Lecture 4- Adjunct Analgesics 2 Flashcards
1
Q
Transient receptor potential channels (TRPs)
A
- named after their role in phototransudction of fruit-flies
- >30 TRPs, 6 families
- molecular sensors of taste, touch, temperature, and pain
2
Q
6 families of TRP channels and their agonists
A
- TRPA: Ankyrin
- TRPP: Polycistin
- TRPC: Canonical
- TRPM: Melastatin
- TRPML: Mucolipin
- TRPV: Vanilloids
3
Q
Thermosensitive TRP channels
A
- open and close within very specific temperature ranges
- can also be activated by chemicals in food and environment
- ex: mint acts on TRPM8, has a cooling sensation, TRPM8 is activated by low temps.
4
Q
capsaicin
A
- hot part of chilli peppers
- acts on sensory nerves
- –> initial sensitatization –> prolonged desensitization
- receptor is TRPV1
- applied to nerve —> immediate burst response (sensitization) —> prolonged desensitization (stops firing)
- ex: eat some spicy shit, things are really hot at the beginning when you first taste it but is less severe at the end —> channels are desensitized
5
Q
TRPV1
A
- the chilli receptor
- expressed on C-fibres and A𝛿 fibres
- also found in laminae I and II of spinal cord (consistent with C and A𝛿 fibres expression)
- non-selective cation channel
- acute low concentration –> sensitization –> desensitization (Ca2+-dependent phosphorylation of ion channel)
- prolonged exposure/high concentration –> destruction of C-fibres and A𝛿 fibres
- destruction recovers in adults, nerve loss permanent when given to neonates
6
Q
Endogenous ligands of TRPV1
A
- Anandamide
- Endovanilloids
7
Q
Exogenous ligands of TRPV1
A
- Capsaicin
- resiniferatoxin
8
Q
Therapeutic potential of TRPV1
A
- topical creams: OCT
- 8% capsaicin patch: approved for neuropathic pain, 30-60min
- Patients not using oral analgesics reported greater pain relief compared to those using oral medications
- Topical capsaicin creams (A535) —> weak
- patches —> need to be heavily sedated because you’re killing the nerves
ADVERSE EFFECTS
- skin irritation
- burning
- edema
9
Q
AMG517
A
- excellent TRPV1 antagonist for treatment of inflammatory pain
- highly potent
- selective
- oral bioavailability
Phase 1 clinical trial
- systemic TRPV1 blockade
- concentration dependent hyperthermia
- blocked thermoregulatory centres in CNS
- withdrawn, still no TRPV1 antagonist in clinical use
patients started becoming hyperthermic
unwanted side effect —> was also blocking TRPV1 in CNS
withdrawn, not used clinically
10
Q
TRPM8
A
- the cool TRP
- member of the “Melastatin” TRP family
- non-selective cation channel
- expressed on 15% of small diameter sensory neurons
- expression increases in neuropathic pain
- neuropathic pain + prodding the paw —> animal feels pain, responds at a lower threshold
- treated with icilin, reduces the pain
11
Q
Exogenous ligands
A
- menthol
- icilin
- spearmint
12
Q
Photocannabinoids
A
- derived from Cannabis plant
13
Q
Synthetocannabinoids
A
man made
14
Q
endocannabinoids
A
- present naturally in the body
- ex: Anandamide
15
Q
2 cannabinoid receptors
A
- CB1 receptors
* located on central and peripheral nerves - CB2 receptors
* associated with immunocytes
16
Q
Sites of action of cannabinoids
A
- Peripheral nervous system
- Dorsal horn of spinal cord
- Supraspinal regions
17
Q
Cannabinoid action at the peripheral nervous system
A
CB1 Agonist on Joint
- ACEA = CB1 agonist
- reduced pain response when given
18
Q
Cannabinoid action at the spinal cord/dorsal horn
A
- inhibits calcium channels —> reduces excitatory NT
- opening of K+ channels —> hyper polarization —> less likely to fire in response to noxious input
19
Q
Cannabinoid action at the supraspinal region
A
- cognitive perception: receptors in brain
- receptors in amygdala: emotional perception of pain
- activation of C receptors can activate descending inhibition, dampens down the signal transmission at the SC level
20
Q
Endocannabinoid synthesis
A
- similar to PG synthesis
- through phospholipids —> PLC —> endocannabinoids
21
Q
Endocannabinoid degradation
A
- one limitation: only produced during tissue damage/injury/inflammation (only on demand)
- don’t hang around long enough
- broken down by FAAH
22
Q
Can the Endocannabinoid System be Exploited for the Management of Arthritis Pain?
Effect of FAAH Inhibition on OA Joint Mechanosensitivity
A
- Block FAAH: accumulation of endocannabinoids at site
- EX: give FAAH inhibitor (URB597) when no inflammation —> no decrease in pain
- give FAAH inhibitor when there is inflammation —> less pain
23
Q
Can Endocannabinoids Alter Joint Inflammation?
A
Leukocyte trafficking
- given URB597, less leukocytes, reduced inflammation
- Inhibition of Endocannabinoid Breakdown Reduces Joint Inflammation
24
Q
Summary
A
- Synthetic cannabinoids can reduce nociception in arthritic joints locally
- Local inhibition of endocannabinoid breakdown reduces nociception and inflammation
- Endocannabinoid system may be an effective way to control arthritis pain and inflammation naturally
25
Q
clinical use of cannabinoids
A
- mostly for arthritis
26
Q
Dronabinol
A
- syntheti THC
- oral capsule
- approved for chemotherap-induced nausea and vomiting and anorexia associated with HIV/AIDS
27
Q
Nabilone
A
- synthetic THC
- oral capsule
- approved for chemotherapy-induced nausea and vomiting and anorexia associated with HIV/AIDS
28
Q
Nabiximols
A
- 50/50 THC: CBD
- oralmucosal spray
- MS associated neuropathic pain, spasticity, and advanced cancer pain
29
Q
Herbal cannabis
A
- various levels of CBs, terpenes, flavinoids
- smoked, vapourized, ingested, oils, topicals
- no formal approval
30
Q
advantages and disadvantages of smoking cannabis
A
Advantages
- rapid pain relief
- improved sleep
- reduced anxiety
- easy to titrate
Disadvantages
- not appropriate for all patients
- psychotropic side effests
- not safest mode of administration
- various levels of cannabinoids and non-cannabinoid chemicals
31
Q
THC and CBD levels in cannabis strains
A
- all over da place
- Average: 17.5% THC, 0.3% CBD
*
32
Q
Published RCTs using cannabinoids
A
33
Q
Ingestion of cannabis
A
- no respiratory irritation
- slower onset of effect
- difficult to titrate best dose
