eLFH - Pharmacological changes during Pregnancy

Question 1

Four pharmacokinetic phases of drug handling

Answer 1

Absorption
Distribution
Elimination
Metabolism

Question 2

Definition of tmax

Answer 2

Time to maximum plasma plasma drug concentration

Question 3

Definition of Cmax

Answer 3

Maximum plasma drug concentration

Question 4

Effect of pregnancy on oral drug absorption

Answer 4

Decreased gut motility

Oral bioavailability is the same but more slowly absorbed over longer period of time
Increased tmax
Reduced Cmax

Question 5

Effect of pregnancy on IM drug absorption

Answer 5

Increased blood flow through muscle

Speeds up absorption of IM drugs
Reduced tmax
Increased Cmax

Question 6

Hormone responsible for decrease in gut motility

Answer 6

Progesterone - peaks in third trimester

Question 7

Factors in pregnancy responsible for increasing volume of distribution of drugs

Answer 7

Increased extracellular fluid
Increased adipose tissue

Decreased serum alpha1 acid glycoprotein
Decreased serum albumin

Question 8

Volume of increase in extracellular fluid by third trimester

Answer 8

6-8L

Question 9

Effect of extracellular fluid in drug distribution

Answer 9

Increased fluid leads to increased dilution of hydrophilic drugs

Thus increases volume of distribution

Question 10

Effect of adipose tissue in drug distribution

Answer 10

Average 4kg increase will sequester lipophilic drugs

Thus increases volume of distribution

Question 11

Effect of alpha1 acid glycoprotein in drug distribution

Answer 11

Drug binding protein
High affinity low capacity binding sites for basic drugs

For highly protein bound drugs, lower protein concentrations leads to decreased total serum concentrations and increased volume of distribution as free drug equilibrates across compartments

Question 12

Effect of albumin in drug distribution

Answer 12

Drug binding protein
Various low affinity high capacity binding sites for variety of drugs

For highly protein bound drugs, lower protein concentrations leads to decreased total serum concentrations and increased volume of distribution as free drug equilibrates across compartments

Question 13

Effect of pregnancy on elimination of drugs

Answer 13

Pregnancy increases renal and pulmonary elimination (increased renal blood flow / GFR and minute ventilation)

Pregnancy decreases biliary elimination (cholestatic effects of oestrogens)

Question 14

Drug examples which have pulmonary elimination

Answer 14

Sevoflurane

Nitrous oxide

Question 15

When will anaesthetic agents have higher elimination in pregnancy

Answer 15

When women are spontaneously ventilation

Elimination will not be increased in mechanically ventilated women

Question 16

Drug examples which have renal elimination

Answer 16

Atenolol

Digoxin

Lithium

Ampicillin

Question 17

Drug examples which have biliary elimination

Answer 17

Rocuronium

Rifampicin

Question 18

Aspects of drug metabolism to consider in pregnancy

Answer 18

Hepatic blood flow
Phase 1 (oxidative metabolism)
Phase 2 (conjugation)
Extra hepatic metabolism
Pharmacogenetics

Question 19

Effect of pregnancy on hepatic blood flow

Answer 19

Increased hepatic blood flow

Question 20

Effect of increased hepatic blood flow on drug metabolism

Answer 20

Most drugs metabolised by hepatic enzyme systems working far below their maximum rate

Therefore clearance depends on rate of delivery of drug to liver

Therefore clearance increases with increasing hepatic blood flow

Question 21

Effect of pregnancy on Phase 1 - oxidative metabolism

Answer 21

Varied changes in hepatic cytochrome P450 activity
Eg:

Increased CYP3A4 and CYP2D6 activity

Decreased CYP1A2 activity

Question 22

Role of CYP3A4 and CYP2D6

Answer 22

Responsible for metabolism of around half of all pharmacological agents

Question 23

Role of CYP1A2

Answer 23

Metabolises caffeine

Question 24

Effect of pregnancy on Phase 2 - conjugation

Answer 24

Increased

Eg increased activity of UGT2B7 and UGT1A4

Question 25

Role of UGT2B7

Answer 25

Glucuronidation of morphine Increased in pregnancy

Question 26

Role of UGT1A4

Answer 26

Glucuronidation of lamotrigine Increased in pregnancy

Question 27

Effect of pregnancy on extra hepatic metabolism

Answer 27

Plasma cholinesterase activity decreases by 25% in pregnancy, and by 33% immediately post partum

Question 28

Effect of pregnancy on metabolism of suxamethonium

Answer 28

Little clinical effect on duration of action of suxamethonium in patients with normal underlying enzyme activity, despite the decrease in plasma cholinesterase activity

Question 29

Five mechanisms of placental transfer

Answer 29

Simple diffusion Facilitated diffusion Active transport Receptor mediated endocytosis General pinocytosis

Question 30

Most common mechanism of drug transfer across placenta

Answer 30

Simple diffusion

Question 31

Equation for rate of diffusion from mother to foetus (Q/t)

Answer 31

Question 32

Factors which increase simple diffusion

Answer 32

Higher concentration gradients Increased diffusion surface area Permeability to drug Shorter diffusion distance Placental binding

Question 33

Factors which increase permeability of drug

Answer 33

Small molecular weight High lipid solubility Increased drug in unionised form

Question 34

Molecular weight at which molecules freely diffuse through placenta

Answer 34

< 400-500 daltons

Question 35

Molecular weight at which placenta becomes impermeable

Answer 35

> 1000 daltons

Question 36

Example of large highly ionised drugs which don't cross placenta

Answer 36

Heparin Protamine

Question 37

Pathologies which decrease area of villous structure of placenta available for diffusion

Answer 37

Abruption HTN Infarction Intrauterine infection Diabetes

Question 38

Diffusion layers in the placenta

Answer 38

Maternal blood in intervillous space Foetal trophoblast Foetal capillary endothelium Foetal blood

Question 39

What makes up foetal trophoblast

Answer 39

Cytotrophoblast Syncytiotrophoblast

Question 40

Pathologies which increase diffusion distance in the placenta

Answer 40

Abruption HTN Infarction Intrauterine infection Diabetes (Same as pathologies which reduce surface area)

Question 41

Factors which affect foetal distribution of drug which crosses placenta

Answer 41

Foetal circulation

Question 42

Foetal cerebral blood flow

Answer 42

Highest proportion of cardiac output Cerebral blood flow increased by foetal hypoxia

Question 43

Foetal pulmonary blood flow

Answer 43

Very low - especially compared to adults where 100% blood passes through lungs

Question 44

Foetal hepatic blood flow

Answer 44

From umbilical vein: - 60-80% blood flows through liver with potential for 1st pass metabolism before entering IVC - 20-40% bypasses liver via ductus venosus directly to IVC

Question 45

Foetal placental shunt

Answer 45

50-60% of foetal blood returns to the placenta without perfusing foetal tissues due to placental shunt In context of drug passing across the placenta, this increases foetal blood concentration of drug so decreases further diffusions from maternal circulation

Question 46

Factors affecting teratogenicity of a drug

Answer 46

If a drug has teratogenic potential, its effect on foetus depends on gestational age and the organogenesis that is in progress at that point

Question 47

Effect of plasma protein binding on drug transfer across placenta

Answer 47

Plasma protein binding is low for albumin and alpha1 acid glycoprotein, therefore free plasma proportion of drug is higher It is free drug that equilibrates across placenta and through foetal compartments

Question 48

Foetal drug metabolism

Answer 48

Oxidative metabolism develops in first trimester Sulphation is well developed Glucuronidation poorly developed even at birth Greater proportion of metabolism is extra hepatic

Question 49

Relevance of metabolic products in foetal circulation

Answer 49

Metabolic products of drug may have crossed placenta from mother so does not demonstrate organ function

Question 50

Total body water percentage by gestation of foetus

Answer 50

94% by mass at 16 weeks 76% at term Higher TBW increases volume of distribution of hydrophilic drugs and lowers serum concentration

Question 51

Body fat of the foetus by gestation

Answer 51

Adipose tissue only laid down in 3rd trimester Foetuses <1 kg have essentially no fat

Question 52

CNS myelination of foetus and relevance for drug metabolism

Answer 52

CNS myelination is low so there is reduced binding of lipophilic drugs Eg phenytoin

Question 53

Foetal elimination of drugs

Answer 53

Primarily via placenta Secondary organs are: Renal Intestinal Skin (permeable to water in foetus)

Question 54

Recirculation of drugs from foetal elimination

Answer 54

All secondary organs excrete into amniotic fluid Some amniotic fluid is swallowed by foetus If any previously excreted drug compounds can be absorbed by gut then it will recirculate in the foetus

Question 55

M:F ratio

Answer 55

Materno:Foetal ratio Ratio of uterine vein concentration to umbilical vein concentration Used to describe degree of placental transfer of drugs

Question 56

Factors which impact M:F ratio

Answer 56

Time since drug dose given to mother Elimination rate in mother Transfer rate to foetus Elimination rate in foetus