Immunopharmacology

Immunopharmacology

Immunosuppressants

Immunosuppressants are the drugs used to suppress immunity. These drugs mainly inhibit cellular or humoral or both immune responses and are used in therapy of autoimmune diseases and to prevent and or treat ogan transplant rejection. Most of the immunosuppressants act in the induction phase of the immunological response by reducing lymphocyte proliferations.

Classification:

I.                   Inhibitors of lymphocyte gene expression to reduce inflammatory response:

Ex: Glucocorticoids

II.                Inhibitors of lymphocyte signaling to prevent immune cell activation and proliferation Ex: cyclosporine, tacrolimus, sirolimus, everolimus.

III.             Cytotoxic agents to reduce lumphocyte proliferation.

a.       Antimetabolites. Ex: azathioprine, methotrexate, mycophenolate, mofetil, leflunomide.

b.      Alkylating agents Ex:cyclophosphamide

IV.             Cytokine inhibitors: entanercept, infliximab, adalimumab, anakinra, daclizumab, basiliximab,

V.                Antibodies against specific immune cells molecules Ex: ATG, alemtuzumab, Muromonab

VI.             Inhibitors of immune cell adhesion Ex: Eflaizumab,

VII.          Tolerogen or inhibitors of immune cell costimulation.

VIII.       Misc: Rho (D) immune globulin.

Glucocorticoids

Mechanism of Action: The immunosuppressive effects have long been known, but specific mechanisms of their immunosuppressive action remains elusive. Glucocorticoids lyse and induce the redistribution of lymphocytes, causing a rapid, transient decrease in peripheral blood lymphocyte counts. To affect longer-term responses, steroids bind to receptors inside cells; these receptors, glucocorticoid-induced proteins, or interacting proteins regulate the transcription of numerous other genes.

Therapeutic Uses

a.       They are combined with other immunosuppressive agents to prevent and treat transplant rejection. High dose pulses of intravenous methylprednisolone sodium succinate are used to reverse acute transplant rejection and acute exacerbations of selected autoimmune.

b.      It is efficacious for treatment of graft-versus-host disease in bone-marrow transplantation.

c.       Used routinely to treat autoimmune disorders such as rheumatoid and other arthritides, systemic lupus erythematosus, systemic dermatomyositis, psoriasis and other skin conditions, asthma and other allergic disorders, inflammatory bowel disease, inflammatory ophthalmic diseases, autoimmune hematologic disorders, and acute exacerbations of multiple sclerosis.

d.      Glucocorticoids limit allergic reactions that occur with other immunosuppressive agents and are used in transplant recipients to block first-dose cytokine storm caused by treatment with muromonad-CD3 and to a lesser extent thymoglobulin.

Toxicity: Use of steroids often results in disabling and life-threatening adverse effects include growth retardation in children, avascular necrosis of bone, osteopenia, increased risk of infection, poor wound healing, cataracts, hyperglycemia, and hypertension.

Cyclosporin

Cyclosporine is a potent inhibitor of antibody-and cell-mediated immune responses and is immunosuppressant of choice for prevention of transplant rejection. It also has application in treatment of autoimmune diseases.

Mechanism of Action

Cyclosporine binds to cytosolic protein cytophilin C. This drug–protein complex inhibits calcineurin phosphatase activity, which leads to decreased synthesis and release of several cytokines, including interleukins IL-2, IL-3, IL-4, interferon-alpha, and tumor necrosis factor. Cyclosporine exhibits a high degree of specificity in its actions on T cells without significantly impairing B-cell activity. It can inhibit T cell–dependent limb of antibody production by lymphocytes by preventing differentiation of B cells into antibody-secreting plasma cells. Because T cells appear to require IL-2 stimulation for their continuous growth, cyclosporine impairs the proliferative response of T cells to antigens. However, once T cells have been stimulated by antigens to synthesize IL-2, cyclosporine cannot suppress proliferation of T cells induced by this cytokine.

Schematic diagram of Mechanism of Action of Cyclosporineis shown below

Absorption, Metabolism, and Excretion

Oral absorption is slow and incomplete. Peak plasma concentrations are reached in 3 to 4 hours, and plasma half-life is 10 to 27 hours. Metabolized by hepatic mixed function oxidase enzymes and excreted via bile into feces. Metabolism results in inactivation of immunosuppressive activity. Agents that enhance or inhibit the mixed-function oxidase enzymes will alter the therapeutic response to cyclosporine.

Clinical Uses

a.       Cyclosporine is used in allogeneic kidney, liver, and heart transplant patients and is under study for use in pancreas, bone marrow, single lung, and heart–lung transplant procedures.

b.      It is recommended that corticosteroids, like prednisone, be used concomitantly; such combined therapy leads to fewer side effects, a decreased incidence of infectious complications, efficacy of lower doses, and better history of patient survival.

c.       Cyclosporine appears to have promise in the treatment of autoimmune diseases.

d.      It has a beneficial effect on the course of rheumatoid arthritis, uveitis, insulin dependent diabetes, systemic lupus erythematosus, and psoriatic arthropathies in some patients.

e.       Toxicity is more of a problem in these conditions than during use in transplantation, since higher doses of cyclosporine are often required to suppress autoimmune disorders.

Adverse Effects

a.       Nephrotoxicity, ranges from severe tubular necrosis to chronic interstitial nephropathy. This effect is reversible with dosage reduction.

b.      Vasoconstriction appears to be an important aspect of cyclosporine-induced nephrotoxicity.

c.       Hypertension occurs in 25% of the patients and in patients with renal dysfunction; the concomitant use of antihypertensive drugs may prove useful.

d.      Hyperglycemia, hyperlipidemia, transient liver dysfunction, and unwanted hair growth is observed.

Drug Interactions: Drug that affects microsomal enzymes, the CYP3A system, may impact cyclosporine blood concentrations. Substances that inhibit this enzyme can decrease cyclosporine metabolism and increase blood concentrations. These include Ca²⁺ channel blockers, antifungal agents, antibiotics, glucocorticoids, HIV-protease inhibitors, and other drugs.

Grapefruit and grapefruit juice block CYP3A and the multidrug efflux pump and should be avoided by patients taking cyclosporine; these effects can increase cyclosporine blood concentrations. In contrast, drugs that induce CYP3A activity can increase cyclosporine metabolism and decrease blood concentrations..

Cytotoxic immunosuppressants

Cytotoxic agents are used to reduce lumphocyte proliferation.

i.                    Antimetabolites. Ex: azathioprine, methotrexate, mycophenolate, mofetil, leflunomide.

ii.                  Alkylating agents Ex:cyclophosphamide

Azathioprine is a cytotoxic agent that preferentially destroys any rapidly dividing cell. Since immunologically competent cells are generally rapidly dividing cells, azathioprine is very effective as an immunosuppressive drug.

Clinical Uses:- It is powerful anti-inflammatory agent. Although it’s beneficial effect in conditions attributable to its direct immunosuppressive action.

Mycophenolate mofetil (MMF) is a semisynthetic derivative of mycophenolic acid, isolated from mold Penicillium glaucum. In vitro, it inhibits T- and B-lymphocyte responses, including mitogen and mixed lymphocyte responses, probably by inhibition of de novo synthesis of purines. Mycophenolate mofetil is hydrolyzed to mycophenolic acid, the active immunosuppressive moiety;

Clinical Uses:

a.       Used in solid organ transplant patients for refractory rejection and, in combination with prednisone, as an alternative to cyclosporine or tacrolimus in patients who do not tolerate those drugs.

b.      It is used to treat steroid-refractory graft-versus-host disease in hematopoietic stem cell transplant patients.

c.       It is also used in combination with tacrolimus or other immunosuppressive as prophylaxis to prevent graft-versus-host disease.

Immunostimulants

Immunostimulants are the agents that enhance immunological and non-specific host defences. It acts by: 1. increasing the humoral antibody responses, 2. Enhancing phagocytic activity of macrophages, 3. Modifying cell-mediated immune responses.

Ex: Levimasole, Thalidomide, Bacillus Calmette-Guerin (BCG), Interleukin-2, and Recombinant Cytokines Ex: interferon alfa-2, Interferon gamma-1b, Interferon beta-1a.