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pharm 4001 > Lecture 4- Adjunct Analgesics 2 > Flashcards

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
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2
Q

6 families of TRP channels and their agonists

A
  1. TRPA: Ankyrin
  2. TRPP: Polycistin
  3. TRPC: Canonical
  4. TRPM: Melastatin
  5. TRPML: Mucolipin
  6. TRPV: Vanilloids
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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.
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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
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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
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6
Q

Endogenous ligands of TRPV1

A
  • Anandamide
  • Endovanilloids
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7
Q

Exogenous ligands of TRPV1

A
  • Capsaicin
  • resiniferatoxin
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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
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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

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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
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11
Q

Exogenous ligands

A
  • menthol
  • icilin
  • spearmint
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12
Q

Photocannabinoids

A
  • derived from Cannabis plant
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13
Q

Synthetocannabinoids

A

man made

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14
Q

endocannabinoids

A
  • present naturally in the body
  • ex: Anandamide
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15
Q

2 cannabinoid receptors

A
  1. CB1 receptors
    * located on central and peripheral nerves
  2. CB2 receptors
    * associated with immunocytes
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16
Q

Sites of action of cannabinoids

A
  1. Peripheral nervous system
  2. Dorsal horn of spinal cord
  3. 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

pharm 4001 (9 decks)

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