FUN2 Pharmacology of Autoimmune diseases
FUN2 Pharmacology of Autoimmune diseases
Inhibit IL-2 singling by binding to FKBP, but does not inhibit Calcineurin.
Same mechanism==> Temsirolimus, Everolimus
Macrolide inhibit protein synthesis
Cyclosporine: Fungal cyclic undecapeptide. Binds to immunophilin known as Cyclophilin.
Tacrolimus: also fungal metabolite. Binds to immunophilin known as FKBP
Both inhibits IL-2 production by binding to Calcineurin
Adverse effects : nephrotoxicity.
All used to prevent organ rejection. Treat certain cancers like renal cell carcinoma and melanoma.
Drugs that block IL-2 binding to its receptor : Daclizumab and Basiliximab.
Selective COX-2 inhibitors
Lower incidence of gastric bleeding.
Increased risk of thrombosis leading to Myocardial Infraction.
Risk of cardiovascular diseases is inversely related to their inhibition of COX-1
Inhibits synthesis of Prostaglandins.
Prostaglandins are produced when phospholipase A2 releases Arachidonic acid from intracellular membrane. Arachidonic acid is the substrate for COX enzyme which converts it to prostaglandins H2.
Acetylating COX in irreversible manner
Dual COX and LOX inhibitor
Gastric ulceration and bleeding
Bleeding: Due to inhibition of COX in platelets(Prevent heart attacks)
Gastric ulceration: Inhibition of COX reduces the mucosal layer in the stomach.
Analgesic effect is mediated by its metabolite NAPQI which activates TRPA1 in the spinal cord producing anti-nociceptive response.
NAPQI is responsable for Hepatotoxicity.
Group of hormones derived from cholesterol.
Sex hormones: Androgens and Oestrogen
Risk of infection
All Leukotrienes are derivative of LTA4, which is the product of LOX.
The 2 major derivatives of LTA4 are LTB4 and LTC4 and its derivatives Cysteinyl leukotrienes (CysLTs)
Meclofenamate has dual Cox and LOX inhibition
Zileuton - Approved for Asthma
LT receptor antagonist
LTB4 binds to LTB1 and LTB2
CysLTs binds to CysLT1 and CusLT2.
CysLT1 antagonist approved for Asthma
Unclear mechanism of action.
Metabolised by gut bacteria into 5-aminosalicylic and sulfapyridine.
Low dosage compared to cancer therapy.
Given once a week.
Side effects: Hepatotoxicity, pulmonary damage, nausea, infection, alopecia.
Inhibitor of Dihydrofolate reductase which inhibits DNA synthesis.
Folic acid supplements to reduce inhibition of folic acid side effects.
AICAR transformylase inhibitor => increases Adenosine levels => Anti-infammatory effect on Adenosine receptors.
Affect cell division
Cause cell arrest of the autoimmune lymphocytes through acting on DHODH. (DHODH is necessary for pyrimidine synthesis)
Inhibit osteoclast production.
Metabolite excreted in urine and feces.
inhibits T-cell and B-cell replication
Affects Cell division
Raises Lysosomes' pH inhibiting the action of lysosomal acidic protease.
Highly lipophilic, and Accumulate inside lysosomes.
Soluble IL-1 receptor antagonist
T-cell activation inhibitor
CD-20 activity blocker
Chimeric monoclonal antibody directed at CD20
Used in combination with Methotrexate.
Treat moderate to sever RA
(TNF)-alpha inhibitors (Anti-TNF)
Genetically engineered, soluble, recombinant, fully human receptor fusion protein.
Binds to TNF-α and blocking its interaction with cell surface TNF receptors. However, does not bind to receptor-bound TNF only free ones
Administrated twice a week subcutaneously.
Adverse effects: Immunological reaction on site of injection, and TB =>(lack of granuloma formation that needs TNF)
Chimeric monoclonal antibody that binds to TNF.
Bind to free or membrane bound TNF.
Given parenterally every 2 or 8 weeks
Thalidomide (Not DMARD only anti-TNF)
Teratogenic and cause severe birth defects (Phocomelia)
Used for Leprosy and HIV
Inhibits TNF production (only one that inhibit production other Anti-TNF bind to TNF)
Adverse effects of all Anti-TNF: Myobacterial infection TB. Patient must be screened for TB before administration of Anti-TNF drugs.
Metabolised by gut bacteria into 5-aminosalicylic acid and sulfapyridine
For RA and Crohn's disease
active agent is 5-aminosalicylic acid that reduces activity of immune cells.
Side effects: skin reactions, hepatitis, pneumonitis, agranulocytosis, and aplastic anaemia.
High molecular weight polypeptide. Induces Th2 response periphery to help with re-myelation of nerves.
Small molecule that shifts immune response from Th1 to Th2
Hydroxychloroquine --See non-biological DMARDs
Drugs that affect cell division
metabolised to mycophenolic acid which inhibits Inosine Monophosphate Dehydrogenase (IMPDH).
IMPDH is essential for Guanine synthesis and inhibiting it impair DNA synthesis.
Metabolised to Mercaptopurine which inhibit protein synthesis
Inhibit cell division
Inhibits adenosine deaminase.
Approved for treatment of hairy cell leukaemia.
Toxicity: Myelosppression and infections.
Active metabolite of Leflunomide.
Inhibits B and T cell replication through Inhibition of DHODH.
Side effects: alopecia and nausea.
Mitoxantrone and Doxorubicin
Intercalate into DNA.
Approved for MS.
Side effect: cardiotoxicity.
Recombinant IFNβ-1a ==> Rebif and Avonex
Not many patient benefit from it and may become resistant.
Anakinra => RA
Rilanocept => Fusion protein approved for some orphan disease.
Co-stimulation in the immune system
LFA-3 fusion protein that binds to CD2 preventing memory cell formation, and induce apoptosis in activated T cells.
Monoclonal antibody to LFA-1 that blocks T-cell binding to endothelial cells.
Monoclonal antibody that binds to alpha4 integrins. Blocks inflammatory cells from binding to endothelial cells
Induce inflammation of the brain known as PML
Both soluble fusion proteins that target B7 to prevent it from interacting with CD28 ==> inhibit T cell activation
For organ transplantation
Monoclonal antibody to treat melanoma
CTLA-4 antagonist that enhance immune response. (Other drugs mentioned act on CTLA-4)
CD28 not recommended as drug target as it can cause SIRS
Fungal metabolite that internalise S1P receptors on the surface of lymphocytes, so they cannot respond to signals.
Oral agent to treat MS
Analogue of Fingolimod for MS but still in trial.
Affect heart rate and conduction.
Increased risk of infection (rare)
Skin cancer (rare)
Immune cell Depletion
Rituximab -- See Biological DMARDS
Monoclonal antibody directed against CD52
MS and T-cell leukemias
Targeting Fc receptors
IgG antibody directed against Fc portion of IgE
Asthma and immune thrombocytopenia