Pharmacology in Pregnancy and Breast Feeding

Question 1

Aprox 50-90% of pregnant women take a medicine during pregnancy

Many pregnancies are unplanned (80% of women of child-bearing age take medication)

Should consider the effect on _________ when prescribing for any women of childbearing age

Answer 1

pregnancy

Question 2

Why may a women be on medicine during pregnancy, childbirth and lactation?

Answer 2

Hypertension

Asthma

Epilepsy

Migraine

Mental health disorders

Long term anticoagulant therapy use

Question 3

Physiological changes during pregnancy have implications for drug therapy and may affect any of the four basic kinetic processes namely:

Answer 3

absorption, distribution, metabolism and elimination, excretion

Question 4

Pharmacokinetic in pregnancy – processes of _________, ________, ________ and _______ – very few pharmacokinetic studies in pregnancy so data is very limited

Answer 4

absorption

distribution

metabolism

excretion

Question 5

what absorption changes happen during pregnancy through the oral route?

Answer 5

May be more difficult “morning sickness” nausea/vomiting

Decrease in gastric emptying and gut motility – this is unlikely to be a problem with regular dosing, but may affect single doses

Question 6

what absorption changes happen during pregnancy through the intramuscular route?

Answer 6

blood flow may be increase, so absorption may also increase using this route

Question 7

what absorption changes happen during pregnancy through the inhalation?

Answer 7

increased cardiac output and decreased tidal volume may cause increased absorption of inhaled drugs

Question 8

how may distribution change in pregnancy?

Answer 8

Increase in plasma volume and fat will change distribution of drugs – increase Vd (volume of distribution)

Greater dilution of plasma will decrease relative amount of plasma proteins – increase fraction of free drug (Free drug which is pharmacodynamically active)

Question 9

what metabolism changes happen in pregnancy?

Answer 9

Oestrogen and progestogens can induce or inhibit liver P450 enzymes, increasing or reducing (drug) metabolism

Examples – phenytoin levels reduced (due to induction of metabolism), theophylline levels increased (due to inhibition of metabolism)

Question 10

what excretion changes happen in pregnancy?

Answer 10

GFR is increased in pregnancy by 50% leading to increased excretion of many drugs. (and reduction in circulating drug levels so may need increase in dose)

This can reduce the plasma concentration, and can necessitate an increase in dose of medicine cleared by the kidney

Question 11

Summary picture showing how absorption, distribution, metabolism and excretion are effected in pregnancy

Answer 11

Question 12

Pharmacodynamics describe what……

Answer 12

the drug does to the body

Question 13

Pharmacokinetics describes what………..

Answer 13

body does to the drug

Question 14

what pharmacodynamic changes happen in pregnancy?

Answer 14

Less well understood

Pregnancy may affect the site of drug action and the receptor response to drug:

• Concentration of drug, metabolites at sites of biological action (changes in blood flow)
• Mechanism of action (changes in receptors)

Efficacy may be different

Adverse effects may be different

Question 15

During pregnancy most drugs can cross the placenta. Factors affecting placental drug transfer and drug effects on the featus include what?

Answer 15

Drug physiochemical properties

Rate at which drug crosses placenta and amount reaching fetus

Duration of drug exposure

Distribution of drug exposure

Distribution in different foetal tissues

Stage of placental and foetal development

Effects of drugs when used in combination

Question 16

placental transfer of drugs depend on what?

Answer 16

molecular weight (smaller sizes will cross more easily)

polarity (unionised molecules cross more readily)

lipid solubility (lipid soluble drugs will cross)

Question 17

Placenta may also _______ some drugs

Safest to assume all drugs will _____ placenta

Answer 17

metabolise

cross

Question 18

Foetal Pharmacokinetics

how is distribution different in the foetus?

Answer 18

Circulation is different (e.g. umbilical vein to liver)

Less protein binding than adults therefore more “free” drug available

Little fat, so distribution different

Relatively more blood flow to brain

Question 19

Foetal Pharmacokinetics

how is metabolism different in the foetus?

Answer 19

Reduced enzyme activity, although this increases with gestation

Fetus exhibits different P450 isoenzymes to adults

Question 20

Foetal Pharmacokinetics

how is excretion different in the foetus?

Answer 20

Excretion is into amniotic fluid – which the foetus swallow leading to recirculation

Drugs and metabolites can accumulate in amniotic fluid (can cause toxicity to the foetus)

Placenta not functioning at delivery so can be issues with excretory function

Question 21

Teratogenicity (____ trimester) – an agent that can disturb the development of the embryo or fetus

Fetotoxicity (________ and _____ trimester)

Answer 21

first

second

third

Question 22

Don’t ________ a chronic illness due to fear of using drugs during pregnancy that may cause _______ foetal risk

Answer 22

undertreat

greater

Question 23

What are the principles of prescribing for women of child-bearing age (not always pregnant)

Answer 23

Always consider possibility of pregnancy (planned or not!)

Warn women of possible risk

When treating medical conditions, advise women to attend before getting pregnant if planning to (optimise treatment)

Discuss contraception

If necessary, do not prescribe without contraception

Question 24

whata re the Principles of prescribing in pregnancy?

Answer 24

If you can, try non-pharmacological treatment first

Use the drug with the best safety record (avoid new unless proven safe)

Check the SPC (Summary product characteristics) for the most upto date information

Use lowest effective dose

Use the drug for the shortest time possible, intermittently if possible

Avoid in the first 10 weeks of pregnancy if possible

Consider stopping or reducing dose before delivery

Never under treat a disease which may be harmful to the mother or foetus

Question 25

_Teratogenicity:_ * Drugs responsible for 2% of foetal abnormalities * Highest risk is during organogenesis (3-8 weeks) what different mechanisms of harm may there be?

Answer 25

Folate antagonism Neural crest cell disruption Endocrine disruption: sex hormones Oxidative stress Vascular disruption Specific receptor or enzyme mediated teratogenesis

Question 26

what is Folate antagonism?

Answer 26

Key process in DNA formation and new cell production Two groups of drugs affect folate metabolism: - Block the conversion of folate to THF by binding irreversibly to the enzyme (eg methotrexate, trimethoprim) - Block other enzymes in the folate pathway (e.g. phenytoin, carbamazepine, valproate) Tend to result in neural tube, oro-facial or limb defects

Question 27

What may cause Neural Crest Cell Disruption and what problems may there be?

Answer 27

* Retinoid drugs (e.g. isotretinoin – cant be used unless patient is on contraception) * Problems – aortic arch abnormalities, ventricular septal defects, craniofacial malformation, oesophageal atresia, pharyngeal gland abnormalities

Question 28

what is Enzyme-mediated teratogenesis?

Answer 28

* Drugs which inhibit or stimulate enzymes to produce therapeutic effects may also interact with specific receptors and enzymes damaging foetal development * Example – NSAIDS causing orofacial clefts and cardiac septal defects

Question 29

what is fetotoxicity?

Answer 29

* Toxic effects on the foetus later in pregnancy * Possible issues: growth retardation, structural malformations, foetal death, functional impairment, carcinogenesis * Example – ACE inhibitors/ARBS cause renal dysfunction and growth retardation

Question 30

what are the issues with drugs and lactation?

Answer 30

* Almost all drugs the mother takes will be present in breast milk * Important to know what concentration will be in breast milk * Remember pharmacokinetics are different in neonate compared to the foetus

Question 31

How do you ensure minimal exposure to the neonate to drugs form breast milk?

Answer 31

* Is maternal drug necessary? If yes, then what is the safest option for the infant * If there is the possibility of harm, monitor infant blood levels of the drug * Minimize infant exposure * If possible minimise drug treatment until the baby in weaned * Une non-pharmacological treatments when possible * If it needs be used then it should be taken right after feeding the baby * Avoid breast feeding during peak drug effect – avoid drugs with long half life, drugs that are highly protein bound are preferred as less likely to dissolve in the lipid component of breast milk, caution if baby severely ill or preterm as full metabolism excretion wont be established

Question 32

are herbal medicines safe in pregnancy and breast feeding?

Answer 32

Herbal medicine can cause harm and almost half of pregnant women use herbal medicines Breast feeding mothers should avoid herbal medicines due to the lack of information and contamination of herbal products with conventional medicines, pesticides or heavy metals Some herbal medicines also have hormonal effects and some may contain constituents with sedative properties

Question 33

what are the principles for prescribing in breast feeding?

Answer 33

* Again avoid unnecessary drug use * Check on up to date drug information – may be lack of information * In licensed and safe in paediatric use (esp under 2 years), a drug is likely to be safe in breast feeding * Choose drugs with pharmacokinetic properties that reduce infant exposure (e.g. highly protein bound, short half-life, low lipid solubility)