Dr Muhammad Raza

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

3. 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

4. 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

5. Methotrexate(Class: Antineoplastic/antimetabolite; antipsoriatic; antiarthritic) • Action • Competitively inhibits dihydrofolic acid reductaseand 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 mycosissymptomatic 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.

6. 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) 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

7. Cyclosporine (Calcineurin inhibitor) • Peptide antibiotic, Regulates gene transcription of ILs. • Binds to cyclophilin----inhibit calcineurin (cytoplasmicphosphatase)----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. • IndicationsProphylaxis 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

8. Tacrolimus(Calcineurin inhibitor) • Peptide antibiotic. • Binds to FK-binding protein----inhibit calcineurin (cytoplasmicphosphatase)----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. • Prophylaxisof 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, ingthe risk of toxicity. • Cyclosporine: Additive nephrotoxicity. • Hydantoins (eg, phenytoin):Tacrolimus plasma levels may be reduced, while hydantoin concentrations may be ed. • Mycophenolatemofetil:Plasma levels of mycophenolatemofetil may be elevated. • Rifamycins (eg, rifampin):Tacrolimus plasma levels may be reduced, ingthe risk of rejection.

9. 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 tacrolimusare: • Diabetes • Pleural and pericardial effusion • Cardiomyopathy in children • Lesshypertension, 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

10. 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, ingthe pharmacologic and adverse effects. • Cytochrome P450 3A4 inducers (eg, carbamazepine, phenytoin):Sirolimus plasma levels may be ed, ingthe 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.

11. MycophenolateMofetil(antiproliferative) • MOA: • This drug is rapidly converted mycophenolic acid, which inhibits inosinemonophosphatedehydrogenase, 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  edthe 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. 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).

12. Azathioprine • MOA: • This prodrug is transformed to antimetabolitemercaptopurine, 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 xanthineoxidase, and toxic effects may be  edby 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.

13. hydroxychloroquine • 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.

14. 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.

15. Gold Salts Contd… • 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.

16. Sulfasalazine • 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 sulfapyridineand 5-aminosalicylic. • Sulfapyridine: well absorbed, excreted after hepatic metabolism (RA). • 5-aminosalicylic: unabsorbed (IBD). • t½6-17hrs. • Reduces the rate of appearance of new joint damage. • Juvenile RA, ankylosingspondylitis. MONITOR: CBC, LFTs, SrCr • Adverse effects • Nausea, vomiting, headache and rash. • Hemolytic Anemia (rare), Neutropenia, thrombocytopenia (very rare).

17. 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.

18. Etanercept • 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

19. Leflunomide • Inhibits dihydroorotatedehydrogenase.Dihydroorotatedehydrogenasecatalyzes 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.

20. AdalimumabTNF 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.

21. 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.

22. 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 cytotoxicimmunosuppressants, the adverse effects of daclizumab are equivalent to those of placebo.

23. 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.

24. 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

25. Summary of site of action of some immunosuppressants