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
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
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
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.
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
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
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.
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
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.
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).
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.
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.
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.
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.
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).
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.
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
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.
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.
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.
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.
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.
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