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IMMUNOSUPPRESSANT DRUGS  Immune system Is designed to protect the host from harmful foreign molecules. This system can result into serious problem. Allograft introduction can elicit a damaging immune response. Immune system include two main arms 1) Cell –mediated im...

IMMUNOSUPPRESSANT DRUGS  Immune system Is designed to protect the host from harmful foreign molecules. This system can result into serious problem. Allograft introduction can elicit a damaging immune response. Immune system include two main arms 1) Cell –mediated immunity. 2) Humoral (antibody –mediated immunity). Cell-mediated Immunity Involves ingestion& digestion of antigen by antigen-presenting cells. Activated TH cells secretes IL-2 IL-2 produced stimulates TH1 & TH2. TH1 produce TNF-β and IFN-γ which. Activate – NK cells (kill tumor & virus-infected cells). – Cytotoxic T cells (kill tumor & virus-infected cells). – Macrophages (kill bacteria). Cell-mediated Immunity Humoral Immunity B-lymphocytes bind to antigen and are induced by interleukins (IL-4 & IL-5) produced by TH2 which in turn causes B-cells proliferation & differentiation into: – memory cells – Antibody secreting plasma cells Humoral Immunity Mutual regulation of T helper lymphocytes TH1 interferon-γ: inhibits TH2 cell proliferation TH2 cells TH2 IL-10: inhibits TH1 cytokine production  Cytokines Cytokines are soluble, antigen-nonspecific signaling proteins that bind to cell surface receptors on a variety of cells. Cytokines include – Interleukins – Interferons (IFNs), – Tumor Necrosis Factors (TNFs), – Transforming Growth Factors (TGFs) – Colony-stimulating factors (CSFs).  IMMUNOSUPPRESSANT DRUGS I. inhibitors of cytokine (IL-2) production or action (Immunophilin ligands): 1) Calcineurin inhibitors Cyclosporine Tacrolimus (FK506) 2) Sirolimus (rapamycin). II. Inhibitors of cytokine gene expression – Corticosteroids III. Cytotoxic drugs Inhibitors of purine or pyrimidine synthesis (Antimetabolites): – Myclophenolate Mofetil – Leflunomide – Azathioprine – Methotrexate Alkylating agents Cyclophosphamide IV. Immunosuppressive antibodies that block T cell surface molecules – antilymphocyte globulins (ALG). – antithymocyte globulins (ATG). – Rho (D) immunoglobulin. – Muromonab-CD3 – Basiliximab – Daclizumab V. Interferon VI. Thalidomide I) Immunophilin ligands: – Inhibitors of cytokines (IL-2) production Calcineurin inhibitors Cyclosporine Tacrolimus (FK506) – Inhibitors of cytokines (IL-2) action Sirolimus (rapamycin).  CYCLOSPORINE Chemistry Cyclosporine is a fungal polypeptide composed of 11 amino acids. Mechanism of action: – Acts by blocking activation of T cells by inhibiting interleukin-2 production (IL-2). – Decreases proliferation and differentiation of T cells. – Cyclosporine binds to cyclophilin (immunophilin) intracellular protein receptors. – Cyclosporine- immunophilin complex inhibits calcineurin, a phosphatase necessary for dephosphorylation of transcription factor (NFATc) required for interleukins synthesis (IL-2). – NFATc (Nuclear Fcator of Activated Tcells). – Suppresses cell-mediated immunity. Pharmacokinetics: – Can be given orally or i.v. infusion – orally (25 or 100 mg) soft gelatin capsules, microemulsion. – Orally, it is slowly and incompletely absorbed. – Peak levels is reached after 1– 4 hours, elimination half life 24 h. – Oral absorption is delayed by fatty meal (gelatin capsule formulation) – Microemulsion ( has higher bioavailability-is not affected by food). – 50 – 60% of cyclosporine accumulates in blood (erythrocytes – lymphocytes). – metabolized by CYT-P450 system (CYP3A4). – excreted mainly through bile into feces, about 6% is excreted in urine. Therapeutic Uses: – Organ transplantation (kidney, liver, heart) either alone or with other immunosuppressive agents (Corticosteroids). – Autoimmune disorders (low dose 7.5 mg/kg/d). e.g. endogenous uveitis, rheumatoid arthritis, active Crohn’s disease, psoriasis, psoriasis, nephrotic syndrome, severe corticosteroid-dependent asthma. – Graft-versus-host disease after stem cell transplants Adverse Effects (Dose-dependent) Therapeutic monitoring is essential – Nephrotoxicity (increased by NSAIDs and aminoglycosides). – Hypertension, hyperkalemia. (K-sparing diuretics should not be used). – Liver dysfunction. – Hyperglycemia. – Viral infections (Herpes - cytomegalovirus). – Lymphoma (Predispose recipients to cancer) – Hirsutism – Neurotoxicity (tremor). – Gum hyperplasia. – Anaphylaxis after I.V. Drug Interactions Clearance of cyclosporine is enhanced by co- administration of Cyt P450 inducers (Phenobarbitone, Phenytoin & Rifampin ) rejection of transplant. Clearance of cyclosporine is decreased when it is co-administered with inhibitors erythromycin, ketoconazole, grapefruit juice cyclosporine toxicity. TACROLIMUS (FK506) a macrolide antibiotic produced by bacteria Streptomyces tsukubaensis. Chemically not related to cyclosporine both drugs have similar mechanism of action. The internal receptor for tacrolimus is immunophilin ( FK-binding protein, FK-BP). Tacrolimus-FKBP complex inhibits calcineurin. Kinetics Given orally or i.v. Oral absorption is variable and incomplete, reduced by fat. Half-life after I.V. form is 9-12 hours. Highly bound with serum proteins and concentrated in erythrocytes. metabolized by P450 in liver. Excreted mainly in bile and minimally in urine. USES as cyclosporine Organ and stem cell transplantation Prevention of rejection of liver and kidney transplants. Atopic dermatitis and psoriasis (topically). Toxic effects Nephrotoxicity (more than CsA) Neurotoxicity (more than CsA) Hyperglycemia ( require insulin). GIT disturbances Hperkalemia Hypertension Anaphylaxis NO hirsutism or gum hyperplasia Drug interactions as cyclosporine. What are the differences between CsA and TAC ? TAC is more favorable than CsA due to: TAC is 10 – 100 times more potent than CsA in inhibiting immune responses. TAC has decreased episodes of rejection. TAC is combined with lower doses of glucocorticoids. But TAC is more nephrotoxic and neurotoxic.  Sirolimus (Rapamycin) SRL is macrolide antibiotic. It is not a calcineurin inhibitor. Sirolimus inhibits the response of T cells to IL-2 and thereby blocks activation of T- & B-cells SRL blocks the progression of activated T cells from G1 to S phase of cell cycle (Antiproliferative action). It does not block the IL-2 production but blocks T cell response to cytokines. Inhibits B cell proliferation & immunoglobulin production. It binds to FK-BP and the formed complex binds to mTOR (mammalian Target Of Rapamycin). mTOR is serine-threonine kinase essential for cell cycle progression, DNA repairs, protein translation. Pharmakinetics Given orally and topically, reduced by fat meal. Extensively bound to plasma proteins metabolized by CYP3A4 in liver. Excreted in feces. Pharmacodynamics Immunosuppressive effects Anti- proliferative action. Equipotent to CsA. USES Synergistic action with CsA Solid organ allografts alone or combined with (CSA, tacrolimus, steroids, mycophenolate). Hematopoietic stem cell transplant recipients. Topically with cyclosporine in uveoretinitis. In halting graft vascular disease. in conjunction with coronary stents to prevent restenosis in coronary arteries following balloon angioplasty. Toxic effects Hyperlipidaemia (cholesterol, triglycerides). Thrombocytopenia Leukopenia Hepatotoxicity Hypertension GIT dysfunction  Inhibitors of cytokine gene expression Corticosteroids – Prednisone – Prednisolone – Methylprednisolone – Dexamethasone They have both anti-inflammatory action and immunosuppressant effects. Mechanism of action Anti-inflammatory action – Induce lipocortin-1 synthesis, which binds to cell membranes preventing the phospholipase A2. This leads to diminished eicosanoid production and cyclooxygenase expression – Decrease production of inflammatory mediators as prostaglandins, leukotrienes, histamine, PAF, bradykinin. – inhibit gene transcription of many inflammatory genes. Immunosuppressant action – suppress the cell-mediated immunity decrease production of cytokines IL-1, IL-2, interferon, TNF & decrease T lymphocyte proliferation. – Glucocorticoids also suppress the humoral immunity by reducing both B cell clone expansion and antibody synthesis Kinetics Can be given orally, parenterally, topically and by inhalation (asthma). Dynamics 1. anti-inflammatory and immunosuppresant. 2. Suppression of response to infection 3. Metabolic effects. Indications – Solid organ allografts & haematopoietic stem cell transplantation. – Autoimmune diseases as refractory rheumatoid arthritis, systemic lupus erythematosus, asthma – Acute or chronic rejection of solid organ allografts. Adverse Effects – Adrenal suppression – Osteoporosis – Hypercholesterolemia – Hyperglycemia – Hypertension – Cataract – Infection III. Cytotoxic drugs  Antimetabolites (Inhibitors of purine or pyrimidine synthesis) – Leflunomide – Azathioprine – Myclophenolate Mofetil – Methotrexate  Alkylating agents Cyclophosphamide  AZATHIOPRINE CHEMISTRY: – Derivative of mercaptopurine. – Prodrug. – Cleaved to 6-mercaptopurine then to 6-mercaptopurine nucleotide, thio-inosine monophosphate (nucleotide analog). – Inhibits de novo synthesis of purines required for lymphocytes proliferation. – Prevents clonal expansion of both B and T lymphocytes. Pharmacokinetics – orally or intravenously. – Widely distributed but does not cross BBB. – Metabolized in the liver to thiouric acid (inactive metabolite) by xanthine oxidase. – excreted primarily in urine. Drug Interactions: – Co-administration of allopurinol with azathioprine may lead to toxicity due to inhibition of xanthine oxidase by allopurinol. USES Acute glomerulonephritis Systemic lupus erythematosus Rheumatoid arthritis Crohn’ s disease. Autoimmune hemolytic anemia. Adverse Effects Bone marrow depression: leukopenia, thrombocytopenia. Gastrointestinal toxicity. Hepatic dysfunction. Increased risk of infections.  MYCOPHENOLATE MOFETIL – Is a semisynthetic derivative of mycophenolic acid from fungus source. – Prodrug; is hydrolyzed to mycophenolic acid. Mechanism of action: – Inhibits de novo synthesis of purines. – mycophenolic acid is a potent inhibitor of inosine monophosphate dehydrogenase (IMP), crucial for purine synthesis deprivation of proliferating T and B cells of nucleic acids. Pharmacokinetics: – Given orally, i.v. or i.m. – rapidly and completely absorbed after oral administration. – It undergoes first-pass metabolism to give the active moiety, mycophenolic acid (MPA). – MPA is extensively bound to plasma protein. – metabolized in the liver by glucuronidation. – Excreted in urine as glucuronide conjugate – Dose : 2-3 g /d CLINICAL USES: In solid organ transplantation – hematopoietic stem cell transplant patients. – Combined with tacrolimus as prophylaxis to prevent graft versus host disease. In autoimmune disorders: – Rheumatoid arthritis, & dermatologic disorders. ADVERSE EFFECTS: – GIT toxicity: Nausea, Vomiting, diarrhea, abdominal pain. – Leukopenia, neutropenia. – Lymphoma Contraindicated during pregnancy  LEFLUNOMIDE  antimetabolite immunosuppressant.  Pyrimidine synthesis inhibitor  Can be given orally  A prodrug  Active metabolite undergoes enterohepatic circulation.  Has long duration of action.  Approved only for rheumatoid arthritis Adverse effects 1. Elevation of liver enzymes 2. Renal impairment 3. Teratogenicity 4. Cardiovascular effects (tachycardia). Methotrexate – a folic acid antagonist – Orally, parenterally (I.V., I.M). – Excreted in urine. – Inhibits dihydrofolate reductase required for folic acid activation (tetrahydrofolate) – Inhibition of DNA, RNA &protein synthesis – Interferes with T cell replication. – In treatment of many neoplastic disorders including acute lymphoblastic leukemia. – Autoimmune disorders as rheumatoid arthritis & psoriasis and Croh’n disease Adverse effects – Pulmonary fibrosis – Nausea-vomiting-diarrhea – Alopecia – Bone marrow depression – Teratogenicity (X) Cyclophosphamide – Alkylating agent to DNA. – Prodrug, activated into phosphamide. – Is given orally& intravenously – Destroy proliferating lymphoid cells. – Anticancer in lymphomas. – Effective in autoimmune diseases – e.g rheumatoid arthritis – Systemic lupus erythrematosus. – Autoimmune hemolytic anemia Side Effects – Alopecia – Hemorraghic cystitis. – Bone marrow suppression – GIT disorders (Nausea –vomiting-diarrhea) – Sterility (testicular atrophy & amenorrhea)  Antibodies are sometimes used as a quick and potent immunosuppressive therapy to prevent the acute rejection reactions Polyclonal antibodies Antilymphocyte globulins (ALG). Antithymocyte globulins (ATG). Monoclonal antibodies - Rho (D) immunoglobulin. – Basiliximab – Daclizumab Antibodies Preparation 1. by immunization of either horses or rabbits with human lymphoid cells producing mixtures of polyclonal antibodies directed against a number of lymphocyte antigens (variable, less specific).  2. Hybridoma technology produce antigen-specific, monoclonal antibody (homogenous, specific). produced by fusing mouse antibody- producing cells with immortal, malignant plasma cells. Hybrid cells are selected, cloned and selectivity of the clone can be determined. Recombinant DNA technology can be used to replace part of the mouse gene sequence with human genetic material (less antigenicity- longer half life). Antibodies from mouse contain Muro in their names. Humanized antibodies contain ZU (humanized) or XI (chimeric) in their names.  Antilymphocyte globulins (ALG) &Antithymocyte globulins (ATG) Polyclonal antibodies obtained from plasma or serum of horses hyper-immunized with human lymphocytes. Binds to the surface of circulating T lymphocytes, which are phagocytosed in the liver and spleen giving lymphopenia and impaired T-cell responses & cellular immunity. Kinetics Given i.m. or slowly infused intravenously. Half life extends from 3-9 days. Uses Combined with cyclosporine for bone marrow transplantation. To treat acute allograft rejection. Steroid-resistant rejection. Adverse Effects: – Antigenicity. – Anaphylactic and serum sickness reactions (Fever, Chills, Flu-like syndrome). – Leukopenia, thrombocytopenia. – Risk of viral infection. Monoclonal antibodies Muromonab-CD3 Is a murine monoclonal antibody Prepared by hybridoma technology Directed against glycoprotein CD3 antigen of human T cells. Given I.V. Metabolized and excreted in the bile. Mechanism of action The drug binds to CD3 proteins on T lymphocytes (antigen recognition site) leading to transient activation and cytokine release followed by disruption of T-lymphocyte function, decreased immune response. Block killing by cytotoxic T cells. Prednisolone, diphenhydramine are given to reduce cytokine release syndrome. Uses Used for treatment of acute renal allograft rejection & steroid-resistant acute allograft To deplete T cells from bone marrow donor prior to transplantation. Adverse effects Anaphylactic reactions. Fever CNS effects (seizures) Infection Cytokine release syndrome (Flu-like illness to shock like reaction).  Monoclonal antibodies Basiliximab and Daclizumab  Obtained by replacing murine amino acid sequences with human ones.  Basiliximab is a chimeric human-mouse IgG (25% murine, 75% human protein).  Daclizumab is a humanized IgG (90% human protein).  Have less antigenicity & longer half lives than murine antibodies Mechanism of action IL-2 receptor antagonists Are Anti-CD25 Bind to CD25 (α-subunit chain of IL-2 receptor on activated lymphocytes) Block IL-2 stimulated T cells replication & T- cell response system Basiliximab is more potent than Daclizumab.  Given I.V. Half life Basiliximab (7 days ) Daclizumab (20 days) are well tolerated - only GIT disorders USES Given with CsA and corticosteroids for Prophylaxis of acute organ rejection in renal transplantation.  INTERFERONS Families: Type I IFNs ( IFN-α, β ): induced by viral infections leukocyte produces IFN-α Fibroblasts & endothelial cells produce IFN-β Type II IFN (IFN-γ): Produced by Activated T lymphocytes. Interferon types and uses: IFN- α: Hepatitis B & C infections Treatment of cancer (malignant melanoma) IFN-β : Multiple sclerosis IFN- γ : treatment of chronic granulomatous diseases  VI. INTERFERONS Recombinant DNA cloning technology. Antiproliferative activity. Antiviral action Immunomodulatory effect. USES: – Treatment of certain infections e.g. Hepatitis C (IFN- α ). – Autoimmune diseases e.g. Rheumatoid arthritis. – Certain forms of cancer e.g. melanoma, renal cell carcinoma. – Multiple sclerosis (IFN- β): reduced rate of exacerbation. – Fever, chills, myelosuppression.