7. Variations in Drug Metabolism

Question 1

What factors can cause a variable biological response to drugs amongst patients?

Answer 1

There are several factors that affect drug handling in different patient groups, for example:

1 > Age, e.g. elderly patients are often volume deplete and so volume of distribution of drug may be decreased.

2 > Race, e.g. there is evidence that ACE inhibitors are less effective at treating heart failure in black patients than in white.

3 > Sex, e.g. men have higher levels of alcohol dehydrogenase than women

4 > Disease state, e.g. in liver disease decreased production of plasma. proteins may alter drug binding; cancer, obesity, heart failure and infection
among other things can alter the activity of drug-metabolising enzymes.

5 > Genetic polymorphism – see below.

Question 2

Explain how genetic polymorphism influences drug

metabolism. What clinical effects can this have?

Answer 2

This question is a clear lead into a discussion about suxamethonium apnoea, but do not forget about other drugs whose actions are also affected by the recipient’s genetics.

Genetic polymorphism is a term that describes the difference in people’s genotype and subsequent variation in phenotypic expression of these
genes. The enzymes that metabolise drugs are subject to genetic polymorphism, and so there can be differences between individuals in the
handling of the same drug.

Question 3

> Suxamethonium genetic variation

Answer 3

• Suxamethonium is broken down by plasma cholinesterases.
• These enzymes are coded for by autosomal genes on chromosome 3.

1. The normal phenotype is Eu (usual).
   A patient with Eu:Eu will break down suxamethonium rapidly so that its duration of action is around 2–6 minutes.

There are several variations of these genes and deviation from the normal means that the resulting enzyme’s activity is decreased.

Consequently, it takes longer to break down the suxamethonium and its duration of action is increased.

2. • Abnormal forms of the gene include Ea (atypical), Es (silent) and Ef (fluoride resistant).

• The most common abnormality is Ea:Eu.
This is carried by 4% of the Caucasian population, and their recovery time following suxamethonium is extended to around 30 minutes.
The incidence of this phenotype is higher in Asians and lower in Afro-Caribbeans.

Incidence and prolongation of block:
Ea:Ea 1/3000 ≥2 hours
Ef: Ef 1/100 000 ≥3 hours
Es:Es 1/250 000 ≥3 hours

Question 4

How would you manage someone with unexpected suxamethonium apnoea?

Answer 4

1. > The problem should be recognised by the lack of muscle contractions in response to supramaximal nerve stimulation applied several minutes
   after giving an intubating dose of suxamethonium.
2. > If the problem has gone unrecognised during surgery and anaesthesia is turned off at the end of the case, the patient’s heart rate and BP might
   rise as an indicator of awareness in the face of sustained paralysis.

3.
> The patient should remain anaesthetised and ventilated until they are able to take good tidal volumes independently.

4.
> FFP could be given theoretically to provide normal plasma cholinesterase. However, the risks of giving it cannot be justified in this situation, instead the patient should remain anaesthetised until the effects of suxamethonium have ‘worn off’.

5.
> The patient and their family should be referred for genetic testing
ascertain their phenotype and the extent of any abnormality

Question 5

How is the enzyme abnormality diagnosed?

Answer 5

The diagnosis and extent of the enzyme abnormality can be made using dibucaine.

> Dibucaine is a local anaesthetic agent that inhibits normal plasma cholinesterase by approximately 80%, but does not inhibit an abnormal enzyme as effectively.

> Benzylcholine is a substrate broken down by plasma cholinesterase.

> Benzylcholine is added to the plasma sample being tested and the degree of benzylcholine breakdown is measured.
If the plasma of a normal patient has benzylcholine solution added to it, it emits a certain wavelength of light, which can be measured.
If dibucaine is added to this solution the reaction is inhibited and so less light is emitted.
In patients with an abnormal enzyme, dibucaine does not inhibit the reaction as much and so light continues to be emitted.

> The dibucaine number is the percentage inhibition of benzylcholine breakdown by plasma cholinesterase in the presence of dibucaine.

A normal number is between 75 and 85, whereas abnormal homozygotes can have numbers as low as 30.

Question 6

Which other esterases are relevant to anaesthetic practice?

Answer 6

> Plasma esterases rapidly metabolise esmolol.
This non-saturatable enzyme system is responsible for esmolol’s short duration of action.

> Tissue and plasma esterases rapidly metabolise remifentanil. Again, this non-saturatable enzyme system ensures the rapid breakdown of
remifentanil and its context-insensitive half-life.

> Red blood cell esterases metabolise aspirin and diamorphine

Question 7

What other drugs are affected by genetic polymorphism?

Answer 7

> Mivacurium is also metabolised by plasma cholinesterase’s and so is subject to the same variations in metabolism as suxamethonium.

> The metabolism of codeine to morphine depends on the enzymes CYZ2D6 and 2C19.
There are three broad groups of codeine
metabolism:
• Poor metabolisers – get little symptomatic relief from codeine (1–7% of the Caucasian population)

• Extensive metabolisers – get good relief
• Ultra-extensive metabolisers – get very good relief and may be at risk of opioid toxicity (1–7% of the Caucasian population).

> Alcohol is broken down by alcohol dehydrogenase. The expression of this enzyme varies between sexes and races.
Men express more than women
and therefore can metabolise alcohol more rapidly. European races express an allele that makes their enzyme more active than that of Asians