Immunopharmacology Flashcards
Glucocorticoids
GLUCOCORTICOIDS
Glucocorticoids have broad anti-inflammatory effects. Glucocorticoids are steroid hormones that act by binding to the cytosolic glucocorticoid receptor. The glucocorticoid-glucocorticoid receptor complex translocates to the nucleus and binds to glucocorticoid response elements (GREs) in the promoter region of specific genes, either up-regulating or down-regulating gene expression.
Glucocorticoids down-regulate the expression of many inflammatory mediators, including key cytokines such as TNF-alpha, IL-1 and IL-4. Glucocorticoids suppress eicosanoid biosynthesis. The overall effect of glucocorticoid administration is profoundly anti-inflammatory and immunosuppressive.
ANTI-INFLAMMATORY MECHANISM OF ACTION OF GLUCOCORTICOIDS
Glucocorticoids relieve pain due to the modulation of inflammatory responses. Glucocorticoids suppress several inflammatory pathways. They can inhibit prostaglandin synthesis through three independent mechanisms:
- Induction of annexin I
- Induction of MAPK phosphatase 1
- Repression of transcription of cyclooxygenase 2.
- Glucocorticoids induce synthesis of annexin I. Annexin I is an antiinflammatory protein that inhibits cytosolic phospholipase A2α (cPLA2α), thus blocking the release of arachidonic acid and its subsequent conversion to eicosanoids.
- A second antiinflammatory protein induced by glucocorticoids is MAPK phosphatase 1. Glucocorticoid-induced MAPK phosphatase 1 dephosphorylates and inactivates MAPKs, thus inhibiting proinflammatory signaling pathways. MAPK phosphatase 1 may also inhibit cPLA2α activity by blocking its phosphorylation by MAPKs
- NF-kB is a transcription factor that stimulates transcription of cytokines and chemokines. NF-kB also induces the transcription of cyclooxygenase 2. Glucocorticoids inhibit NF-kB, thus reducing the expression of COX2
Glucocorticoids also modulate the activity of other transcription factors.
ADVERSE EFFECTS
Adverse effects seen with short-term administration of corticosteroids include hypertension, hyperglycemia, immunosuppression, psychotic reactions, and cognitive impairment.
Adverse effects associated with long-term use include osteoporosis, weight gain, fluid retention, cataracts, poor wound healing, gastric ulcers, GI bleeding, hyperglycemia, hypertension, adrenal suppression and increased risk of infection.
USES
Glucocorticoids are used to prevent and treat transplant rejection. For transplantation the most common agents used are prednisone and methylprednisolone.
Glucocorticoids are used to treat autoimmune disorders such as rheumatoid arthritis, 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. For autoimmune conditions prednisone and prednisolone are typically used.
In palliative care, glucocorticoids are often used to alleviate symptoms such as pain, nausea, fatigue, anorexia, and malaise, and improve overall quality of life.
Glucocorticoids may be beneficial for a variety of types of pain, including neuropathic and bone pain. Dexamethasone is usually preferred for the management of cancer-related pain, because of its long half-life and low mineralocorticoid effects.
Cyclosporine
CALCINEURIN INHIBITORS
CYCLOSPORINE
Cyclosporine is the agent that ushered in the modern era of organ transplantation, increasing rates of early engraftment, extending graft survival for kidneys, and making cardiac and liver transplantation possible.
Cyclosporine is a peptide antibiotic. Cyclosporine binds to cyclophilin, a member of a class of intracellular proteins called immunophilins. Cyclosporine and cyclophilin form a complex that inhibits the cytoplasmic phosphatase, calcineurin, which is necessary for the activation of a T- cell-specific transcription factor. This transcription factor, NF-AT, is involved in the synthesis of interleukins (eg, IL-2) by activated T cells. Cyclosporine inhibits the gene transcription of IL-2, IL-3, IFN-γ, and other factors produced by antigen-stimulated T cells.
ADVERSE EFFECTS
Toxicities are numerous and include: nephrotoxicity, tremor, hypertension, hyperglycemia, hyperlipidemia, osteoporosis, hirsutism, gum hyperplasia.
Nephrotoxicity is limiting and occurs in the majority of patients treated. It is the major indication for cessation or modification of therapy.
Cyclosporine causes very little bone marrow toxicity.
Cyclosporine is primarily metabolized by CYP3A4; therefore it is involved in many drug interactions.
USES
Cyclosporine is used in organ transplantation, uveitis, rheumatoid arthritis, and psoriasis.
Tacrolimus
CALCINEURIN INHIBITORS
TACROLIMUS
Tacrolimus binds to the immunophilin FK-binding protein (FKBP). The tacrolimus-FKBP complex inhibits calcineurin, which is necessary for the activation of the T-cell-specific transcription factor NF-AT.
ADVERSE EFFECTS
Adverse effects are similar to those of cyclosporine: nephrotoxicity, neurotoxicity, hyperglycemia, hypertension, hyperkalemia, and GI complaints.
USES
Tacrolimus is used for the prevention of rejection of transplanted kidneys, liver, or heart. A topical formulation is used for atopic dermatitis and psoriasis.
Sirolimus
PROLIFERATION SIGNAL INHIBITORS
SIROLIMUS
Structurally similar to tacrolimus. Sirolimus binds to FKBP, but the sirolimus-FKBP complex does not inhibit calcineurin. Instead, it binds to and inhibits the serine-threonine kinase mTOR. Blockade of mTOR blocks IL-2-driven T-cell proliferation.
ADVERSE EFFECTS
Adverse effects include myelosuppression, hepatotoxicity, diarrhea, hypertriglyceridemia, pneumonitis, and headache.
Nephrotoxicity is less common than with calcineurin inhibitors.
USES
Sirolimus is approved for use in renal transplantation.
Sirolimus-eluting coronary stents are used to inhibit restenosis of the blood vessels in patients with severe coronary artery disease by reducing cell proliferation.
Thalidomide
INHIBITORS OF ANGIOGENESIS
THALIDOMIDE
Its mechanism of action is unclear. Thalidomide inhibits synthesis of TNF-α and inhibits angiogenesis. Thalidomide is now termed an immunomodulatory drug.
ADVERSE EFFECTS
Teratogenesis
Peripheral neuropathy, constipation, rash, fatigue, hypothyroidism.
Increased risk of DVT.
USES
Indicated for the treatment of patients with erythema nodosum leprosum, and multiple myeloma.
Azathioprine
AZATHIOPRINE
Purine antimetabolite. Prodrug of 6-mercaptopurine. Azathioprine is converted to 6- mercaptopurine, which, in turn, is converted to additional metabolites, which inhibit de novo purine synthesis. This leads to suppression of B and T cell function, of immunoglobulin production and of IL-2 secretion.
ADVERSE EFFECTS
Toxicity includes bone marrow suppression, GI disturbances, and some increase in infections and malignancies.
DRUG INTERACTIONS
Much of the drug’s inactivation depends on xanthine oxidase, therefore patients who are also receiving allopurinol for control of hyperuricemia should have the dose of azathioprine reduced to prevent excessive toxicity.
USES
Azathioprine is indicated for prevention of organ transplant rejection and in severe rheumatoid arthritis.
Methotrexate
METHOTREXATE
Methotrexate’s main mechanism of action at the low doses used in the rheumatic diseases is inhibition of aminoimidazolecarboxamide ribonucleotide (AICAR) transformylase. AICAR, which accumulates intracellularly, competitively inhibits AMP deaminase, leading to an accumulation of AMP.
AMP is released and converted extracellularly to adenosine, which is a potent inhibitor of inflammation. Adenosine,acting on A2b receptors, suppresses NF-κB activation induced by TNF and other inflammatory stimuli. As a result, the inflammatory functions of neutrophils, macrophages, dendritic cells, and lymphocytes are suppressed.
There is some effect on dihydrofolate reductase and this affects lymphocyte and macrophage function, but this is not its principal mechanism of action.
ADVERSE EFFECTS
Nausea and mucosal ulcers are the most common toxicities.
Leukopenia, anemia, stomatitis, GI ulcerations, alopecia.
Progressive dose-related hepatotoxicity in the form of enzyme elevation occurs frequently, but cirrhosis is rare.
Hypersensitivity pneumonitis.
Methotrexate is eliminated primarily by renal excretion. Serious toxicity is more likely in patients with decreased creatinine clearance.
Methotrexate toxicity can be reduced in rheumatoid arthritis –though possibly at some cost in efficacy- by giving leucovorin 24 hours after each weekly dose of methotrexate or by the use of daily folic acid.
Methotrexate is contraindicated in pregnancy.
USES
Methotrexate is used in rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, polymyositis, dermatomyositis, Wegener’s granulomatosis, giant cell arteritis, systemic lupus erythematosus, and vasculitis. Methotrexate has also been used in the treatment of graft-versus- host disease.
Mycophenolate Mofetil
MYCOPHENOLATE MOFETIL
Mycophenolate mofetil is converted into mycophenolic acid, which inhibits inosine monophosphate dehydrogenase, an enzyme in the de novo pathway of guanosine triphosphate (GTP) 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 GTP synthesis.
ADVERSE EFFECTS
Nausea, vomiting, diarrhea, abdominal pain.
Headache, hypertension, and reversible myelosuppression.
USES
Prophylaxis of transplant rejection. It is used off label in SLE.
Leflunomide
Dihydroorotate > orotate > orotidine 5’-monophosphate > UMP
Inhibited by leflunomide
LEFLUNOMIDE
Leflunomide is a prodrug of an inhibitor of pyrimidine synthesis, teriflunomide. This metabolite inhibits dihydroorotate dehydrogenase, decreasing levels of UMP, which is essential for the synthesis of all pyrimidines.
ADVERSE EFFECTS
Diarrhea.
Reversible alopecia, rash, myelosuppression and increases in aminotransferase activity.
Complete blood counts and liver function tests should be monitored.
Leflunomide is carcinogenic and teratogenic in animals. Contraindicated in pregnancy.
USES
Leflunomide is approved only for rheumatoid arthritis, but has shown efficacy in the treatment of other immune diseases, such as SLE and myasthenia gravis.
Cyclophosphamide
CYCLOPHOSPHAMIDE
The alkylating agent cyclophosphamide is one of the most efficacious immunosuppressive drugs available. Cyclophosphamide destroys proliferating lymphoid cells but also appears to alkylate DNA and other molecules in some resting cells.
ADVERSE EFFECTS
Toxicities include significant dose-limiting infertility in both men and women, bone marrow suppression, hemorrhagic cystitis and, rarely, bladder carcinoma.
Acrolein, one of the drug’s metabolites, is responsible for the urinary toxicities.
Long-term use increases the risk of infection and malignancy.
USES
It is used to treat SLE and other autoimmune diseases.
Hydroxychloroquine
HYDROXYCHLOROQUINE
The mechanism of anti-inflammatory action is unclear. The following mechanisms have been proposed: suppression of T lymphocyte responses to mitogens, decreased leukocyte chemotaxis, stabilization of lysosomal enzymes, inhibition of DNA and RNA synthesis, and the trapping of free radicals.
ADVERSE EFFECTS
Serious adverse effects are rare.
Hemolysis may occur in patients with G6PD deficiency.
Retinal damage is a rare complication that can be avoided if vision is monitored, dosage is kept low, the drug is discontinued promptly when signs of retinal toxicity first appear, and it is not used in patients with significant renal insufficiency.
A complete ophthalmologic exam is recommended before treatment and annually for those at high risk (age >60, liver disease, retinal disease); patients at low risk should be examined every 5 years.
Use of hydroxychloroquine during pregnancy is thought to be relatively safe.
USES
Hydroxychloroquine is moderately effective for mild rheumatoid arthritis and is usually well tolerated. It is often used with other drugs, particularly methotrexate and sulfasalazine. It is also used for lupus erythematosus.
The drug’s effectiveness may require 3-6 months to become apparent.
Sulfasalazine
SULFASALAZINE
Sulfasalazine consists of sulfapyridine and 5-aminosalicylic (5-ASA) connected by a diazo bond. It is metabolized by bacteria in the colon to the constituent moieties.
The sulfapyridine is probably the active moiety in the treatment of rheumatoid arthritis. The 5- ASA moiety is thought to be important in ulcerative colitis.
After reaching the colon, 10-20% of the sulfasalazine dose remains intact and can be absorbed as such.
ADVERSE EFFECTS
Nausea, vomiting, headache and rash.
Neutropenia occurs in 1-5% of patients.
Thrombocytopenia is very rare.
Drug-induced lupus is rare.
Hemolysis may occur in patients with G6PD deficiency.
USES
Sulfasalazine is used for the treatment of ulcerative colitis, rheumatoid arthritis, Crohn’s disease, and ankylosing spondylitis.
Immunosuppressive Antibodies
POLYCLONAL ANTIBODIES
ANTILYMPHOCYTE & ANTITHYMOCYTE ANTIBODIES
Two types of antisera directed against lymphocytes are available:
Antilymphocyte globulin (ALG)
Antithymocyte globulin (ATG)
Both are produced in horses or sheep by immunization against human thymus cells.
Antibodies in these preparations bind to T cells involved in antigen recognition and initiate their destruction by serum complement.
ALG and ATG are used before stem cell transplantation to prevent graft-versus-host reaction. Also used in combination with other immunosuppressants for solid organ transplantation.
RH O (D) IMMUNE GLOBULIN
Rho(D) immune globulin is a preparation of human IgG containing antibodies against the Rho (D) antigen of the red cell.
Rh-negative women may be sensitized to the Rh antigen usually at the time of birth of an Rho (D)-positive infant, when fetal red cells leak into the mother’s bloodstream. If the women have a primary immune response, they will make antibodies to Rh antigen. In subsequent pregnancies, maternal antibody against Rh-positive cells is transferred to the fetus during the third trimester, leading to the development of erythroblastosis fetalis (hemolytic disease of the newborn), a life- threatening syndrome.
USES
Rho(D) immune globulin is used for prevention of Rh hemolytic disease of the newborn. Administration of Rho(D) immune globulin to Rho(D) negative mothers at time of antigen exposure (ie birth of an Rho(D) positive child) blocks the primary immune response to the foreign cells. Therefore, maternal antibodies to Rh-positive cells are not produced in subsequent pregnancies, and hemolytic disease of the neonate is averted.
TNF-α INHIBITORS
TNF- α effects are mediated by specific membrane-bound TNF receptors (TNFR1, TNFR2).
Blocking TNF-α from binding to TNF receptors on inflammatory cells results in suppression of downstream inflammatory cytokines and adhesion molecules involved in leukocyte activation and migration.
An increased risk of infection or reactivation of M tuberculosis, hepatitis B virus, and invasive systemic fungi is common to each of these anti-TNF monoclonal antibodies. Patients may also be at increased risk for malignancies including lymphoma.
