Immunopharmacology Flashcards
Steps in cell mediated cytotoxicity (6)
- Macrophage processing of antigen
- Presentation of antigen to T-lymphocyte
- Expression of IL-1 and IL-2 receptors on T-lymphocytes
- Secretion of IL-1 by macrophages
- IL-1 promotes IL-2 release from helper T-lymphocytes
- IL-2 acts on lymphocytes to promote replication of cytotoxic cells
Uses of Immunosuppression
Prevention of allograft rejection
Treatment of autoimmune diseases
Immunosupressant Drugs
- Mechanisms
- Uses
- Side Effects
- Mechanisms: block proliferation or interaction of immune cells or block actions or release of cytokines
- Uses: treat autoimmune diseases and prevent allograft rejection
- Side Effects: rapidly proliferating cells—bone marrow, liver or GI tract
Corticosteroids (Effect on immunity)
Reduce access of cells to target tissue
Prednisolone: Cell traffic or accumulation
- Lymphocytopenia and monocytopenia - redistribution of cells out of vascular space
- Prevent neutrophil adherence to endothelium
- Inhibit action of chemotactic factors
Prednisolone: Cell Function
- Interferes with macrophage antigen processing
- Blocks the actions of lymphokines
- Inhibits binding to Fc receptors
Prednisolone is used in combination with other drugs to treat ________ ________ and to prevent ______ _________
Autoimmune diseases; graft rejection
Prednisolone: Toxicity
- Suppression of adrenal-pituitary axis. Acute adrenal insufficiency on abrupt withdrawal
- Cushing’s syndrome
Prednisolone is contraindicated in the presence of ___________
Existing infection
Cytotoxic agents characteristics (4)
- These drugs kill rapidly proliferating immune cells
- Kill high percentage of precursor cells
- Relevant clone stimulated by antigen will be selectively killed
- Administered in low daily dosage to block immunoproliferation continually
Azathioprine
Metabolism:
Administration:
Function:
Uses:
Side Effects:
Metabolism: Metabolized to 6-mercaptopurine
Administration: Orally active
Function: Purine anti-metabolite that inhibits purine biosynthesis (both De Novo and Salvage pathways)
Uses: Inhibits rejction of transplanted organs and in some autoimmune diseases such as rheumatoid arthritis
Side Effects: Bone marrow depression; gastrointestinal and hepatic toxicity
Azathioprine mechanism of action
- 6-Mercaptopurine is converted to Thioinosinic Acid which blocks the production of AMP and GMP from IMP
- Thioinosinic Acid is further converted to ThioGMP which blocks synthesis of RNA and DNA by GMP
Cyclophosphamide
Administration:
Function:
Uses:
Side Effects:
Toxicity:
Administration: Orally active
Function: An alkylating agent that results in cross linking of DNA to kill replicating and non-replicating cells
Uses: Treatment of autoimmune diseases in combination with other drugs; not effective in preventing graft rejection
Side Effects: Bone marrow depression is major side effect
Toxicity: Toxic effect more pronounced on B cells (humoral immunity)
Methotrexate
Function:
Uses:
Toxicity:
Function: Inhibitor of dihydrofolate reductase - inhibits folate dependent steps in purine synthesis - inhibits DNA synthesis
Uses: Used to treat autoimmune diseases
Toxicity: Hepatic toxicity
Methotrexate mechanism of action
Conversion of dihydrofolate to its active form, tetrahydrofolate, is blocked by MTX inibition of enzyme dihydrofolate reductase (DHFR).
Mycophenolate Mofetil
Metabolism:
Administration:
Uses:
Function:
Side Effects:
Metabolism: Metabolized to active mycephenolic acid
Administration: Orally active
Uses: To treat autoimmune diseases - rheumatoid arthritis and refractory psoriasis
Function: Used w/ cyclosporine and corticosteroids to prevent renal allograft rejection (less toxicity)
Side Effects: Infection, leukopenia, anemia - should not be used with pregnancy (assoc. w/ pregnancy loss)
Mycophenolate Mofetil mechanism of action
Lymphocyte selective immunosupressant
- Inhibits IMP dehydrogenase: IMP →GMP (no effect on salvage pathway)
- Lymphocytes cannot make GMP via salvage pathway
- Inhibits lymphocyte proliferation and expression of cell surface molecules
- More selective than azathioprine or methotrexate
Cyclosporine
Classification:
Administration:
Uses:
Side Effects:
Classification: A lipophilic peptide antibiotic
Administration: Orally Active
Uses: To prevent rejection of transplanted organs. More effective than other agents used with fewer side effects - used for some autoimmune diseases
Side Effects: Nephrotoxicity is a major side effect (25-40% of patients with high doses) - Hepatotoxicity possible
Cyclosporine Mechanism of Action
- Binds to a cellular receptor and inhibits calcium dependent phosphatase - blocks activation of transcription factor (NFAT) necessary for IL-2 production
- Inhibits mRNA synthesis that codes for lymphokines as IL-2
- By blocking IL-2 synthesis, it blocks T-cell helper function so inhibits T-cell proliferation and cytotoxicity
- Does not alter T-cell response to IL-2
- Selective in its action
Tacrolimus
Function:
Action:
Toxicity:
Function: Binds FK binding protein (FK BP-12), a cyclophilin-related protein. Same mechanism of action as cyclosporine
Action: Same as cyclosporine but 50-100 times more potent
Toxicity: Less nephro- and hepatotoxicity
Cyclosporine and Tacrolimus Pathway
Sirolimus
Function:
Action:
Uses:
Function: Inhibits T-cell activation and proliferation downstream of IL-2
Action: Binds FKBP-2 - complex does not bind calcineurin or affect calcineurin activity - binds and inhibits mTOR, a kinase involved in cell cycle progression - blocks G1 → S transition
Uses: Same as cyclosporine; coating of cardiac stents
Sirolimus Pathway
The Big Picture
