Download Pharm MD 4 (Immunosuppressants)

IMMUNOSUPPRESSANT
THERAPY
DR FATAI OLUYADI
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IMMUNOSUPPRESSANT (OVERVIEW)
These drugs prevent the rejection of transplanted organ as well as for the
treatment of autoimmune diseases.
Many of them interfere with the lymphocyte cell signalling pathways
Common side effects include immunosuppression and susceptibility to
Opportunistic infections such as Cytomegalovirus infections.
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GROUPS
SELECTIVE INHIBITORS OF CYTOKINE PRODUCTION AND FUNCTION
IMMUNOSUPPRESSIVE ANTIMETABOLITES
ANTIBODIES
CORTICOSTEROIDS
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Calcium/Calcineurin Pathway
Cyclosporine
Tacrolimus
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SELECTIVE INHIBITORS OF CYTOKINE
PRODUCTION AND FUNCTION
CYCLOSPORINE
TACROLIMUS
SIROLIMUS
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CYCLOSPORINE
Inhibits calcineurin by binding cyclophilins . This prevents the transcription of
genes responsible for the production of Interleukin 2. Also causes a decrease in
expression of Interferon-gamma. Cummulatively results in decreased activity
and decreased growth of T-Lymphocytes.
Clinical uses
This was the first widely used drug to prevent transplant rejection. It is also used
to treat autoimmune diseases such as psoriasis and Rheumatoid arthritis. Used
as an ophthalmic solution in the treatment of dry eyes.
Predominantly metabolized by cytochrome CYP3A4. Watch drug interactions
wth CYP inhibitors and inducers.
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CYCLOSPORINE
Adverse effects:
Dose-limiting nephrotoxicity
Neuropathy
Gingival hyperplasia
Hypertension
Hyperlipidemia
Hirsuitism
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TACROLIMUS
Similar to Cyclosporine but binds to FK binding proteins to inhibit calcineurin.
Prevents Interleukin 2 transcription and blocking activation and growth of T-cells.
Used for transplant rejection prophylaxis and autoimmune diseases e.g ulcerative
colitis and vitiligo.
Adverse effects
Similar to Cyclosporine with the Nephrotoxicity and Neurotoxicity. Can increase
risk of diabetes. It does not cause any hirsuitism and ginigival hyperplasa
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SIROLIMUS(RAPAMYCIN)
Inhibits mTOR, a serine/threonine kinase involved in cell growth, proliferation
and motility. Involved also in T-cell growth and activation.
Clinical Uses
Anti-rejection drug that is used most commonly in kidney transplant recipients.
Preferred over cyclosporine and tacrolimus for kidney transplant patients due to
the latter drugs nephrotoxicity. Sirolimus does not cause nephrotoxicity.
It is also used as a coating on cardiac stents to prevent restenosis following ballon
angioplasty.
Adverse effects: Can cause Interstitial Pneumonitis, Anemia, Thrombocytopenia,
Leukopenia, Insulin resistance and hyperlipidemia.
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IMMUNOSUPPRESSIVE
ANTIMETABOLITES
AZATHIOPRINE
MYCOPHENOLATE MOFETIL
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AZATHIOPRINE
This drug is a precursor of 6-Mercaptopurine. Both drugs will inhibit PRPP
amidotransferase in the purine synthesis pathway
Clinical uses
To prevent transplant rejection. Also used in the treatment of autoimmune
diseases such as rheumatoid arthritis, crohn’s disease, glomerulonephritis.
Adverse effects: Leukopenia, anemia, thrombocytopenia.
*Toxicity is increased by Allopurinol
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MYCOPHENOLATE MOFETIL
This drug inhibits 5’-monophosphate dehydrogenase, an enzyme in the purine
synthesis pathway, specifically for Guanine. Prevents DNA synthesis and
decrease in proliferation of immune cells.
Clinical use
Used fpr prevention of allograft rejection. Also used for the treatment of
autoimmune diseases.
Adverse effects: Opportunistic infections and cytopenias are the most common
serious adverse effects.
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ANTIBODIES
ANTITHYMOCYTE GLOBULINS
MUROMONAB-CD3 (OKT3)
DACLIZUMAB/BASILIXIMAB
ALEMTUZUMAB
ADALIMUMAB /INFLIXIMAB
ECULIZUMAB
NATALIZUMAB
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ANTITHYMOCYTE GLOBULINS
These are antibodies developed against thymocytes(T-cell precursors).
The antibodies bound to these developing T-cells trigger immune cell activity
against these cells via complement mediated destruction, antibody dependent
cytotoxicity, apoptosis and opsonisation.
Clinical uses:
Combine with immune suppressive agents to prevent early allograft rejection, to
treat severe rejection episodes or corticosteroid-resistant acute rejection.
Adverse effects include chills, fever, leukopenia and thrombocytopenia
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MUROMONAB
Monoclonal antibody directed against CD3 glycoproteins on on human T-cells.
Prevents Signal transduction and activation of the T-cells.
Clinical uses
Treatment of of acute rejection of renal allografts as well as for corticosteroidresistant acute allograft rejection in cardiac and hepatic transplant patients.
Adverse effects
Anaphylactoid reactions may occur, CNS effects such as seizures,
encephalopathy, cerebral edema, asceptic meningitis, and headache may occur.
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DACLIZUMAB/BASILIXIMAB
These are Monoclonal antibodies against Interleukin 2 receptor. Prevents T-cell
proliferation and activation.
Clinical uses
Used for prophylaxis of acute rejection in renal transplant in combination with
cyclosporine. Not used in the treatment of ongoing transplant rejection.
Adverse effects: GI toxicity. Edema, Hypertension and tremors can also be seen.
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ALEMTUZUMAB
Monoclonal antibody directed against CD52. Exerts its effect by causing
profound depletion of T cells from the peripheral circulation.
Clinical uses
It is mainly used for the treatment of Refractory Chronic lymphocytic
Lymphoma, however it can be used in combination with Sirolimus to prevent
organ transplant rejection.
Adverse effects include Neutropenia, anemia and rarely Pancytopenia.
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ADALIMUMAB/INFLIXIMAB
Humanized monoclonal antibody directed against tumor necrosis factor alpha.
Clinical uses
Autoimmune diseases: Rheumatoid arthritis, Ankylossing spondylitis, Psoriasis,
Crohn Disease, Ulcerative colitis.
Adverse effects: Risk of bone marrow suppression, with increased rate of
serious infections. Reactivation of hepatitis B, Fungal Infections and
Tuberculosis.
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MISCELLANEOUS
ECULIZUMAB
Antibody against complement protein C5. Used in the treatment of Paroxysmal
Nocturnal Hemoglobinuria
NATALIZUMAB
Antibody against Alpha4-integrin. Used in the treatment of Multiple sclerosis
and Crohn’s disease. Risk of Progressive Multifocal Leukoencephalopathy by JC
virus.
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CORTICOSTEROIDS
REFER TO LECTURE ON ADRENOCORTICAL PHARMACOLOGY
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