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Immunosuppressants Prof. Alhaider, 1431 H Definition

Immunosuppressants Prof. Alhaider, 1431 H Definition Clinical Uses (Organ transplants & Autoimmune diseases) Pre-requisite to understand immunosuppressive drugs (Basic immunology). Review of immune system (see Table 56-1) Cell mediated vs humoral immunity Importance of cytokines

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Immunosuppressants Prof. Alhaider, 1431 H Definition

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  1. Immunosuppressants Prof. Alhaider, 1431 H Definition Clinical Uses (Organ transplants & Autoimmune diseases) Pre-requisite to understand immunosuppressive drugs (Basic immunology). Review of immune system (see Table 56-1) Cell mediated vs humoral immunity Importance of cytokines Immunophilins Calcineurin

  2. Classification of Immunosuppressant (Based on Mechanism of Action) • A) Antiprolifirative Agents 1) Drugs Acting on Immunophilins: a) Selective Inhibitors of Cytokine production ) (Calcineurin Inhibitors) (e.g:Cyclosporine; Tacrolimus) b) Inhibitor of cytokine function (e.g. Sirolimus). 3) Antimetabolites (Azathioprine; Mycophenolate Mofetil) 4) Alkylating Agents (Cyclophosphamide) B) Lymphocyte Depletion Agents 1) Corticosteroids 2. Immunosuppressive Antibodies a) Polyclonal Antibodies (Antilymphocyte Globulin) b) Monoclonal Antibodies (Selective inhibitors of IL2 (Basiliximab; Daclizumab)

  3. Non-selective Corticosteroids Prednisone (PO) & Methylprednisolone (IV) Antimetabolite (DNA synthesis inhibitors) Azathioprine & Myclophenolate mofetil Immunoglobulins Anti-lymphocyte antibodies Selective Calcineurin Inhibitors Cyclosporine Tacrolimus (Rapamycin) Selective IL-2 Receptor antagonists Basiliximab, Daclizumab & Infliximab Mamalian target of Rapamycin (mTOR) inhibitors Sirolimus Immunosuppressant Classes

  4. Selective Inhibitors of Cytokine Production (Drugs Acting on Immunophilins) • 1) Cyclosporine (Cyclic peptide from Soil Fungus (1971) • MOA: (See Figure 40.4) • CsA binds to cyclophillin forming a comlex Bind to Calcineurin dephosphorylationNFATc Synthesis of IL 2 proliferation of T cells • Thus, decreases the level of IL-2, the primary chemical stimulus for increasing the number of T lymphocytes • Note: Suppress only cell immunity with no effect on humoral immunity.

  5. PK • CsA available as oral (capsule) or parental (i.v) • Oral bioavailability (20-50%), it undergoes extensive hepatic metabolism by CytP450 (CYP3A4) (Affected by some drugs EXAMPLES) and mainly excreted in the bile.

  6. Clinical Uses of Cyclosporine: • 1) Drug of choice for preventing organ transplant rejection in combination with steroids and other immunosuppressants. • 2) Severe active rheumatoid arthritis, as alternative for methotrexate • 3) Lower doses (7.5 mg/kg/d) for autoimmune diseases (Uveitis; RA; early Rx of DM 1) • 3) Psoriasis and asthma ?. • Side Effects (remember most immunosuppressant are very toxic) • Dose-dependent nephrotoxicity ( Risk of Rejection); enhanced of given with other nephrotoxic drugs (Aminoglycosides; NSADs) • Hepatotoxicity • Neurotoxicity as tremor and hallucination • Infection How? • Lymphoma and cancer How? • Hypertension; hyperlipedemia; Hyperkalemia; D.M; Osteoporosis Hirsutism and gum hyperplacia (So What)

  7. 2. Tacrolimus (FK 506): • More potent than Cyclosporine • MOA: Similar to Cyclosporine (Calcineurin Antagonist) but it bind to different immunophilin (FKBP) Figure 40.6. • PK: Almost Similar to Cyclosporine • Side Effects: differ from Cyclosporine, that it ((Tac) has no hirsutism or gum hyperplasia but may show more hyperglycemia than cyclosporine. • Note: It is like cyclosporine, could lead to nephrotoxicity and hyperglycemia (more hyperglycemia than cyclosporine) , and hyperlipedemia.

  8. Clinical uses of Tacrolimus: • Preferred over CsA because: • of more potency (50-100 times more potent than cyclosporine). • lower rejection episodes, • and lower doses of glucocorticoids are used with lower side effects • Better first choice for woman? • Severe refractory atopic dermatitis, local application of an ointment • An ointment for psoriasis. • 3. Sirolimus (RapamycinMaclolides) • MOA: • 1) Binds to the same immunophilin as Tacrolimus, but does not form a complex with calcineurin, instead, it binds to mTOR (Mammalian Target of Rapamycin) which is essential for many cellular functions (See Figure 40.6) • 2) Potent inhibitor of B-cell proliferation and immunoglobulin production (humor immunity)

  9. 3. Sirolimus (Rapamycin Maclolides) • MOA: • 1) Binds to the same immunophilin as Tacrolimus, but does not form a complex with calcineurin, instead, it binds to mTOR (Mammalian Target of Rapamycin) which is essential for many cellular functions (See Figure 40.6) • 2) Sirolimus does not affect IL-2 production, unlike CsA & TAc, rather inhibits T-cell response to it (Blocks cytokine-stimulated cell proliferation) • 3) Potent inhibitor of B-cell proliferation and immunoglobulin production (humor immunity)

  10. Uses of Sirolimus: • 1) can be used together with cyclosporine (to increases the activity of cyclosporine for organ transplanted patients. • 2) As replacement of cyclosporine if transplanted patient developed cancer of skin or lips. • 3) used in cardiac catheter stint to prevent stenosis?? • 4) as an ointment for atopic dermatitis and psoriasis • Side Effects: • 1) Pneumonitis • 2) hyperlipedemia (more then calcineurin-antagonist)

  11. Antiproliferatives (Continue…) • 2. Antimetabolites (Cytotoxic Drugs) • 1) Azathioprine: is a prodrug of mercaptopurine. • Cytotoxic, rarely used as chemotherapeutic drug, but commonly used for immunosuppression. • It is a pro-drug converted in the body to the active metabolite, 6-mercaptopurine and thioinosinic acid. • MOA: (see Figure) • Simply, it inhibits purine synthesis (antimetabolite), thus interfering with nucleic acid metabolism and lead to inhibition of the proliferation of leukocytes and lymphocytes. • Why it is considered as cytotoxic agent? • Because the purine analog of Azathioprine can destroy lymphoids cells. • Why it is very important to know the structure of azathioprine?.

  12. Metabolic pathway for azathioprine 6-thiouracil (-) Xanthine Alloburinol Oxidase Nonenzymatic HPRT AZA 6-MP thioiosinic acid 6-thioguanine (TIMP) ( 6-TG) TPMT TPMT 6-MMP 6-MMP ribonucleides

  13. Cliniclal Uses of Azathioprine (ImuranR) • 1) maintenance of renal allograft and other transplantations together with steroids and cyclosporine. • 2) Can be used for glomerulonephtitis and SLE; RA; Crohn’s disease and multiple sclerosis. • Side Effects • 1) it is like cyclosporine, not teratogenic (Unlike TAC or Siro) but carcinogenic if given together with alkylating agents. (here higher doses are used as compared to autoimmune diseases. • 2) strong bone marrow suppression (Leucopenia; anemia; thrombocytopenia How? • 3) Hepatic dysfunction as increase AP and mild jaundice. • 4)Hypersensitivity reactions (as rashes, fever, diarrhea) Why?.

  14. Adverse Effects: bone marrow suppression (leukopenia, thrombocytopenia, anemia), hepatotoxicity, • Combination with ACEIs or cotrimoxazole can cause severe leukopenia in renal transplants • It can be given both orally and by IV

  15. 2) Mycophenolate Mofetil (CellceptR) • The most important discovery among the immunosuppressant agents. • MOA: (See Figure) • Mycophenolic acid acts as non-competitive, selective 7 reversible inhibitor of inosine monophosphate dehydrogenase • Decreases GMP, which is a key enzyme in the de novo pathway of purine synthesis. This leads to suppression of both B and T lymphocyte activation. • PK: Good oral absorption; • Side Effects • Less than azathioprine, Bone marrow suppresion (leukopenia and anemia); NV and diarrhea (decresed by Enteric-coated form). • Unlike azathiorine it is teratogenic.

  16. Clinical Uses • 1) As a replacement for the more cytotoxic drug, azathioprine in renal allograft patients as well as liver, heart et act. Why? • As replacement of azathioprine or cyclophosphamide for autoimmune diseases (RA, SLE (especialy before lupus nephritis); Glomerulonephritis • Has good oral bioavailability • Note: in renal or liver transplant, patients may take the followings: • Corticosteriods as prednisolone (Low dose) + cyclosporine or Tac + Mycophenolate Mofetil

  17. 3. Lefunomide: - A Pro-drug of an inhibitor ofn PYRIMIDINE synthesis rather than purine like azathioprine and mycophenolate. • Orally active used only for RA • Side effects: Alopecia; increase LFT, nephrotoxicity, teratogenicity. • 3. Alkylating Agents (e.g. Cyclophosphamide) • The most potent immunosuppressant • Destroys proliferating lymphoid cells (cytotoxic agent) also alkylate some resting cells (Thus, it is very toxic) • Clinical Uses: • Before the discovery of Mycophenolate, cyclophosphamide was the drug of choice for treatment of many autoimmune diseases like SLE; autoimmune hemolytic diseases and RA. • Side Effects • Pancytopenia • Hemorrhagic cystitis • Infertility • Teratogenic

  18. B) Lymphocyte Depletion Agents • 1. Corticosteroids • The most commonly used immunosuppressant • MOA: • At biochemical level: act on gene expression, which lead to decrease synthesis of PGs; LKTs; cytokines and other signaling molecules that participate in immune response. • At the cellular level: they inhibit the proliferation of T lymphocytes (cell mediated) and slightly dampen humoral immunity (by increasing the catabolism of immunoglobulins). • At immunosuppressive doses, Corticosteroids are cytotoxic and continuous uses lowers IgG.

  19. Uses: • In combination with other immunossppressants for transplanted patients (To prepare the patients as well as maintenance). • To Rx acute rejection episodes (high doses) • To Rx undesirable immunoreactions (to drugs or asthma). • To autoimmune diseases (ITP; IBD; RA; SLE; GN) • Side Effects:

  20. Adverse effects: (revise endocrine system) • Increased blood pressure How? • hyperglycemia due to increased gluconeogenesis, insulin resistance, and impaired glucose tolerance ("steroid diabetes"); • Osteoporosis • Visceral and truncal fat deposition (central obesity) and appetite stimulation • Weight gain (water & salt retention) How? • Muscle breakdown (proteolysis), weakness; reduced muscle mass and repair • Increased skin fragility, easy bruising • Cataracts • Adrenal cortex suppression (NO ABRUPT WITHDRAWAL) • Increase tendency to infections How?

  21. 2. Immunosuppressive Antibodies a) Polyclonal Antibodies (Antilymphocyte Globulins) Definition: Thymocytes are considered as T-cell precursors. What are the differences between polyclonal and monoclonal antibodies? 1) Antithymocyte (Antilymphocyte)Globulins (ALG): this antisera can be obtained by immunization of large animals (e.g.rabbits) with human lymphoid cells. MOA:Antibodies bind to the surface of circulating T lymphocytes forming a comlex. This complex will be phagocytosed in liver or spleen and leading to destruction or inactivation of T cells. ALG mainly affects the cellular immunity with no effect on humoral, resulting in antibodies against these foreign proteins. PK: Administered by IM or slow IV infusion with long half-life of 3-9 days Side Effects: 1) Mainly result from the introduction of foreign proteins obtained from heterogeneous serum (Anaphylactic and serum sickness reactions; Local pain and erythema at site of injection). 2) Chills & fever and Leukopenia & thrombocytopenia 3) Viral infections and skin rashes 4) Lymphoma and cancer

  22. Polyclonal Antibodies (continue…) Clinical Uses of ALG : 1) Rx of hyperacute phase of allograft rejection 2) To prepare the bone marrow transplanted patient (Large doses of ALG for 7 days) 2) Immune globulin Intravenous (IGIV): - Prepared from a pool of thousands of healthy donors. Uses: 1) Refractory ITP Advantages: Has no antigenicity

  23. B) Monoclonal Antibodies (Muromonab; Basiliximab; Abciximab; Daclizumab. 1) Muromonab-CD3 (IL-2-antagonist): From its name, it is murine monoclonal antibody that prepared by hypridoma technology and directed against the glycoprotien CD3 antigen of human T cells. Used mainly for cases of acute allograft rejections of kidney, heart and liver. it is also used to deplete T cells from donor bone marrow before transplantation. Advantage over ALG: More specific and T lymphocytes return to normal within 24 hr. Side Effects: 1) Cytokine release syndrome (Anaphylactoid reactions) Why; and seizure (contraindication) Therefore it is not used.

  24. Side Effect of Muromonab • Its use has been declined much because of multiple side effects and the emergence of newer and more selective antibodies therapy • Anaphylaxis may occur • Cytokine release syndrome, flu-like to dangerous shock-like reactions can occur, & high fever • CNS: Seizures, encephalopathy, cerebral edema & headache • Infection like CMV • Contraindicated with pregnancy, breast feeding, history of seizures, uncompensated heart failure

  25. 2) ModifiedTypes of monoclonal antibodies (e.g: Selective Inhibitors of IL2): • Note: Monoclonal Antibodies are not limited for immunosuppression but could be utilized for other purposes (See Table 56-3) • By using the genetic engineering, most murine amino acids of Muromonab have been replaced by human ones; producing monoclonal antibody designated humanized (e.g. Daclizumab; Transtuzumab). While the chimeric (Mixed) antibodies contain XI in their name (e.g. Abciximab; Infliximab; Rutuximab). • Clinical Uses: See Table 56-3 • Advantages over polyclonal antibodies

  26. B- Selective IL-2 Receptor AntagonistsBasiliximab&Daclizumab • Basiliximab is a chimeric antibody composed of 25% murine & 75% human protein. Block IL • Daclizumab is humanized antibody composed of 90% human protein • Therapeutic Use: • Prophylaxis against acute rejection of kidney transplantation • Used in combination with steroids or CsA

  27. Selective IL-2 Receptor AntagonistsBasiliximab&Daclizumab (Continue…) • Mechanism of action: • They are anti-CD25 antibodies • They bind to the -chain of the IL-2R (CD25 or TAC subunit) on the activated T-cells • Then, IL-2 binding to IL-2R is prohibited & T-cell activation and proliferation are suppressed

  28. VI- Selective IL-2 Receptor AntagonistsBasiliximab&Daclizumab (Continue...) • Pharmacokinetics: Given by IV route • Daclizumab has serum half-life of 20 days & receptor blockade for 120 days • Administered in 5 doses; the first 24 hours before transplantation and next 4 doses at 14-days intervals • Basiliximab has serum half-life of 7 days • Administered in two doses; the first at 2-hours before transplantation & the second at 4 days after surgery

  29. Selective IL-2 Receptor AntagonistsContiue..)) Basiliximab&Daclizumab • Adverse Effects: • Both are well-tolerated • Gastrointestinal toxicity is the major one • NO antibodies, of clinical relevance, to the drugs are produced • Infection & malignancy are not reported

  30. Alemtuzumab: • Humanized monoclonal antibody directed against CD-52, and produce profound depletion of T cells. • Used for refractory B- cell chronic lymphocytic leukemia. However, it is currently in use for organ transplant.

  31. 3- RhoD Immunoglobulin • Rho(D) Immune Globulin (Rhogam) • Rhogam is an immunoglobulin that recognizes the Rho(D) antigen • Prepared from pooled sera from Rho-negative volunteers immunized with D+ erythrocytes • It prevents erythroblastosis fetalis or hemolytic disease of the newborn • When a Rho(D)-negative mother carries a Rho(D)-positive fetus, mother becomes sensitized • Subsequent pregnancies can strengthen response increasing chance of Ab transfer to fetus

  32. RhoD Immunoglobulin • It is usually given to the mother within 72 hours after the birth of Rh-positive baby • This would prevent hemolytic anemia that may occur in subsequent pregnancies • Adverse Effects: • Chills • Fever • Anaphylaxis (rare)

  33. Rho(D) Immune Globulin: • Used to prevent Rh hemolytic disease in newborn. • Thus, Rho(D) Immune Globulin antibodies are given to the mother within 72 Hrs after birth of Rh positive baby. • Uses: • Erythroblastosis Faetalis • Miscarriages

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