Pharmacology in Pregnancy & Breastfeeding

Question 1

Physiological changes during pregnancy affecting maternal pharmacokinetics (ADME)

Answer 1

ABSORPTION

* ORAL ROUTE - May be more difficult e.g. MORNING SICKNESS, NAUSEA/VOMITING + REDUCED GASTRIC EMPTYING & GUT MOTILITY - unlikely to be a problem w/ regular dosing, may affect single doses - however, not as much a problem as VOMITING
* IM ROUTE - INCREASED BLOOD FLOW - INCREASED ABSORPTION via IM route
* INHALATION - INCREASED CO & DECREASED TIDAL VOL. - INCREASED ABSORPTION of INHALED DRUGS

DISTRIBUTION

* INCREASED PLASMA VOL. & FAT = CHANGES DRUG DISTRIBUTION
* GREATER PLASMA DILUTION = DECREASES RELATIVE PLASMA PROTEINS = INCREASED FRACTION of FREE DRUG (plasma proteins bind to drug, making them inactive)

METABOLISM

• OESTROGEN & PROGESTROGENS = INDUCE/INHIBIT LIVER P450 ENZYMES = INCREASE/REDUCE METABOLISM e.g. reduced phenytoin lvls (metabolism induces), increased theophylline lvls (metabolism inhibited)

EXCRETION

• 50% GFR INCREASE in pregnancy = INCREASED EXCRETION of many DRUGS = can REDUCE [PLASMA], may req. INCREASED DOSE of RENALLY CLEARED DRUGS

Question 2

Physiological changes during pregnancy affecting maternal pharmacodynamics

Answer 2

• PREGNANCY MAY AFFECT SITE of ACTION & RECEPTOR RESPONSE to DRUGS

○ [DRUG], METABOLITES at SITES of BIOLOGICAL ACTION (CHANGES IN BLOOD FLOW)
○ MECHANISM of ACTION (CHANGES IN RECEPTORS)

• EFFICACY + ADVERSE EFFECTS MAY BE DIFFERENT

PLACENTAL TRANSFER:

* Depends on: MOLECULAR WGT. (smaller sizes cross more easily), POLARITY (non-polar cross more readily), LIPID SOLUBILITY (lipid-soluble drugs will cross)
* PLACENTA may also METABOLISE SOME DRUGS
* SAFEST to ASSUME ALL DRUGS CROSS PLACENTA + DEVELOPING FOETUS has MORE BLOOD FLOW to BRAIN and NO BBB (As it's still developing)

Question 3

Foetal pharmacokinetics (ADME)

Answer 3

DISTRIBUTION

* DIFFERENT CIRCULATION = e.g. umbilical vein - liver; when drugs pass through placenta they may go to amniotic fluid but more likely to go to umbilical vein, then foetal liver - which may metabolise drug & then release it into foetal circulation, this is then excreted into amniotic fluid, but foetus swallow that fluid, so drug lvls keep rising
* LESS PROTEIN BINDING than ADULTS = MORE FREE DRUG AVAILABLE
* LITTLE FAT = DIFFERENT DISTRIBUTION
* Relatively MORE BLOOD FLOW to BRAIN

METABOLISM

* LESS ENZYME ACTIVITY = INCREASES w/ GESTATION
* DIFFERENT ISOENZYMES to ADULTS

EXCRETION

* EXCRETION is INTO AMNIOTIC FLUID = this is SWALLOWED & can ALLOW RECIRCULATION
* DRUGS & METABOLITES can ACCUMULATE in AMNIOTIC FLUID
* PLACENTA NON-FUNCTIONING at DELIVERY = ISSUES w/ EXCRETORY FUNCTION

Question 4

Drug Effects during Different Trimesters

Answer 4

1ST TRIMESTER = TERATOGENICITY (early teratogenicity = tends to spontaneously miscarry) = structural defects

2ND & 3RD TRIMESTER = FETOTOXICITY = functional/growth defects

Question 5

Teratogenicity

Answer 5

BIGGEST RISK DURING ORGANOGENESIS (structural defects) = 3-8 weeks

6 Mechanisms:

Folate antagonism - DNA formation + new cell production; 2 groups of drug - blocks conversion of folate - THF by irreversibly binding to enzyme (methotrexate, trimethoprim) + blocks other enzymes in pathway (phenytoin, valproate) - risks = NTD, limb defect, oro-facial defect

Neural crest disruption - retinoid drugs e.g. isotretinoin - risks = aortic arch abnormalities, centricular septal defects, craniofacial malformations, oesophageal atresia, pharyngeal gland abnormalities - pregnancy test every 1-2 months + at least 1 form of contraception

Specific receptor/enzyme mediated teratogenesis - drugs interacting w/ enzymes for therapeutic effect can also interact w/ enzyme + receptors imp. for foetal development e.g. NSAIDs causing orofacial clefts, cardiac septal defects

Vascular disruption
Endocrine disruption
Oxidative stress

Question 6

Fetotoxicity

Answer 6

TOXIC EFFECT ON FOETUS LATER IN PREGNANCY

POSS. ISSUES

	○ GROWTH RETARDATION/RESTRICTION
	○ STRUCTURAL MALFORMATION
	○ FOETAL DEATH
	○ FUNCTIONAL IMPAIRMENT
	○ CARCINOGENESIS

Question 7

Drugs & Lactation

Answer 7

MOST DRUGS PRESENT IN LOWER DOSES THROUGH BREAST-FEEDING than IN-UTERO - so has to be v. toxic to have an effect, imp. to know conc, in breastmilk

	○ ALMOST EVERY DRUG WILL GO INTO BREASTMILK esp. if LIPID-SOLUBLE

NEONATE PHARMACOKINETICS DIFFERENT to that of a FOETUS

Question 8

Minimise drug exposure to neonate during lactation

Answer 8

• IS MATERNAL DRUG NECESSARY - IF YES, FIND SAFEST OPTION for INFANT
  
  • IF POSSIBILITY of HARM = MONITOR INFANT BLOOD LVLS of DRUG
  • MINIMISE INFANT EXPOSURE e.g. take immediately after infant breastfed, postpone drug treatment after baby is weaned, avoid breastfeeding during peak effect (avoid drug w/ long half-life/active metabolites, use highly protein bound drugs, CAUTION - SEVERELY ILL BABY, NEONATE, PRETERM)
  • USE NON-PHARMACOLOGICAL STRATEGIES WHEN POSS. e.g. MASSAGE

DO NOT USE HERBAL MEDICATIONS e.g. hepatotoxicity, hormonal effects, sedative effects

Question 9

Principles for Prescribing for Women of Child-Bearing Age

Answer 9

• ALWAYS CONSIDER POSSIBILITY of PREGNANCY (PLANNED/NOT)

• WARN WOMEN of POSS. RISKS
• WHEN TREATING MEDICAL CONDITION = ADVISE WOMEN to ATTEND BEFORE GETTING PREGNANT IF PLANNING TO (to optimise treatment) + CONTACT WHEN THEY WISH to GET PREGNANT
• DISCUSS CONTRACEPTION + WRITE IN NOTES
• IF NECESSARY = DON’T PRESCRIBE W/O CONTRACEPTION

Question 10

Principles of Prescribing in Pregnancy

Answer 10

RY NON-PHARMACOLOGICAL Rx 1ST

• USE DRUG w/ BEST SAFETY RECORD (avoid new drugs unless proven safe - once a drug starts being widely used, new effects are always found)
• CHECK SPC for MOST UP-TO-DATE INFO (SUMMARY of PRODUCT CHARACTERISTICS)
• USE LOWEST EFFECTIVE DOSE
• USE DRUG for SHORTEST AMOUNT of TIME, INTERMITTENTLY if POSS.
• AVOID 1ST 10 WEEKS of PREGNANCY if POSS.
• CONSIDER STOPPING/REDUCING DOSE BEFORE DELIVERY
• DON’T UNDER-TREAT DISEASE which may be HARMFUL to FOETUS e.g. avoid stopping drugs for chronic illness - depression etc.

SPECIALIST INPUT VITAL!! Esp. in CHRONIC ILLNESS

Question 11

Principles of Prescribing during Breastfeeding

Answer 11

• AVOID UNNECESSARY DRUG USE
• CHECK on UP-TO-DATE INFO - may be a LACK of INFO
• IF LICENSED & SAFE IN PAEDIATRIC USE = esp. < 2YRS, LIKELY TO BE SAFE IN BREASTFEEDING
• CHOOSE DRUGS w/ PHARMACOKINETIC PROPERTIES that REDUCE INFANT EXPOSURE e.g. HIGHLY PROTEIN-BOUND