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Immunosuppressive drugs

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1 Immunosuppressive drugs
Drugs which suppress all immune responses to bacteria, fungi, and even malignant cells All immunosuppressive agents are non specific (except Rho Immunoglobulins) Dr Muhammad Raza

2 OBJECTIVES Classify immunomodulating drugs
Describe the MOA of immunomodulating drugs List clinical uses of immunosuppressive drugs Describe the MOA of Calcineurin inhibitors drugs Mention the uses of Calcineurin inhibitors drugs Enumerate the Toxicity of Calcineurin inhibitors drugs Describe the MOA of cytotoxic agents Mention the uses of Cytotoxic agents Mention the side effects of immunomodulating drugs

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4 Opioid-induced immunomodulation is mediated by opioid receptors found on immunocytes and in the central nervous system.

5 Prednisone (Glucocorticoids)
Action Intermediate-acting glucocorticoid that depresses formation, release and activity of endogenous mediators of inflammation, including PGs, kinins, histamine, liposomal enzymes and complement system. Also modifies body's immune response Leads to: Inhibit. lymphoid proliferation Lyses of either suppressor or helper T cells Monocyte- macrophage system inhibit chemotaxis Inhibit. of IL6 & IL1, IL2, TNF, PAF, leukotriens, PGS. Inhibits the antibody response Decrease amount of antibody Indications for the use of Prednisone Endocrine disorders; rheumatic disorders; collagen diseases; dermatologic diseases; allergic states; allergic and inflammatory ophthalmic processes; respiratory diseases; hematologic disorders; neoplastic diseases; edematous states (because of nephrotic syndrome); GI diseases; multiple sclerosis; tuberculous meningitis; trichinosis with neurologic or myocardial involvement.

6 Prednisone (Glucocorticoids)
Dose Maintenance: 5-10 mg PO qd Contraindications Documented hypersensitivity; viral, fungal, tubercular skin, or connective tissue infections; peptic ulcer disease; hepatic dysfunction; GI ulceration Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals Precautions abrupt discontinuation of glucocorticoids may cause adrenal crisis; other adverse effects hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections Glucocorticoids These agents, used alone or in conjunction with other medications, may reduce the symptomatology associated with RA. These drugs can be given at low doses daily for maintenance or in large doses pulsed over 3 days for a rheumatoid flare. Low-dose prednisone (10 mg qd) May substitute for NSAID Used as bridge therapy If used long term, consider prophylactic treatment for osteoporosis Intra-articular steroids Useful for flares

7 Methotrexate (Class: Antineoplastic/antimetabolite; antipsoriatic; antiarthritic)
Action Competitively inhibits dihydrofolic acid reductase and thereby inhibits DNA synthesis and cellular replication. In rheumatoid arthritis, believed to reduce immune function Indications Treatment and prophylaxis of acute meningeal lymphocytic leukemia; treatment of breast cancer, epidermoid cancers of head and neck, advanced mycosis symptomatic control of severe psoriasis and severe rheumatoid arthritis. Unlabeled use(s): Reduction of corticosteroid requirements in patients with severe corticosteroid-dependent asthma, believed to reduce immune function t½ 6-9hrs, increase with hydroxychloroquine. Excreted in urine (70%), Bile (30%) Contraindications Use in nursing mothers. in pregnancy, alcoholism, alcoholic liver disease, chronic liver disease, overt or laboratory evidence of immunodeficiency syndrome and preexisting blood dyscrasias (eg, leukopenia, thrombocytopenia). Adverse Effects: Nausea and mucosal ulcer. Hepatoxicity. “hypersensibility” reaction to the Lung.

8 Cyclophosphamide Orally active prodrug  transformed by liver enzymes to an alkylating agent that is cytotoxic to proliferating lymphoid cells. Greater effect on B cells than T lymphocytes inhibit an established immune response. PO- Well absorbed -bioavailability > 75%. Plasma protein binding of unchanged drug is low, but some metabolites are > 60% bound. Metabolized by the P450 system in the liver. Metabolites excreted (5-25% unchanged) Clinical use: Effective in autoimmune diseases (including hemolytic anemia), antibody-induced red cell aplasia, bone marrow transplants, and possibly other organ transplant procedures. Cyclophosphamide does not prevent the graft- versus-host reaction in bone marrow transplantation. Adverse Effects. Large doses of the drug (usually needed for immunosuppression) cause Hemorrhagic cystitis Bone marrow suppression pancytopenia Alopecia may cause sterility GI distress Bladder carcinoma (very rare) Myelosuppression: A condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets. Myelosuppression is a side effect of some cancer treatments. When myelosuppression is severe, it is called myeloablation. ADULTS: PO/IV Dosage regimens that include cyclophosphamide are too numerous to list. Usual doses range from 500 to 1500 mg/m2 per course of therapy. In myelosuppressed patients, reduce initial loading dose by 33 to 50%. ADULTS: PO 60 to 120 mg/m2/day for initial and maintenance therapy

9 Cyclosporine (Calcineurin inhibitor)
Peptide antibiotic, Regulates gene transcription of ILs. Binds to cyclophilin----inhibit calcineurin (cytoplasmic phosphatase)----inhibit production of cytokines Inhibits IL-1 and IL-2 receptor. Inhibits macrophage-T cell interaction and T cell responsiveness. Erratic absorption, new preparations give up to 20-30% bioavailability. Grapefruit  bioavailability up to 62%. (Inhibition of CYP450) Metabolized by CYP3A (many drug interaction). Retards the appearance of new bony erosions. Could be used in SLE, Wegener’s granulomatosis, polymyositis, juvenile chronic arthritis. Indications Prophylaxis of organ rejection in kidney, liver and heart allogeneic transplants in conjunction with adrenal corticosteroid therapy; treatment of chronic rejection in patients previously treated with other immunosuppressive agents. Unlabeled use(s): Prophylaxis in other transplant procedures; treatment of aplastic anemia, atopic dermatitis, biliary cirrhosis, Crohn's disease, rheumatoid arthritis, severe psoriasis, nephrotic syndrome, ulcerative colitis, alopecia areata. Nephrotoxicity. Renal dysfunction Others: hypotension, hyperkalemia, hepatotoxicity, hirsutism. Interactions: diltiazem, K-sparing diuretics, other CYP3A inhibitors (Ketoconazole. Itraconazole. Fluconazole. Cimetidine. Clarithromycin. Erythromycin. Troleandomycin. Grapefruit juice ) ADULTS & CHILDREN: PO 15 mg/kg/day (range 14–18 mg/kg/day) beginning 4–12 hr before transplantation. Continue for 1–2 wk postoperatively then taper dose by 5%/wk to maintenance level of 5–10 mg/kg/day. IV 5–6 mg/kg/day as single IV dose starting 4–12 hr before transplantation. Switch to oral form as soon as patient can tolerate

10 Tacrolimus (Calcineurin inhibitor)
Peptide antibiotic. Binds to FK-binding protein----inhibit calcineurin (cytoplasmic phosphatase)----inhibit production of cytokines (Calcineurin regulates production of cytokines) Inhibits IL-1 and IL-2 receptor. Inhibits macrophage-T cell interaction and T cell responsiveness by decreasing T cell receptors response. USES: PO and IV: Prophylaxis of organ rejection in patients receiving allogenic liver or kidney transplants. Used in conjunction with adrenal corticosteroids Topical: Atopic dermatitis. Prophylaxis of rejection for patients receiving kidney, bone marrow, cardiac, pancreas, pancreatic island cell, and small bowel transplantation. Interactions: Azole antifungal agents (eg, fluconazole, ketoconazole), calcium channel blockers (eg, diltiazem, nifedipine), clotrimazole, macrolide antibiotics (eg, erythromycin): Tacrolimus plasma levels may be elevated, ing the risk of toxicity. Cyclosporine: Additive nephrotoxicity. Hydantoins (eg, phenytoin): Tacrolimus plasma levels may be reduced, while hydantoin concentrations may be ed. Mycophenolate mofetil: Plasma levels of mycophenolate mofetil may be elevated. Rifamycins (eg, rifampin): Tacrolimus plasma levels may be reduced, ing the risk of rejection. Allogeneic: Taken from different individuals of the same species. Two or more individuals are said to be allogeneic to one another when the genes at one or more loci are not identical.

11 Tacrolimus (Calcineurin inhibitor) contd……
Pharmacokinetics More water soluble than cyclosporine More predictable absorption. Metabolized in liver, bile excretion Intermediate t½ 7H Unwanted effects Similar to cyclosporine except: More toxic esp. nephrotoxicity, neurotoxicity (convulsions, halucinations) Other effects more common with tacrolimus are: Diabetes Pleural and pericardial effusion Cardiomyopathy in children Less hypertension, hyperlipidemia, hirsutism, or gum hyperplasia Prophylaxis of Organ Rejection Liver Transplants: Adults: PO 0.1 to 0.15 mg/kg/day in 2 divided daily doses q 12 hr no sooner than 6 hr after transplantation. IV 0.03 to 0.05 mg/kg/day as continuous infusion

12 Sirolimus (M-TOR inhibitors; m-target of rapamycin inhibitor)
Actions Inhibits T-lymphocyte activation and proliferation that occurs in response to antigenic and cytokine stimulation; potent inhibition of B cell proliferation, inhibits antibody production, and mononuclear cell response colony-stimulating factors Pharmacokinetics Oral preparation only Rapid absorption Helped by glycoprotein Metabolism by P450 Very long half life Indications Prophylaxis of organ rejection in patients receiving renal transplants. Treatment of psoriasis. Interactions Cyclosporine: Sirolimus plasma concentrations may be ed; administer sirolimus 4 hr after cyclosporine. Cytochrome P450 3A4 inhibitors (eg, erythromycin, protease inhibitors [eg, ritonavir], verapamil): Sirolimus plasma levels may be elevated, ing the pharmacologic and adverse effects. Cytochrome P450 3A4 inducers (eg, carbamazepine, phenytoin): Sirolimus plasma levels may be ed, ing the pharmacologic effects. Diltiazem, ketoconazole: Sirolimus plasma concentrations may be ed. Rifampin: Sirolimus plasma concentrations may be ed. Vaccination: Response to vaccination may be less effective. Toxicity Hyperlipedemia Hematopoietic cell injury (anemia, leukopenia, thrombocytopenia) Hypokalemia Arthralgia, Rash Impaired wound healing ADULTS: PO Recommended loading dose of 6 mg with a daily maintenance dose of 2 mg (ie, loading dose 3 times the maintenance dose) in a regimen with cyclosporine and corticosteroids. M TOR (m target of rapamycin) inhibitors

13 Mycophenolate Mofetil (antiproliferative)
MOA: This drug is rapidly converted  mycophenolic acid, which inhibits inosine monophosphate dehydrogenase, an enzyme in the de novo pathway of purine synthesis. This action suppresses both B and T lymphocyte activation. Lymphocytes are particularly susceptible to inhibitors of the de novo pathway because they lack the enzymes necessary for the alternative salvage pathway for purine synthesis. Clinical use: The drug has been used successfully as a sole agent in kidney, liver, and heart transplants. In renal transplants, its use with low-dose cyclosporine has reduced cyclosporine-induced nephrotoxicity. Toxicity: Apart from its gastrointestinal side effects, the drug appears to be quite safe. Interactions Probenecid: May  plasma concentrations of mycophenolate. Salicylates: Co-administration  ed the free fraction of MPA. Phenytoin: MPA decreased protein binding of phenytoin & theophylline and may, therefore,  free phenytoin & theophylline levels. Theophylline: MPA decreased protein binding of theophylline and may, therefore, increase free theophylline levels. MPA=mycophenolic acid; de novo is a Latin expression meaning "from the beginning," "afresh," "anew," "beginning again." Renal Transplantation ADULTS: PO/IV 1 g administered over ≥2 hours bid (daily dose of 2 g). Cardiac Transplantation ADULTS: PO/IV 1.5 g administered over ≥ 2 hours bid (daily dose of 3 g).

14 Azathioprine MOA: This prodrug is transformed to  antimetabolite mercaptopurine, which upon further metabolic conversion inhibits enzymes involved in purine metabolism. Azathioprine is cytotoxic in the early phase of lymphoid cell proliferation and has a greater effect on the activity of T cells than B cells. Suppresses inosiniz acid synthesis, B and T cell function, immunoglobulin productions and IL-2 secretions Clinical use: Azathioprine is used in autoimmune diseases eg. SLE, rheumatoid arthritis and for immunosuppression in renal homografts. The drug has minimal effects on established graft rejections. Also used in psoriasis Toxicity: The major toxic effect is bone marrow suppression, but GI T irritation, skin rashes, and liver dysfunction also occur. The active metabolite of azathioprine, mercaptopurine, is metabolized by xanthine oxidase, and toxic effects may be  ed by allopurinol given for hyperuricemia. Monitor: CBC, LFTs ADRs: chills, fever, nausea, vomiting, leukopenia; thrombocytopenia Precautions Bone marrow suppression. GI disturbances, risk for infections. Increase risk for lymphomas. Rarely: rash, fever and hepatotoxicity.

15 hydroxychloroquine Ocular toxicity (check-ups each 12 months)
Anti-malarial Suppression of the T lymphocytes response to mitogens, decrease leukocyte chemotaxis, trapping free radicals. Deaminated by the liver, half-life up to 45 days. Indicated for RA, but not very efficacious. Improve symptoms. No effect in protecting bone alterations. Takes 3 – 6 months to obtain response. Other uses: skin manifestation of SLE. Monitor: CBC; LFTs Adverse effects Ocular toxicity (check-ups each 12 months) Dyspepsia, nausea, vomiting, headach, myopathy, ocular toxicity.

16 Gold Salts Approved in 1960s. Aurothiomalate, aurothioglucose (IM), auranofin (PO) Today are infrequently used (very toxic). IM formulas 50% elemental gold, PO 29%. Alters morphology and capabilities of macrophages. Inhibits: chrematistic factor-1, IL-8, IL-1B, vascular endothelial growth factor. IM: alter lysosomal enzyme activity, inhibits histamine release, inactive 1st component of complement, suppresses PMN phagocytosis. High bioavailability, concentration in synovial membranes, liver, kidney, spleen lymph nodes and bone marrow. IM: 75-80% eliminated in one month but total half-life is 1 year.

17 Gold Salts Contd… Adverse effects Excreted 66% urine, 33% feces.
Slow radiographic progression in RA. Also used in Sjogren’s syndrome, juvenile RA. PO: less effective than IM. Adverse effects Pruritic skin rashes, Stomatitis and metallic taste. Thrombocytopenia, leukopenia and pancytopenia. Aplastic anemia (rare). Nephrotic syndrome Enterocolitis, cholestatic jaundice, peripheral neuropathy and pulmonary infiltrates.

18 Sulfasalazine Adverse effects MONITOR: CBC, LFTs, SrCr Salycilate.
Metabolites treat RA. Decreased production of IgA and IgM rheumatoid factor. No clear mechanism action related to the efficacy. PO: 10-20% absorbed. Fraction undergoes enterohepatic recirculation and is reduce by colonic bacteria into sulfapyridine and 5-aminosalicylic. Sulfapyridine: well absorbed, excreted after hepatic metabolism (RA). 5-aminosalicylic: unabsorbed (IBD). t½ 6-17hrs. Reduces the rate of appearance of new joint damage. Juvenile RA, ankylosing spondylitis. MONITOR: CBC, LFTs, SrCr Adverse effects Nausea, vomiting, headache and rash. Hemolytic Anemia (rare), Neutropenia, thrombocytopenia (very rare).

19 TNFα Blocking agents TNFα cytokines are the heart of the inflammatory process. Has TNF receptor. Anti-TNF antibodies, can cross-link the receptor. Curative for refractory cases. Adalimumab, Infliximab, Etanercept.

20 Etanercept Slowly absorbed and t½ is 4.5 days.
Recombinant fusion proteins of TNF p75 receptors linked to the Fc of the IgG1. Binds TNFα molecules and inhibits lymphotoxin-α.  ILs and adhesion molecules Antiinflammatory effects through TNF antagonism Slowly absorbed and t½ is 4.5 days. Available only PARENTERAL PREP; 25mg SQ 2x/WK anti-inflammatory effect through TNFα antagonism Decreases the rate of new erosions like methotrexate alone. Same indications as infliximab. Effective in RA, ulcerative colitis, Juvenile RA, Psoriasis, etc Adverse effects. Lower incidence of TB reactivation. Similar incidence of opportunistic infections. Must be alert for lymphomas (as other TNF agents). Lupus-like syndrome higher incidence. 16% can produce antibodies. Monitor: s/s of infection

21 Leflunomide Adverse effects.
Inhibits dihydroorotate dehydrogenase. Dihydroorotate dehydrogenase catalyzes the fourth step in the de novo biosynthesis of pyrimidine. Leads to inhibition of lymphocyte division and maturation. Arrests lymphocytes in G1 phase of the cell cycle Inhibits T cell proliferation and B cell antibody production. Completely absorbed. t½ 19 days. Cholestyramine enhances clearance by 50%. As effective as Methotrexate for RA. Inhibition of bony damage. Can be combined. Adverse effects. Diarrhea, loose bowels. Elevation of liver enzymes. Mild alopecia, weight gain, increase BP. Contraindicated in pregnancy. Dihydroorotate dehydrogenase is an enzyme that catalyzes the fourth step in the de novo biosynthesis of pyrimidine.

22 Adalimumab TNF monoclonal antibody
Recombinant human TNF monoclonal antibody. Down regulation of macrophages and T cell function. Half-life of 9-14 days. Methotrexate decrease clearance. Produces antimonoclonal antibodies 12% cases (reduce to 4% with methotrexate) Decreases the rate of the formation of new erotions. Effective alone or in combination with methotrexate. Tested for SLE, juvenile RA, Psoriasis. Adverse Effects Increase macrophage-dependent infection. Tuberculosis and opportunistic infections. Drug-induce lupus is extremely rare. Rare: leukopenia, vasculitis.

23 Monoclonal Antibodies
Monoclonal antibodies (MAbs) have the potential advantage of high specificity, since they can be developed for interaction with a single molecule. "Humanization" of murine monoclonal antibodies has reduced the likelihood of formation of neutralizing antibodies and of immune reactions. 1. Muromonab-CD3: This MAb binds to the CD3 antigen on the surface of human thymocytes and mature T cells. It blocks the killing action of cytotoxic T cells and probably interferes with other T cell functions. Altered antigen recognition USES: Muromonab-CD3 is used to manage a renal homograft rejection crisis. First-dose effects include fever, chills, dyspnea, and pulmonary edema. Hypersensitivity reactions may also occur.

24 Monoclonal Antibodies
2. Daclizumab: Daclizumab is a highly specific MAb that binds to the alpha subunit of the IL-2 receptor expressed on T cells and prevents activation by IL-2 . Altered antigen recognition USES: While it facilitates the actions of other immunosuppressants in renal transplants, daclizumab is not used for acute rejection episodes. In contrast to cyclosporine, tacrolimus, or cytotoxic immunosuppressants, the adverse effects of daclizumab are equivalent to those of placebo.

25 Monoclonal Antibodies
3. Infliximab Chimeric monoclonal antibody High affinity for the TNF receptors. (mechanism similar to that of etanercept since it is targeted against TNF-c) IV route. Half-life 9-12 days. Effective in RA, ulcerative colitis, Juvenile RA, Psoriasis, etc. Used alone or in combination with methotrexate. Other DMARDs can be use in combination In combination with methotrexate, infliximab improves symptoms in patients with rheumatoid arthritis. It also is effective in the treatment of inflammatory bowel disease. Adverse Effects Respiratory tract infections, nausea, headache, sinusitis, rash and cough. Associated with TB reactivation. Infusion site reaction. Infusion reactions and an increased rate of infection may occur.

26 Anti-D (Rho) Immunoglobulin [Rho(D)]
A concentrated solution of human IgG containing a high titre of antibodies against Rho (D) antigen of the red cell Clinical use: Rho(D) immune globulin is used for prevention of Rh hemolytic disease of the newborn. In women treated with Rho(D ) immune globulin, maternal antibodies to Rh-positive cells are not produced in subsequent pregnancies, and hemolytic disease of the neonate is averted. Dose and Administration: 500 units IM injected to the Rh –ve mother within 72 h after birth of an Rh +ve baby. It could be injected antenatal at 28 W of pregnancy or after abortion or miscarriage or receiving Rh +ve to Rh –ve recipient. Suppresses the mother’s antibody response Rh + sensitization to Rh –ve during blood transfusion Contraindications: Rh +ve women Rh –ve previous conception of RH +ve blood Rho(D) Immune Globulin is given by intramuscular injection that is used to prevent the immunological condition known as Rhesus disease (or hemolytic disease of newborn). This is a solution of IgG anti-D (anti-RhD) antibodies that bind to, and lead to the destruction of, fetal Rh D positive red blood cells that have passed from the fetal circulation to the maternal circulation. Therefore, in a Rhesus negative mother it can prevent sensitization of the maternal immune system to Rh D antigens, which can cause rhesus disease in the current or in subsequent pregnancies.

27 Summary of site of action of some immunosuppressants

28 Hazards of immunosuppression:
Immunosuppressive drugs - Some Autoimmune Disorders Treated with Immunosuppressive Therapy Indications Autoimmune hemolytic anemia Myasthenia gravis Cranial arteritis Idiopathic thrombocytopenic purpura Membranous glomerulonephritis Polymyalgia rheumatica Polymyositis Psoriatic arthropathies Rheumatoid arthritis Systemic lupus erythematosus Ulcerative colitis Uveitis Wegener’s granulomatosis Hazards of immunosuppression: Bone marrow suppression (cytotoxic agents) Hazards of cortisone (long term) Teratogenicity Impaired immune response Carcinogenicity and mutagenicity (cytotoxic) Contraindicated during pregnancy


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