PK and pregnancy

Question 1

Which physiological changes in pregnancy are relevant to PK? (cardiovascular changes)

Answer 1

To meet the needs of the gestating foetus/placenta and demands of the uterus.
To deliver oxygen to meet the needs of the pregnancy, there must be an increase in cardiac output.

Question 2

How is cardiac output calculated?

Answer 2

cardiac output (CO) = stroke volume x heart rate 
(An increase in cardiac output of 50% by the end phase of pregnancy). 

Heart rate increases (by 15-25%)

systematic vascular resistance decreases
(more blood is pumped out on each contraction of the heart. This is achieved through the vasodilatory effects of progesterone and oestrogen on vascular smooth muscle).

Question 3

Which physiological changes in pregnancy are relevant to PK? (respiratory changes)

Answer 3

The increased demand for oxygen and need for excretion of waste products (CO2) necessitates a change in the respiratory system. Airway resistance is reduced, mediated by progesterone driven smooth muscle relaxation.
This increases the amount of air that can go in and out of the lungs. The respiratory rate also increases – caused by an increased sensitivity to CO2

Question 4

Which physiological changes in pregnancy are relevant to PK? (GI changes)

Answer 4

Gastric emptying and intestinal motility are reduced

Question 5

Which physiological changes in pregnancy are relevant to PK? (Liver changes)

Answer 5

Increased Cardiac output increases blood flow through the liver
= Reduced protein concentration = changes to enzyme levels

Question 6

Which physiological changes in pregnancy are relevant to PK? (renal system)

Answer 6

Increase in cardiac output leads to an increase in glomerular filtration

Question 7

Absorption
What is the most likely effect of delayed gastric emptying and reduced intestinal motility?

Answer 7

Delayed gastric emptying may reduce the time taken for the drug to be absorbed and (Tmax).
Cmax is unlikely to be higher (may be lower).
AUC should not be affected since the total amount of drug absorbed is likely to be the same/similar

Question 8

Absorption:
What is the most likely effect of delayed gastric emptying and reduced intestinal motility?

Answer 8

Delayed gastric emptying may reduce the time taken for the drug to be absorbed and (Tmax).
Cmax is unlikely to be higher (may be lower).
AUC should not be affected since the total amount of drug absorbed is likely to be the same/similar

Question 9

Distribution:
What is the most likely effect of increased volume of distribution?

Answer 9

Dilutional effect

(may be important for drugs with significant concentration dependent pharmacodynamics)

Question 10

What is the definition of clearance?

Answer 10

Volume of blood cleared of drug per unit time

Question 11

The hepatic extraction ratio

Answer 11

(Ca - Cv/ Ca) x Qh = hepatic extraction ratio

Ca - concentration of drug in drug in blood delivered to the liver

Cv - concentration of drug in blood leaving the liver

Question 12

Definition of hepatic extraction ratio

Answer 12

The fraction of the drug in the blood entering the liver that is irreversibly removed during one pass of the blood through the liver

Question 13

What are the three significant factors of hepatic clearance (CLh)

Answer 13

• Fraction of unbound drug (fu)
• Intrinsic ability of liver to clear drug (intrinsic clearance, Cl int)
• Blood flow (Qh)

Question 14

Roland’s equations

Answer 14

ClH = Qh. (fu.CLint/Qh + fu . Cl int)

Question 15

List examples of drugs with high extraction ratio

Answer 15

Morphine
Lidocaine
Verapamil
Propanolol
Nicotine

Question 16

List examples of drugs with low extraction ratio

Answer 16

Warfarin
Phenytoin

Question 17

CYP450 and pregnancy - methadone

Answer 17

Methadone is an opioid with a long half-life.
It is used to treat pain and opioid withdrawal.
Its metabolised to inactivate metabolites via CYP3A4
In pregnancy this may reduce half life from 24 hrs to 12 hrs.

Question 18

What is Fh (hepatic bioavailability)?

Answer 18

The fraction of dose delivered to the liver that reaches the systemic circulation unchanged

FH = 1 - fu. CLint/Qh + fu. Clint

Question 19

Extraction ratio, ER

Answer 19

The fraction of the drug in the blood entering the liver that is irreversibly removed during one pass of the blood through the liver

ER = fu. CLint/Qh + fu. Clint

Question 20

AUCoral =

Answer 20

AUC oral = F dose / CL = Dose . Fg/fu . Cl int

Question 21

The effect of protein binding on clearance for non-hepatically cleared drugs

Answer 21

Question 22

Phenytoin and pregnancy

Answer 22

Phenytoin is an anti-epileptic, highly protein bound

It has a low extraction ratio

So in pregnancy the total drug concentration will be reduced

(Total drug concentrations will be decreased but free will remain the same)

Question 23

Low molecular weight heparin (anti-thrombotic drugs) in pregnancy

Answer 23

Cleared by renal excretion

In pregnancy the increase in blood flow to the kidneys increases GFR

LMWH concentrations reduced

So in pregnancy LMWH is dosed twice a day (instead of once)

Question 24

Give examples of other drugs with enhanced clearance in pregnancy

Answer 24

Penicillins

Digoxin

Metformin

Lithium

Question 25

P-glycoprotein expression in pregnancy

Answer 25

P-glycoprotein expression is upregulated

In addition to the increased flow/filtration,

also enhanced intrinsic clearance of the organ

Question 26

Define teratogenic effect

Give examples

Answer 26

persistent structural or functional adverse effects due to the influence of the drug on foetal development

• Alter chromosomes
• Prevent implantation
• Cause foetal death or abortion
• Growth retardation

Question 27

Drug distribution and metabolism in the foetus

Answer 27

• Relatively high brain blood flow
• Developing blood brain barrier
• Relative scarcity of metabolizing enzymes in the foetus