Pharmacology: Immunosuppressants - Mechanisms Of Action

Front 1

What is the mechanism of action of the glucocorticoid drugs (prednisone, prednisolone)?

Back 1

Corticosteroids:
They mimic cortisol in the body. It works by regulating gene transcription of MANY things. Specifically:
Less production of cytokines (interleukins and interferons, etc.),
Less production of chemokines (signals that direct cell movement to a location: chemotaxis).
Decreased eicosanoid production (immune signalling molecules made by oxidation of essential fatty acids), Decreased accumulation of leukocytes: white blood cells= eosinophils, neutrophils, basophils, T-cells, B-cells, Natural killer cells, and monocytes (pre-macrophages),
Decreased vascular permeability.
Overall the effect is immunosuppressive.

Front 2

What is the mechanism of action of the calcineurin inhibitor drugs (cyclosporin, tacrolimus)?

Back 2

Calcineurin inhibitors:
These block the binding of calcineurin to cyclophillin (aka FKBP) within T-cells. This prevents the activation of nuclear factor (NFAT), a transcription factor which turns on IL-2 gene expression. IL-2 generally signals T-cell proliferation; but in the case of calcineurin inhibitors, IL-2 expression is down-regulated leading to less T-cell proliferation.

Front 3

What is the mechanism of action of sirolimus (an antiproliferative and antimetabolic drug)?

Back 3

mTOR inhibitors:
Blocks the binding of mTOR to FKBP, a pathway generally induced by IL-2 receptor binding. By blocking a protein kinase involved in cell cycle progression, this blocks T-cell activation and proliferation.

Front 4

What is the mechanism of action of azathioprine (an antiproliferative and antimetabolic drug)?

Back 4

Purine synthesis inhibitors:
A pro-drug which is converted to active metabolites 6-mercaptopurine and 6-thioinosinic acid.
Causes inhibition of synthesis of purines (adenine and guanine) which causes false nucleotide incorporation into DNA. The end effect is inhibiting the proliferation of cells, particularly leukocytes (white blood cells= eosinophils, neutrophils, basophils, T-cells, B-cells, natural killer cells, and monocytes.)

Front 5

What is the mechanism of action of mycophenolate mofetil (an antiproliferative and antimetabolic drug)?

Back 5

Inosine monophosphate dehydrogenase inhibitors:
"Mycophenolate is an inhibitor of inosine monophosphate dehydrogenase and de novo pathway of guanine nucleotide synthesis. B and T cells are highly dependent on this pathway, while other cells have redundant pathways they can use."-Bild

Front 6

What is the mechanism of action of cyclophosphamide (an antiproliferative and antimetabolic drug)?

Back 6

Nitrogen mustard alkylating agents:
It is a prodrug, activated in cells with low levels of ALDH to phosphoramide mustard. "Phosphoramide mustard forms DNA crosslinks both between and within DNA strands at guanine N-7 positions (known as interstrand and intrastrand crosslinkages, respectively). This is irreversible and leads to cell death."-Wikipedia

Front 7

What is the mechanism of action of antithymocyte globulin (an antilymphocyte drug)?

Back 7

Immunosuppressant antibodies:
Purified gamma globulin from rabbits against human thymocytes. These are cytotoxic antibodies which bind receptors on T-lymphocytes (T-cells).

Front 8

What is the mechanism of action of muromonab CD3 (OKT3) (an antilymphocyte drug).

Back 8

Anti-CD3 Monoclonal Antibodies:
Blocks antigen recognition on T-cell receptor complex.
"Antibodies directed against the epsilon chain of the T cells receptor CD3.
Treatment induces rapid internalization of the TCR and is followed by depletion and extravasation of T cells from the blood and lymphoid organs (redistribution to the lungs)"

Front 9

What is the mechanism of action of the IL-2 receptor antagonists (basiliximab and daclizumab)?

Back 9

Anti-IL-2 (CD25) Receptor Antibodies:
These are humanized, chimeric, monoclonal antibodies which bind the alpha chain (CD25) of the IL-2 receptor on T-cells, blocking IL-2-mediated T-cell activation, and inhibiting clonal expansion.