P.03 NSAID Drugs, DMARDs, & Nonopioid Analgesics Used in Gout PDF

PCC SOM 2026 PHARMACOLOGY AND THERAPEUTICS P.03 NSAID DRUGS, DMARDs, & NONOPIOD ANALGESICS USED IN GOUT PHARMACOLOGY LECTURE LECTURER: Dr. Desi James Ojascastro DATE: JANUARY 18, 2024 TOPIC OUTLINE I. THE IMMUNE RESPONSE II. THERAPEUTIC STRATEGIES III. NON-STEROIDAL ANTI-INFLAMMATORY DRUGS IV. DISEA...

PCC SOM 2026 PHARMACOLOGY AND THERAPEUTICS P.03 NSAID DRUGS, DMARDs, & NONOPIOD ANALGESICS USED IN GOUT PHARMACOLOGY LECTURE LECTURER: Dr. Desi James Ojascastro DATE: JANUARY 18, 2024 TOPIC OUTLINE I. THE IMMUNE RESPONSE II. THERAPEUTIC STRATEGIES III. NON-STEROIDAL ANTI-INFLAMMATORY DRUGS IV. DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS V. VI. VII. COMBINATION THERAPY WITH DMARDS OTHER ANALGESIC DRUGS USED IN GOUT THE IMMUNE RESPONSE - - - occurs when immunologically competent cells are activated in response to foreign organisms or antigenic substances liberated during the acute or chronic inflammatory response. Chronic inflammation involves the release of multiple cytokines and chemokines (late phase of inflammatory response that comes out) plus a very complex interplay of immunoactive cells. The whole range of autoimmune diseases (e.g., Rheumatoid Arthritis, vasculitis, SLE) and inflammatory conditions (e.g., gout) derive from abnormalities in this cascade. THERAPEUTIC STRATEGIES - The treatment of patients with inflammation involves two primary goals: o Relief of symptoms (target the source of the inflammation and source of pain) and the maintenance of function, which are usually the major continuing complaints of the patient. o Slowing or arrest of the tissuedamaging process If the main source is not addressed the patient will have continuous symptoms and if the main source of inflammation or reactions is not N O T E TA K E R : X y controlled, you must slow down the damage to the tissues. - In RA, several validated combined indices are used to define response: o Disease Activity Score28 [DAS28] o American College of Rheumatology Response Index [ACR Response] o Clinical Disease Activity Score [CDAI] o Simplified Disease Activity Index [SDAI] - Reduction of inflammation with NSAIDs often results in relief of pain for significant periods. (Depends on what NSAID you are using) - Furthermore, most of the nonopioid analgesics (aspirin, etc.) have anti-inflammatory effects, so they are appropriate for the treatment of both acute and chronic inflammatory conditions. GLUCOCORTICOIDS - Have powerful anti-inflammatory effects - this was one of the things which are considered as a primary treatment for inflammatory diseases such as inflammatory arthritis. - When first introduced, they were considered to be the ultimate answer to the treatment of inflammatory arthritis. - Data indicating that low-dose corticosteroids have disease-modifying properties, particularly in the early phase of RA,(side effects hinders their prolong use) their toxicity makes them less favored than other medications. - continue to have a significant role in the longterm treatment of arthritis. DISEASE-MODIFYING ANTI RHEUMATIC DRUGS Including biologics (subset of the DMARDS) - - Decrease inflammation, improve symptoms, and slow the bone damage associated with RA. Affect more basic inflammatory mechanisms than do glucocorticoids or the NSAIDs. o They may also be more toxic than those alternative medications. Basically, helps in preventing the progression of the medications or slowing down disease process. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS - Salicylates and other similar agents used to treat rheumatic disease share the capacity to P a g e 1 | 24 PCC SOM 2026 - PHARMACOLOGY AND THERAPEUTICS P.03 NSAID DRUGS, DMARDs, & NONOPIOD ANALGESICS USED IN GOUT suppress the signs and symptoms of inflammation including pain and swelling. Also exert antipyretic effects. Since aspirin, the original NSAID, has a number of adverse effects, many other NSAIDs have been developed in attempts to improve upon aspirin’s efficacy and decrease its toxicity - - A. CHEMISTRY & PHARMACOKINETICS - - - - - Grouped in several chemical classes. Chemical diversity yields a broad range of pharmacokinetic characteristics. All but one of the NSAIDs are weak organic acids as given. o The exception, NABUMETONE, is a ketone prodrug that is metabolized to the acidic active drug. Most of these drugs are well absorbed, and food does not change their bioavailability. o By practice patients take the medications after eating to prevent gastritis Most of the NSAIDs are highly metabolized, some by phase I followed by phase II mechanisms and others by direct glucuronidation (phase II) alone. Most of the NSAIDs are highly protein-bound (~ 98%), usually to albumin. Most of the NSAIDs (e.g., ibuprofen, ketoprofen) are racemic mixtures, while one, naproxen, is provided as a single enantiomer and a few have no chiral center (e.g., diclofenac). All NSAIDs can be found in synovial fluid after repeated dosing. Drugs with short half-lives remain in the joints longer than would be predicted from their halflives, while drugs with longer half-lives disappear from the synovial fluid at a rate proportionate to their half-lives. B. PHARMACODYNAMICS - NSAID anti-inflammatory activity is mediated chiefly through inhibition of prostaglandin biosynthesis N O T E TA K E R : X y - - - - - - Various NSAIDs have additional possible mechanisms of action, including inhibition of chemotaxis, down-regulation of IL-1 production, decreased production of free radicals and superoxide, and interference with calciummediated intracellular events. Aspirin irreversibly acetylates and blocks platelet COX, while the non- COX-selective NSAIDs are reversible inhibitors. Selectivity for COX-1 versus COX-2 is variable and incomplete for the older NSAIDs, but selective COX-2 inhibitors have been synthesized. Selective COX-2 inhibitors do not affect platelet function at their usual doses. o Unlike the aspirin, which is acts also as antiplatelet Efficacy of COX-2-selective drugs equals that of the older NSAIDs, while GI safety may be improved. o On the other hand, selective COX-2 inhibitors increase the incidence of edema, hypertension, and possibly, myocardial infarction. Celecoxib has a U.S Food and Drug ADMINISTRATION (FDA) “black box” warning concerning cardiovascular risks. o It has been recommended that all NSAID product labels be revised to mention cardiovascular risks. study found that NSAID use was associated with increased risk of serious bleeding and cardiovascular events after myocardial infarction. o The risk is higher among users of celecoxib and diclofenac, and lower among users of ibuprofen and naproxen. To varying degrees, all newer NSAIDs are analgesic, anti-inflammatory, and antipyretic, and all (except the COX-2–selective agents and the nonacetylated salicylates) inhibit platelet aggregation. 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. P a g e 2 | 24 PCC SOM 2026 - - PHARMACOLOGY AND THERAPEUTICS P.03 NSAID DRUGS, DMARDs, & NONOPIOD ANALGESICS USED IN GOUT May be associated to ulcer and bleeds especially those prolonged or chronic intake such as naproxen Nephrotoxicity, reported for all NSAIDs, is due, in part, to interference with the autoregulation of renal blood flow, which is modulated by prostaglandins. Hepatotoxicity also can occur with any NSAID. Several NSAIDs (including aspirin) reduce the incidence of colon cancer when taken chronically. C. ADVERSE EFFECTS - are generally quite similar for all of the NSAIDs - Central nervous system: o Headaches, o tinnitus, o Dizziness, and o rarely, aseptic meningitis. - Cardiovascular: o Fluid retention, o Hypertension, o edema, and o rarely, myocardial infarction and congestive heart failure (CHF). - Gastrointestinal: o Abdominal pain, o dyspepsia, o nausea, o vomiting, and o rarely, ulcers or bleeding. - Hematologic: o Rare thrombocytopenia, o neutropenia, or even o aplastic anemia. - Hepatic: o Abnormal liver function test results and rare liver failure. - Pulmonary: o Asthma. - Skin: o Rashes, all types, pruritus. - Renal: o Renal insufficiency o renal failure, o hyperkalemia, and o proteinuria. N O T E TA K E R : X y I. A. - ASPIRIN PHARMACOKINETICS: Aspirin (aka Acetylsalicylic acid; ASA) pKa of 3.5 Aspirin is absorbed as such and is rapidly hydrolyzed (serum half-life 15 minutes) to acetic acid and salicylate by esterases in tissue and blood B. MECHANISM OF ACTION: - Aspirin irreversibly inhibits platelet COX so that aspirin’s antiplatelet effect lasts 8–10 days (the life of the platelet). - Aspirin should be stopped a few days before surgery. - In other tissues, synthesis of new COX replaces the inactivated enzyme so that ordinary doses have a duration of action of 6–12 hours. C. CLINICAL USES: - Aspirin decreases the incidence of transient ischemic attacks, unstable angina, coronary artery thrombosis with myocardial infarction, and thrombosis after coronary artery bypass grafting - Epidemiologic studies suggest that long-term use of aspirin at low dosage is associated with a lower incidence of colon cancer, possibly related to its COX-inhibiting effects. D. ADVERSE EFFECTS: - In addition to the common side effects listed above, aspirin’s main adverse effects at antithrombotic doses are gastric upset (intolerance) and gastric and duodenal ulcers. → Hepatotoxicity, asthma (triggered by aspirin), rashes, GI bleeding, and renal toxicity rarely if ever occur at antithrombotic doses. - antiplatelet action of aspirin contraindicates its use by patients with hemophilia. Although previously not recommended during pregnancy, aspirin may be valuable in treating preeclampsia-eclampsia. II. - NON-ACETYLATED SALICYLATES MAGNESIUM CHOLINE SALICYLATE SODIUM SALICYLATE P a g e 3 | 24 PCC SOM 2026 PHARMACOLOGY AND THERAPEUTICS P.03 NSAID DRUGS, DMARDs, & NONOPIOD ANALGESICS USED IN GOUT - SALICYL SALICYLATE - COX inhibitors All non-acetylated salicylates are effective antiinflammatory drugs, and they do not inhibit platelet aggregation. - may be preferable when COX inhibition is undesirable such as in patients with asthma, those with bleeding tendencies, and even (under close supervision) those with renal dysfunction. - Non-acetylated salicylates are administered in doses up to 3–4 g of salicylate a day and can be monitored using serum salicylate measurements. III. COX-2 SELECTIVE INHIBITORS - CELECOXIB - MELOXICAM (These are one of the more common NSAIDs that are given to patients. Examples: celecoxib (most common), rofecoxib, valdecoxib, etoricoxib) - COX-2 selective inhibitors, or coxibs, were developed in an attempt to 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. - But in contrast, they do inhibit COX-2mediated 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. A. CELECOXIB - Celecoxib is a selective COX-2 inhibitor—about 10–20 times more selective for COX-2 than for COX-1. N O T E TA K E R : X y - Does not affect platelet aggregation at usual doses. Interacts occasionally with warfarin—as would be expected of a drug metabolized via CYP2C9. Usually used as mainstay for pain relief - B. MELOXICAM - Meloxicam is an enolcarboxamide related to piroxicam that 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. - 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. IV. NON-SELECTIVE COX INHIBITORS A. DICLOFENAC - a phenylacetic acid derivative that is relatively nonselective as a COX inhibitor. - Gastrointestinal ulceration may occur less frequently than with some other NSAIDs. - combination of diclofenac and omeprazole was also effective with respect to the prevention of recurrent bleeding, but renal adverse effects were common in high-risk patients. - Diclofenac, 150 mg/d, appears to impair renal blood flow and glomerular filtration rate. - Elevation of serum aminotransferases occurs more commonly with this drug than with other NSAIDs. o A 0.1% ophthalmic preparation is promoted for prevention of postoperative ophthalmic inflammation and can be used after intraocular lens implantation and strabismus surgery o A topical gel containing 3% diclofenac is effective for solar keratoses. o Rectal suppository form can be considered for preemptive analgesia and postoperative nausea. P a g e 4 | 24 PCC SOM 2026 PHARMACOLOGY AND THERAPEUTICS P.03 NSAID DRUGS, DMARDs, & NONOPIOD ANALGESICS USED IN GOUT B. DIFLUNISAL - derived from salicylic acid, it is not metabolized to salicylic acid or salicylate. - undergoes an enterohepatic cycle with reabsorption of its glucuronide metabolite followed by cleavage of the glucuronide to again release the active moiety. - rarely used today. C. ETODOLAC - is a 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. D. FLURBIPROFEN - propionic acid derivative with a possibly more complex mechanism of action than other NSAIDs. - Hepatic metabolism is extensive - also available in a topical ophthalmic formulation for inhibition of intraoperative miosis. - Intravenously is effective for perioperative analgesia in minor ear, neck, and nose surgery and in lozenge form for sore throat. - its adverse effect profile is similar to that of other NSAIDs in most ways, flurbiprofen is also rarely associated with cogwheel rigidity, ataxia, tremor, and myoclonus. E. - IBUPROFEN More common one and it is available a simple derivative of phenylpropionic acid In doses of about 2400 mg daily, ibuprofen is equivalent to 4g of aspirin in anti-inflammatory effect. available over the counter in low-dose forms. Ibuprofen oral and IV effective in closing patent ductus arteriosus in preterm infants, with much the same efficacy and safety as indomethacin. N O T E TA K E R : X y - liquid gel preparation of ibuprofen, 400 mg, provides prompt relief and good overall efficacy in postsurgical dental pain. In comparison with indomethacin, ibuprofen decreases urine output less and also causes less fluid retention. relatively contraindicated in individuals with nasal polyps, angioedema, and bronchospastic reactivity to aspirin. septic meningitis (particularly in patients with SLE), and fluid retention have been reported. concomitant administration of ibuprofen and aspirin antagonizes the irreversible platelet inhibition induced by aspirin. treatment with ibuprofen in patients with increased cardiovascular risk may limit the cardioprotective effects of aspirin. F. INDOMETHACIN - An indole derivative - Potent nonselective COX inhibitor and may also inhibit phospholipase A and C, reduce neutrophil migration, and decrease T-cell and B-cell proliferation. - Has been used to accelerate closure of patent ductus arteriosus. - ophthalmic preparation is efficacious for conjunctival inflammation and to reduce pain after traumatic corneal abrasion. - GI effects may include pancreatitis - Headache is experienced by 15–25% of patients and may be associated with dizziness, confusion, and depression. - Renal papillary necrosis has also been observed. G. KETOPROFEN - propionic acid derivative that inhibits both COX (nonselectively) and lipoxygenase. - Concurrent administration of probenecid elevates ketoprofen levels and prolongs its plasma half-life. - effectiveness of ketoprofen at dosages of 100– 300 mg/d is equivalent to that of other NSAIDs. - major adverse effects are on the GI tract and the central nervous system - Available also as liquid gel P a g e 5 | 24 PCC SOM 2026 H. - I. - - - J. - PHARMACOLOGY AND THERAPEUTICS P.03 NSAID DRUGS, DMARDs, & NONOPIOD ANALGESICS USED IN GOUT NABUMETONE only nonacid NSAID in current use resembles naproxen in structure half-life of more than 24 hours Renal impairment results in a doubling of its half-life and a 30% increase in the area under the curve. NAPROXEN a naphthylpropionic acid derivative − only NSAID presently marketed as a single enantiomer. – no binder effective for the usual rheumatologic indications and is available in a slow-release formulation, as an oral suspension, and over the counter topical preparation and an ophthalmic solution are also available. incidence of upper GI bleeding in over-the counter use is low but still double that of over the-counter ibuprofen (perhaps due to a dose effect). Rare cases of allergic pneumonitis, leukocytoclastic vasculitis, and pseudoporphyria as well as the common NSAID-associated adverse effects have been noted. OXAPROZIN propionic acid derivative NSAID its major difference from the other members of this subgroup is a very long half-life (50–60 hours) does not undergo enterohepatic circulation. It is mildly uricosuric. K. PIROXICAM - nonselective COX inhibitor that at high concentrations also inhibits polymorphonuclear leukocyte migration, decreases oxygen radical production, and inhibits lymphocyte function. - can be used for the usual rheumatic indications. - When used in dosages higher than 20 mg/d, an increased incidence of peptic ulcer and bleeding (relative risk up to 9.5) is encountered. L. SULINDAC - a sulfoxide prodrug N O T E TA K E R : X y - reversibly metabolized to the active sulfide metabolite and has enterohepatic cycling. this prolongs the duration of action to 12–16 hours. Suppresses familial intestinal polyposis and it may inhibit the development of colon, breast, and prostate cancer in humans. severe adverse reactions, Stevens-Johnson epidermal necrolysis syndrome, thrombocytopenia, agranulocytosis, and nephrotic syndrome; all have been observed M. TOLMETIN - a nonselective COX inhibitor with a short halflife (1–2 hours) and is not often used. CHOICE OF NSAID - All NSAIDs, including aspirin, are about equally efficacious o Although you have to choose what is appropriate to the patient. Like aspirin kapag binigay niyo in high doses it may be beneficial in patients who have coronary artery disease or acute coronary syndrome o you have your other medications like ibuprofen which is readily available – choose which has the lowest side effects and which is effective to your patients -some patients may have different reactions to the same dose compared to the other patients that given with the same medications - - - tolmetin seems not to be effective for gout, and aspirin is less effective than other NSAIDs (eg, indomethacin) for AS. the GI and renal side effects of ketorolac limit its use. Indomethacin and tolmetin are the NSAIDs associated with the greatest toxicity, while salsalate, aspirin, and ibuprofen are least toxic. For patients with renal insufficiency, nonacetylated salicylates may be best. selective COX-2 inhibitor celecoxib is probably safest for patients at high risk for GI bleeding but may have a higher risk of cardiovascular toxicity. P a g e 6 | 24 PCC SOM 2026 - - PHARMACOLOGY AND THERAPEUTICS P.03 NSAID DRUGS, DMARDs, & NONOPIOD ANALGESICS USED IN GOUT Celecoxib or a nonselective NSAID plus omeprazole or misoprostol may be appropriate in patients at highest risk for GI bleeding. choice of an NSAID thus requires a balance of efficacy, cost-effectiveness, safety, and numerous personal factors (e.g., other drugs also being used, concurrent illness, compliance, medical insurance coverage) NOTE: “There is no best NSAID for all patients. There may, however, be one or two best NSAIDs for a specific person.” DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS - - - - RA is a progressive immunologic disease that causes significant systemic effects, shortens life, and reduces mobility and quality of life. → Decreases quality of life Effects of disease-modifying therapies may take 2 weeks to 6 months to become clinically evident. These therapies include conventional synthetic (cs) and biologic (b) disease-modifying antirheumatic drugs (recently designated csDMARDs and bDMARDs, respectively). conventional synthetic agents include small molecule drugs o methotrexate, azathioprine, chloroquine and hydroxychloroquine, cyclophosphamide, cyclosporine, leflunomide, mycophenolate mofetil, and sulfasalazine o Tofacitinib, though marketed as a biologic, is actually a targeted synthetic DMARD (tsDMARD) Biologics are large-molecule therapeutic agents, usually proteins, which are often produced by recombinant DNA technology. o bDMARDs approved for RA include a Tcell– modulating biologic (abatacept), a B-cell cytotoxic agent (rituximab), an anti–IL-6 receptor antibody (tocilizumab), IL-1– inhibiting agents (anakinra, rilonacept, canakinumab), N O T E TA K E R : X y o and the TNF-α–blocking agents (five drugs) bDMARDs are further divided into biological original (or legacy) products and biosimilar DMARDs (boDMARDs and bsDMARDs, respectively) A. ABATACEPT MECHANISM OF ACTION - Abatacept is a co-stimulation modulator biologic that inhibits the activation of T cells PHARMACOKINETICS - recommended dose of abatacept for the treatment of adult patients with RA is three intravenous infusion “induction” doses (day 0, week 2, and week 4), followed by monthly infusions. - Dose is based on body weight; patients weighing less than 60 kg receiving 500 mg, those 60–100 kg receiving 750 mg, and those more than 100 kg receiving 1000 mg. - also available as a subcutaneous formulation and is given as 125 mg subcutaneously once weekly. - JIA can also be treated with abatacept with an induction schedule at day 0, week 2, and week 4, followed by intravenous infusion every 4 weeks. - recommended dose for patients 6–17 years of age and weighing less than 75 kg is 10 mg/kg, while those weighing 75 kg or more follow the adult intravenous doses to a maximum not to exceed 1000 mg. - terminal serum half-life is 13–16 days. Coadministration with methotrexate, NSAIDs, and corticosteroids does not influence abatacept clearance. - Most patients respond to abatacept within 12– 16 weeks after the initiation of the treatment; however, some patients can respond in as few as 2–4 weeks. INDICATIONS - can be used as monotherapy or in combination with methotrexate or other DMARDs in patients with moderate to severe RA or severe PJIA. It has been tested in combination with P a g e 7 | 24 PCC SOM 2026 PHARMACOLOGY AND THERAPEUTICS P.03 NSAID DRUGS, DMARDs, & NONOPIOD ANALGESICS USED IN GOUT methotrexate in early rapidly progressing RA and methotrexate- naive patients. ADVERSE EFFECTS - slightly increased risk of infection (as with other biologic DMARDs), predominantly of the upper respiratory or urinary tracts. - Concomitant use with TNF-α antagonists or other biologics is not recommended due to the increased incidence of serious infection - All patients should be screened for latent tuberculosis and viral hepatitis before starting this medication. - Live vaccines should be avoided in patients while taking abatacept and up to 3 months after discontinuation. - Infusion-related reactions and hypersensitivity reactions, including anaphylaxis, have been reported but are rare. Anti-abatacept antibody formation is infrequent (