1 / 45

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

jmarcell
Download Presentation

Immunosuppressants Prof. Alhaider, 1431 H Definition

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  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

More Related