Immunosuppressants, Immunomodulators, Treatment of Rheumatoid Arthritis Flashcards
Drug Categories: Immunosuppressants
Corticosteroids Cyclosporin New Immunosuppressants Cytotoxic Agents Antibodies
Corticosteroids as Immunosuppressants
Mechanism of Action
Medical Use
Side Effects
Mechanism of Action
Inhibit expression of Phospholipase A2 via
upregulation of lipocortin 1
Downregulate: COX2, inflammatory cytokines (IL3, IL4,
IL5, TNF alpha), TFs (NFkB, TGF- beta)
Inhibit primary and secondary Immune cells
(macrophages, T cells granulocytes, fibroblasts,
endothelial cells)
Medical Use: AI Disorders (SLE, IBD, AI haemolytic anaemia)
Side Effects:
Cushings, Infection, Ulceration, Addisons
Corticosteroids as Immunosuppressants
Names
Cortisol Fludrocortisone Desoxycorticosterone Prednisone Methylprednisone Betamethasone Dexamethasone
Cyclosporine as an Immunosuppressant
Mechanism of Action
Medical Use
Side Effects
Is a cyclic peptide AB
Bind cyclophyllin–> complex inhibits calcineurin (resp for lymphokine production)
Acts in
early stage of Ag induced T Cell differentiation+ blocks
their activation
Inhibits HSR 4 via relative selective action on T Cells
Inhibits expression of IL 2 R on T Cells
Inhibits T Cell dep B Cell response
Blocks transcription of genes for IL3, IL4
Inhibits histamine release from monocytes
Medical Use AI Disorders (transplantation, RA, early 1 DM)
Side Effects
Renal Toxicity!
Hyperlipidemia
New Immunosuppressants
Tacrolimus, Sirolimus (= rapamycin)
Are non AB macrolides
Tacrolimus is a calcineurin inhibitor (binds to FK binding protein)
Sirolimus is an mTOR inhibitor (= serine/threonine K)
Cytotoxic Agents as Immunosuppressants
Azathioprine: prodrug of 6 Mercaptopurine
Destroyes stimulated lymphoid cells
Inhibits nucleic acid synthesis in prolif. cells
Block cellular immunity, serum AB response
Side Effects: Hyperuricemia, depression BM, nausea
Contraindication: Allopurinol: blocks excretion of 6
mercaptopurine–> accumulates
Cyclophosphamide
Is an alkylating agent
Destroys proliferating lymphoid cells (B over T)
Methotrexate
Is a folate analogue
Inhibits T Cells (and B Cells)
Antibodies as Immunosuppressants
Background on Monoclonal ABs
A monoclonal AB is a product of a definitive clone
(plasmacytoma)
Mouse AB are immunogenic–> repeated admin not possible
Need to be chimeric or humanised AB because mouse ABs constant region don’t bind to human effector cells
Antibodies as Immunosuppressants
Names and characteristics
Basiliximab
Act against IL2 R–> inhibition of T Cell modulated resp
–> Used in transplantation
Infliximab
Anti TNF alpha mouse-human chimeric AB
Used in RA
Trastuzumab
AB against epidermal GF R (EGFR, HER2)
Rituximab
Anti CD 20 AB–> target is B Cell
Immunostimulants
Clinical Use
Drugs and their characteristics
Clinical Use:
Immunodeficiencies, chronic infectious diseases,
lymphomas
Levamisol:
Synthetic compound; increases T Cell med. HSR 4
Used for th of helminthiasis
BCG= Bacillus Calmette Guerin (attenuated M. Bovis)
Increases NK Cells
Local th: tumore of urinary bladder
Immunomodulators
Background
Immunomodulators: active agents of immunotherapy
Here–> cytokines
Cytokines:
produced by macrophages, lymphocytes, granulocytes,
endothelial cells, fibroblasts
Regulate inflammatory and immune response
Most of them not synthesized constitutively
Act on high affinity specific R
Main Cytokine Families:
IL
IFN: inducible cytokine (viral infection or cytokines)
INF Gamma: prod by lymphocytes; possible use: RA
TNF
CSF
Basic Concepts: RA
RA is a chronic progressive polyarthritis
causing significant systemic effects, deformation: joints
Aims of therapy:
Inhibition of disease activity
Improvement of physical condition
Slowing down of development of structural damages
Categories of Drug Therapy
Disease Modifying Antirheumatic Drugs (DMARDs)
NSAIDs
Steroids
Last two have no effect on progression of disease
DMARDs
Methotrexate (First Choice)
Folate Analogue; much lower dose than in cancer th
Mode of Action with low dose:
Inhibition of AICAR transformylase
Inhibition of thymidilate synthetase
Some effect on DHF reductase
Side Effects:
Dose related hepatotoxicity (can be reduced with folic
acid)
Nausea
Mucosal Ulceration
Pregnancy is a contraindication
DMARDs
Cyclosporine
Is a cyclic peptide AB
Bind cyclophyllin–> complex inhibits calcineurin (resp for lymphokine production)
Acts in
early stage of Ag induced T Cell differentiation+ blocks
their activation
Inhibits HSR 4 via relative selective action on T Cells
Inhibits expression of IL 2 R on T Cells
Inhibits T Cell dep B Cell response
Blocks transcription of genes for IL3, IL4
Inhibits histamine release from monocytes
Medical Use AI Disorders (transplantation, RA, early 1 DM)
Side Effects
Renal Toxicity –> monitor se Creatinine
Hyperlipidemia
Grape Fruit increase bioavailability
DMARDs
Cyclophosphamide
Is a alkylating agent
Major active metabolite: phosphamide mustard–> cross links DNA to prevent cell proliferation
Suppresses T and B Cell function by 30-40%
Side Effects:
BM suppression
Cystitis
