contraception?
- Can you treat non-pharmacologically?
What else should you think about when prescribing to a breast feeding woman? [2]
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? [2]
What do you normally give but what are the associated dangers? [2]
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 at least 1 form of contraception and undergoes monthly pregnancy checks to avoid Neural crest Cell Disruption.
What are 4 prescribing practices in pregnant women?
NB Don’t under treat a disease that could damage the foetus
- Use lowest effective dose
- Use shortest treatment possible
- If possible avoid 1st 10 wks of pregnancy
- If possible stop or reduce before delivery
