Lecture 4: Immunopharmacology

Question 1

Mechanisms of action of the classes of immunosuppressant drugs

Answer 1

1. Corticosteroids: Prednisolone
2. Cytotoxic Agents: Azathiaprine, Methotrexate, Cyclophosphamide, Mycophenolate Mofetil
3. Cyclosporine-like drugs: Cyclosporine, Tacrolimus, Sirolimus

Question 2

Prednisolone

Answer 2

Responses: 1. Lymphocytopenia and monocytopenia, Prevent neutrophil adherence to endothelium, Inhibit action of chemotactic factors
2. Interferes with macrophage antigen processing, blocks the actions of lymphokines, inhibits binding to Fc receptors

Toxicity: 1. Suppression of adrenal-pituitary axis (acute adrenal insufficiency on abrupt withdrawal
2. Cushing’s syndrome

Contraindication: in presence of existing infection

Uses: in combination with other drugs in autoimmune diseases and to prevent graft rejection

Question 3

Azathioprine

Answer 3

Mechanism: Metabolized to 6-mercaptopurine, a purine antimetabolite that inhibits purine biosynthesis thereby inhibitng DNA synthesis, inhibits De novo AND salvage pathways.

Pharmacology: Orally active

Used to inhibit rejection of transplanted organs and some autoimmune diseases such as rheumatoid arthritis

SE: Bone marrow depression, GI and hepatic toxicity

Question 4

Cyclophosphamide

Answer 4

Mechanism: alkylating agent that cross links DNA to kill replicating and nonreplicating cells.

Pharmacology: Toxic effect more pronounced on B cells so more effective in suppressing humoral immunity.
Orally active.

Use: treatment of autoimmune diseases in combination with other drugs.
NOT EFFECTIVE IN PREVENTING GRAFT REJECTION

SE: Bone marrow depression

Question 5

Methotrexate

Answer 5

Mechanism: inhibitor of dihydrofolate reductase, inhibits folate dependent steps in purine synthesis, inhibiting DNA synthesis

Use: treat autoimmune diseases

SE: Hepatic toxicity

Question 6

Mycophenolate Mofetil

Answer 6

Mechanism: Lymphocyte selective immunosuppressant by inhibiting IMP dehydrogenase (necessary for de novo purine synthesis w no effect on salvage pathway). Lymphocytes cannot make GMP via salvage. More selective than AZA or methotrexate but equally effective

Pharmacology: Orally active
Used with cyclosporine and corticosteroids to prevent renal allograft rejection (allowing lower dose of cyclosporine)

Use: treat autoimmune diseases– rheumatoid arthritis and refractory psoriasis

Contraindications: Active GI disease, reduced renal function and infections. Also pregnancy (loss and congenital malformations)

SE: infection, leukopenia, anemia

Question 7

Cyclosporine

Answer 7

Mechanism: binds to cellular receptor Cyclophilin and inhibits calcineurin (a calcium dependent phosphatase), blocking activation of transcription factor NFAT necessary for IL 2 production. Blocks T cell helper function.

Pharmacology: Orally active

Use: Prevent rejection of transplanted organs. some autoimmune diseases. more effective than other agents used with fewer side effects

SE: nephrotoxicity. Hepatotoxicity

Question 8

Tacrolimus

Answer 8

Mechanism: binds FK binding protein a cyclophilin related protein, same mechanism as cyclosporine. Spectrum is same but 50-100 more potent

SE: less nephro and hepatotoxicity

Question 9

Sirolimus

Answer 9

Mechanism: Inhibits T cell activaiton and proliferation downstream of IL-2. Binds FKBP-12, binds and inhibits mTOR (not calcineurin), this mTOR is a kinase involved in cell cycle progression blocking G1->S transition

Use: Same as cyclosporine. Coating of cardiac stents.