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Anaesthetic FRCA Primary - eLFH Obstetrics > eLFH - Pharmacological changes during Pregnancy > Flashcards

eLFH - Pharmacological changes during Pregnancy Flashcards

1
Q

Four pharmacokinetic phases of drug handling

A

Absorption
Distribution
Elimination
Metabolism

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2
Q

Definition of tmax

A

Time to maximum plasma plasma drug concentration

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3
Q

Definition of Cmax

A

Maximum plasma drug concentration

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4
Q

Effect of pregnancy on oral drug absorption

A

Decreased gut motility

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

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5
Q

Effect of pregnancy on IM drug absorption

A

Increased blood flow through muscle

Speeds up absorption of IM drugs
Reduced tmax
Increased Cmax

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6
Q

Hormone responsible for decrease in gut motility

A

Progesterone - peaks in third trimester

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7
Q

Factors in pregnancy responsible for increasing volume of distribution of drugs

A

Increased extracellular fluid
Increased adipose tissue

Decreased serum alpha1 acid glycoprotein
Decreased serum albumin

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8
Q

Volume of increase in extracellular fluid by third trimester

A

6-8L

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9
Q

Effect of extracellular fluid in drug distribution

A

Increased fluid leads to increased dilution of hydrophilic drugs

Thus increases volume of distribution

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10
Q

Effect of adipose tissue in drug distribution

A

Average 4kg increase will sequester lipophilic drugs

Thus increases volume of distribution

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11
Q

Effect of alpha1 acid glycoprotein in drug distribution

A

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

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12
Q

Effect of albumin in drug distribution

A

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

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13
Q

Effect of pregnancy on elimination of drugs

A

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

Pregnancy decreases biliary elimination (cholestatic effects of oestrogens)

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14
Q

Drug examples which have pulmonary elimination

A

Sevoflurane

Nitrous oxide

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15
Q

When will anaesthetic agents have higher elimination in pregnancy

A

When women are spontaneously ventilation

Elimination will not be increased in mechanically ventilated women

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16
Q

Drug examples which have renal elimination

A

Atenolol

Digoxin

Lithium

Ampicillin

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17
Q

Drug examples which have biliary elimination

A

Rocuronium

Rifampicin

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18
Q

Aspects of drug metabolism to consider in pregnancy

A

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

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19
Q

Effect of pregnancy on hepatic blood flow

A

Increased hepatic blood flow

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20
Q

Effect of increased hepatic blood flow on drug metabolism

A

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

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21
Q

Effect of pregnancy on Phase 1 - oxidative metabolism

A

Varied changes in hepatic cytochrome P450 activity
Eg:

Increased CYP3A4 and CYP2D6 activity

Decreased CYP1A2 activity

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22
Q

Role of CYP3A4 and CYP2D6

A

Responsible for metabolism of around half of all pharmacological agents

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23
Q

Role of CYP1A2

A

Metabolises caffeine

24
Q

Effect of pregnancy on Phase 2 - conjugation

A

Increased

Eg increased activity of UGT2B7 and UGT1A4

25
Q

Role of UGT2B7

A

Glucuronidation of morphine

Increased in pregnancy

26
Q

Role of UGT1A4

A

Glucuronidation of lamotrigine

Increased in pregnancy

27
Q

Effect of pregnancy on extra hepatic metabolism

A

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

28
Q

Effect of pregnancy on metabolism of suxamethonium

A

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

29
Q

Five mechanisms of placental transfer

A

Simple diffusion
Facilitated diffusion
Active transport
Receptor mediated endocytosis
General pinocytosis

30
Q

Most common mechanism of drug transfer across placenta

A

Simple diffusion

31
Q

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

A
32
Q

Factors which increase simple diffusion

A

Higher concentration gradients

Increased diffusion surface area

Permeability to drug

Shorter diffusion distance

Placental binding

33
Q

Factors which increase permeability of drug

A

Small molecular weight
High lipid solubility
Increased drug in unionised form

34
Q

Molecular weight at which molecules freely diffuse through placenta

A

< 400-500 daltons

35
Q

Molecular weight at which placenta becomes impermeable

A

> 1000 daltons

36
Q

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

A

Heparin
Protamine

37
Q

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

A

Abruption
HTN
Infarction
Intrauterine infection
Diabetes

38
Q

Diffusion layers in the placenta

A

Maternal blood in intervillous space

Foetal trophoblast

Foetal capillary endothelium

Foetal blood

39
Q

What makes up foetal trophoblast

A

Cytotrophoblast
Syncytiotrophoblast

40
Q

Pathologies which increase diffusion distance in the placenta

A

Abruption
HTN
Infarction
Intrauterine infection
Diabetes

(Same as pathologies which reduce surface area)

41
Q

Factors which affect foetal distribution of drug which crosses placenta

A

Foetal circulation

42
Q

Foetal cerebral blood flow

A

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

43
Q

Foetal pulmonary blood flow

A

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

44
Q

Foetal hepatic blood flow

A

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
45
Q

Foetal placental shunt

A

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

46
Q

Factors affecting teratogenicity of a drug

A

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

47
Q

Effect of plasma protein binding on drug transfer across placenta

A

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

48
Q

Foetal drug metabolism

A

Oxidative metabolism develops in first trimester

Sulphation is well developed

Glucuronidation poorly developed even at birth

Greater proportion of metabolism is extra hepatic

49
Q

Relevance of metabolic products in foetal circulation

A

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

50
Q

Total body water percentage by gestation of foetus

A

94% by mass at 16 weeks

76% at term

Higher TBW increases volume of distribution of hydrophilic drugs and lowers serum concentration

51
Q

Body fat of the foetus by gestation

A

Adipose tissue only laid down in 3rd trimester

Foetuses <1 kg have essentially no fat

52
Q

CNS myelination of foetus and relevance for drug metabolism

A

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

Eg phenytoin

53
Q

Foetal elimination of drugs

A

Primarily via placenta

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

54
Q

Recirculation of drugs from foetal elimination

A

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

55
Q

M:F ratio

A

Materno:Foetal ratio

Ratio of uterine vein concentration to umbilical vein concentration

Used to describe degree of placental transfer of drugs

56
Q

Factors which impact M:F ratio

A

Time since drug dose given to mother

Elimination rate in mother

Transfer rate to foetus

Elimination rate in foetus

Anaesthetic FRCA Primary - eLFH Obstetrics (6 decks)

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