Immuno-pharmacology 4th Class Dr Sherzad Kh. RASHID MD PhD Pharmacology

ELEMENTS OF THE IMMUNE SYSTEM NORMAL IMMUNE RESPONSES The Innate Immune System the innate immune response exists prior to infection, is not enhanced by repeated infection, and is generally not antigen-specific. An intact skin or mucosa is the first barrier to infection.

ELEMENTS OF THE IMMUNE SYSTEM The Adaptive Immune System

The adaptive immune system has a number of characteristics that contribute to its success in eliminating pathogens. (1) respond to a variety of antigens, each in a specific manner (2)discriminate between foreign (“non-self”) antigens (pathogens) and self antigens of the host; (3) respond to a previously encountered antigen in a learned way by initiating a vigorous memory response.

Immunosuppressants

Immunosuppressants Immunosuppressive drugs can be categorized by their mechanism of action: 1) interference with cytokine production or action; 2) disruption of cell metabolism, preventing lymphocyte proliferation; and 3) mono- and polyclonal antibodies that block T-cell surface molecules.

SELECTIVE INHIBITORS OF CYTOKINE PRODUCTION AND FUNCTION Drugs that interfere with the production or activity of IL-2 significantly dampen the immune response and, thereby, decrease graft rejection. These drugs can be further divided into three main classes: 1) calcineurin inhibitors (cyclosporine and tacrolimus), 2) costimulation blockers (belatacept), and 3) mTOR inhibitors (sirolimus and everolimus).

A. Cyclosporine a calcineurin inhibitor, is a lipophilic cyclic polypeptide extracted from the soil fungus Beauveria nivea. Mechanism of action: preferentially suppresses cell-mediated immune reactions, whereas humoral immunity is affected to a far lesser extent. Therapeutic uses: To prevent rejection of kidney, liver, and cardiac allogeneic transplants combined in a double-drug or triple-drug regimen with corticosteroids and an antimetabolite such as mycophenolate mofetil. also be used for recalcitrant psoriasis.

Pharmacokinetics: Cyclosporine may be given either orally or by intravenous (IV) infusion About 50% of the drug is bound to erythrocytes. Cyclosporine is extensively metabolized, primarily by hepatic CYP3A4. Adverse effects: Nephrotoxicity hepatotoxicity infections are common and may be life threatening. Lymphoma hypertension, hyperlipidemia, hyperkalemia (K+-sparing diuretics should be avoided in these patients), tremor, hirsutism, glucose intolerance, and gum hyperplasia.

Tacrolimus Mechanism of action: Tacrolimus exerts its immunosuppressive effects in the same manner as cyclosporine, except that it binds to a different immunophilin, FKBP-12 (FK-binding protein)and the complex then binds to calcineurin. Therapeutic uses: Tacrolimus is currently approved for preventing liver and kidney rejections (along with glucocorticoids). It is also used in heart and pancreas transplants and rescue therapy in patients after failure of standard rejection therapy. An ointment preparation is approved for moderate to severe atopic dermatitis unresponsive to conventional therapies.

Pharmacokinetics: The drug and its metabolites are primarily eliminated in the feces. Adverse effects: Nephrotoxicity and neurotoxicity (tremor, seizures, and hallucinations) tend to be more severe with tacrolimus than with cyclosporine

Costimulation blocker Belatacept a second-generation co-stimulation blocker, is a recombinant fusion protein that targets signal 2 in the immune activation cascade. It is used for long-term maintenance immunosuppressive therapy. Mechanism of action: Belatacept blocks CD28-mediated costimulation of T lymphocytes (signal 2) by binding to CD80 and CD86 on APCs. This prevents the downstream stimulatory signals promoting T-cell survival, proliferation, and IL-2 production.

Therapeutic uses: Belatacept is used in kidney transplantation in combination with basiliximab, mycophenolate mofetil, and corticosteroids. Pharmacokinetics: Belatacept is the first IV maintenance immunosuppressant and is dosed in two phases. The initial high-dose phase is administered on a more frequent interval. Belatacept clearance is not affected by age, sex, race, renal, or hepatic function.

Adverse effects: the risk of posttransplant lymphoproliferative disorder (PTLD), particularly of the central nervous system. Common adverse events include anemia, diarrhea, urinary tract infection, and edema. Sirolimus binds to the same cytoplasmic FK-binding protein as tacrolimus Everolimus

IMMUNOSUPPRESSIVE ANTIMETABOLITES A. Azathioprine It is a prodrug that is converted first to 6-mercaptopurine (6-MP) and then to the corresponding nucleotide, thioinosinic acid. Its major nonimmune toxicity is bone marrow suppression. Allopurinol, an agent used to treat gout, significantly inhibits the metabolism of azathioprine. Therefore, the dose of azathioprine must be reduced. Nausea and vomiting are also encountered

B. Mycophenolate mofetil It has been successfully used in heart, kidney, and liver transplants. As an ester, it is rapidly hydrolyzed in the GI tract to mycophenolic acid. This is a potent, reversible, noncompetitive inhibitor of inosine monophosphate dehydrogenase, which blocks the de novo formation of guanosine phosphate, it deprives the rapidly proliferating T and B cells of a key component of nucleic acids. The glucuronide metabolite is excreted predominantly in urine. adverse effects are GI, including diarrhea, nausea, vomiting, and abdominal pain. High doses of mycophenolate mofetil are associated with a higher risk of CMV infection

IV. ANTIBODIES The use of antibodies plays a central role in prolonging allograft survival. They are prepared by immunization of either rabbits or horses with human lymphoid cells (producing a mixture of polyclonal antibodies or monoclonal antibodies) or by hybridoma technology (producing antigen-specific monoclonal antibodies). Antithymocyte globulins at the time of transplantation to prevent early allograft rejection. also be used to treat severe rejection episodes or corticosteroid resistant acute rejection. The antibodies are slowly infused intravenously, and their half-life extends from 3 to 9 days.

IV. ANTIBODIES adverse effects include chills and fever, leukopenia and thrombocytopenia, infections due to CMV or other viruses, and skin rashes B. Muromonab-CD3 (OKT3) is directed against the glycoprotein CD3 antigen of human T cells. C. Basiliximab Basiliximab is approved for prophylaxis of acute rejection in renal transplantation in combination with cyclosporine and corticosteroids. It is not used for the treatment of ongoing rejection. Basiliximab is competitve of IL2 on alpha chain of IL2 receptor on T lymphocyte against CD25

V. CORTICOSTEROIDS For transplantation, the most common agents are prednisone and methylprednisolone, whereas prednisone and prednisolone are used for autoimmune conditions. they are effective against a wide variety of autoimmune conditions, including refractory rheumatoid arthritis, systemic lupus erythematosus, temporal arthritis, and asthma. The exact mechanism responsible for the immunosuppressive action of the corticosteroids is unclear. The T lymphocytes are affected most.

MONOCLONAL ANTIBODIES Monoclonal antibodies have become an active area of drug development for anticancer therapy and other non neoplastic diseases, because they are directed at specific targets and often have fewer adverse effects. They are created from B lymphocytes (from immunized mice or hamsters) fused with “immortal” B-lymphocyte tumor cells. The resulting hybrid cells can be individually cloned, and each clone will produce antibodies directed against a single antigen type.

Recombinant technology has led to the creation of “humanized” antibodies that overcome the immunologic problems previously observed following administration of mouse (murine) antibodies. The monoclonal antibodies trastuzumab, rituximab, bevacizumab and cetuximab are used in the treatment of cancer. Many other monoclonal antibody treatments are available, examples of which include alemtuzumab, which is used in the treatment of refractory B-cell chronic lymphocytic leukemia, panitumumab, which is effective in metastatic colorectal tumors.

Abciximab, eptifibatide, and tirofiban Natalizumab: Natalizumab is a monoclonal antibody indicated for Multiple sclerosis in patients who have failed first-line therapies. Abciximab, eptifibatide, and tirofiban Mechanism of action: The GP IIb/IIIa receptor plays a key role in stimulating platelet aggregation. A chimeric monoclonal antibody, Abciximab inhibits the GP IIb/IIIa receptor complex. By binding to GP IIb/IIIa, abciximab blocks the binding of fibrinogen and von Willebrand factor and, consequently, aggregation does not occur.

Eptifibatide and tirofiban act similarly to abciximab, by blocking the GP IIb/IIIa receptor. Eptifibatide is a cyclic peptide that binds to GP IIb/IIIa at the site that interacts with the arginine–glycine–aspartic acid sequence of fibrinogen. Tirofibanis not a peptide, but it blocks the same site as eptifibatide. Therapeutic use: These agents are given intravenously, along with heparin and aspirin, as an adjunct to PCI for the prevention of cardiac ischemic complications. Abciximab is also approved for patients with unstable angina not responding to conventional medical therapy when PCI is planned within 24 hours.

Omalizumab is a recombinant DNA-derived monoclonal antibody that selectively binds to human immunoglobulin E (IgE). This leads to decreased binding of IgE to its receptor on the surface of mast cells and basophils. Reduction in surface-bound IgE limits the release of mediators of the allergic response. Indicated for the treatment of moderate to severe persistent asthma in patients who are poorly controlled with conventional therapy. Adverse effects include serious anaphylactic reaction (rare), arthralgias, fever, and rash. Secondary malignancies have been reported.

Denosumab Is a monoclonal antibody that targets receptor activator of nuclear factor kappa-B ligand and inhibits osteoclast formation and function. Denosumabis approved for the treatment of postmenopausal osteoporosis in women at high risk of fracture. It is administered via subcutaneous injection every 6 months. Denosumab has been associated with an increased risk of infections, dermatological reactions, hypocalcemia, osteonecrosis of the jaw, and atypical fractures. It should be reserved for women at high risk of fracture and those who are intolerant of or unresponsive to other osteoporosis therapies

Adalimumab is a recombinant monoclonal antibody that binds to TNF-α, thereby interfering with endogenous TNF-α activity by blocking its interaction with cell surface receptors. This agent is indicated for treatment of moderate to severe RA, either as monotherapy or in combination with methotrexate. It is also indicated for psoriatic arthritis, ankylosing spondylitis, and Crohn disease. Adalimumab is administered subcutaneously weekly or every other week. It may cause headache, nausea, agranulocytosis, rash, reaction at the injection site, or increased risk of infections, such as urinary tract infections, upper respiratory tract infections, and sinusitis.

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