Block E - IP lecture 3 Flashcards
what are classical DMARDs/ convential cynthetic DMARDs ?
These are disease modifying anti rheumatoid drugs , not used for pain management normally used in combination.
examples ?
Sulphazalazine,
Methotrexate,
Leflunomide
hydroxylchloroquine
wxplain how sulphazalzine came about ?
Designed in 1938 specially for use in rheumatoid arthritis, the idea was to combine an antibacterial drug and anti-inflammatory agent. Two drugs are mesalazine and sulphapyridine, 90% of sulphapyridine is absorbed compared to 20-30% of mesalazine absorbed.
what can it also be used for .
ulcerative colitis (UC)
mode of action ?
Both breakdown products may contribute, as well as intact molecule,
Inhibits B cell activity- reduces IgG and rheumatoid factor (RF) production
Inhibition of NFκB translocation to nucleus for in vivo studies
Inhibition of cytokine, chemokine and adhesion molecule synthesis
Osteoclast formation
adverse effects ?
Skin reactions - rashes
gastro-intestinal intolerance
Hematological effects - especially in patients with RA
leucopenia
neutropenia
Thrombocytopenia
Blood counts should be undertaken during first 3 months
why is it a pharmacological nightmare ?
Not a very potent or selective drug (affinity moderate- need to use lots of drug),
Therefore, the potential for off-target effects is high - leads to adverse effects,
However - it works, is cheap and side-effects manageable,
Safe to use in pregnancy at a low dose alongside folic acid supplement and can be continued preoperatively.
Contains short half-life of 3-4 hours
methotrexate mode of ation. ?
Defined Mechanisms of Action (differ between high and low doses).
inhibits dihydrofolate reductase - therefore inhibits purine/pyrimidine synthesis, DNA synthesis and cell proliferation, including T-cell and B-cell populations, osteoclasts and fibroblasts
Stimulates the release of adenosine (low dose therapy) - Adenosine has potent anti-inflammatory effects through A2a and A3 receptors
A first-line drug in treating rheumatoid arthritis
Often used in combination with other agents such as sulphasalazine and steroids
Highly effective in a significant proportion of patients
Adverse effects are predictable from inhibition of cell proliferation and dependent on dose used
e.g. Bone marrow depression and blood dyscrasias
adverse effects ?
Skin reactions - rashes
gastro-intestinal intolerance
Hematological effects - especially in patients with RA
leucopenia
neutropenia
Thrombocytopenia
Liver issues
Elevation of liver enzymes
CNS problems – fatigue and headaches
Not recommend in pregnancy
why does mechanims matter
Develop better drugs/medicines that mimic the true effect of Sulphalazine/Methotrexate (targeted approach - without side effects).
Better biomarkers which can recognise quickly if csDMARD is working
Pharmacogenomics - Improve personalised medicine
what are modern DMARDs- biologics ?
This is targeted where the mechanism of action is known.
Biological DMARDs (bDMARD);
Immunomodulatory (target cytokines and immune cells),
Antibodies designed to target inflammatory mediators
Used if patients respond inadequately to classical DMARDs such as methotrexate,
Blood cells counts, liver and kidney functions need to be taken before biological DMARDs are used.
target for immuno-modulation ?
Can target pro inflammatory cytokines including IL-6, IL-23, IL-1 , Il-17 and TGF beta.
Can also directly target B and T cell function to modify disease progression
what cytokines do bMARDs target ?
So from our knowledge of RA what would be the key inflammatory cytokines to target?
Tumour necrosis factor alpha (TNFα) produced by B/T cells and macrophages causes potent inflammation and leads to cartridge destruction.
Interleukin 1 beta (IL-1β) contributes to RA by recruiting and activating other immune cells
Interleukin 6 (IL-6),
Interleukin 17 (IL-17)
2 forms of TNF alpha ?
1st form is membrane bound TNF alpha which is converted to 2nd soluble form by TNF converting enzyme (TACE).
When targeting TNF alpha need to be aware there are 2 forms with different molecular weights
TNF alpha receptors ?
There are 2 TNF alpha receptors (TNFR-1 and TNFR-2), share similarities in structure , both are trimers and contain extracellular portions. However, the intracellular portions differ with different downstream effects.
TNFR2 ?
TNFR2 predominantly signal with TRAF 2 leading to NFkB
TNFR 1 ?
TNFR1 is associated with apoptosis
transcriptional productis of TNF alpha signalling ?
TNFa - binds to receptor to produce more TNF and IL-1 considered an autocrine route
Il-1b
Upregulation of adhesion molecules (ICAM-1, VCAM-1)
Cytokines that further enhance the immune response
Activators of inflammatory pathways (arachidonic acid metabolites, super-oxides and nitric oxide)
strucutre of infliximab ( remicade ) ?
This targets TNF, Fc portion of antibody is on the bottom and Fab portions are present on the arms. The first generation used chimeric human and mouse antibody, the human portion prevents rejection by body.
Infliximab is a monoclonal IgG1 antibody for treatment of RA developed in 2000.
mechanism of action ?
Binds and neutralizes both soluble and membrane bound TNFa - inhibits further activity.
By antibody binding to the soluble and insoluble form of TNF alpha receptors this prevents TNF alpha from binding to receptors and downstream signalling of NFkB and apoptosis.
Administered intravenously every 8 weeks at a dosage of 3-5mg/kg
other postilated mechanisms ?
Antibody dependent cell-mediated cytotoxicity (ADCC)
Lysis of TNFa-expressing cells through complement (C’) activation .
Infliximab binds to membrane bound TNF on T cells , initiating the complement cascade which results in complement coating the antibody and recruiting dendritic cells which engulf and breakdown T cells.
Entenercept ?
Etanercept is a recombinant fusion developed in the year 2000 for the soluble TNF receptor linked to the Fc portion of human IgG. This binds to the TNF receptor inhibiting TNF mediated responses.
Etanercept is not recombinant antibody- Soluble TNFα receptor fused to Fc domain of human IgG
Adalimumab ?
Adalimumab recombinant IgG antibody which binds to soluble and insoluble TNF alpha receptors with high affinity.
Anakinra ?
Anakinra
Recombinant human IL-1 receptor antagonist – binds directly to IL-1 receptor preventing binding of Il-1 , administered sub cutaneous
Targeting T cells ?
T-cells respond to APCs and expand/differentiate leading to the release of pro-inflammatory mediators
Anti CD80/86-CD28 inhibitor development (Abatacept),
Abatacept is a fusion protein constituted by an Ig fused to the extracellular domain of a cytotoxic T-lymphocyte antigen-4 (CTL4),
It binds with high affinity to the CD80/86 ligand on APCs,
It blocks the interaction between the APC and T-cell.
Abatacept ?
Abatacept results in decreased T cell proliferation and cytokine production , it is administered intravenously.
side effects ?
Side effects include hypersensitivity , risk of serious infections, no studies about use in pregnancy.
Targeting T cell activation ?
CD28 is found on T cells, CD80/CD86 are found on APC which can be macrophages and dendritic cells. Abatacept binds directly to CD80/CD86 and prevents the interaction between CD28 on APC and CD80/CD86 on APC.
Targeting B cels ?
B-cells not only give rise to antibody producing plasma cells but are also highly effective APCs,
Anti-CD20 antibody development (Rituximab) – to deplete B cells
Chimeric murine-human monoclonal antibody – binds to the CD20 membrane receptor
Beneficial when anti-TNF therapy has failed
Side effects – infusion reaction (30-40% of patients) – consists of headache, fever, rash, hypotension, amongst others.
CD20 ?
on B cells
rituximab ?
CD20 on B cells , rituximab binds to the receptors on B cells and depletes B cell population, particular beneficial in RA patients who are autoantibody positive.
targeted synthetic DMARDs ?
tsDMARDs – JAK inhibitors (New group of small molecule drugs to target RA)
Target the Janus-kinase (JAK) pathway
Receptor associated intracellular proteins critical for signal transduction from some cytokine receptors, not TNF alpha.
IL-2, IL-6 and Interferons of particular interest.
Inhibitors - Effective in inflammatory disease by intracellularly blocking tyrosine kinase.
JAK inhibitors ?
JAK are important mediators of down stream pro inflammatory cytokines. Once the ligand binds to it’s receptors could be IL-2, this phosphorylates JAK leading to phosphorylation and activation of STAT. STAT dimers form after phosphorylation and these translocate to the nucleus where they lead to transcription of inflammatory cytokines.
By blocking this pathway , this prevents several pro inflammatory cytokine transcription pathways form occurring.
2 JAK inhibitors have been approved for use in RA - pharmacological aspects ?
Two JAK inhibitors approved for use in RA these contain a small molecular weight and specific targets
Tofactinib ?
JAK 1 & 3 inhibitor (little affinity for JAK 2)
- Effective in moderate-severe RA in monotherapy or in combination with methotrexate.
Effective in patients who show little efficacy for classical DMARDs
Side effects include increased susceptibility to infections , headaches, hypertensions, naseua and diarrhoea
High doses are associated with deep vein thrombosis and pulmonary emboli
Barcitinib ?
Baricitinib
- JAK 1 & 2 inhibitor – no affinity for JAK 3
- Administered as a monotherapy or in combination with methotrexate.
Side effects include increased cholesterol levels , upper airway infections , nausea
Not recommended with patients with impaired kidney functions
