Pharmacology Lec 3 PDF

Pharmacology Biologic DMARDs Lec 3 Pharmacology | Biologic DMARDs Contents : Glucocorticoids 4 Adalimumab 8 Certolizumab 9 Etanercept 10 Golimumab 11 Infliximab 12 Abatacept 14 Rituximab 16 Tocilizumab and sarilumab 19 Pharmacology | Biologic DMARDs Contents : Other Drugs for Rheumatoid Arthritis 21...

Pharmacology Biologic DMARDs Lec 3 Pharmacology | Biologic DMARDs Contents : Glucocorticoids 4 Adalimumab 8 Certolizumab 9 Etanercept 10 Golimumab 11 Infliximab 12 Abatacept 14 Rituximab 16 Tocilizumab and sarilumab 19 Pharmacology | Biologic DMARDs Contents : Other Drugs for Rheumatoid Arthritis 21 Drugs Used for the Treatment of Gout 25 Colchicine 32 Allopurinol 38 Febuxostat 43 Probenecid 45 Pegloticase 47 Pharmacology | Biologic DMARDs Glucocorticoids IL-1 and TNF-α are proinflammatory cytokines involved in the pathogenesis of RA. When secreted by synovial macrophages, IL-1 and TNF-α stimulate synovial cells to proliferate and synthesize collagenase, thereby: degrading cartilage. stimulating bone resorption. Inhibiting proteoglycan synthesis. Pharmacology | Biologic DMARDs Biologic DMARDs include the TNF-α inhibitors, as well as the non-TNF biologic agents (abatacept, rituximab, tocilizumab). The TNF-α inhibitors (adalimumab, certolizumab, etanercept, golimumab, and infliximab) are biologic DMARDs which have been shown to: Decrease signs and symptoms of RA. Reduce progression of structural damage. And improve physical function. Clinical response can be seen within 2 weeks of therapy. Pharmacology | Biologic DMARDs TNF-α inhibitors should be used cautiously in those with heart failure, as they can cause and/or worsen preexisting heart failure. An increased risk of lymphoma and other cancers has been observed with the use of TNF-α inhibitors. Like TNF-α inhibitors, non-TNF biologics are generally used in RA after a patient has an inadequate response to traditional DMARDs. Patients receiving biologic DMARDs are at increased risk for infections, such as tuberculosis, fungal opportunistic infections, and sepsis. Pharmacology | Biologic DMARDs Reactivation of hepatitis B may occur with the use of these agents. Live vaccinations should not be administered to patients taking any of the biologic DMARDs. Note: TNF-α inhibitors and non-TNF biologic agents should not be used together due to the risk of severe infections. Pharmacology | Biologic DMARDs Adalimumab Adalimumab is a recombinant monoclonal antibody that binds to TNF-α and interferes with its activity by blocking interaction of TNF-α with cell surface receptors. Adalimumab is administered subcutaneously weekly or every other week. It may cause headache, nausea, agranulocytosis, rash, reaction at the injection site, and increased risk of infections. Pharmacology | Biologic DMARDs Certolizumab Certolizumab is a humanized antibody that neutralizes biological actions of TNF-α. It is combined with polyethylene glycol (pegylated) and is administered every 2 weeks via subcutaneous injection. Adverse effects are similar to other TNF-α inhibitors. Pharmacology | Biologic DMARDs Etanercept Etanercept is a genetically engineered fusion protein that binds to TNF-α, thereby blocking its interaction with cell surface TNF-α receptors. Etanercept is given subcutaneously once weekly and is generally well tolerated. Pharmacology | Biologic DMARDs Golimumab Golimumab neutralizes the biological activity of TNF-α by binding to it and blocking its interaction with cell surface receptors. It is administered subcutaneously once a month in combination with methotrexate. Golimumab may increase hepatic enzymes. Pharmacology | Biologic DMARDs Infliximab Infliximab is a chimeric monoclonal antibody composed of human and murine regions. The antibody binds specifically to human TNF-α and inhibits binding with its receptors. This agent is not indicated for monotherapy, as this leads to the development of anti-infliximab antibodies and reduced efficacy. Pharmacology | Biologic DMARDs Infliximab should be administered with methotrexate. Infliximab is administered as an IV infusion every 8 weeks. Infusion-related reactions, such as fever, chills, pruritus, and urticaria, may occur. Pharmacology | Biologic DMARDs Abatacept T lymphocytes need two interactions to become activated: 1. The antigen-presenting cell (macrophages or B cells) must interact with the receptor on the T cell. 2. The CD80/CD86 protein on the antigen-presenting cell must interact with the CD28 protein on the T cell. Abatacept is a recombinant fusion protein and co- stimulation modulator that competes with CD28 for binding on CD80/CD86 protein, thereby preventing full T cell activation and reducing the inflammatory response. Pharmacology | Biologic DMARDs Abatacept is administered as an IV infusion every 4 weeks. Common adverse effects include infusion-related reactions, headache, upper respiratory infections, and nausea. Pharmacology | Biologic DMARDs Rituximab In RA, B lymphocytes can perpetuate the inflammatory process in the syovium by 1. Activating T lymphocytes. 2. producing autoantibodies and rheumatoid factor. 3. Producing proinflammatory cytokines, such as TNF-α and IL-1. Rituximab is a chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. Pharmacology | Biologic DMARDs Administration of rituximab results in B-cell depletion. Rituximab is administered as an intravenous infusion every 16 to 24 weeks. Pharmacology | Biologic DMARDs To reduce infusion reactions, methylprednisolone, acetaminophen, and an antihistamine are administered prior to each infusion. Infusion reactions (urticaria, hypotension, and angioedema) are the most common complaints and typically occur during the first infusion. Pharmacology | Biologic DMARDs Tocilizumab and sarilumab Tocilizumab and sarilumab are recombinant monoclonal antibodies that bind to IL-6 receptors and inhibit activity of the proinflammatory cytokine IL-6. Both tocilizumab and sarilumab are administered as a subcutaneous injection every 2 weeks. Tocilizumab may also be administered as an intravenous infusion every 4 weeks. Pharmacology | Biologic DMARDs Adverse reactions include: 1. Elevated liver function tests. 2. Hyperlipidemia. 3. Neutropenia. 4. Hypertension. 5. Infusion-related and injection site reactions. Pharmacology | Biologic DMARDs Other Drugs for Rheumatoid Arthritis Janus kinases are intracellular enzymes that modulate immune cell activity in response to the binding of inflammatory mediators to the cellular membrane. Tofacitinib is a synthetic small molecule that is an oral inhibitor of Janus kinases. It is indicated for the treatment of moderate to severe established RA in patients who have had an inadequate response or intolerance to methotrexate. Pharmacology | Biologic DMARDs Hemoglobin concentrations must be greater than 9 g/dL to start Tofacitinib and must be monitored during therapy due to the risk for anemia. Likewise, lymphocyte and neutrophil counts should be checked prior to initiation of therapy and monitored during treatment. Tofacitinib treatment may also increase the risk for new primary malignancy and opportunistic infections. Pharmacology | Biologic DMARDs Due to long-term safety concerns, Tofacitinib is usually reserved for patients who have inadequate response or intolerance to other agents. Note: Anakinra, azathioprine, cyclosporine, gold, and minocycline are other agents used infrequently in the treatment of RA due to their adverse effect profile or the availability of other agents with more proven efficacy. Drugs Used for the Treatment of Gout Pharmacology | Biologic DMARDs Drugs Used for the Treatment of Gout Gout is a metabolic disorder characterized by high levels of uric acid in the blood (hyperuricemia). Hyperuricemia can lead to deposition of sodium urate crystals in tissues, especially the joints and kidney. The deposition of urate crystals initiates an inflammatory process involving the infiltration of granulocytes that phagocytize the urate crystals. Pharmacology | Biologic DMARDs Pharmacology | Biologic DMARDs Acute flares of gout usually present as pain, swelling, tenderness, and redness in the affected joints (for example, big toe, knees, ankles, wrists, or elbows). The cause of hyperuricemia in gout is an imbalance between overproduction of uric acid and/or the inability to excrete uric acid renally. Most therapeutic strategies for gout involve lowering the uric acid level below the saturation point (6 mg/dL). Pharmacology | Biologic DMARDs This can be accomplished by interfering with uric acid synthesis or increasing uric acid excretion. Treatment of acute gout: Acute gout attacks can result from a number of conditions, including excessive alcohol consumption, a diet rich in purines, and kidney disease. NSAIDs, corticosteroids, and colchicine are effective agents for the management of acute gouty arthritis. Pharmacology | Biologic DMARDs Patients are candidates for prophylactic urate-lowering therapy if they have more than two attacks per year or they have chronic kidney disease, kidney stones, or tophi (deposit of urate crystals in the joints, bones, cartilage, or other body structures). Pharmacology | Biologic DMARDs Treatment of chronic gout: Urate-lowering therapy for chronic gout aims to reduce the frequency of attacks and complications of gout. Treatment strategies include the use of xanthine oxidase inhibitors to reduce the synthesis of uric acid or use of uricosuric drugs to increase its excretion. Xanthine oxidase inhibitors (allopurinol, febuxostat) are firstline urate lowering agents. Pharmacology | Biologic DMARDs Uricosuric agents (probenecid) may be used in patients who are intolerant to xanthine oxidase inhibitors or fail to achieve adequate response with those agents. Note: Initiation of urate-lowering therapy can precipitate an acute gout attack due to rapid changes in serum urate concentrations. Medications for the prevention of an acute gout attack (low-dose colchicine, NSAIDs, or corticosteroids) should be initiated with urate-lowering therapy and continued for at least 6 months Pharmacology | Biologic DMARDs Colchicine Colchicine, a plant alkaloid, is used for the treatment of acute gouty attacks. It is neither a uricosuric nor an analgesic agent, although it relieves pain in acute attacks of gout. Mechanism of action: Colchicine binds to tubulin, a microtubular protein, causing its depolymerization. Pharmacology | Biologic DMARDs This disrupts cellular functions, such as the mobility of neutrophils, thus decreasing their migration into the inflamed joint. Furthermore, colchicine blocks cell division by binding to mitotic spindles. Pharmacology | Biologic DMARDs Therapeutic uses: The anti-inflammatory activity of colchicine is specific for gout, usually alleviating the pain of acute gout within 12 hours. NSAIDs have largely replaced colchicine in the treatment of acute gouty attacks for safety reasons. Colchicine is also used as a prophylactic agent to prevent acute attacks of gout in patients initiating urate-lowering therapy. Note: Colchicine must be administered within 36 hours of onset of attack to be effective. Pharmacology | Biologic DMARDs Pharmacokinetics: Colchicine is administered orally and is rapidly absorbed from the GI tract. Colchicine is metabolized by hepatic CYP450 3A4 and other tissues. It undergoes enterohepatic recirculation and exhibits high interpatient variability in the elimination half-life. Pharmacology | Biologic DMARDs A portion of the drug is excreted unchanged in the urine. Adverse effects: 1. Nausea, vomiting, abdominal pain, and diarrhea. 2. Chronic administration may lead to myopathy. 3. Neutropenia, aplastic anemia. 4. Alopecia. The drug should not be used in pregnancy and should be used with caution in patients with hepatic, renal, or cardiovascular disease. Pharmacology | Biologic DMARDs Dosage adjustments are required in patients taking CYP3A4 inhibitors (for example, clarithromycin and itraconazole) or Pglycoprotein efflux pump inhibitors (for example, amiodarone and verapamil) and those with severe renal impairment. Pharmacology | Biologic DMARDs Allopurinol Allopurinol, a xanthine oxidase inhibitor, is a purine analog. It reduces the production of uric acid by competitively inhibiting the last two steps in uric acid biosynthesis that are catalyzed by xanthine oxidase. Pharmacology | Biologic DMARDs Therapeutic uses: Allopurinol is an effective urate-lowering therapy in the treatment of gout and hyperuricemia secondary to other conditions, such as that associated with certain malignancies (those in which large amounts of purines are produced, particularly after chemotherapy) or in renal disease. Pharmacology | Biologic DMARDs Pharmacokinetics: Allopurinol is completely absorbed after oral administration. The primary metabolite alloxanthine (oxypurinol) is also a xanthine oxidase inhibitor with a half-life of 15 to 18 hours. Thus, effective inhibition of xanthine oxidase can be maintained with once-daily dosing. Pharmacology | Biologic DMARDs The drug and its active metabolite are excreted in the urine. Dose adjustment is needed if estimated glomerular filtration rate is less than 30 mL/min/1.73 m2. Pharmacology | Biologic DMARDs Adverse effects: 1. Allopurinol is well tolerated by most patients. 2. Hypersensitivity reactions, especially skin rashes, are the most common adverse reactions. 3. The risk is increased in those with reduced renal function. Pharmacology | Biologic DMARDs Febuxostat Febuxostat is an oral xanthine oxidase inhibitor structurally unrelated to allopurinol. Its adverse effect profile is similar to that of allopurinol, although the risk for rash and hypersensitivity reactions may be reduced. Febuxostat does not have the same degree of renal elimination as allopurinol and thus requires less adjustment in those with reduced renal function. Pharmacology | Biologic DMARDs Febuxostat should be used with caution in patients with a history of heart disease or stroke, as this agent may be associated with a greater risk of these events as compared to allopurinol. Pharmacology | Biologic DMARDs Probenecid Probenecid is an oral uricosuric drug. It is a weak organic acid that promotes renal clearance of uric acid by inhibiting the urate-anion exchanger in the proximal tubule. At therapeutic doses, it blocks proximal tubular reabsorption of uric acid. Pharmacology | Biologic DMARDs Probenecid should be avoided if the creatinine clearance is less than 50 mL/min. Adverse effects include: nausea, vomiting. dermatologic reactions. Rarely, anemia or anaphylactic reactions. Pharmacology | Biologic DMARDs Pegloticase Pegloticase is a recombinant form of the enzyme urate oxidase or uricase. It acts by converting uric acid to allantoin, a water-soluble nontoxic metabolite that is excreted primarily by the kidneys. Pegloticase is indicated for patients with gout who fail treatment with standard therapies such as xanthine oxidase inhibitors. Pharmacology | Biologic DMARDs It is administered as an IV infusion every 2 weeks. Infusion-related reactions and anaphylaxis may occur with pegloticase, and patients should be premedicated with antihistamines and corticosteroids.