Analgesics

Question 1

What are the 4 opioid receptor types?

Answer 1

1. Mu
2. Kappa
3. Delta
4. NOP (nociceptin)

Question 2

What type of receptor are opioid receptors?

Answer 2

All of these receptors are Gai/o-coupled, which means that binding of agonist decreases cAMP and inhibits inwardly rectifying K+ channels.

Question 3

Where do opioids inhibit? (2)

Answer 3

1. Inhibit the release of nociceptive signals peripherally and centrally
2. Complimentary control with other mechanisms & receptor systems

Question 4

What are the 4 most common endogenous opioids?

Answer 4

1. Enkephalin
2. Dynorphin
3. Substance P
4. Endorphin

Question 5

What are endogenous opioids? (3)

Answer 5

1. Short peptide molecules
2. Coded on genes as “pre-pro” peptides and subject to post-translational modifications
3. Released from synaptic vesicles

Question 6

What are exogenous opioids? (2)

Answer 6

1. Aminoalkylindole compounds naturally occurring in nature and synthesized de novo
2. Drugs and pro-drugs with variable PD and PK depending on drug and excipients

Question 7

How does acetaminophen work? (3)

Answer 7

1. CNS-selective cyclooxygenase inhibitor
2. Anandamide reuptake inhibitor (boosts endocannabinoid levels)
3. TRPV1 agonist

Question 8

How is acetaminophen metabolized?

Answer 8

Via CYP2E1, 3A4; UGTs

Question 9

What distinguishes endogenous opioids from exogenous opioid drugs?

Answer 9

Endogenous opioids are peptides

Question 10

Opioids and cannabinoids both do what same thing to limit pain perception?

Answer 10

Both inhibit neurotransmitter release from the pre-synaptic neuron

Question 11

How are NSAIDs metabolized?

Answer 11

Undergo Phase I metabolism (CYP2C9, 2D6) and are excreted in urine

Question 12

What are the major effects of mu receptors? (5)

Answer 12

1. Analgesia
2. Respiratory depression
3. Sedation
4. Euphoria
5. Constipation

Question 13

What is the main polymorphism seen in mu receptors? What does that lead to?

Answer 13

1. 118 AΔG
2. Lower analgesic response - greater consumption

Question 14

What are the major effects of the kappa receptors? (4)

Answer 14

1. Spinal analgesia
2. Respiratory depression
3. Sedation
4. Dysphoria

Question 15

What is the main polymorphism seen in kappa receptors? What does that lead to?

Answer 15

36 GΔT correlated with addictive potential and abuse liability

Question 16

What are the major effects of delta receptors? (2)

Answer 16

1. Dysphoria
2. Psychomimetic

Question 17

What is the main polymorphism seen in delta receptors? What does that lead to?

Answer 17

2 major SNPs, no effect

Question 18

Explain gene polymorphism in the PTSG gene when it comes to NSAID efficacy. (3)

Answer 18

1. Subjects homozygous GG for PTGS2 SNP2 demonstrated a better response to analgesic effect of rofecoxib compared with ibuprofen administration.
2. Subjects identified as GC or CC for PTGS2 SNP2 demonstrated a better response to ibuprofen.
3. PTGS2 polymorphisms influence the expression of PTGS1 and PTGS2 and consequently analgesic effect of NSAIDs.

Question 19

What is a poor metabolizer (PM) defined as?

Answer 19

At least 2 loss of function alleles

Question 20

What is an ultra metabolizer (UM) defined as?

Answer 20

At least 3 copies of functional alleles

Question 21

Polymorphisms that reduce metabolism may lead to what?

Answer 21

High drug concentration and reduced safety

Question 22

Polymorphisms that enhance drug metabolism may lead to what?

Answer 22

Will reduce drug efficacy and may be misconstrued as drug-seeking behaviour

Question 23

If drugs are pro-drugs or metabolism produces an active compound, then polymorphisms that increase metabolism will do what?

Answer 23

Will increase drug efficacy and ADRS and reduce safety

Question 24

If an individual is a CYP2D6 poor metabolizer they will take codeiene and experience:
a) Greater analgesia than a NM
b) Less analgesia than an NM
c) The same amount of analgesia compared to an NM
d) Far more constipation but no change in analgesia compared to an NM

Answer 24

b)

Question 25

If an individual is a CYP2E1 ultrametabolizer for acetaminophen, they are likely to experience?

Answer 25

Hepatotoxicity

Question 26

138 patients who underwent open abdominal surgery received continuous epidural analgesia with fentanyl or morphine. The distribution of the OPRM1 genotypes for the 118 A>G SNP was: 1. 41 (29.7%) for AA (normal MOR) 2. 70 (50.7%) for AG (less-functional MOR) 3. 27 (19.6%) for GG (poorly-functional MOR) What was the result for these patients?

Answer 26

The 24-hour postoperative opioid dose requirement was significantly higher in patients with the GG genotype compared to patients with the AG and the AA genotype for the OPRM1 (p <0.05)

Question 27

Pain management is critical in clinical practice because uncontrolled pain can: (5)

Answer 27

1. Delay healing, 2. Decrease appetite, 3. Introduce and augment stress, 4. Disturb sleep, 5. Lead to anxiety and depression

Question 28

True or False? Personalization of opioid therapy is very common

Answer 28

False - not widely practiced

Question 29

What are the 2 drugs and enzymes that are listed as 'actionable' when it comes to PK variability?

Answer 29

1. Codeine and CYP2D6 2. Tramadol and CYP2D6

Question 30

What is the drug and enzyme that is listed as 'moderately actionable' when it comes to PK variability?

Answer 30

Morphine and OPRM1

Question 31

What are the 4 drugs and enzymes that are listed as 'further research needed' when it comes to PK variability?

Answer 31

1. Oxycodone and CYP2D6 2. Hydromorphone and CYP2D6 3. Fentanyl and OPRM1 4. Methadone

Question 32

True or False? It is not practical at this time to test every patient for whom codeine is prescribed

Answer 32

True

Question 33

Two patients – both of whom have a history of narcotics use – are prescribed opioid-based medicines to manage their post-surgical in-hospital pain: - Patient 1 is prescribed fentanyl and they are found to be a CYP3A4 UM. - Patient 2 is prescribed codeine and they are found to be a CYP2D6 PM. During follow-up both patients complain that they are not receiving any benefit from their opioids and request a higher dose. You are concerned this is a drug seeking behaviour, but how else might their actions be explained?

Answer 33

1. Fentanyl is the active analgesic form. If ultra-metabolized then there is less of the active form so they will not experience analgesia. Could give them codeine. 2. Patient 2 has the opposite problem and could be given fentanyl for example.