Immunosuppressants
Tofacitinib (Xeljanz) is what type of drug? How does it work?
Janus kinase inhibitor. Basically stops transcription factor activation via JAK3 cell signaling --> less immune activity
If a drug ends with -mab, it is...
Monoclonal antibody.
Why do people tend to discontinue use of methotrexate?
Adverse effects: - Liver damage - Malaise - Neutropenia/immunosuppression
Differentiate: Allopurinol Uricase Probenecid NSAIDs, colchicine, and corticosteroids Colchicine Febuxostat for use with gout
A. Allopurinol: Blocks uric acid formation B. Uricase: Breaks down uric acid C. Probenecid: Increase excretion of uric acid in urine D. This group of drugs reduces inflammation E. Prevents polymerization via tubulin and leukocyte migration --> prophylaxis and acute attacks F. More effective than Allopurinal in decreasing plasma urate --> more expensive alternative for long term treatment
Which IMDH inhibitors did we discuss? How do their uses differ?
A. Azathioprine, mycophenolate: - RA, Crohn's, transplant B. Leflunomide: - Also an antirheumatic - Chemotherapy agent in HER-2 negative breast cancer
Differentiate Basiliximab and Moromonab.
A. Basil: Bind CD25 subunit of IL-2 receptor B. Bind CD3 receptor on T-lymphos Both are T-cell receptor MABs
What types of drugs are cyclosporine and tacrolimus? How do they differ?
A. Calcineurin inhibitors B. Cyclosporine: - 24 hour halflife - Metab by CYP4A4 - Gingival side effects Tacrolimus: - Shorter halflife of 11 hrs - Metab by CYP3A4 and CYP3A5 - No gingival SEs *Both are used to prevent tissue rejection: Former for grafts, latter for organ*
What are the major classes of immunosuppressants?
A. Corticosteroids B. Calcineurin inhibitors C. mTOR inhibitors D. IMDH inhibitors E. Biologics (they're all biologics, but eh...) F. Monoclonal antibodies
Perhaps the most important endogenous anti-inflammatory molecule in the body is... They are produced by... The general MOA by which they act as anti-inflammatory agents is...
A. Corticosteroids, such as adrenal steroids, glucocorticoids, corticosteroids, anti-inflammatory steroids. B. Adrenal gland C. - Block expression of genes induced by inflammatory agents like COX-2, PLA2, cytokines, etc. - Promote gene expression of lipocortin --> Inhibits PLA2 --> less free AA
What are the 2 main uses of methotrexate?
A. DHFR inhibition --> chemotherapeutic B. Purine metabolic effects --> combat RA progression - Inhibits T and B cells, reduce ICAM - Interfere with IL-1B receptor binding
Anakinra (Kineret) is what type of drug? How does it work?
A. IL-1 receptor antagonist (DMARD) B. Blocks IL-1 binding by taking over binding site --> less inflammation
What is the first-line drug for pathological process of RA? What is next when this fails?
A. NSAIDs B. Biologics/DMARDs --> usually the DMARD methotrexate
Which 2 mTOR inhibitors did we discuss? How do their uses differ?
A. Sirolimus and Everolimus B. Siro: - Prevent organ transplant rejection - Coating on coronary stents Everolimus: - Also reduce organ rejection - Chemotherapy agent in HER-2 negative breast cancer
Abatacept (Orencia) is what type of drug? How does it work?
A. T-cell costimulatory blocker (DMARD) B. Prevents T-cell activation by antigen presenting cells --> less self inflammation.
Which MAB for IL-6 receptor did we discuss? Why would this be used over TNF-a variant?
A. Tocilizumab (Actemra) B. Pt did not respond to TNF targeting
If all other DMARD treatments fail, try...
Abatacept (Orencia), a T-cell costimulatory blocker
Any drug that interrupts or slows progression of RA is known as...
Biologic/DMARD
Matchin' time: Biologics DMARDs Small molecule drugs Large molecule drugs
Biologics - Large DMARDs - Small
How do IMDH inhibitors work?
Block DNA synth --> thus blocks the proliferation of lymphocyte populations --> less immune response.
All the discussed drugs that bind to TNF-a end in -mab... except...
Etanercept (Enbrel) --> sucks TNF away from cells by acting on external receptor for TNF
How are second gen rapalogs (mTOR inhibitors) different from first gen?
Prevent ATP binding at catalytic (enzyme) sites that allow aggregation of complexes with mTOR. Same effect, different mech.
Uric acid crystals in gout are derived from the metab of what molecule?
Purines
In general, how do calcineurin inhibitors work?
Suppress IL-2 production/secretion in T-lymphocytes Calcineurin dephosphorylates cNF-AT transcription factor --> allows upregulation of IL-2 --> growth and differentiation of T cell response. Inhibitors stop this process.
How do drugs that bind to TNF-a work?
These are usually -mabs, except for Etanercept (Enbrel). TNF produced by synovial macrophages and lymphos --> mediate tissue damage --> bone and cartilage destruction --> These drugs bind to soluble TNF in plasma or TNF bound in joints --> sequester from acting on cells
How do mTOR inhibitors work?
They block mTOR from aggregating with other molecules --> this interaction is crucial for the ability to signal a pathway that allows cell growth and T-lymphocyte proliferation.
