NSAIDs - Drugs - PDF

PHARMACOLOGY 2 NSAIDS AND OTHERS THE IMMUNE RESPONSE b. Biologic DMARDs  The immune response occurs when immunologically competent – TNF-alpha neutralizing agents: infliximab, etanercept, & cells are activated in response...

PHARMACOLOGY 2 NSAIDS AND OTHERS THE IMMUNE RESPONSE b. Biologic DMARDs  The immune response occurs when immunologically competent – TNF-alpha neutralizing agents: infliximab, etanercept, & cells are activated in response to foreign organisms or antigenic adalimumab, certolizumab, golimumab substances liberated during the acute or chronic inflammatory – IL-1 neutralizing agents: anakinra response. – Depletes B cells: rituximab  The outcome of the immune response for the host may be – Interferes T cell activation: abatacept deleterious if it leads to chronic inflammation without resolution of – Anti-IL-6 receptor antibody: rocilizumab the underlying injurious process.  Chronic inflammation involves the release of multiple cytokines NONSTEROIDAL ANTI-INFLAMMATORY DRUGS and chemokines plus a very complex interplay of immunoactive  Salicylates and other similar agents used to treat rheumatic cells. disease share the capacity to suppress the signs and symptoms of  The whole range of autoimmune diseases (eg, RA, vasculitis, inflammation including pain. These drugs also exert antipyretic SLE) and inflammatory conditions (eg, gout) derive from effects. abnormalities in this cascade.  The cell damage associated with inflammation acts on cell Chemistry & Pharmacokinetics membranes to release leukocyte lysosomal enzymes; arachidonic  The NSAIDs are grouped in several chemical classes: acid is then liberated from precursor compounds, and various eicosanoids are synthesized. Indole derivative Indomethacin  The lipoxygenase pathway of arachidonate metabolism yields Fenamate Meclofenamic acid leukotrienes, which have a powerful chemotactic effect on Pyrrolealkanoic acid derivative Tolmetin eosinophils, neutrophils, and macrophages and promote Pyrazolone derivative Phenylbutazone bronchoconstriction and alterations in vascular permeability. Phenylacetic acid derivative Diclofenac  During inflammation, stimulation of the neutrophil membranes Propionic acid derivative Ibuprofen produces oxygen-derived free radicals and other reactive molecules Phenylalkanoic acid derivative Flurbiprofen such as hydrogen peroxide and hydroxyl radicals.  The interaction of these substances with arachidonic acid results Oxicam Piroxicam in the generation of chemotactic substances, thus perpetuating Naphthylacetic acid prodrug Nabumetone the inflammatory process.  All NSAIDs are weak organic acids except Nabumetone, which THERAPEUTIC STRATEGIES is a ketone prodrug that is metabolized to the acidic active drug. Primary goals in the treatment of patients with inflammation:  Most of these drugs are well absorbed, and food does not 1. relief of symptoms and the maintenance of function, which are substantially change their bioavailability. usually the major continuing complaints of the patient;  Most of the NSAIDs are highly metabolized, some by phase I 2. slowing or arrest of the tissue-damaging process. followed by phase II mechanisms and others by direct glucuronidation (phase II) alone. NSAID metabolism proceeds, in Indices used to define response in Rheumatoid arthritis: large part, by way of the CYP3A or CYP2C families of P450  DAS (Disease Activity Index) enzymes in the liver.  ACR Response (American College of Rheumatology Response  Renal excretion is the most important route for final elimination, Index) nearly all undergo varying degrees of biliary excretion and  These indices often combine joint tenderness and swelling, reabsorption (enterohepatic circulation). patient response, and laboratory data.  In fact, the degree of lower gastrointestinal (GI) tract irritation correlates with the amount of enterohepatic circulation. GENERAL APPROACHES  Most of the NSAIDs are highly protein-bound (~ 98%), I. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) usually to albumin. – Often results in relief of pain for significant periods  Most of the NSAIDs (eg, ibuprofen, ketoprofen) are racemic – Appropriate for treatment of both acute & chronic mixtures, except Naproxen, which is provided as a single inflammatory conditions enantiomer – control the s/s of local inflammatory process and have minimal  Few have no chiral center (eg, diclofenac). effect on the progression of the disease.  All NSAIDs can be found in synovial fluid after repeated dosing.  Drugs with short half-lives remain in the joints longer than would II. Glucocorticoids be predicted from their half-lives – Powerful anti-inflammatory effects  Drugs with longer half-lives disappear from the synovial fluid at a – Considered to be the ultimate answer to treatment of rate proportionate to their half-lives. inflammatory arthritis – Low-dose corticosteroids have dse-modifying properties but toxicity makes them less favored – For long term treatment of arthritis III. Disease modifying antirheumatic drugs (DMARDs) – decrease inflammation, improve symptoms, & slow the bone damage associated with RA – affect more basic inflammatory mechanisms than do glucocorticoids or the NSAIDs. – more toxic than those alternative medications a. Non-biologic DMARDs a. Methotrexate, sulfasalazine, chloroquine & hydroxychloroquine, leflunomide, cyclosporine, azathioprine, cyclophosphamide, mycophenolate mofetil b. Have the capacity to decrease elevated levels of acute phase reactants → modify inflammatory component & its destructive capacity Pharmacodynamics  OA  NSAID anti-inflammatory activity is mediated chiefly  localized musculoskeletal syndromes (eg, sprains and through strains, low back pain) inhibition of prostaglandin biosynthesis.  Gout (excep tolmetin, which appears to be ineffective in gout)  Adverse effects are generally quite similar for all of the NSAIDs: 1. CNS: Headaches, tinnitus, dizziness, and rarely, aseptic meningitis. 2. CVS: Fluid retention, hypertension, edema, and rarely, myocardial infarction and congestive heart failure (CHF). 3. GI: Abdominal pain, dysplasia, nausea, vomiting, and rarely, ulcers or bleeding. 4. Hematologic: Rare thrombocytopenia, neutropenia, or even aplastic anemia. 5. Hepatic: Abnormal liver function test results and rare liver failure. 6. Pulmonary: Asthma. 7. Skin: Rashes, all types, pruritus. 8. Renal: Renal insufficiency, renal failure, hyperkalemia, and proteinuria. CHOICE OF NSAID  All NSAIDs, including aspirin, are about equally efficacious with a few exceptions—tolmetin seems not to be effective for gout, and aspirin is less effective than other NSAIDs (eg, indomethacin) for AS.  Thus, NSAIDs tend to be differentiated on the basis of toxicity and cost- effectiveness.  For example, the GI and renal side effects of ketorolac limit its use.  Some surveys suggest that indomethacin and tolmetin are the Various NSAIDs have additional possible mechanisms of action, NSAIDs associated with the greatest toxicity, while salsalate, including: aspirin, and ibuprofen are least toxic.  inhibition of chemotaxis  For patients with renal insufficiency, nonacetylated salicylates may  down-regulation of IL-1 production be best.  decreased production of free radicals and superoxide  Diclofenac and sulindac are associated with more liver function  interference with calcium-mediated intracellular events. test abnormalities than other NSAIDs.  The relatively expensive, selective COX-2 inhibitor celecoxib is  Aspirin irreversibly acetylates and blocks platelet COX, while the probably safest for patients at high risk for GI bleeding but may non- COX-selective NSAIDs are reversible inhibitors. have a higher risk of cardiovascular toxicity.  Selectivity for COX-1 versus COX-2 is variable and incomplete for  Celecoxib or a nonselective NSAID plus omeprazole or the older NSAIDs, but selective COX-2 inhibitors have been misoprostol may be appropriate in patients at highest risk for GI synthesized. bleeding; in this subpopulation of patients, they are cost-effective  The selective COX-2 inhibitors do not affect platelet function at despite their high acquisition costs. their usual doses.  The choice of an NSAID thus requires a balance of efficacy, cost-  The efficacy of COX-2-selective drugs equals that of the older effectiveness, safety, and numerous personal factors (eg, other NSAIDs, while GI safety may be improved. drugs also being used, concurrent illness, compliance, medical  Sselective COX-2 inhibitors increase the incidence of insurance coverage), so that there is no best NSAID for edema, hypertension, and possibly myocardial infarction. allpatients. There may, however, be one or two best NSAIDs for a  As of August 2011, celecoxib and the less selective meloxicam specific person. were the only COX-2 inhibitors marketed in the USA.  Celecoxib has an FDA-initiated ―black box‖ warning concerning cardiovascular risks. It has been recommended that all NSAID product labels be revised to mention cardiovascular risks.  The NSAIDs decrease the sensitivity of vessels to bradykinin and histamine, affect lymphokine production from T lymphocytes, and reverse the vasodilation of inflammation.  All newer NSAIDs are analgesic, anti-inflammatory, and antipyretic  All inhibits platelet aggregation except the COX-2-selective agents and the nonacetylated salicylates  NSAIDs are all gastric irritants and can be associated with GI ulcers and bleeds as well, although as a group the newer agents tend to cause less GI irritation than aspirin.  Nephrotoxicity, reported for all NSAIDs, is due, in part, to interference with the autoregulation of renal blood flow, which is modulated by prostaglandins.  Hepatotoxicity can also occur with any NSAID.  Although these drugs effectively inhibit inflammation, there is no evidence that—in contrast to drugs such as methotrexate, biologics, and other DMARDs—they alter the course of any arthritic disorder.  Several NSAIDs (including aspirin) reduce the incidence of colon cancer when taken chronically (50% reduction in relative risk for this neoplasm when the drugs are taken for 5 years or longer)  Although not all NSAIDs are approved by the FDA for the whole range of rheumatic diseases, most are probably effective in:  RA  Sero-negative spondyloarthropathies (eg, PA and arthritis associated with inflammatory bowel disease) NONACETYLATED SALICYLATES Magnesium choline  All nonacetylated salicylates are effective anti-inflammatory drugs, although they may be less effective analgesics than aspirin. salicylate Sodium  Do not inhibit platelet aggregation, they may be preferable when COX inhibition is undesirable such as in patients with asthma, salicylate those with bleeding tendencies, and even (under close supervision) those with renal dysfunction. Salicyl salicylate  The nonacetylated salicylates are administered in doses up to 3–4 g of salicylate a day and can be monitored using serum salicylate measurements. COX-2 SELECTIVE INHIBITORS  inhibit prostaglandin synthesis by the COX-2 isozyme induced at sites of inflammation without affecting the action of the constitutively active ―housekeeping‖ COX-1 isozyme found in the GI tract, kidneys, and platelets.  COX-2 inhibitors at usual doses have no impact on platelet aggregation, which is mediated by thromboxane produced by the COX-1 isozyme.  Inhibit COX-2-mediated prostacyclin synthesis in the vascular endothelium.  As a result, COX-2 inhibitors do not offer the cardioprotective effects of traditional nonselective NSAIDs.  Recommended doses of COX-2 inhibitors cause renal toxicities similar to those associated with traditional NSAIDs.  Clinical data suggested a higher incidence of cardiovascular thrombotic events associated with COX-2 inhibitors such as rofecoxib and valdecoxib, resulting in their withdrawal from the market. Celecoxib  It interacts occasionally with warfarin—as would be expected of a drug metabolized via CYP2C9.  selective COX-2 inhibitor—about 10–20 times more selective for COX-2 than for COX-1.  It does not affect platelet aggregation at usual doses.  Celecoxib is associated with fewer endoscopic ulcers than most other NSAIDs.  Probably because it is a sulfonamide, celecoxib may cause rashes Meloxicam  enolcarboxamide related to piroxicam  preferentially inhibits COX-2 over COX-1, particularly at its lowest therapeutic dose of 7.5 mg/d.  not as selective as celecoxib and may be considered ―preferentially‖ selective rather than ―highly‖ selective.  It is associated with fewer clinical GI symptoms and complications than piroxicam, diclofenac, and naproxen.  Similarly, while meloxicam is known to inhibit synthesis of thromboxane A2, even at supratherapeutic doses, its blockade of thromboxane A2 does not reach levels that result in decreased in vivo platelet function NONSELECTIVE COX INHIBITORS Aspirin  Aspirin’s long use and availability without prescription diminishes its glamour compared with that of the newer NSAIDs. (acetylsalicylic  rarely used as an anti-inflammatory medication  Antiplatelet effects: 81–325 mg once daily acid; ASA) Pharmacokinetics Clinical uses:  Salicylic acid is a simple organic acid with a pKa of 3.0.  Aspirin decreases the incidence of transient ischemic attacks, unstable angina,  Aspirin (acetylsalicylic acid; ASA) has a pKa of 3.5 coronary artery thrombosis with myocardial infarction, and thrombosis after coronary  Aspirin is absorbed as such and is rapidly hydrolyzed (serum half-life 15 artery bypass grafting. inutes) to acetic acid and salicylate by esterases in tissue and blood.  Epidemiologic studies suggest that long-term use of aspirin at low dosage is associated  Salicylate is nonlinearly bound to albumin. with a lower incidence of colon cancer, possibly related to its COX-inhibiting effects.  Alkalinization of the urine increases the rate of excretion of free Adverse effects: salicylate and its water-soluble conjugates.  Main adverse effects at antithrombotic doses are gastric upset (intolerance) and MOA: gastric and duodenal ulcers.  Aspirin irreversibly inhibits platelet COX so that aspirin’s antiplatelet  Hepatotoxicity, asthma, rashes, GI bleeding, and renal toxicity rarely if ever occur at effect lasts 8–10 days (the life of the platelet). antithrombotic doses.  In other tissues, synthesis of new COX replaces the inactivated enzyme  The antiplatelet action of aspirin contraindicates its use by patients with hemophilia. so that ordinary doses have a duration of action of 6–12 hours. Although previously not recommended during pregnancy, aspirin may be valuable in treating preeclampsia-eclampsia. Diclofenac  Phenylacetic acid derivative; relatively nonselective  Elevation of serum aminotransferases occurs more commonly with this drug  Gastrointestinal ulceration may occur less frequently than than with other NSAIDs. with some other NSAIDs.  A 0.1% ophthalmic preparation is promoted for prevention of postoperative  A preparation combining diclofenac and misoprostol ophthalmic inflammation and can be used after intraocular lens implantation decreases upper gastrointestinal ulceration but may and strabismus surgery. result in diarrhea.  A topical gel containing 3% diclofenac is effective for solar keratoses.  Another combination of diclofenac and omeprazole was also  Diclofenac in rectal suppository form can be considered for preemptive effective with respect to the prevention of recurrent bleeding, analgesia and postoperative nausea. but renal adverse effects were common in high-risk patients.  In Europe, diclofenac is also available as an oral mouthwash and for  Diclofenac, 150 mg/d, appears to impair renal blood flow intramuscular administration. and glomerular filtration rate. Diflunisal  Although diflunisal is derived from salicylic acid, it is  RA recommended dose: 500–1000 mg daily in two divided doses. not metabolized to salicylic acid or salicylate.  Effective for cancer pain with bone metastases and for pain control in dental  It undergoes an enterohepatic cycle with reabsorption of its (third molar) surgery. glucuronide metabolite followed by cleavage of the  2% diflunisal oral ointment is a clinically useful analgesic for painful oral lesions. glucuronide to again release the active moiety.  Because its clearance depends on renal function as well as hepatic metabolism,  Diflunisal is subject to capacity-limited metabolism, with serum diflunisal’s dosage should be limited in patients with significant renal half- lives at various dosages approximating that of salicylates. impairment. Etodolac  racemic acetic acid derivative with an intermediate half-life  Analgesic dosage of etodolac is 200– 400 mg three to four times daily.  Recommended dose in OA and RA is 300 mg twice or three times a day up to 500 mg twice a day initially followed by a maintenance of 600 mg/d. Flurbiprofen  propionic acid derivative with a possibly more complex  Available in a topical ophthalmic formulation for inhibition of mechanism of action than other NSAIDs. intraoperative miosis.  Its (S)(−) enantiomer inhibits COX nonselectively, but  Intravenously is effective for perioperative analgesia in minor ear, neck, and it has been shown in rat tissue to also affect tumor nose surgery and in lozenge form for sore throat. necrosis factor-α (TNF-α) and nitric oxide synthesis.  Although its adverse effect profile is similar to that of other NSAIDs in most  Hepatic metabolism is extensive; its (R)(+) and (S) (−) ways, flurbiprofen is also rarely associated with cogwheel rigidity, ataxia, enantiomers are metabolized differently, and it does not tremor, and myoclonus. undergo chiral conversion .  It does demonstrate enterohepatic circulation. Ibuprofen  Phenylpropionic acid derivative  Liquid gel preparation of ibuprofen, 400 mg, provides prompt relief and  In doses of about 2400 mg daily, ibuprofen is equivalent to 4 good overall efficacy in postsurgical dental pain. g of aspirin in anti-inflammatory effect.  In comparison with indomethacin, ibuprofen decreases urine output less and  Oral ibuprofen is often prescribed in lower doses (