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Obstetric IAC > Pharmacological changes during pregnancy > Flashcards

Pharmacological changes during pregnancy Flashcards

1
Q

In pregnancy, gut motility is decreased - how does this affect oral bioavailability, tmax and Cmax?

A

Transit of drugs to and through the small bowel is slowed.

This does not affect total oral bioavailability, the drug is absorbed more slowly and over a longer period of time:

tmax (time to maximum plasma drug concentration) is increased

Cmax (maximum plasma drug concentration) is lower

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2
Q

What happens to tmax and Cmax in IM injection in pregnancy?

A

Blood flow is increased to muscle so this will speed absorption of IM drugs.

tmax is decreased

Cmax is increased

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3
Q

Is the effects of pregnancy on oral and IM absorption more important in acute or chronic treatments?

A

It’s more important in a single dose, because in chronic treatments as steady state concentration will have been achieved.

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4
Q

Which of the changes of pregnancy are responsible for increased volume of distribution?

A
  • increased extracellular water
  • increased body fat
  • decreased serum alpha1 acid glycoprotein
  • decreased serum albumin
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5
Q

How many litres does extracellular water increase by in the 3rd trimester? How does this affect hydrophilic drugs?

A

6-8L which increases dilution of hydrophilic drugs, thus increasing their Vd

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6
Q

How much does body fat increase by in pregnancy, and how does this affect lipophilic drugs?

A

About 4kg - this sequesters lipophilic drugs, increasing their volume of distribution

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7
Q

How does the decrease in alpha1 acid glycoprotein and serum albumin in pregnancy affect volume of distribution?

A

Both α1 acid glycoprotein and albumin are important drug binding proteins.

α1 acid glycoprotein has high affinity low capacity binding sites for basic drugs in particular, whilst albumin has various low affinity high capacity binding sites for a large variety of agents.

For highly protein bound drugs, falling protein concentrations will decrease total serum concentration and Vd will increase as the free drug equilibrates across compartments.

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8
Q

How does pregnancy affect elimination of durgs excreted via the kidney, lungs and bile?

A

Elimination via kidney and lungs is increased.

Biliary excretion falls.

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9
Q

How are rifampicin and rocuronium excreted? What happens in pregnancy?

A

Biliary excretion.

In pregnancy biliary excretion falls - decreased elimination as a result of cholestatic effects of oestrogens.

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10
Q

Why is renal excretion increased in pregnancy?

A

Due to increased renal blood flow, GFR and tubular secretion.

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11
Q

Why is pulmonary elimination increased in pregnancy?

A

Due to increased alveolar ventilation - more rapid elimination of anaesthetic agents in sponanteously breathing patients (not ventilated ones though).

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12
Q

What happens to hepatic blood flow in pregnancy?

A

It’s markedly increased in pregnancy.

Most drugs are metabolized by hepatic enzyme systems working well below their maximum rate, therefore clearance depends upon the rate of delivery of drug to the liver.

Clearance rises in line with the increasing hepatic blood flow.

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13
Q

What effect does pregnancy have on Phase 1 (oxidative metabolism)?

A

Changes in cytochrome P450

  • increased CYP3A4 and CYP2D6 (responsible for metabolism of about 1/2 of all pharmacological agents)
  • decreased activity of CYP1A2, which metabolizes caffeine
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14
Q

What effects does pregnancy have on Phase 2 metabolism (conjugation)?

A

Often increased.

Eg glucuronidation of morphine and lamotrigine

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15
Q

What effect does pregnancy have on extra hepatic metabolism?

A

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

Little clinical effect on duration of action of suxamethonium in patients with normal underlying enzyme activity.

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16
Q

What effects does pregnancy have on pharmacogenetics?

A

10-20% of the population are genetically predisposed to reduced enzyme activity which may decrease further in pregnancy.

Eg patients with variants of plasma cholinesterase that have reduced activity against sux may have clinically prolongation of action

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17
Q

What is the most important of the mechanisms for placental transfer?

A

Simple diffusion

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18
Q

What will cause increased diffusion rate across the placenta?

A
  • basic drugs pKa about 7.4 (the closer the pKa is to body pH, more will be unionized in the lipid soluble form - eg opioids and local anaesthetics)
  • low molecular weight of drug
  • increased placental surface area
  • high lipid solubility of drug
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19
Q

What will cause decreased diffusion across the placenta?

A
  • low materno:fetal drug concentration gradient
  • drug highly ionized at body pH
  • increased diffusion distance
20
Q

What is the equation for rate of diffusion from mother to foetus?

A

Q/t = kA (Cm - Cf) / D

k = drug permeability

A = surface area available for diffusion

(Cm - Cf) is the materno-fetal concentration gradient of free drug

D is diffusion distance

21
Q

What size of molecules can diffuse freely through the placenta?

A

400-500 daltons.

Above 1000 daltons the placenta becomes impermeable.

22
Q

What drugs cannot cross the placenta?

A

Large highly ionized compounds such as heparin and protamine.

23
Q

What is the surface area of the placenta?

A

It has a villous structure.

Surface area of approx 11m2

Surface area for exchange is only 1.8m2

24
Q

What is the area of the placenta for exchange decreased by?

A
  • abruption
  • hypertension
  • infarction
  • intrauterine infection
  • diabetes
25
Q

What are the diffusion layers of the placenta?

A
  • maternal blood in intervillous space
  • fetal trophoblast (made of cytotrophoblast and syncytiotrophoblast)
  • fetal capillary endothelium
  • fetal blood
26
Q

How does maternal blood reach the placenta bed?

A

Through the uterine spiral arteries

27
Q

How does a fall in maternal BP affect the perfusion of the placenta?

A

It’s not autoregulated so it will be reduced

28
Q

What happens in placental failure?

A

Many pregnancy-associated co-morbidities lead to a degree of chronic placental failure, such as:

  • pre-eclampsia
  • pregnancy induced HTN
  • diabetes
  • postmaturity

It’s associated with decreased placental perfusion and reduced drug transfer.

If the placenta acutely fails severe foetal hypoxia results.

29
Q

How does binding affect the placenta?

A

Binding decreases the amount transferred to the foetus and increases the time to equilibration

30
Q

What is the metabolic activity of the placenta?

A
  • placenta is an active tissue consuming oxygen and metabolising glucose, lipids, low density lipoproteins (LDLs) and proteins
  • possesses enzymes so has the potential to biotransform drugs, usually only at low rates
31
Q

What are the placental factors affecting drug transfer across the placenta?

A
  • placental blood flow
  • surface area of exchange
  • diffusion distance
  • placental binding
  • placental metabolism
32
Q

What are the drug factors affecting drug transfer across the placenta?

A
  • molecular size
  • lipid solubility
  • ionisation
  • protein binding
  • molecular configuration
33
Q

How much drug reaches the lungs in the foetus?

A
  • fetal pulmonary blood flow is very low
  • very little blood/drug reaches the lungs
  • this compares with an IV bolus in an adult/child where 100% passes through the lungs
34
Q

What is the blood flow to the liver in the foetus?

A
  • from the umbilical vein
    • 60-80% of blood flows to the liver with the potential for 1st pass metabolism before draining into the IVC
    • 20-40% bypasses the liver via the ductus venosus directly to the IVC
  • once in the IVC the umbilical venous blood is diluted by venous return from the lower extremities and splanchnic bed
35
Q

What is the placental shunt?

A
  • 50-60% of fetal blood returns to the placenta without perfusing fetal tissues
  • this will increase the fetal drug concentration at the placenta and so decrease further diffusion from the maternal circulation
36
Q

How does drug pass from maternal to fetal circulation?

A

Maternal blood surrounds each placental villous. Free drug diffuses along the concentration gradient between maternal and fetal blood.

37
Q

Where is blood flow highest in the fetus?

A
  • cerebral blood flow is highest as a proportion of cardiac output
  • large proportion of drug will be delivered to the brain
  • fetal hypoxia increases cerebral blood flow further
  • however hypoxia is usually a result of poor placental perfusion so drug transfer is low
38
Q

How does plasma protein binding affect the fetus?

A

Plasma protein binding is low for both albumin and α1 acid glycoprotein, therefore free plasma proportion is higher.

Free drug equilibrates across the placenta.

For highly protein bound drugs, total plasma concentration in the fetus is lower when the free concentration is the same as maternal blood.

39
Q

When does organ metabolism develop in the fetus?

A
  • oxidative metabolism develops in the 1st trimester
  • sulphation is well developed
  • glucuronidation is poorly developed, even at birth
  • a greater proportion of metabolism is extra hepatic
  • metabolic products in the foetus can have crossed from mother so detection doesn’t guarantee organ function
40
Q

What is the total body water at 16 weeks gestation?

A

94% by mass

41
Q

What is the total body water at term?

A

76%

42
Q

What does a high total body water do?

A

Increases the volume of distribution of hydrophilic drugs and reduce their serum concentration.

43
Q

How much body fat does a foetus have?

A

Fat is laid down only in 3rd trimester.

Fetuses <1kg have no fat.

44
Q

Is CNS myelination high or low in the fetus?

A

It’s low - so decreased binding of lipophilic drugs.

45
Q

Where does fetal elimination occur?

A
  • the placenta is primary organ of elimination
  • secondary organs
    • renal
    • intestinal
    • skin (permeable to water in fetus)
  • recirculation
    • all 2ndry organs excrete into amniotic fluid, a proportion of which is swallowed by the fetus
    • any previously excreted compounds can be absorbed from the gut will then recirculate in the fetus
46
Q

What is the M:F ratio?

A

The materno:fetal ratio. The ratio of uterine vein concentration to umbilical vein concentration.

It’s a ratio of total concentrations, so is dependent upon differences in protein binding as well as ease of placental transfer.

Not fixed for any drug (depends on time since given to mother, elimination rate in mother, transfer rate to fetus, elimination rate in fetus).

47
Q
A

Obstetric IAC (9 decks)

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