Pharm - Variations in Drug Metabolism

Question 1

What factors cause variable biological response to drugs amonst patients?

Answer 1

• Age e.g. elderly have a lower Vd
• Race e.g. ACEI less effective in heart failure for afrocarribean than european descent
• Sex e.g. men have higher levels alcohol dehydrogenase than women
• Disease state e.g. liver disease-decreased plasma proteins may alter freely available drug concentration
• Genes e.g. sux apnoea

Question 2

How does genetic polymorphism influence drug metabolism?

Answer 2

Genetic polymorphism is a term to describe variations in genotype which subsequently affects expression and phenotype. Enzymes that metabolise drugs are subject to genetic polymorphism, so there can be differences in was an individual handles a drug.

An example of this is suxamethonium apnoea.
- Suxamethonium is broken down by plasma cholinesterases
- The enzymes are coded for by autosomal genes on chromosome 3. The normal genotype is Eu (u is for usual), and a patient with Eu:Eu will break down suxamethonium rapidly and so the duration will be 2-6 minutes
- Other variations include Ea (atypical), Es (silent), Ef (fluoride resistant) –> an individual with these genes will take longer to break down suxamethonium and so the duration of action will be increased
- The most common abnormality is Ea:Eu, expressed in 4% of caucasians. Recovery from suxamethonium can take 30 minutes. Incidence is higher in asians and lower in afrocarrbeans.
- Ea:Ea takes >2 hrs, 1/3000
- Ef:Ef takes >3 hrs, 1/100 000
- Es:Es takes >3hrs, 1.250 000

Question 3

How would you manage someone with suxamethonium apnoea?

Answer 3

1. Identify - pre-op assessment or lack of muscle contraction to supramaximal nerve stimulation applied several minutes after intubating dose of suxamethonium
2. Avoid - only identifying when anaesthetic has worn off and patient is aware but paralysed (BP and HR high but no movement)
3. Maintain - anaesthetic and ventilation until patient is able to maintain good tidal volumes independently
4. Refer - family and patient for genetic testing

Question 4

How is suxamethonium apnoea diagnosed on gene testing?

Answer 4

• Dibucaine testing

Dibucaine is a local anaesthetic that inhibits normal plasma cholinesterase by 80% but is less effective against abnormal plasma cholinesterase
Benzylcholine is broken down by plasma cholinesterase and in doing so emits a certain wavelength of light

Mixtures of plasma, dibucaine and benzycholine are passed under a light detector. Higher levels of light emission signify less inhibition of plasma cholinesterase, which indicates abnormal enzyme.

The dibucaine number is the percentage inhibition of benzylcholine breakdown by plasma cholinesterase. Normal numbers are 75-85, but homozygotes for abnormal enzyme can have as low as 30.

Question 5

Tell me about other esterases

Answer 5

Esterases are non specific enzymes and so involved in several metabolic reactions

For example:
1. Red cell esterases metabolise aspirin and diamorphine
2. Plasma esterases metabolise esmolol - this is a non saturatable reaction and is responsible for esmolol’s short duration of action
3. Tissue and plasma esterases rapidly metabolise remifentanil. The non saturatable enzyme system ensures short duration and context-insensitive half life.
4. Mivacurium is metabolised by plasma cholinesterases and is also subject to genetic polymorphisms.

Question 6

What drugs are subject to genetic polymorphisms?

Answer 6

1. Suxamethonium
2. Mivacurium
3. Codeine (metabolised to morphine by CYZ2D6 and CY2C19 - there are poor metabolisers, extensive metabolisers and ultra-sensitive metabolisers)
4. Alcohol (variations in alcohol dehydrogenase expression)