Katzung, Part 6, Chapter 36. NSAIDs, Acetaminophen, & Drugs used in RA & Gout

Katzung, Part 6, Chapter 36. NSAIDs, Acetaminophen, & Drugs used in RA & Gout

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  Part 6 Chapter 36 NSAIDs,Acetaminophen, & Drugs Used in RA & Gout INTRO Inflammation Characteristics & Functions: • A complex response to cell injury • Primarily occurs in vascularized connective tissue. • Involves the immune response. • The mediators of inflammation function to eliminate the cause of cell injury and clear away debris. • Serves as a preparation for tissue repair. • Also causes pain. • If the cause of cell injury persists (not eliminated), may lead to chronic pain and tissue damage, as seen in RA. Inflammation Treatment • The NSAIDs and acetaminophen are often effective in controlling inflammatory pain. • Other treatment strategies applied to the reduction of inflammation are aimed at immune processes. These include glucocorticoids and DMARDs. • DMARDs include: o csDMARD (small molecule) o bDMARD Gout Definition and Treatment • A metabolic disease • Associated with precipitation of uric acid crystals in joints. • Treatment of acute episodes targets inflammation • Treatment of chronic gout targets both: o Inflammatory processes o Production and elimination of uric acid ASPIRIN & OTHER NONSELECTIVE NSAIDS Classification and Prototypes Aspirin (ASA) • The prototype of the salicylates and other NSAIDs The other older nonselective NSAIDs • Vary in their potency, analgesic and anti-inflammatory effectiveness, and duration of action. • Ibuprofen and naproxen have moderate effectiveness. • Indomethacin has greater anti-inflammatory effectiveness
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  • Ketorolac hasgreater analgesic effectiveness. Celecoxib • The first COX-2-selective inhibitor (a newer NSAID subgroup) • Developed to reduce the GI toxicity associated with COX inhibition while maintaining efficacy. • Selective COX-2 inhibitors have a higher risk of cardiovascular thrombotic events than nonselective NSAIDs. Mechanism of Action COX Function • The enzyme that converts arachidonic acid into the endoperoxide precursors of PGs. (PGs are important mediators of inflammation) COX Two Isoforms: • COX-1 and COX-2 COX Expression • COX-1 is primarily expressed in noninflammatory cells • COX-2 is expressed in activated lymphocytes, PMNs, and other inflammatory cells. COX Inhibition Aspirin and nonselective NSAIDs • Inhibit both COX isoforms; As a result: o PG and thromboxane synthesis decreases throughout the body o Release of PGs necessary for homeostatic functions as PGs involved in inflammation is disrupted. COX-2-selective inhibitors • Have less effect on the PGs involved in homeostatic function, particularly those in the GI tract. The major difference between aspirin and other NSAIDs • Aspirin acetylates and thereby irreversibly inhibits COX. (But aspirin’s active metabolite, salicylate, has not this effect.) • Other NSAIDs inhibit COX reversibly. Aspirin – Antiplatelet Action • Aspirin is an antiplatelet drug (due to inhibition of TXA2 synthesis in platelets) • The basis of its antiplatelet use is: o Longer duration of its antiplatelet effect due to irreversible COX inhibition. COX Inhibitors Effects • Arachidonic acid derivatives (eicosanoids) are important mediators of inflammation. Antiinflammatory effect • They reduce the manifestations of inflammation. • Have no effect on underlying tissue damage or immunologic reactions. Antipyretic effect • They suppress the PG synthesis in the CNS that is stimulated by pyrogens and thereby reduce fever.
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  Analgesic effect • Lesswell understood. • They reduce PG production in injured tissue, resulting in diminished activation of peripheral pain sensors. • A central mechanism is operative. Disruption of homeostasis • They interfere with the homeostatic function of PGs. • They reduce PG-mediated: o Cytoprotection in the GI tract (COX-1) That is why COX-2-selective inhibitors have less GI adverse effects. o Autoregulation of renal function (COX-1 and COX-2) Pharmacokinetics and Clinical Use Aspirin Therapeutic Dose Ranges • Low range (<300 mg/d) o Effective in reducing platelet aggregation • Intermediate doses (300-2400 mg/d) o Antipyretic and analgesic effects • High doses (2400-4000 mg/d) o Used for an anti-inflammatory effect Absorption & Metabolism • Aspirin is readily absorbed and is hydrolyzed in blood and tissues to acetate and salicylic acid (salicylate). Salicylate Function • The active metabolite of aspirin • A reversible nonselective COX inhibitor. Elimination & Half-life • At low doses o Elimination is first order. o Half-life: 3-5 h • At high (anti-inflammatory) doses o Elimination becomes zero order. o Half-life: Increases to 15 h or more Salicylate Excretion • Via the kidney
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  Other NSAIDs • Wellabsorbed after oral administration. Ibuprofen • Half-life: ≈2 h • Relatively safe • The least expensive of the older, nonselective NSAIDs. Naproxen and Piroxicam • Noteworthy because of their longer half-lives, which permit less frequent dosing. Nonselective NSAIDs Clinical use • Primarily for treatment of mild to moderate pain Especially the pain of musculoskeletal inflammation (e.g., arthritis and gout) • Other usages: o Dysmenorrhea o Headache o PDA in premature infants Ketorolac • Used mainly as a systemic analgesic, not as an anti-inflammatory (although it has typical nonselective NSAID properties) • The only NSAID available in a parenteral formulation. Polyp Attenuation • Nonselective NSAIDs reduce polyp formation in patients with primary FAP. Toxicity Aspirin Gastric upset • The most common adverse effect • By therapeutic high (anti-inflammatory doses) of aspirin • Due to COX-1 inhibition Chronic use can result in: • Gastric ulceration • Upper GI bleeding • Renal effects including: o Acute renal failure o Interstitial nephritis Bleeding • Aspirin increases the bleeding time (due to its antiplatelet effect)
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  Aspirin hypersensitivity • Byeven small doses of aspirin, patients with aspirin hypersensitivity can experience asthma. • Especially associated with nasal polyps • Mechanism : o Due to increased synthesis of leukotrienes. • Precludes treatment with any NSAID. At Higher Doses • Tinnitus • Vertigo • Hyperventilation, resulting in respiratory alkalosis Salicylates stimulate the respiratory center → hyperventilation At Very High Doses • Metabolic acidosis • Dehydration • Hyperthermia • Collapse, coma, and death • N/V Combined respiratory water loss + sweating + vomiting → dehydration Salicylates uncouple oxidative phosphorylation → increased heat production → sweating Rey syndrome • Aspirin use in children (<19 years of age) with viral infections increases the risk of Reye syndrome • A rare but serious syndrome of rapid liver degeneration and encephalopathy. Pregnancy • NSAIDs use in pregnancy at 20 weeks or later: o Can result in low amniotic fluid production by the fetus o Not recommended No Antidote • There is no specific antidote for aspirin. Nonselective NSAIDs • Significant GI disturbance (but the incidence is lower than with aspirin) • Renal damage o With any of the NSAIDs o Especially in patients with preexisting renal disease. • Preexisting Renal damage results in higher, more toxic serum concentrations. (because these drugs are cleared by the kidney) • Parenteral ketorolac use is restricted to 72 h because of the risk of GI and renal damage with prolonged use. • Serious hematologic reactions have been noted with indomethacin.
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  COX-2-selective inhibitors • e.g.,Celecoxib, rofecoxib, valdecoxib • Lower risk of GI effects, including gastric ulcers and serious GI bleeding. • Risk of renal damage (similar to nonselective COX inhibitors) (presumably because COX-2 contributes to homeostatic renal effects) Risk of MI and stroke • Highly selective COX-2 inhibitors such as rofecoxib and valdecoxib carry an increased risk of MI and stroke. • Increased risk of arterial thrombosis is due to: o Greater inhibitory effect of COX-2 inhibitors on endothelial prostacyclin synthesis than on platelet TXA₂ synthesis. • Prostacyclin and TXA2 physiology: o Prostacyclin promotes vasodilation and inhibits platelet aggregation o TXA2 promotes vasoconstriction and platelet aggregation Removed Drugs • Highly selective COX-2 inhibitors (rofecoxib, valdecoxib) have been removed from the market Warning Sign • The remaining drug, celecoxib, carries a warning of increased thrombosis risk. ACETAMINOPHEN Classification and Prototype • It is analgesic and antipyretic • It is not antiinflammatory Phenacetin • A toxic prodrug that is metabolized to acetaminophen • Still available in some countries. Mechanism of Action • The mechanism its analgesic action is unclear. • It is only a weak COX-1 and COX-2 inhibitor in peripheral tissues. (which accounts for its lack of anti-inflammatory effect) • It may inhibit a third enzyme, COX-3, in the CNS. Effects • Analgesic and antipyretic • Lacks antiinflammatory or antiplatelet effects.
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  Clinical Use • Itis effective for the same indications as intermediate-dose aspirin. • It is useful as an aspirin substitute, especially in: o Children (<19 years of age) with viral infections o Those with any type of aspirin intolerance. Pharmacokinetic • Well absorbed orally • Metabolized in the liver • Half-life: o 2-3 h (in persons with normal hepatic function) o Unaffected by renal disease Toxicity • Negligible toxicity in most persons in therapeutic dosages Hepatotoxicity • Acetaminophen is a dangerous Hepatotoxin when taken: o In overdose o By patients with severe liver impairment Acetaminophen Hepatic Metabolism (should be discussed before its toxicity) • Phase II conjugation (the primarily pathway) o Glucuronidation (major pathway) o Sulfation (minor pathway) • Phase I oxidation by CYP450 (normally minor) o Produces reactive metabolite NAPQI • Detoxification: o NAPQI is conjugated with glutathione to form non-toxic metabolites, which are excreted in urine. Sequence of Events Leading to Acetaminophen Toxicity 1. Under the following conditions: o In overdose, when Phase II conjugation pathways become saturated. o In the absence of enough substrates for Phase II conjugation reactions (sulfate and glucuronide) 2. Acetaminophen is oxidized by Phase I pathway to cytotoxic metabolite NAPQI. 3. Glutathione quickly binds with NAPQ1 to form a non-toxic metabolite 4. When glutathione is exhausted (depleted), NAPQI accumulates. Mechanism of Hepatotoxicity • NAPQI binds to hepatic proteins, causing cellular stress that leads to hepatic necrosis and haptic failure N-acetylcysteine (NAC) – The Antidote • A sulfhydryl donor • Its prompt administration may be lifesaving after an acetaminophen overdose.
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  Alcohol • Risk ofacetaminophen-induced hepatotoxicity increases with regular ≥3 alcoholic drinks consumption per day. DISEASE-MODIFYING ANTIRHEUMATIC DRUGS (DMARDS) Classification • DMARD is a heterogeneous group of agents with antiinflammatory actions in several CTDs. They are Disease-Modifying Drugs • Because they slow or even revers joint damages (an effect never seen with NSAIDs) They are Slow-Acting Antirheumatic Drugs • Because it may take 6 weeks to 6 months for their benefits to become apparent. Corticosteroids • Including glucocorticoids alongside DMARDs does not imply that they are a type of DMARD • Anti-inflammatory drugs • Intermediate rate of action: o Slower than NSAIDs but faster than other DMARDs • Too toxic for routine chronic use • Reserved for temporary control of severe exacerbations • Long-term use may be required in patients with severe disease not controlled by other agents. Mechanisms of Action and Effects • The mechanisms of action of most DMARDs in treating RA are complex. Cytotoxic Drugs • Include: Methotrexate (MTX) • Act by reducing the number of available immune cells • Many are also used in cancer treatment Disruptor of T Lymphocyte Activity • Sulfasalazine (SSZ) • Hydroxychloroquine (HCQ) • Cyclosporine (CsA) • Leflunomide (LEF) • Mycophenolate mofetil (MMF) • Abatacept Disruptor of B Lymphocyte Activity • Rituximab Disruptor of Macrophages Activity • Gold compounds TNF-α Inhibitor • Include: Infliximab, Adalimumab, Etanercept IL-1R Antagonist • Anakinra (A recombinant human IL-1Ra) (IL-1Ra is naturally present in the body)
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  Pharmacokinetics Route of Administration •SSZ, HCQ, MTX, CsA, Penicillamine, LEF are used orally. • Anti-TNF-α drugs are used parenterally. • Gold compounds o Parenteral from (gold sodium thiomalate and aurothioglucose) o Oral form (auranofin) o Considered obsolete (not part of routine therapy today) Clinical Use RA • DMARDs, especially low-dose MTX, are started early in moderate to severe RA to slow disease progression. Other rheumatic diseases • SLE, SS-associated arthritis, Juvenile rheumatoid arthritis, AS Other immunologic disorders Toxicity • All DMARDs can activate latent TB and cause severe toxicities. • Careful monitoring is mandatory. DRUGS USED IN GOUT Classification and Prototypes • Gout is associated with increased serum uric acid levels. • Acute attacks involve joint inflammation initiated by precipitation of uric acid crystals. Treatment Strategies • Antiinflammatory drugs o Reduce inflammation during acute attacks o Colchicine, NSAIDs, or glucocorticoids • Uricosuric drugs o Accelerate renal excretion of uric acid o Probenecid or sulfinpyrazone • Xanthine oxidase inhibitors (XOI) o Reduce the conversion of purines to uric acid o Allopurinol or febuxostat • Uricase drugs o Convert uric acid to the soluble allantoin o Pegloticase
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  Anti-Inflammatory Drugs Usedfor Gout Mechanisms NSAIDs • Such as indomethacin (a classic NSAID for acute gout) • Inhibit the inflammation of acute gouty arthritis • Reduce PG formation, thereby inhibiting urate crystal phagocytosis by macrophages. Colchicine • A selective inhibitor of microtubule assembly • Reduces leukocyte migration and phagocytosis • May also reduce production of LTB4 and decrease free radical formation. Effects NSAIDs and glucocorticoids • Reduce the synthesis of inflammatory mediators in the gouty joint. Colchicine • A general mitotic poison (because it reacts with tubulin and interferes with microtubule assembly.) (Tubulin is necessary for normal cell division, motility, and many other processes.) Clinical use NSAID and glucocorticoid • Treatment of acute gouty arthritis Colchicine • Can be used for acute attacks, but the doses required cause significant GI disturbance, particularly diarrhea. • Prevention of attacks with lower doses of colchicine in patients with a history of multiple acute attacks. • Valuable in management of FMF o A disease of unknown cause o Characterized by fever, hepatitis, peritonitis, pleuritis, arthritis, and, occasionally, amyloidosis Pharmacokinetics • Indomethacin, some glucocorticoids, and colchicine are used orally • Parenteral preparations of glucocorticoids and colchicine are also available. Toxicity NSAIDs • Renal damage • Indomethacin can additionally cause bone marrow depression. Glucocorticoids • Short courses of glucocorticoids can cause behavioral changes and impaired glucose control.
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  Colchicine • Colchicine canseverely damage the liver and kidney • Therefore, its dosage must be carefully limited and monitored. • Overdose is often fatal. Uricosuric Agents • Include: Probenecid, sulfinpyrazone Mechanism 1. Normally, >90% of the uric acid filtered by the kidney is reabsorbed in the proximal tubules. 2. There is a weak acid transport mechanism in the proximal tubules for weak acid reabsorption. 3. Probenecid and sulfinpyrazone are weak acids. 4. Therefore, they compete with uric acid for reabsorption in the proximal tubules. 5. Uric acid excretion increases. Low Dose Weak Acid • At low doses, these agents may also compete with uric acid for secretion and elevate serum uric acid levels. • Aspirin (another weak acid), over much of its dose range, also elevates uric acid levels by this mechanism. Effects • Also inhibit the secretion of a large number of other weak acids (eg, penicillin, MTX) Pharmacokinetics and clinical use • Used orally • Treatment of chronic gout caused by under-excretion of uric acid. • No value in acute episodes • Contraindicated in overproducers of uric acid Patients who overproduce uric acid already excrete large amounts of uric acid in their urine. Probenecid further increases urinary uric acid excretion & concentration in the urine, increasing the risk of uric acid kidney stones. Toxicity • Precipitation of an attack of acute gout during the early phase of their action. (This can be avoided by simultaneously administering colchicine or indomethacin.) • As they are sulfonamides, they may share allergenicity with other classes of sulfonamide drugs o Diuretics, antimicrobials, oral hypoglycemic drugs Patients with a history of sulfonamide allergy may also develop an allergic reaction to these drugs. Xanthine Oxidase Inhibitors (XOIs) • XO Inhibition reduces uric acid production. • XO is the enzyme that converts hypoxanthine to xanthine and xanthine to uric acid. • 2 Types o Purine inhibitor of XO: Allopurinol o Nonpurine inhibitor of OX: Febuxostat
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  Mechanism Allopurinol • A purineinhibitor of XO • Allopurinol (which resembles hypoxanthine) is converted to oxypurinol (alloxanthine) by XO. • Alloxanthine is an irreversible suicide inhibitor of the enzyme. The XO catalyzes the reaction that generates the molecule that permanently disables itself. In other words, the enzyme's own catalytic activity leads to its inactivation—hence the term "suicide inhibitor." • Less selective (also inhibit other enzymes involved in purine and pyrimidine metabolism) Febuxostat • A newer drug • A nonpurine inhibitor of OX • More selective than allopurinol and alloxanthine Effects • The levels of the more soluble hypoxanthine and xanthine increases. • The levels of the less soluble uric acid decreases. • Precipitation of uric acid crystals in joints and tissues decreases. • Febuxostat is more effective than allopurinol in lowering serum uric acid. Pharmacokinetics and clinical use • Administered orally. • Management of chronic gout • Withheld for 1-2 weeks after an acute episode of gouty arthritis (like uricosuric agents) • Administered in combination with colchicine or an NSAID to avoid an acute attack. (like uricosuric agents) • Allopurinol is also used as an adjunct to cancer chemotherapy to: o Slow uric acid formation from purines released by the death of large numbers of neoplastic cells. Toxicity and drug interactions Allopurinol • Cause GI upset, rash • Rarely, peripheral neuritis, vasculitis, or bone marrow dysfunction, including aplastic anemia. • Allopurinol hypersensitivity syndrome (AHS) o Allopurinol can induce a severe, potentially fatal AHS in patients with the HLA-B*5801 allele. o Genetic screening is recommended in populations of interest. • Contraindicated in renal insufficiency. • Inhibits the metabolism of mercaptopurine and azathioprine, drugs that depend on XO for elimination. Mercaptopurine is the active metabolite of Azathioprine.
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  Febuxostat • Can beused in renal insufficiency. • Cause liver function abnormalities, headache, and GI upset. • It carries a black box warning for increased risk of cardiovascular death and all-cause mortality. Uricase • Pegloticase is a recombinant mammalian uricase. • Humans lack uricase. Mechanism • Pegloticase converts uric acid to the soluble allantoin, which can be eliminated by the kidney. Effect • An IV dose of pegloticase lowers urate levels within 24-72 hours. Clinical use • Treatment of refractory chronic gout Adverse effects • Gout flares, especially during the first 3–6 months of treatment, require NSAID or colchicine prophylaxis. • The drug is extremely expensive. SKILL KEEPER: OPIOID ANALGESICS AND ANTAGONISTS • NSAIDs and acetaminophen are extremely useful for the treatment of mild to moderate pain • However, adequate control of more intense pain often requires treatment with an opioid. Questions 1. Name one strong, one moderate, and one weak opioid drug. 2. Briefly describe the most common adverse effects of strong and moderate opioids. 3. What drug should be administered in the event of an opioid overdose? ANSWER Strong, Moderate, & Weak Opioid Drug: • Morphine is the prototype strong opioid. • Fentanyl is a strong agent with a rapid onset that is commonly used in the hospital. • Methadone is a strong agonist used in maintenance programs for patients addicted to opioids. • Codeine, oxycodone, and hydrocodone are moderate agonists. • Propoxyphene is a weak agonist. The Most Common Adverse Effects of Opioids • Constipation and sedation occur with therapeutic doses; • Constipation should be managed with stool softeners or opioid antagonists that do not enter the CNS.
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  • Opioid overdosetriad: o Pinpoint pupils o Coma o Respiratory depression Opioid Antagonist • Naloxone, a nonselective opioid receptor antagonist, is an antidote for opioid overdose. KEY POINTS FROM “QUESTIONS” SECTION • Aspirin o The NSAID of choice in individuals who need antiplatelet therapy after PCI (stenting) o It is unique among NSAIDs, because it irreversibly inhibits COX. • MTX, like other weak acids, is eliminated by active proximal tubular secretion. • Probenecid competes with MTX for binding to the proximal tubule transporter, reducing MTX clearance. • Ketorolac o Exerts typical NSAID effects. o Prolongs the bleeding time. o Impair renal function, especially in a patient with preexisting renal disease. o Primary use: Parenteral agent for pain management, especially in postoperative patients. • Acetaminophen overdose, causes fulminant liver failure. (As a result of its conversion by hepatic cytochrome P450 enzymes to a highly reactive metabolite NAPQI.) • Colchicine dose-dependent side effects: o High doses of colchicine needed to treat acute gout, frequently cause significant diarrhea. o Lower doses used in chronic gout prophylaxis, cause less GI adverse effects. • Low-dose aspirin slows renal secretion of uric acid; thus, it should not be used in gout. • COX-2-selective inhibitors o e.g., Celecoxib o Have the advantage over nonselective NSAIDs of reduced GI toxicity o More likely to cause arterial thrombotic events. o Should be avoided is there is a history of MI. Abbreviations: AS = ankylosing spondylitis ASA = acetylsalicylic acid bDMARDs = biologic DMARDs COX = cyclooxygenase csDMARDs = conventional synthetic small molecule DMARDs CTDs = connective tissue diseases DMARDs = disease-modifying antirheumatic drugs FAP = familial adenomatous polyposis FMF = familial Mediterranean fever GI = gastrointestinal IL = interleukin IL-1Ra = IL-1 receptor antagonist LT = leukotriene MI = Myocardial infarction MTX = methotrexate NSAIDs = nonsteroidal anti-inflammatory drugs PCI = percutaneous coronary intervention PDA = Patent ductus arteriosus PG = prostaglandin PMNs = polymorphonuclear cells Prostacyclin = PGI2 RA = rheumatoid arthritis SLE = systemic lupus erythematosus SS = Sjögren syndrome TB = tuberculosis TXA2 = thromboxane A2