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Pharm 4001 > Lecture 5- Adjunct Analgesics 3 > Flashcards

Lecture 5- Adjunct Analgesics 3 Flashcards

1
Q

Proteinases

A
  • enzymes that hydrolyse peptide bonds in proteins
  • Generate physiologically active peptides
  • Coagulation cascade
  • Inflammation
  • Tissue destruction/remodelling
  • Signal pain
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2
Q

Types of proteinases + function

A
  • Metalloproteinases
  • Aspartic proteinases
  • Cysteine proteinases
  • Threonine proteinases
  • Serine proteinases
  1. All attack specific substrate residues in the protein
  2. Serine proteinases involved in pain
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3
Q

Proteinase Activated Receptors (PARs)

A
  • GPCRs
  • extracellular loop, has ligand binding domain
    1. tethered ligand sequence won’t bind due to amino group

proteinase will selectively degrade tail piece, remove it and expose the tether ligand sequence —> can bind

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4
Q

PAR activation by peptide ligands

A
  • activated: N terminus removed
  • could cleave upstream of tether ligand sequence —> disarm the receptor
  • antagonists that block the extracellular loop (competitive)
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5
Q

Types of PARs + function

A
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6
Q

Osteoarthritis (OA)

A
  • most common form of arthritis
  • degenerative disease
  • destruction elicited by serine proteinases
  • could serine proteinases be one ource of OA pain?
  • proteinase inhibitors: constitutively expressed
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7
Q

Role of neutrophil elastase in joint pain

A
  • produced in neutrophils
  • weight bearing: animals sit on hind legs, underneath paws are force plates, see how much weight he bears on each leg
  • von frey hair algesiometer: filament applied to hind paw of increasing forces, see when they withdraw
  • give neutrophil elastase into local joint:
  • weight bearing: animal shifts weight over from injected leg, pain response lasts for like 24 hr
  • VFH: give NE into joint, animal feels pain in that leg, referred pain/secondary allodynia (pain felt in place thats not the site)
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8
Q

Role of mast cell tryptase in joint pain (hindlimb weight bearing)

A
  • tryptase injected into knee joint
  • reduction in hindlimb weight bearing (caused pain)
  • effect reduced in TRPV1 knockout mice
  • animal feels pain in response to tryptase

tryptase has its effect through TRPV1 dependent mechanism

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9
Q

Effect of mast cell tryptase on tactile allodynia

A
  • tryptase injected into knee joint
  • reduction in paw touch sensitivity (caused allodynia)
  • effect reduced in TRPV1 KO mice
  • tactile allodynia: reduce amount of force required for response, TRPV1 dependent mechanism
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10
Q

Potential role of PAR2

A
  • give PAR2 activating peptide (ligrlo), there is peripheral sensitization —> driving the pain response
  • cleavage/activation of PAR 2 with synthetic ligand was able to sensitize joint afferents leading to pain response
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11
Q

Mechanism of proteinase signalling via PAR2

A
  • par2 on sensory nerve terminals
  • PAR2 cleavage leads to activation of TRPV1 —> release of inflammatory neuropeptides
  • Substance P binds to NK1 receptors —> peripheral sensitization of pain
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12
Q

Mechanism of proteinase signalling via PAR 1

A
  • analgesic
  • cleaved by thrombin
  • cleavage —> released of endogenous opioids (endomorphin 1) —> binds to mu opioid receptors —> desensitization of nerve terminal —> analgesia
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13
Q

Mechanism of proteinase signalling via PAR 4

A
  • hyperalgesic and analgesic
  • cleaved by thrombin and cathespsin G
  • activate or inhibit PAR4 on nerve terminal
  • can also cleave mast cells —> bradykinin —> B2 receptors —> pain
  • in joints —> peripheral sensitization of pain
  • GI —> analgesic
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14
Q

Cytokines

A
  • extracellular signalling molecules (8-30kDa)
  • mostly water soluble
  • synthesis activated by mitogen-activated protein kinase (MAPK)
  1. Interleukins (IL-): 1-35
  2. Transforming growth factors (TGF-)
  3. Interferons (IFN-)
  4. Tumor necrosis factors (TNF-)
  5. Chemokines (CC, CXC, others)
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15
Q

IL-1alpha and IL-1beta

A

act on IL-1R1

  • interleukins increase in production during inflammation and injury
  • decrease in mechanosensitivity threshold = increase pain
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16
Q

IL-1Ra

A
  • endogenous receptor antagonist
  • blocks LPS-induced hyperalgesia
17
Q

IL-1B

A
  • decreases mechanosensitivity threshold
  • decreases thermosensitivity threshold
18
Q

Anakinra

A

interleukin antagonist shown to block pain

19
Q

IL-6

A
  • requires alpha receptor (IL-6R) AND gp130 s
  • increases pain
20
Q

IL-10

A
  • inhibits cytokine production from activated T cells
  • anti-inflammatory (TH2) cytokine
  • intracellular pathway: JAK/STAT
  • decreases pain
21
Q

TNF-a

A
  • cytokine producing inflammation, pain, joint erosion
  • 2 isoforms:
  1. Membrane-bound TNF (mTNF)
  2. Soluble TNF (sTNF)
22
Q

2 TNF receptors

A
  1. TNF-R1
  2. TNF-R2
23
Q

Activation of TNF receptors

A
  • leukocyte expressing mTNF
  • binds TNF-R2 on target cell : direct activation
  • TNFR1: requires presence of TACE
  • TACE works at TNF-r1 and mTNF
  • TACE causes cleavage of TNFR1: circulating freely in blood
  • mTNF + TACE= dissociated, circulates as soluble TNF —> binds to form complex, activates target cell
24
Q

TNF-a blockers

A
  • 2 ways of blocking:
    1. soluble receptors: binds TNF-a, TNF-a no longer able to bind to target site on tissue
    2. monoclonal ab: bind TNF-a, can no longer activate receptor
  • decreases acute flares and pain
  • can reverse disease
  • usually taken with methotrexate
  • works in 2/3 patients
  • efficacy decreases over time

Side effects

  • fever
  • infection
  • COST $
25
Q

Etanercept

A
  • Enbrel
  • inhibitor of soluble TNF receptor
26
Q

Infliximab

A
  • Remicade
  • monoclonal antibody inhibitor of TNF receptor
27
Q

Adalimumab

A
  • Humira
  • monoclonal antibody inhibitor of TNF receptor
28
Q

Biosimilar

A
  • a biologic product that is highly similar to an approved biologic product (the reference/ originator/ bio-originator)
  • and has no clinically meaningful differences in safety or effectiveness as compared to the reference product
  • not identical to originator (due to biological source)
  • genetic drift and evolution

Nomenclature

  • originator name + 4 letter suffix
  • ex: infliximab-dyyb
29
Q

How are biosimilars made?

A
  • take ab, clone it into a vector, vectors can be infected into host cell
  • culture the cells, purify the shit, formulate the end product
  • potential for problems
  • more quality control required
30
Q

Generic drugs

A
  • chemical structure identical to reference product
  • pharmacokinetic equivalence
31
Q

Problems with biosimilars

A

Immunogenicity

  • antidrug antibodies found in patients previously on “originator” treatment
  • poor efficacy

Variable manufacture of reagent

Extrapolation of indication

  • can bypass phase III clinical trials

Substitution

  • physician, pharmacists: improve efficacy, avoid side-effects
  • non-prescriber (ex: insurance company)- minimize cost

Pharm 4001 (9 decks)

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