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
2
Q
Types of proteinases + function
A
- Metalloproteinases
- Aspartic proteinases
- Cysteine proteinases
- Threonine proteinases
- Serine proteinases
- All attack specific substrate residues in the protein
- Serine proteinases involved in pain
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
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)
5
Q
Types of PARs + function
A
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
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)
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
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
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
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
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
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
14
Q
Cytokines
A
- extracellular signalling molecules (8-30kDa)
- mostly water soluble
- synthesis activated by mitogen-activated protein kinase (MAPK)
- Interleukins (IL-): 1-35
- Transforming growth factors (TGF-)
- Interferons (IFN-)
- Tumor necrosis factors (TNF-)
- Chemokines (CC, CXC, others)
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
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:
- Membrane-bound TNF (mTNF)
- Soluble TNF (sTNF)
22
Q
2 TNF receptors
A
- TNF-R1
- 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
Etanercept
* Enbrel
* inhibitor of soluble TNF receptor
26
Infliximab
* Remicade
* monoclonal antibody inhibitor of TNF receptor
27
Adalimumab
* Humira
* monoclonal antibody inhibitor of TNF receptor
28
Biosimilar
* 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
How are biosimilars made?
* 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
Generic drugs
* chemical structure identical to reference product
* pharmacokinetic equivalence
31
Problems with biosimilars
**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
