Classification
- Calcineurin inhibitors: Cyclosporine, Tacrolimus
- Antiproliferative drugs: Azathioprine, Sirolimus,
Cyclophosphamide, Methotrexate, Mycophenolate mofetil (MMF)
- Antibodies: Muromonab-CD3
- Glucocorticoids: Prednisolone
- Immunostimulants: BCG, Interferons, Interleukin-2
1. Calcineurin Inhibitors
Cyclosporine
MOA Cyclosporine binds to an intracellular protein called cyclophilin in T-lymphocytes.
This cyclosporine–cyclophilin complex inhibits the enzyme calcineurin, a phosphatase required for T-cell activation.
Inhibition of calcineurin prevents dephosphorylation of NFAT (nuclear factor of activated T-cells), blocking its movement into the nucleus.
As a result, interleukin-2 (IL-2) and other cytokine gene transcription are suppressed, leading to decreased T-cell proliferation and immune response.
Therapeutic Uses: Organ transplantation, rheumatoid arthritis, psoriasis.
Adverse Effects: Nephrotoxicity, hypertension, tremors, hirsutism.
Contraindication/Interactions: Avoid with nephrotoxic drugs (aminoglycosides, NSAIDs); metabolized by CYP3A4 (interaction with erythromycin, ketoconazole).
Tacrolimus
MOA
Tacrolimus binds to an intracellular protein called FK-binding protein-12 (FKBP-12) in T-lymphocytes.
The tacrolimus–FKBP-12 complex inhibits the phosphatase enzyme calcineurin, which is essential for T-cell activation.
This inhibition prevents dephosphorylation and nuclear translocation of NFAT (nuclear factor of activated T-cells).
Consequently, the transcription of interleukin-2 (IL-2) and other cytokines is suppressed, leading to reduced T-cell proliferation and immune response.
Therapeutic Uses: Organ transplant rejection prophylaxis, atopic dermatitis.
Adverse Effects: Nephrotoxicity, neurotoxicity, hyperglycemia.
Contraindication/Interactions: CYP3A4 inhibitors (azole antifungals, macrolides) increase toxicity.
2 Antiproliferative Drugs
Azathioprine
MOA
Azathioprine is a prodrug that is converted into 6-mercaptopurine (6-MP) in the body.
·6-Mercaptopurine is further metabolized into active nucleotides that inhibit the de novo synthesis of purine bases (adenine and guanine).
This inhibition interferes with DNA and RNA synthesis, particularly in rapidly dividing cells.
As a result, proliferation of T and B lymphocytes is suppressed, leading to immunosuppressive effects.
Therapeutic Uses: Organ transplantation, autoimmune diseases.
Adverse Effects: Bone marrow suppression, hepatotoxicity.
Contraindication/Interactions: Avoid with allopurinol (inhibits xanthine oxidase and increases toxicity).
Sirolimus (Rapamycin)
MOA
Sirolimus binds to an intracellular protein called FK-binding protein-12 (FKBP-12).
The sirolimus–FKBP-12 complex inhibits the mammalian target of rapamycin (mTOR), a key kinase involved in cell cycle progression.
Inhibition of mTOR blocks signal transduction pathways activated by interleukin-2 (IL-2).
Consequently, T-cell proliferation and clonal expansion are suppressed, producing immunosuppressive effects.
Therapeutic Uses: Kidney transplant rejection prophylaxis, stent coating.
Adverse Effects: Hyperlipidemia, myelosuppression, delayed wound healing.
Contraindication/Interactions: CYP3A4 inhibitors increase sirolimus levels.
Cyclophosphamide
MOA:
Cyclophosphamide is a prodrug that is metabolized in the liver to its active alkylating metabolites (phosphoramide mustard and acrolein).
These active metabolites form covalent bonds with DNA, leading to cross-linking of DNA strands.
This cross-linking interferes with DNA replication and transcription, preventing cell division.
As a result, rapidly proliferating lymphocytes are destroyed, producing immunosuppressive and cytotoxic effects.
Adverse Effects: Bone marrow suppression, hepatotoxicity.
Contraindication/Interactions: Avoid with allopurinol (inhibits xanthine oxidase and increases toxicity).
Sirolimus (Rapamycin)
MOA
Sirolimus binds to an intracellular protein called FK-binding protein-12 (FKBP-12).
The sirolimus–FKBP-12 complex inhibits the mammalian target of rapamycin (mTOR), a key kinase involved in cell cycle progression.
Inhibition of mTOR blocks signal transduction pathways activated by interleukin-2 (IL-2).
Consequently, T-cell proliferation and clonal expansion are suppressed, producing immunosuppressive effects.
Therapeutic Uses: Kidney transplant rejection prophylaxis, stent coating.
Adverse Effects: Hyperlipidemia, myelosuppression, delayed wound healing.
Contraindication/Interactions: CYP3A4 inhibitors increase sirolimus levels.
Cyclophosphamide
MOA:
Cyclophosphamide is a prodrug that is metabolized in the liver to its active alkylating metabolites (phosphoramide mustard and acrolein).
These active metabolites form covalent bonds with DNA, leading to cross-linking of DNA strands.
This cross-linking interferes with DNA replication and transcription, preventing cell division.
As a result, rapidly proliferating lymphocytes are destroyed, producing immunosuppressive and cytotoxic effects.
Therapeutic Uses: Autoimmune disorders, nephrotic syndrome, cancers.
Adverse Effects: Myelosuppression, hemorrhagic cystitis.
Contraindication/Interactions: Avoid with other myelotoxic drugs; mesna reduces bladder toxicity.
Methotrexate
MOA
Methotrexate acts as a competitive inhibitor of the enzyme dihydrofolate reductase (DHFR).
Inhibition of DHFR prevents the conversion of dihydrofolate to tetrahydrofolate, which is essential for purine and thymidylate synthesis.
This blockade impairs DNA, RNA, and protein synthesis, particularly in rapidly dividing cells.
Consequently, T-cell proliferation and immune responses are suppressed, leading to immunosuppressive and antineoplastic effects.
Therapeutic Uses: Autoimmune diseases, psoriasis, cancers.
Adverse Effects: Hepatotoxicity, myelosuppression, mucositis.
Contraindication/Interactions: Avoid with NSAIDs; leucovorin reduces toxicity.
Mycophenolate Mofetil (MMF)
MOA:
Mycophenolate mofetil is a prodrug that is converted to its active form, mycophenolic acid (MPA) in the body.
MPA inhibits the enzyme inosine monophosphate dehydrogenase (IMPDH), which is crucial for de novo guanine nucleotide synthesis.
Since lymphocytes rely mainly on this de novo pathway for purine synthesis, guanine depletion selectively suppresses T- and B-cell proliferation.
As a result, immune responses are inhibited, producing potent immunosuppressive effects.
Inhibition of DHFR prevents the conversion of dihydrofolate to tetrahydrofolate, which is essential for purine and thymidylate synthesis.
This blockade impairs DNA, RNA, and protein synthesis, particularly in rapidly dividing cells.
Consequently, T-cell proliferation and immune responses are suppressed, leading to immunosuppressive and antineoplastic effects.
Therapeutic Uses: Autoimmune diseases, psoriasis, cancers.
Adverse Effects: Hepatotoxicity, myelosuppression, mucositis.
Contraindication/Interactions: Avoid with NSAIDs; leucovorin reduces toxicity.
Mycophenolate Mofetil (MMF)
MOA:
Mycophenolate mofetil is a prodrug that is converted to its active form, mycophenolic acid (MPA) in the body.
MPA inhibits the enzyme inosine monophosphate dehydrogenase (IMPDH), which is crucial for de novo guanine nucleotide synthesis.
Since lymphocytes rely mainly on this de novo pathway for purine synthesis, guanine depletion selectively suppresses T- and B-cell proliferation.
As a result, immune responses are inhibited, producing potent immunosuppressive effects.
Therapeutic Uses: Organ transplant rejection prophylaxis.
Adverse Effects: GI upset, leukopenia, infections.
Contraindication/Interactions: Antacids and cholestyramine reduce absorption.
3 Antibodies
Muromonab-CD3
MOA: ·
Adverse Effects: GI upset, leukopenia, infections.
Contraindication/Interactions: Antacids and cholestyramine reduce absorption.
3 Antibodies
Muromonab-CD3
MOA: ·
Muromonab-CD3 is a murine monoclonal antibody directed against the CD3 antigen found on the surface of T-lymphocytes.
Binding of Muromonab-CD3 to the CD3 receptor blocks antigen recognition and T-cell activation.
This interaction also causes initial activation followed by rapid depletion of circulating T-cells through complement-mediated lysis.
Consequently, cell-mediated immune responses are suppressed, helping to prevent acute transplant rejection.
Binding of Muromonab-CD3 to the CD3 receptor blocks antigen recognition and T-cell activation.
This interaction also causes initial activation followed by rapid depletion of circulating T-cells through complement-mediated lysis.
Consequently, cell-mediated immune responses are suppressed, helping to prevent acute transplant rejection.
Therapeutic Uses: Acute transplant rejection.
Adverse Effects: Cytokine release syndrome, fever, chills.
Contraindication/Interactions: Hypersensitivity reactions; avoid concurrent immunosuppressants initially.
4 Glucocorticoids
Prednisolone
MOA
Adverse Effects: Cytokine release syndrome, fever, chills.
Contraindication/Interactions: Hypersensitivity reactions; avoid concurrent immunosuppressants initially.
4 Glucocorticoids
Prednisolone
MOA
Prednisolone binds to intracellular glucocorticoid receptors, forming a complex that translocates into the nucleus.
This complex modulates gene transcription by inhibiting pro-inflammatory cytokine genes and promoting anti-inflammatory protein synthesis.
As a result, it suppresses T-cell proliferation and reduces the activity of macrophages and other immune cells.
Overall, immune and inflammatory responses are diminished, producing potent immunosuppressive and anti-inflammatory effects.
Therapeutic Uses: Autoimmune diseases, organ transplantation, inflammatory disorders.
Adverse Effects: Hyperglycemia, osteoporosis, Cushingoid features.
Contraindication/Interactions: Live vaccines; may increase risk with NSAIDs (GI bleed).
Immunostimulants
BCG (Bacillus Calmette–Guérin)
MOA:
BCG is a live attenuated strain of Mycobacterium bovis that is taken up by macrophages.
It activates macrophages and dendritic cells, enhancing antigen presentation.
This activation stimulates T-cell mediated immune responses, particularly Th1-type immunity.
As a result, cell-mediated immunity is enhanced, providing protection against tuberculosis and certain cancers (e.g., bladder cancer).
Therapeutic Uses: Immunization against tuberculosis, bladder cancer therapy.
Adverse Effects: Local inflammation, fever, malaise.
Contraindication: Immunocompromised state, active TB infection.
Interferons (α, β, γ)
MOA:
This complex modulates gene transcription by inhibiting pro-inflammatory cytokine genes and promoting anti-inflammatory protein synthesis.
As a result, it suppresses T-cell proliferation and reduces the activity of macrophages and other immune cells.
Overall, immune and inflammatory responses are diminished, producing potent immunosuppressive and anti-inflammatory effects.
Therapeutic Uses: Autoimmune diseases, organ transplantation, inflammatory disorders.
Adverse Effects: Hyperglycemia, osteoporosis, Cushingoid features.
Contraindication/Interactions: Live vaccines; may increase risk with NSAIDs (GI bleed).
Immunostimulants
BCG (Bacillus Calmette–Guérin)
MOA:
BCG is a live attenuated strain of Mycobacterium bovis that is taken up by macrophages.
It activates macrophages and dendritic cells, enhancing antigen presentation.
This activation stimulates T-cell mediated immune responses, particularly Th1-type immunity.
As a result, cell-mediated immunity is enhanced, providing protection against tuberculosis and certain cancers (e.g., bladder cancer).
Therapeutic Uses: Immunization against tuberculosis, bladder cancer therapy.
Adverse Effects: Local inflammation, fever, malaise.
Contraindication: Immunocompromised state, active TB infection.
Interferons (α, β, γ)
MOA:
Interferons bind to specific cell surface receptors on target cells.
This binding triggers intracellular signaling pathways that induce the expression of antiviral and immunomodulatory proteins.
These proteins inhibit viral replication and modulate immune cell activity, including activation of NK cells and macrophages.
Consequently, immune defense against viral infections and tumor cells is enhanced.
This binding triggers intracellular signaling pathways that induce the expression of antiviral and immunomodulatory proteins.
These proteins inhibit viral replication and modulate immune cell activity, including activation of NK cells and macrophages.
Consequently, immune defense against viral infections and tumor cells is enhanced.
Therapeutic Uses: Chronic hepatitis B & C, Kaposi’s sarcoma, multiple sclerosis.
Adverse Effects: Flu-like symptoms, depression, myelosuppression.
Contraindication: Severe liver disease, autoimmune disorders.
Interleukin-2
MOA:
IL-2 is a cytokine that binds to IL-2 receptors on T-cells and NK cells.
This binding stimulates proliferation and differentiation of cytotoxic T-cells and natural killer (NK) cells.
It also enhances the cytolytic activity of these immune cells, increasing their ability to destroy infected or malignant cells.
As a result, cell-mediated immunity is strengthened, improving immune surveillance and tumor control.
Therapeutic Uses: Renal cell carcinoma, malignant melanoma.
Adverse Effects: Hypotension, capillary leak syndrome.
Contraindication: Cardiac and pulmonary diseases.
Adverse Effects: Flu-like symptoms, depression, myelosuppression.
Contraindication: Severe liver disease, autoimmune disorders.
Interleukin-2
MOA:
IL-2 is a cytokine that binds to IL-2 receptors on T-cells and NK cells.
This binding stimulates proliferation and differentiation of cytotoxic T-cells and natural killer (NK) cells.
It also enhances the cytolytic activity of these immune cells, increasing their ability to destroy infected or malignant cells.
As a result, cell-mediated immunity is strengthened, improving immune surveillance and tumor control.
Therapeutic Uses: Renal cell carcinoma, malignant melanoma.
Adverse Effects: Hypotension, capillary leak syndrome.
Contraindication: Cardiac and pulmonary diseases.
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