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Pharmacology II > Adjunct Analgesics > Flashcards

Adjunct Analgesics Flashcards

1
Q

4 steps in the pain pathway

A
  1. Nociception (Adelta and C fibers)
  2. Neurotransmission (up ascending pathways in spinothalamic path)
  3. Sensation, cognition, emotion (somatosensory cortex, limbic system, amygdala)
  4. Neuromodulation (descending pathways can turn the signal up or down)
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2
Q

A delta fibers

A 
1-5 micrometers
5-30 m/s
Myelinated
Mechanosensation
Nociception
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3
Q

C fibers

A 
<1.5 um
<2 m/s
Unmyelinated
Temperature
Nociception
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4
Q

Crude way of analyzing pain

A

Visual analog scale
7+ is severe
5-6 is moderate
1-4 is mild

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5
Q

3 types of pain

A

Nociceptive
Inflammatory
Neuropathic

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6
Q

5 things that can activate nociceptors

A 
Mechanical
Heat
Cold
Pathogens
Chemicals
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7
Q

4 causes of neuropathic pain in the periphery

A

Trauma
Metabolic disorders
Infection
Chemotherapy-induced neuropathy

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8
Q

3 causes of neuropathic pain in the CNS

A

Spinal cord injury
Stroke
Multiple sclerosis

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9
Q

Tricyclic Antidepressants (TCAs)

A

Very effective for chronic neuropathic pain
Ex: Amitriptyline
Analgesic effect occurs separately from mood change
Blocks neuronal uptake of NA and Serotonin in the spinal cord (increases descending inhibition)
Also blocks NMDA receptors and some ion channels
Side effects: dry mouth and drowsiness

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10
Q

Serotonin-noradreniline reuptake inhibitors (SNRIs)

A

Ex: duloxetine, venlafaxine
Not as effective as TCAs at reducing pain
Side effect profile decreases
Fewer side effects than amitriptyline because it doesn’t block NMDA receptors

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11
Q

Selective serotonin reuptake inhibitors (SSRIs)

A

Ex: Fluoxetine, fluvoxamine
Fewer side-effects due to high selectivity
But low efficacy for diabetic neuropathic pain

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12
Q

Antidepressant order for

  1. Efficacy
  2. Side effects
A
  1. TCAs> SNRIs > SSRIs

2. TCAs > SNRIs > SSRIs

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13
Q

Anticonvulsants

A

Developed for use in epilepsy
Interferes with neuronal excitability
Effective for postherpetic neuralgia, diabetic neuralgia, fibromyalgia
Side effects: drowsiness, dry mouth, weight gain, dizziness
Ex: gabapentin, pregabalin

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14
Q

Gabapentinoids

A

Binds to alpha 2 delta subunit of Ca channel
Inhibits release of excitatory NTs
Also modulates Na, K activity (altered neuronal excitability)

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15
Q

Gabapentin and Joint Pain study

A

Gabapentin given locally into joint
The drug reduced mechanosensitivity in normal and inflamed joints
Effect greater in normal than arthritic joints
Inflammation may alter gabapentin binding to the alpha 2 delta subunit of Ca channel
Not ideal for inflammatory pain

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16
Q

4 states of a voltage-gates sodium channel

A

Closed (primed) - gate is open, pore is shut
Open (activated) - both are open
Open inactivated (fast) - pore is open, gate is shut
Closed inactivated (slow)- both are closed

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17
Q

Where are

  1. TTX sensitive channels
  2. TTX resistant channels
A
  1. Muscle, CNS

2. Some sensory neurones

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18
Q

Gain of Function Mutation in Na V1.7

A 
Mutation in SCN9A gene
Familial erythromelagia (tissues look very red)
Burning and intense pain
Higher than normal levels of Na V1.7 channels
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19
Q

Loss of Function Mutation in Na V1.7

A

Loss of function in SCN9A gene
Congenital insensitivity to pain
Self harm, unknown injuries
The patients suffer acute mental illness – crave feeling of pain and do self-harm

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20
Q

Lidocaine

A

Local anaesthetic
Binds to intracellular pore (channel inactivation)
Can be delivered as a patch to control neuropathic pain
Can be administered in IV
Not selective so can inhibit cardiac Na channels at high concentration

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21
Q

Amitriptyline

A

Antidepressant
Preferentially binds to inactivated channels keeping them in the inactive state
Interacts with the local anaesthetic binding site
Effective in treating neuropathic pain
Non-selective for Na channel subtypes so can affect cardiac and skeletal muscle activity

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22
Q

Carbamazepine

A

Anticonvulsant
Preferentially binds to inactivated channels and keeps them in the inactive state
Inhibits both TTX sensitive and resistant Na channels
Used to treat trigeminal neuralgia and migraine
Non-selective for Na channel subtypes so can effect cardiac and skeletal muscle activity

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23
Q

Effect of Na V1.8 blockade on joint pain

A

The number of APs decrease when administered locally

Can tell the pain is decreasing because they start to shift their weight back to the osteoarthritic joint

24
Q

Voltage-gated Ca channels

A

Open in response to changes in membrane potential
Classified based on type of voltage required to activate them (low or high threshold)
Subclassified based on the alpha 1 pore forming subunit structure and pharmacological properties

25
Q

L-type Ca channel

  1. Examples (2)
  2. Results (2)
A

“Long lasting”

  1. Nifedipine, verpamil (channel blockers)
  2. decrease substance P release and decrease pain
26
Q

N-type Ca channel

A

“Neuronal”
omega conotoxin causes decreased substance P release and decreased pain
Knockout animals have decreased inflammatory and neuropathic pain

27
Q

P/Q type Ca channel

A

“Purkinje”

omega agatoxin causes decreased substance P release and decreased migraine

28
Q

R-Type Ca channel

A

“Residual”

SNX-482 from tarantula causes decreased substance P release

29
Q

T-Type Ca channel

  1. Example
  2. Results in
A

“Transient”

  1. Mibefradil (partial channel blocker)
  2. Decreased pain
30
Q

Proteinases

A

Enzymes that hydrolyse peptide bonds in proteins
Generally physiologically active peptides
Coagulation cascade
Inflammation
Tissue destruction/remodelling
Signal pain

31
Q

Which class of proteinases signal pain?

A

Serine proteinases

32
Q

How do proteinase activated receptors work?

A

A proteinase has to cleave off a sequence at the N terminal, and leave the tethered ligand sequence exposed
This can then bind to the extracellular ligand binding domain on the receptor

33
Q

From an inactive receptor, you can get cleavage and what 3 resultant forms?

A

Activated receptor
Disarmed receptor
Antagonist blockade

34
Q

PAR 1

  1. Proteinase
  2. Physiological functions (2)
A
  1. Thrombin

2. Vasorelaxation, decreases pain

35
Q

PAR 2

  1. Proteinases (3)
  2. Physiological functions (2)
A
  1. Trypsin, Tryptase, Elastase

2. Vasorelaxation, increases pain

36
Q

PAR 3

  1. Proteinase
  2. Physiological function
A
  1. Thrombin

2. Unknown

37
Q

PAR 4

  1. Proteinase (2)
  2. Physiological functions (2)
A
  1. Thrombin, Cathepsin G

2. Vasorelaxation, increases or decreases pain depending on the tissue

38
Q

Osteoarthritis

A

Most common form of arthritis
Degenerative disease
Destruction elicited by serine proteinases
Loss of articular cartilage and remodelling of subchondral bone

39
Q

2 ways to measure pain in rats

A

Weight bearing

vo Frey Hair Algesiometer

40
Q

Neutrophil elastase

A

Will see rats move their weight to the other leg if you give this
It’s signalling pain

41
Q

Mast cell tryptase

A

Caused pain when injected into knee joint
Can see it in reduced hindlimb weight bearing and reduction in paw touch sensitivity
Effect reduced in TRPV1 knockout mice

42
Q

How does PAR2 signalling work?

A

Neutrophils and mast cells release elastase and tryptase respectively
They act on the PAR2 receptor on the afferent nerve terminal
PAR2 activates TRPV1
Releases substance P
Acts on NK1 to cause pain

43
Q

How does PAR1 signalling work?

A

Release of thrombin can act on PAR 1
Activation of par 1 causes release of endogenous opioids
They act on mu opioid receptors present on sensory receptors
Get analgesic effect

44
Q

How does PAR4 signalling work?

A

Cathespin G and thrombin can act on mast cells (where PAR4 is expressed)
Mast cells release bradykinin
Acts on afferent nerve terminals
Also are PAR4 receptors directly on the nerve terminal
If its in the GI tract, causes analgesia
If its in the joint, causes pain

45
Q

Cytokines

A

Extracellular signalling molecules
Mostly water soluble
Synthesis is activated by mitogen-activated protein kinase

46
Q

When do interleukins increase?

A

During inflammation and injury

Antagonists can block pain

47
Q

IL-6

A

Requires receptor alpha and gp130 signal transducing subunit of cytokine class 1 receptor superfamily
Needs both receptor, and subunit to signal
Increases pain

48
Q

IL-10

A

Inhibits cytokine production from activated T cells
Used Jak/Stat pathway
Decreases pain

49
Q

TNF-alpha

A

Cytokine producing inflammation, pain, joint erosion
Can be membrane bound or soluble
2 receptors

50
Q

2 main classes of TNF-alpha blockers

A

Soluble receptors

Monoclonal antibodies

51
Q

3 TNF-alpha blocker drugs

A

Etanercept
Infliximab
Adalimumab

52
Q

TNF-alpha blocker drugs

A 
Decrease acute flares and pain
Can reverse disease
Some patients go into complete remission
Usually taken with methotrexate
Works in 2/3 patients
Efficacy decreases over time
Side effects: fever, infection, cost
53
Q

Biosimilar

A

Antibodies that are highly similar to an originator, but are not the exact same
Genetic drift and evolution occurs

54
Q

Where can biosimilars go different? (6)

A 
Different genetic sequence
Different DNA vector
Different recombinant cell system
Different in-process controls
Different purification protocol
Different formulation
55
Q

4 problems with biosimilars

A

Immunogenicity (people can have poor efficacy from antibodies neutralizing the biosimilar)
Variable manufacture of reagent
Extrapolation of indication (can bypass phase III clinical trials)
Substitution (by prescribers or non-prescribers)

Pharmacology II (24 decks)

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