Pharmacology

Question 1

What is the biggest risk period for teratogenic drugs?

Answer 1

Organogenesis or weeks 3-8

Question 2

What are the major mechanisms of teratogenesis?

Answer 2

• Folate Antagonism (prevents DNA/cell formation)
• Neural Crest Cell Disruption
• Specific recepotr or enzyme/mediated teratogensis
• Sex Hormone disruption
• Oxidative Stress
• Vascular Disruption

Question 3

What drugs can disrupt the production of DNA and new cells by ANTAGONISING folate?

Answer 3

1-Bind to enzyme which converts folate to THF?
Methotrexate
Trimethoprim

2- Block other enzymes in pathway
Anti-convulsants:
- Phenytoin
- Carbamazepine
- Valproate

Question 4

What defects does folate antagonism cause?

Answer 4

• Neural Tube
• Oro-facial
• Limb

Question 5

What drugs can disrupt neural crest cells?

Answer 5

Notably Retinoids like isotretinoin

Question 6

What defects does Neural Crest Cell disruption cause?

Answer 6

• Aortic Arch anomalies
• Ventricular Septal Defects
• Craniofacial malformation
• Oesophageal atresia
• Pharyngeal Gland Abnormalities

Question 7

How does specific receptor/enzyme-mediated teratogenesis work?

Answer 7

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

Question 8

Some drugs are dangerous to the foetus in the 2nd/3rd trimester, i,e. fetotoxic instead of teratogenic. What issues can they cause?

Answer 8

Growth retardation
Structural malformation
Foetal death
Functional impairment
Carcinogenesis

Question 9

Example of a fetotoxic drug?

Answer 9

Any ACEI or ARB is fetotoxic

Causing Renal Dysfunction and growth retardation

Question 10

How do we categorize the danger of a drug to a foetus?

Answer 10

A, B. C. D & X.

With A being good and X being bad

Question 11

What does a drug of risk A mean?

Answer 11

Human studies show no foetal risk

Question 12

What does a drug of Risk B mean?

Answer 12

Either:

• Animal studies safe & no human studies
• Animal studies risky but human studies safe

Question 13

What does a drug of Risk C mean?

Answer 13

Either:

• No adequate studies
• Animal studies risky & no human studies

Question 14

What does a drug of risk D mean?

Answer 14

Proven foetal risk in humans but sometimes outweighed by benefit

Question 15

What does a drug of risk X mean?

Answer 15

Proven foetal risk is never outweighed by benefit

Question 16

What about a drug promotes placental transfer?

Answer 16

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

Question 17

In what way are foetal Pharmacokinetics different to adults?

Answer 17

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

Question 18

How does pregnancy affect the mothers Absorption of drugs?

Answer 18

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

Question 19

How does pregnancy affect a woman’s distribution of drugs?

Answer 19

Increased Plasma & fat –> Increased Volume of Distribution (requires higher dose)

Increased plasma –> Lower proportion of proteins –> More free drug fraction

Question 20

How does pregnancy affect a woman’s metabolism of drugs?

Answer 20

Oestrogen/progestogens affect P450 enzymes in the liver:

• Induces enzymes –> drop in phenytoin levels
• Inhibits others –> Rise in theophylline levels

Question 21

How does pregnancy affect a woman’s Excretion of drugs?

Answer 21

GFR increases by 50% so renally cleared drugs are excreted faster

Question 22

Name some major drug classes that should be avoided in pregnancy?

Answer 22

• Some anticonvulsants (phenytoin, carbamazepine & valproate)
• Warfarin
• ACEI/ARBs
• NSAIDs
• Alcohol
• Retinoids

Question 23

Whats the major danger of NSAIDs in pregnancy?

Answer 23

Premature closure of the Ductus Arteriosus

Question 24

Whats the major danger of warfarin in pregnancy?

Answer 24

Foetal or maternal Haemorrhage

Also teratogenic –> CNS/Skeletal malformations

Question 25

What drugs should be avoided during breastfeeding?

Answer 25

Immunosuppressants
Some Anti-convulsants
Amiodarone
Lithium
Radio-iodine

Question 26

What should you consider when prescribing to a woman of childbearing age?

Answer 26

• 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

Question 27

What else should you think about when prescribing to a breast feeding woman?

Answer 27

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

Question 28

Case - 35yr old overweight woman presents with new diagnosis of hypertension but wants to get pregnant in the next year, what do you do?

Answer 28

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

Question 29

Case - 17yr old girl with severe acne is offered Isotretinoin, what else should you think about?

Answer 29

Ensure shes on atleast 1 form of contraception and undergoes monthly pregnancy checks to avoid Neural crest Cell Disruption.

Actually demanded in the BNF