Pharmacogenomics and Pain- Heemer

Codeine is metabolized into what? using what enzyme?

codeine metabolized to morphine using CYP2D6 enzyme

If there is decreased metabolic capacity, then what is needed?

Decrease dose of substrate medication

If there is increased metabolic capacity, how will the patient respond?

• pt. not likely to respond to the medication

• there will not be therapeutic effect

• generally, need higher dose for therapeutic effect

What are the indications for codeine?

• mild-mod pain

• prevent/tx cough

___________ of codeine into morphine by CYP2D6 is a minor pathway in extensive metabolizers.

O-Demethylation

What metabolites of morphine have analgesic effect? which don’t?

• morphine-3-glucuronide: no analgesic effect

• morphine-6-glucuronide: analgesic effect

About 80% of codeine is converted to inactive metabolites using what methods?

Do the inactive metabolites have any analgesic effect?

• glucuronidation to codeine-6-glucoronide via UGT2B7

  • analgesic effect not known

• N-demethylation to norcodeine via CYP3A4

  • no analgesic effects

What response following codeine admin would be seen in:

• ultrarapid metabolizer of CYP2D6

• extensive metabolizer of CYP2D6

• intermediate metabolizer of CYP2D6

• poor metabolizer of CYP2D6

• ultrarapid metabolizer of CYP2D6

  • increased formation of morphine

• extensive metabolizer of CYP2D6

  • normal morphine formation

• intermediate metabolizer of CYP2D6

  • greatly reduced morphine formation

• a poor metabolizer of CYP2D6

  • decreased morphine levels

  • decreased analgesia levels

What do activity scores measure? ranges?

• measures how well a person’s enzymes (like CYP2D6) metabolize drugs

• AS ranges from 0 to 3.0

What do each of the following activity scores mean? (ex: poor, intermediate, extensive, or ultrarapid metabolize)

• AS= 0

• AS= 0.5 (now 0-1.25)

• AS= 1-2 (now 1.25-2.25)

• AS >2 (now >2.25)

(idk why she has both the old and updated ranges in there)

• AS= 0 —> poor metabolizer

• AS= 0.5 (now 0-1.25)—> intermediate metabolizer

• AS= 1-2 (now 1.25-2.25) —> extensive metabolizer

• AS >2 (now >2.25) —> ultrarapid metabolizer

What are the most common side effects of codeine?

• Drowsiness

• dizziness

• lightheadedness

• sedation

• n/v

What are the serious side effects of codeine?

• respiratory depression and arrest

• circulatory depression

• cardiac arrest

• shock

It’s recommended to use alternative agents in patients who CYP2D6:

a. poor metabolizers

b. extensive metabolizers

c. ultrarapid metabolizers

d. intermediate metabolizers

a, c

In addition to codeine, what other opioids are O-DEMETHYLATED by CYP2D6?

• Tramadol

• Hydrocodone

• Oxycodone (only about 11%—> minor CYP2D6 involvement)

What form of tramadol is responsible for opioid receptor-mediated analgesia?

O-desmethyltramadol (aka tramadol after its been o-demethylated)

What response following TRAMADOL admin would be seen in:

• poor metabolizers of CYP2D6

• ultrarapid metabolizers CYP2D6 compared to extensive metabolizers

• poor metabolizers of CYP2D6

  • decreased AUC-time curve of the active metabolite of tramadol

  • often no or decreased analgesia response to tramadol

  • reduced clinical efficacy of tramadol

• ultrarapid metabolizers CYP2D6 ompared to extensive metabolizers

  • higher plasma concentrations

  • greater analgesia

  • higher incidence of nausea

Hydrocodone via CYP2D6 is metabolized into _______________.

hydromorphone

Poor metabolizers have __ _________ after hydrocodone administration compared to extensive metabolizers.

a. lower concentration of hydromorphone

b. higher concentration of hydromorphone

c. no effect on hydromorphone concentration

a. Lower concentration of hydromorphone

CYP2D6 metabolizer phenotype may be affected by medications which __.

Inhibit CYP2D6 activity

A small amount of oxycodone is O-demethylated by CYP2D6 into what metabolite?

oxymorphone

If a patient is a poor metabolizer of oxycodone, what would happen to peak concentration of oxymorphone? (compared to extensive metabolizers)

LOWER peak concentrations

What other considerations with CYP2D6 need to be taken into account in addition to the patient’s phenotype?

• medications that inhibit CYP2D6 activity

• CYP2D6 may be increased during pregnancy

Do current CPIC guidelines make recommendations on whether or not to order test for genotypes?

no! (CPIC guidelines make recommendations on WHAT to do if you have the results)

PRACTICE:

For a pharmacogenetic test, it is important to have which of the following?

a) Appropriate consent

b) Clarification that the pharmacogenetic testing is voluntary

c) Confidentiality for test results

d) Established reliability of genetic tests

e) All of the above

e)

PRACTICE:

Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines make recommendations how to use genotypes for dosing if information about genotype is known.

a) True

b) False

a)