nsaids_block4_posting.pptx

Pain Relievers, NSAIDS & Gout Objectives 1. Know the nomenclature and biochemical pathways for eicosanoid production and the effects produced by the eicosanoids and their mechanism of action. 2. Understand the consequences of blockade of synthesis or action of the eicosanoids. 3. Describe the mechan...

Pain Relievers, NSAIDS & Gout Objectives 1. Know the nomenclature and biochemical pathways for eicosanoid production and the effects produced by the eicosanoids and their mechanism of action. 2. Understand the consequences of blockade of synthesis or action of the eicosanoids. 3. Describe the mechanisms of action and clinical application of the NSAIDs. 4. Know the mechanisms of action of the anti-gout drugs. 5. Know the guidelines for therapeutic uses of NSAIDs, anti-gout drugs and DMARDs. Biochemical Mediators of Inflammation Vasoactive amines (Histamine, Serotonin) Platelet activating factor (PAF) Complement system Kinin system Cytokines Nitric oxide Adhesion Molecules Arachidonic acid metabolites (eicosanoids): o Thromboxane A2 (TXA2) o HETE (hydroxy-eicosatetraenoic acid) o Leukotrienes (LTs) o Prostaglandins (PGs) mediated by cyclooxygenases (COXs) Cyclooxygenases Constitutive Inducible Structural basis for cyclooxygenase-2 (COX-2)-selective inhibition. The active centers of COX-1 and COX-2 are shown crystallized with the nonselective inhibitor flurbiprofen (COX-1) and the experimental COX-2 inhibitor SC-558. The active center of COX-2 is characterized by a larger side pocket, which can accommodate molecules with bulkier side chains than COX-1. Eicosanoid Metabolism LT - leukotrienes 5-lipoxygenase activating protein neutrophil chemotaxis Vaso-, bronchoconstriction TX – thromboxane PG - prostaglandin Eicosanoid Metabolism Platelet aggregation Vaso-, bronchoconstriction Mobilizes [Ca2+]i uterine tone Required for fever response Vaso-, bronchodilators Sensitizes nerves Protects gastric mucosa Platelet aggregation Vascular tone (endothelium) Protects gastric mucosa Immune cells inflammatory actions uterine tone Vaso-, bronchoconstriction Prototypic Drugs MECHANISMS NSAIDS COMMON AGENTS ACTIVITY PROFILE Ipuprofen Diclofenac Indomethacin Naproxen Ketorolac Meloxicam Piroxicam Sulindac Acetylsalicylic acid (aspirin) Analgesic Antipyretic Anti-inflammatory Anti-platelet effects (aspirin) NSAIDS are effective against mild to moderate pain, due to inflammation myalgia, arthralgia and neuralgia respond well. COX-2 Inhibitors (selective NSAID) Celeboxib Analgesic Anti-inflammatory Other non-opioid analgesics Acetaminophen Analgesic Antipyretic Classification of NSAIDs by chemical similarity (panel A), cyclooxygenase (COX) isoform selectivity (panel B), and plasma t1/2 (panel C). The COX selectivity chart is plotted from data published in Warner et al., 1999, and FitzGerald and Patrono, 2001. tNSAIDs, traditional nonsteroidal anti-inflammatory drugs. 2/27/2022 ASPIRIN (acetylsalicylate) MECHANISM OF ACTION: Irreversible inhibitor of COX-1 & COX-2 Inhibition of COX-1 in the bloodstream  decreases production of TXA2  increases bleeding time, useful as an antiplatelet medication Inhibition of COX-2  decreases prostaglandin production  decreases inflammation, pain, fever INDICATIONS: Dose dependent Low doses < 300 mg/day Antiplatelet activity used long-term to prevent heart attacks, strokes, blood clot formation Medium doses 300-2400 mg/day Antipyretic and analgesic High doses >2400 mg/day Anti-inflammatory Contraindicated in: febrile illness in individuals < 19 years of age due to risk of Reyes Syndrome ASPIRIN & URIC ACID Low-dose aspirin (2g/d) Blocks both secretion & reabsorption of uric acid Uricosuric, lowers serum uric acid RENAL FUNCTION IMPAIRMENT Blocking prostaglandin E2 production decreases renal blood flow worsens hypertension Analgesic nephrophathy Can occur with prolonged NSAID use Renal ischemia, chronic nephritis Rising BUN and creatinine in the plasma SALICYLATE TOXICITY (Acute poisoning) 1. Salicylate uncouples oxidative phosphorylation in skeletal muscle ↑ O2 consumption and ↑ CO2 production ↑ heat production and ↑ production of lactic acid 2. ↑ CO2 production compensated by ↑ respiratory depth no significant change in pCO2. 3. Salicylates directly stimulate the respiratory center in the medulla hyperventilation (↑ rate and depth) = respiratory alkalosis compensated for in kidney by loss of HCO3-, Na+ and K+ plasma pH is lowered to normal with a loss of fixed anion In Children: Respiratory alkalosis is followed by a ↓ plasma pH, low plasma HCO3- with near normal pCO2. Soon, however, ↑ CO2 production due to ↓ ventilation leads to ↑pCO2 and acidosis (uncompensated due to the loss of HCO3-). Metabolic acidosis is in part due to the presence of the salicylic acid itself, increased accumulation of lactic acid and decreased excretion of acids due to decreased blood flow to the kidney secondary to vasomotor depression SALICYLATE TOXICITY Salicylism (overdose or poisoning with > 5g/d of aspirin or salicylate) In adults, tinnitus, hearing loss, vertigo occurs as initial sign of toxicity In children, the common signs of toxicity include acidosis and hyperventilation, with accompanying lethargy. Rescue: of a potential fatal emergency i.v. NaHCO3: alkalization of urine with bicarbonate to reduce salicylate reabsorption promote the excretion Correction of acid—base disturbances Replacement of electrolytes and fluids Cooling Forced diuresis, hemodialysis Gastric lavage or emesis NSAIDS: NON-SELECTIVE REVERSIBLE COX INHIBITORS COMMON AGENTS Proprionic acid derivatives Indoles Ibuprofen Naproxen ACTIVITY PROFILE Used to treat fever, pain, and/or inflammation. ↓ inflammation during an acute gout attack Indomethacin is used to treat rheumatoid arthritis, musculoskeletal pain Indomethacin is used intravenously for the treatment of patent ductus arteriosus Indomethacin Suldinac Sulindac is metabolized to a sulfide which is the active drug. SIDE EFFECTS GI distress (less severe than aspirin or indomethacin Increased bleeding time Potential for serious drug-drug interaction with warfarin and possibly oral hypoglycemics. Indomethacin has a high incidence (35-50%) of adverse effects including gastrointestinal, hematopoietic and hypersensitivity reactions. Indomethacin may cause the decreased renal excretion of aminoglycosides or digitalis Suldinac has less GI toxicity NSAIDS: NON-SELECTIVE REVERSIBLE COX INHIBITORS COMMON AGENTS Phenylacetic acids ACTIVITY PROFILE Accumulates in synovial fluid Useful in the treatment of RA, osteoarthritis and ankylosing spondylitis Diclofenac (Voltaren) Acetic Acid Ketorolac (Toradol) Short-term management of moderate to severe pain (e.g., postoperative pain relief). 40 times as potent an anti-inflammatory as ibuprofen. Can be given by im injection or orally. Enolic Acids Meloxicam Piroxicam May block the release of arachidonic acid in leukocytes for some of its anti-inflammatory effects Meloxicam possesses relative COX-2 selectivity. Meloxicam is useful as an analgesic in RA and gout. Piroxicam is ypically used for the management of pain caused by osteoarthritis or RA SIDE EFFECTS GI distress Hepatotoxicity Embryotoxic Fewer GI side effects compared to aspirin and is generally well tolerated Meloxicam can only when prescribed during the first 6 months of pregnancy. May interact with lithium, ACE inhibitors, aspirin or other NSAIDs NSAIDS: SELECTIVE COX-2 INHIBITORS COMMON AGENTS Celeboxib (Celebrex) INDICATIONS SIDE EFFECTS Pain, inflammation Effective in rheumatoid arthritis and osteoarthritis CV Increased risk of heart attack & stoke Less risk GI ulcers/bleeding Lacks antiplatelet effects since doesn’t act on COX-1, can be combined with aspirin Renal Deterioration of chronic renal failure Increase in blood pressure Sulfa drugs so can’t use with allergies ACETAMINOPHEN (Paracetamol) Hepatotoxicity due to acetaminophen overdose MECHANISM OF ACTION: Inhibits COX-1 & COX-2 Crosses the blood-brain-barrier INDICATIONS: Analgesic Antipyretic Poor anti-inflammatory activity in the periphery ACETAMINOPHEN VS. ASPIRIN Acetaminophen has no effect on the respiratory system does not cause acid-base changes does not cause gastric irritation does not affect excretion of uric acid does not block leukocyte adherence does not increase bleeding time Treatment is N-acetylcysteine (NAC) to replenish glutathione stores in the liver. REVIEW – PURINE METABOLISM & URIC ACID GOUT PHARMACOTHERAPY FOR GOUT INDICATION MECHANISM OF ACTION ADVERSE EFFECTS CONTRAINDICATIONS Acute gouty arthritis Binds and stabilizes tubulin subunits → inhibition of microtubule polymerization → inhibition of urate crystal phagocytosis, neutrophil activation, migration, and degranulation Severe diarrhea, GI symptoms Rhabomyolysis Polyneuropathy Urate lowering therapy for chronic gout Xanthine Oxidase Inhibitors (XOI) Reduces production of uric acid As an alternative or addition to XOI Inhibition of uric acid reabsorption in proximal tubules to ↑ renal elimination Failure of first and second line medications Glucocorticoids NSAIDs (naproxen) Colchicine Allopurinol (competitive) Febuxostat (selective) Probenecid Nausea, diarrhea Uric acid stones GI symptoms Infusion reactions Pegloticase Recombinant uricase that catalyzes the breakdown of uric acid to allantoin Rheumatoid Arthritis Rheumatoid arthritis is a long-term, progressive, and disabling autoimmune disease causing inflammation, swelling, and pain in and around the joints and organs (heart, lungs, kidney). Rheumatoid arthritis (RA) usually affects the hands and feet first, but it can occur in any joint. NSAIDs, in particular aspirin were once the drug of choice NSAIDs still have utility early in the treatment of RA. DMARDs, disease modifying anti-rheumatic agents are now the preferred treatment and include chemotherapeutics such as methotrexate and biologics. Management of RA Pros to NSAIDs Effective (±) control of inflammation and pain Effective reduction in swelling Improves mobility, flexibility, range of motion Improve quality of life Low-cost DMARDs Cons to NSAIDs Does not affect disease progression GI toxicity common Renal complications (e.g., irreversible renal insufficiency, papillary necrosis may occur) Hepatic dysfunction CNS toxicity with high dose (salicylates) MECHANISM OF ACTION Methotrexate Competitively inhibits dihydrofolate reductase Hydroxchloroquine Anti-malarial that decreases complement-dependent antigen-antibody reactions. reversibly inhibits dihydroorotate dehydrogenase → impaired pyrimidine synthesis → inhibition of Tcell proliferation A pro-drug that is converted into the active metabolite, 5-aminosalicylic acid (5-ASA), which acts as an anti-inflammatory Etanercept Fusion protein synthesized by recombinant DNA as a decoy receptor that binds to TNF-α and IgG1 Fc Infliximab Chimeric anti-TNF-α monoclonal antibody Lefluomide Sulfasalazine Objectives 1. Know the nomenclature and biochemical pathways for eicosanoid production and the effects produced by the eicosanoids and their mechanism of action. 2. Understand the consequences of blockade of synthesis or action of the eicosanoids. 3. Describe the mechanisms of action and clinical application of the NSAIDs. 4. Know the mechanisms of action of the anti-gout drugs. 5. Know the guidelines for therapeutic uses of NSAIDs, anti-gout drugs and DMARDs. SUMMARY OF NSAIDS MECHANISMS NSAIDS COMMON AGENTS ACTIVITY PROFILE Analgesic Antipyretic Anti-inflammatory Anti-platelet effects (aspirin) Ipubrofen Diclofenac Indomethacin Naproxen Ketorolac Meloxicam Piroxicam Sulindac Aspirin SIDE EFFECTS GI Gastric, intestinal ulcers, bleeding Renal Acute renal failure Analgesic nephropathy CV Worsen hypertension Increased risk of heart attack & stoke (except aspirin/naproxen) CV Increased risk of heart attack & stoke COX-2 Inhibitors (selective NSAID) Celeboxib Analgesic Anti-inflammatory Other non-opioid analgesics Acetaminophen Analgesic Antipyretic Renal Deterioration of chronic renal failure Increase in blood pressure Hepatotoxicity Limited nephrotoxicity NSAIDS: SELECTIVE COX-2 INHIBITORS COMMON AGENTS Celeboxib (Celebrex) INDICATIONS SIDE EFFECTS Pain, inflammation Effective in rheumatoid arthritis and osteoarthritis CV Increased risk of heart attack & stoke Less risk GI ulcers/bleeding Lacks antiplatelet effects since doesn’t act on COX-1, can be combined with aspirin Renal Deterioration of chronic renal failure Increase in blood pressure Sulfa drugs so can’t use with allergies PHARMACOTHERAPY FOR GOUT INDICATION MECHANISM OF ACTION ADVERSE EFFECTS CONTRAINDICATIONS Acute gouty arthritis Binds and stabilizes tubulin subunits → inhibition of microtubule polymerization → inhibition of urate crystal phagocytosis, neutrophil activation, migration, and degranulation Severe diarrhea, GI symptoms Rhabomyolysis Polyneuropathy Urate lowering therapy for chronic gout Xanthine Oxidase Inhibitors (XOI) Reduces production of uric acid As an alternative or addition to XOI Inhibition of uric acid reabsorption in proximal tubules to ↑ renal elimination Failure of first and second line medications Glucocorticoids NSAIDs (naproxen) Colchicine Allopurinol (competitive) Febuxostat (selective) Probenecid Nausea, diarrhea Uric acid stones GI symtpons Infusion reactions Pegloticase Recombinant uricase that catalyzes the breakdown of uric acid to allantoin