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Pharmacology II > Adjuncts and Pain > Flashcards

Adjuncts and Pain Flashcards

1
Q

Transient Receptor Potential Channels (TRPs) : how many families? They are the molecular sensors of what?

A

6 families

Molecular sensors of taste, touch, temperature and pain

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2
Q

What are the 6 families of TRPs?

A 
TRPVs (Vanilloids)
TRPA (Ankyrin)
TRPPs (Polycistin)
TRPCs (Canonical)
TRPMs (Melastatin)
TRPMLs (Mucolipin)
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3
Q

Which TRP is sensitive to garlic, horseradish and cinnamon?

A

TRPA1

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4
Q

Which TRP is sensitive to Mint?

A

TRPM8

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5
Q

Which TRP is sensitive to BAA?

A

TRPV4

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6
Q

Which TRP is sensitive to Camphor?

A

TRPV3 and TRPV1

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7
Q

Which TRP is sensitive to Chili and garlic on top of camphor?

A

TRPV1

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8
Q

Put these TRPs in order of who is sensitive to the coolest to the hottest temperature :
TRPM8, TRPV4, TRPV3, TRPV2, TRPA1, TRPV1

A 
Coolest
TRPA1
TRPM8
TRPV4
TRPV3
TRPV1
TRPV2
Hottest
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9
Q

What is the hot component of chilli peppers? Where do they act?

A

Capsaicin

They act of sensory nerves

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10
Q

What is the MOA of Capsaicin?

A

Initial sensitization of the nerve, then a prolonged desensitization

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11
Q

What type of receptor is the capsaicin receptor? Where are they expressed?

A

TRPV1

Expressed on C-fibres and A-delta fibres

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12
Q

6 activators of TRPV1?

A 
Capsaicin
Endogenous agonists
Acidosis
Heat
Na
Ca
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13
Q

Is TRPV1 a selective or non-selective cation channel?

A

non-selective

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14
Q

Endogenous ligands of TRPV1? (2)

Exogenous ligands? (2)

A

Anandamine
Endovanilloids

Capsaicin
Resiniferatoxin

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15
Q

What happens when acute low concentrations activate TRPV1s?

A

Ca-dependent phosphorylation of ion channels, depolarization and action potential into the sensory neuron and pain, eventual desensitization

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16
Q

What happens when prolonged exposure or high concentrations act on TRPV1s?

A

Ca overload, mitochondrial dysfunction, destruction of nerves (C and A-delta fibres)

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17
Q

Two therapeutic potentials of TRPV1?

What are the adverse effects?

A

Topical capsaicin creams
8% capsaicin patch
Effects: skin irritation, burning, oedema

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18
Q

Example of a TRPV1 antagonist? What does is treat?
Low potency or high potency?
Selective or non-selective?

Why did it get withdrawn from clinical trials?

A

AMG517, treats inflammatory pain

Highly potent
Selective

Withdrawn because is caused concentration-dependent hyperthermia that lasted days and blocked the thermoregulatory centres in the CNS

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19
Q

TRPM8:
Selective or non-selective?
Where is it expressed?
Expression increases in models of _________ _____

A

Non-selective
Expressed in 15% of small diameter sensory neurones
Expression increases in models of neuropathic pain

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20
Q

What are 3 exogenous ligands for TRPM8?

A

Menthol
Icilin
Spearmint

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21
Q

Which cannabinoids are derived from the Cannabis plant? Which are man-made? Which are present naturally in the body?

A

Plant: Phytocannabinoids
Man-made: Synthetocannabinoids
Naturally in the body: Endocannabinoids

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22
Q

What are the two cannabinoid receptors? Where are they located?

A

CB1 : On central and peripheral nerves

CB2 : Associated with immunocytes

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23
Q

How do CB1 agonists given in the peripheral nerve affect Joint Mechanosensitivity?

A

It decreases firing frequency in neurons, essentially diminishing action potential

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24
Q

Dorsal horn of the spinal cord : How do cannabinoids act in this location?

A
  • CB1 receptors are activated
  • Opening of K ion channels, increase in potassium conductance to the primary afferent neuron, causing it to hyperpolarize
  • Closes Ca channels
  • Decreases excitatory NT release
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25
Q

What are the three sites of action of cannabinoids?

A

Peripheral nerve
Dorsal horn of the spinal cord
Suprapinal Regions

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26
Q

What do cannabinoids target in the suprapinal regions? (4)

A

Cortex
Amygdala
Periaqueductal gray
Rostral ventromedial medulla

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27
Q

what are the periaqueductal gray and the rostral ventromedial medulla involved in?

A

Descending inhibition

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28
Q

When cannabinoids act of the cortex, what does this cause?

A

Alters cognitive perception of pain

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29
Q

When cannabinoids act on the amygdala, what does this cause?

A

Alters emotional perception of pain

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30
Q

Which endocannabinoids are synthesized from phospholipids and Arachidonic acid? (5)

A
  1. Anandamide
  2. Noladin
  3. Virodhamine
  4. 2-AG: 2-Arachidonoylglycerol
  5. NADA: N-Arachidonyl Dopamine
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31
Q

what is the process of anandamide degradation?

A

It interacts with CB receptor, Anandamide membrane transport rapidly transports it into the cell where FAAH degrades it into ehtanolamine and AA

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32
Q

How do you inhibit the degradation of endocannabinoids?

A

block the enzymes that cause degradation

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33
Q

Which drug inhibits FAAH from degrading anandamine?

A

URB597

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34
Q

What are the effects of inhibiting FAAH on OA Joint mechanosensivity?

A

Decrease in neuronal firing

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35
Q

Describe leukocyte trafficking in an inflamed joint

A

Leukocytes usually travel freely in vascular space.
A signal from the endothelium is made when there is inflammation
Leukocytes undergo a rolling process to cross the membrane into the extravascular space
Releases mediators once in the specific tissue

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36
Q

What 6 diseases use medical cannabis? %?

A 
Arthritis 36%
Spinal Cord Injury 16%
AIDS/HIV 15%
MS 14%
Spinal Cord Disease 10%
Cancer 6%
Epilepsy 3%
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37
Q

Name 4 prescription cannabinoids

A

Dronabinol
Nabilone
Nabiximols
Herbal Cannabis

38
Q

Which two prescription cannabinoids are oral capsules? What are they approved for? (2)

A

Dronabinol
Nabilone

Chemotherapy-induced nausea and vomiting
Anorexia associated with HIV/AIDS

39
Q

What are nabiximols approved for? (3)

How are they injnected?

A

MS-associated neuropathic pain
Spasticity
Advanced cancer pain

Oralmucosal spray

40
Q

Which prescription cannibinoid is not formally approved?

A

herbal cannabis

41
Q

What are 4 advantages to smoking cannabis?

A

Rapid pain relief
Improved sleep
Reduced anxiety
Easy to titrate

42
Q

What are 4 disadvantages to smoking cannabis?

A

Not appropriate or all patients
Psychotropic side-effects
Smoking isn’t the safest mode of administration
Various levels of cannabinoids and non-cannabinoid chemicals

43
Q

What is the average THC and CBD levels in Cannabis Strains in 2015?

A

17,5% THC

0.3% CBD

44
Q

What are three ways to ingest cannabis?

A

Oil
Butter
Brownies

45
Q

What is to onset of effects inhaled vs. ingested cannabis?

A

Inhaled 10min

Ingested 3h

46
Q

What is the duration of effects inhaled vs. ingested cannabis?

A

Inhaled 0-30min

Ingested 30min-2h

47
Q

What is one advantage of ingesting cannabis?

Two disadvantages?

A

No respiratory irritation
Slower onset of effect
Difficult to titrate best dose

48
Q

What are proteinases?

A

enzymes that hydrolyse peptide bonds in proteins

49
Q

What are 5 mechanisms that proteinases are involved in?

A 
Generate active peptides
Coagluation cascade
Inflammation
Tissue destruction/remodelling
Signal pain
50
Q

5 types of proteinases?

A 
Metalloproteinases
Threonine proteinases
Cysteine proteinases
Aspartic proteinases
Serine proteinases
51
Q

How do Proteinase Activated Receptors function as opposed to regular ligand-receptor binding?

A

Proteinase cleaves the N-terminal part of the tethered ligand sequence of the GPCR
Once it is cleaved, it is capable of binding to the ligand binding domain

52
Q

How do you bypass the need for a proteinase and the cleavage of the receptor sequence when you want to activate the PAR?

A

You can synthetically create a peptide that will bind to the

53
Q

What are 4 different ways a PAR can be modified?

A
  1. Normal state (cleavage site intact)
  2. Activated Receptor (Proteinase cleaves N-terminus)
  3. Disarmed Receptor (Entire ligand binding domain is cleaved off by proteinase)
  4. Antagonist blockade (Antagonist can block ligand binding domain)
54
Q

4 types of PAR? Which proteinase activates each?

A

PAR1 : thrombin
PAR2 : Trypsin, Tryptase, Elastase
PAR3 : Thrombin
PAR4 : Thrombin, Cathepsin G, Plasmin

55
Q

What is the function of PAR1?

A

Vasorelaxation

Decrease pain

56
Q

What is the function of PAR2?

A

Vasorelaxation

Increase pain

57
Q

What is the function of PAR3?

A

Unknown

58
Q

What is the function of PAR4?

A

Vasorelaxation

Increase or decrease pain depending on tissue

59
Q

What is the most common form of arthritis?

A

Osteoarthritis

60
Q

Osteoarthritis is a _____________ disease.

A

degenerative disease

61
Q

Destruction in osteoarthritis is elicited by what?

A

serine proteinases

62
Q

two types of pain behaviour tests for joint pain?

A

Weight bearing

von Frey Hair Algesiometer

63
Q

What is the effect of neutrophil elastase (weight bearing test and the von Frey test) on joint pain?

A

Weight bearing : % weight on ipsilateral paw decreases, more pain
Von Frey : Need less force to withdraw paw, meaning more pain

64
Q

Which receptor does Mast Cell Tryptase activate?

A

PAR2

65
Q

What is the effect of Mast Cell Tryptase on Hind limb weight bearing?
Effect reduced in what type of mice?

A

Reduction in hind limb weight bearing (difference in distribution)
TPRV1 knockout mice

66
Q

What is the effect of Mast Cell Tryptase on Tactile Allodynia?
Effect reduced in what type of mice?

A

Reduction in paw touch sensitivity

Effect reduced in TRPV1 knockout mice

67
Q

What is the potential role of PAR2?

A

-Sensitization of Joint Afferents by Proteinase Signaling

68
Q

Explain the mechanism of proteinase signaling via PAR2

A
  • Neutrophil elastase or Mast Cell Tryptase cleave PAR2
  • Activation of TRPV1
  • Sensitizes the nerve and activates SP and NK1
  • Leads to peripheral sensitization (nerve firing increases)
69
Q

Explain the mechanism of proteinase signaling via PAR1

A
  • Thrombin released to extravascular space
  • Cleaves PAR1
  • Peripheral release of endogenous opioids
  • Act on u-opioid receptor which causes analgesia
70
Q

Explain the mechanism of proteinase signaling via PAR4

Remember it depends on tissue!!

A

-Direct activation of PAR4 in the peripheral nerve by thrombin and cathepsin G to cause analgesia in digestive tract
-PAR4 expression on mast cells which releases bradykinin
activates B2 on nerve terminals, leads to pain in joints

71
Q

What are cytokines?
Are they soluble in water?
Synthesis is activated by what?

A

Extracellular signaling molecules
Mostly water soluble
Synthesis activated by mitogen-activated protein kinase (MAPK)

72
Q

Name 5 types of cytokines

A
  1. Interleukins
  2. Tumour necrosis factors
  3. Chemokines
  4. Interferons
  5. Transforming growth factors
73
Q

IL-1

What acts on IL-1R1 ?

A

IL-1alpha

IL-1beta

74
Q

Name an endogenous receptor antagonist of IL-1R

This antagonist blocks which disease?

A

IL-1Ra

LPS-induced hyperalgesia

75
Q

Does IL-1 increase or decrease during inflammation and injury?

A

Increase

76
Q

Two types of IL-1beta? What is the effect of each?

A

IL-1B (i.pl) : decreases mechanosensitivity threshold

IL-1B (i.p) : decreases thermosensitivity threshold

77
Q

IL-6
Signaling requires what?
Does IL-6 increase or decrease pain?

A 
IL-6R and gp130 signal transducing subunit of cytokine class I receptor superfamily
Increases pain
78
Q

Is IL-6R soluble or membrane bound?

A

BOTH

79
Q

What drug can bind to IL-6R to block binding of IL-6?

A

Tocilizumab

80
Q

What does IL-10 do?
Which intracellular pathway does it follow?
Does it increase or decrease pain?

A

Inhibits cytokine production from T-cells
JAK/STAT pathway
Decreases pain

81
Q

Explain the JAK/STAT pathway

A
  • IL-10 binding to IL-10R activates JAK
  • JAK autophosphorylates and phosphorylates to receptor
  • STATs are recruited and are phosphorylated by JAK
  • STATs dimerize
  • STATs translocate to nucleus to modulate target gene expression
82
Q

What is TNF-alpha?
Two isoforms?
2 TNF receptors?

A

Cytokine producing inflammation, pain, joint erosion

Two isoforms:
Membrane bound TNF (mTNF)
Soluble TNF (sTNF)

2 Receptors:
TNF-R1
TNF-R2

83
Q

soluble TNF binds to what receptor? What is the mechanism to get this receptor soluble?

A

Binds to TNF-R1

TACE cleaves TNF-R1 from surface of the cell

84
Q

TACE (TNFalpha converting enzyme) cleaves what? (2)

A

TNF-R1

mTNF to make it sTNF

85
Q

What are two types of TNFalpha blockers?

A

Soluble Receptor

Monoclonal Ab

86
Q

Name a drug that is a soluble receptor TNFalpha blocker

A

Etanercept

87
Q

Name two drugs that are monoclonal Ab TNFalpha blockers

A

Infliximab

Adalimumab

88
Q

TNFalpha blockers are usually taken with what?
How effective is it?
What are side effects? (3)

A

Methotrexate
Works in 2/3 patients
Side-effects : fever, infection, cost

89
Q

What is a biosimilar?

What is the nomenclature of biosimilars?

A

Biologic product that is very similar to an approved product and has no clinical difference in safety of effectiveness
Nomenclature is the non-proprietary name of the originator + 4 letter suffix

90
Q

What is the process of manufacturing biologics? (6)

What could be a difference at each step in different companies?

A
  1. Clone Gene into DNA vector (same AA-maybe same genetic sequence)
  2. Transfer into Host (diff. vector)
  3. Cell culture of fermentation (different recombinant cell system)
  4. Downstream processing (Diff. in-process controls)
  5. Purification (diff. purification protocol)
  6. Formulate product for use (maybe different formulation)
91
Q

4 facts about biosimilars that make it different from originator

A
  1. Immunogenicity (poor efficacy if Ab found previously on originator)
  2. Variable manufacture
  3. Can bypass phase III trial
  4. Can substitute from originator to improve efficacy, avoid side effects an minimize cost

Pharmacology II (21 decks)

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