Analgesics Flashcards
What are the 4 opioid receptor types?
- Mu
- Kappa
- Delta
- NOP (nociceptin)
What type of receptor are opioid receptors?
All of these receptors are Gai/o-coupled, which means that binding of agonist decreases cAMP and inhibits inwardly rectifying K+ channels.
Where do opioids inhibit? (2)
- Inhibit the release of nociceptive signals peripherally and centrally
- Complimentary control with other mechanisms & receptor systems
What are the 4 most common endogenous opioids?
- Enkephalin
- Dynorphin
- Substance P
- Endorphin
What are endogenous opioids? (3)
- Short peptide molecules
- Coded on genes as “pre-pro” peptides and subject to post-translational modifications
- Released from synaptic vesicles
What are exogenous opioids? (2)
- Aminoalkylindole compounds naturally occurring in nature and synthesized de novo
- Drugs and pro-drugs with variable PD and PK depending on drug and excipients
How does acetaminophen work? (3)
- CNS-selective cyclooxygenase inhibitor
- Anandamide reuptake inhibitor (boosts endocannabinoid levels)
- TRPV1 agonist
How is acetaminophen metabolized?
Via CYP2E1, 3A4; UGTs
What distinguishes endogenous opioids from exogenous opioid drugs?
Endogenous opioids are peptides
Opioids and cannabinoids both do what same thing to limit pain perception?
Both inhibit neurotransmitter release from the pre-synaptic neuron
How are NSAIDs metabolized?
Undergo Phase I metabolism (CYP2C9, 2D6) and are excreted in urine
What are the major effects of mu receptors? (5)
- Analgesia
- Respiratory depression
- Sedation
- Euphoria
- Constipation
What is the main polymorphism seen in mu receptors? What does that lead to?
- 118 AΔG
- Lower analgesic response - greater consumption
What are the major effects of the kappa receptors? (4)
- Spinal analgesia
- Respiratory depression
- Sedation
- Dysphoria
What is the main polymorphism seen in kappa receptors? What does that lead to?
36 GΔT correlated with addictive potential and abuse liability
What are the major effects of delta receptors? (2)
- Dysphoria
- Psychomimetic
What is the main polymorphism seen in delta receptors? What does that lead to?
2 major SNPs, no effect
Explain gene polymorphism in the PTSG gene when it comes to NSAID efficacy. (3)
- Subjects homozygous GG for PTGS2 SNP2 demonstrated a better response to analgesic effect of rofecoxib compared with ibuprofen administration.
- Subjects identified as GC or CC for PTGS2 SNP2 demonstrated a better response to ibuprofen.
- PTGS2 polymorphisms influence the expression of PTGS1 and PTGS2 and consequently analgesic effect of NSAIDs.
What is a poor metabolizer (PM) defined as?
At least 2 loss of function alleles
What is an ultra metabolizer (UM) defined as?
At least 3 copies of functional alleles
Polymorphisms that reduce metabolism may lead to what?
High drug concentration and reduced safety
Polymorphisms that enhance drug metabolism may lead to what?
Will reduce drug efficacy and may be misconstrued as drug-seeking behaviour
If drugs are pro-drugs or metabolism produces an active compound, then polymorphisms that increase metabolism will do what?
Will increase drug efficacy and ADRS and reduce safety
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
b)
If an individual is a CYP2E1 ultrametabolizer for acetaminophen, they are likely to experience?
Hepatotoxicity
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?
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)
Pain management is critical in clinical practice because uncontrolled pain can: (5)
- Delay healing,
- Decrease appetite,
- Introduce and augment stress,
- Disturb sleep,
- Lead to anxiety and depression
True or False? Personalization of opioid therapy is very common
False - not widely practiced
What are the 2 drugs and enzymes that are listed as ‘actionable’ when it comes to PK variability?
- Codeine and CYP2D6
- Tramadol and CYP2D6
What is the drug and enzyme that is listed as ‘moderately actionable’ when it comes to PK variability?
Morphine and OPRM1
What are the 4 drugs and enzymes that are listed as ‘further research needed’ when it comes to PK variability?
- Oxycodone and CYP2D6
- Hydromorphone and CYP2D6
- Fentanyl and OPRM1
- Methadone
True or False? It is not practical at this time to test every patient for whom codeine is prescribed
True
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?
- 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.
- Patient 2 has the opposite problem and could be given fentanyl for example.
