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112 Cards in this Set
- Front
- Back
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What is the prototype of the salicylates?
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Aspirin
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What are Ibuprofen and Indomethacin?
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Nonselective NSAIDs
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What is cyclooxygenase?
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Converts arachidonic acid to prostaglandin precursors
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What is the difference between COX-1 and COX-2?
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COX-1 is expressed in non-inflammatory cells
COX-2 is expressed in activated lymphocytes, PMN's and other inflammatory cells |
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Which form of COX do Aspirin and non-selective NSAIDs inhibit?
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both COX-1 and COX-2
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What's the difference main difference between Aspirin/nonselective NSAIDs and COX-2-selective inhibitors?
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The NSAIDs inhibit the release of prostaglandins involved in the inflammatory response plus the PG's involved in normal homeostasis
COX-2 selectives block PG's involved in inflammation only *NSAIDs have a particularly harsh effect on the GI tract, and COX-2 selectives do not |
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What is the difference between aspirin and other NSAIDs?
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Aspirin IRREVERSIBLY inhibits COX
other NSAIDs Reversibly inhibit COX |
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What is special about Aspirin's irreversible blockage of COX?
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It irreversibly blocks the enzyme, rendering it ineffecive. Platelets can't make a new enzyme themselves, so you have to wait for that platelet to die and new ones to form, which takes a few days.
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What is the effect of the LOW range does of Aspirin?
(<300 mg/day) |
Reduces platelet aggregation
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What is the effect of the INTERMEDIATE range does of Aspirin?
(300-2400 mg/day) |
Antipyretic and analgesic effects
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What is the effect of the HIGH range does of Aspirin?
(2400-4000 mg/day) |
Anti-inflammatory effect
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What is the difference between Aspirin and salicylate (its active metabolite)?
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Aspirin = acetylsalicylic acid, and irreversibly inhibits COX
Salicylate is a reversible non-selective inhibitos of COX |
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What are the other NSAIDs used for mainly?
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Mild to Moderate pain, esp. pain from musculoskeletal inflammation like arthritis or gout
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What is the main use for Ketorolac?
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As a systemic analgesic, not as an anti-inflammatory
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Which NSAID is available parenterally?
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Ketorolac
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How are NSAIDs useful for patients with Primary Familial adenomatous polyposis?
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Non-selective NSAIDs reduce polyp formation in these patients
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Long-term use of NSAIDs reduces the risk of what cancer?
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Colon Cancer
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What side effects does aspirin have on non-allergic patients?
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Gastric Upset:
- Gastric ulceration - Upper GI Bleeding Renal effects: - Acute renal failure - Interstitial nephritis |
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What does Small doses of aspirin cause in pt's with aspirin hypersensitivity?
(esp. those assoc. w/ nasal polyps) |
Asthma from the increased leukotriene synthesis
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What does Moderate doses of aspirin cause in pt's with aspirin hypersensitivity?
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Tinnitus
Vertigo Hyperventilation Respiratory ALKALOSIS |
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What does Very High doses of aspirin cause in pt's with aspirin hypersensitivity?
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Metabolic ACIDOSIS
Dehydration Hyperthermia Collapse Coma Death |
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A child has a viral infection, and the mother gives her aspirin. What is this child at increased risk for?
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Reye's Syndrome:
serious rapid Liver degeneration + encephalopathy |
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Side effects of other NSAIDs
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GI disturbances + Renal damage
Esp. in renal damage pts, b/c these drugs are renally excreted, so renal impairment --> increased plasma levels |
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Parenteral use of Ketorolac should be limited to how many hours?
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72 hours b/c of risk of GI and renal damage with longer use
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What side effects are seen with indomethacin?
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Hematologic reactions
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What is the advantage of COX-2 inhibitors?
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Reduced risk of GI effects like gastric ulcers and serious GI bleeds
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What effect do COX-2 selective inhibitors have on Renal function?
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Carry the same risk of renal damage as nonselective COX inhibitors
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What are examples of COX-2 inhibitors?
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Celecoxib
Rofecoxib Valdecoxib |
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What side effect do Rofecoxib and Valdecoxib have?
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Increased risk of MI, stroke, and increased risk of arterial thrombosis.
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Why do they increase risk for arterial thrombosis?
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PGI2 promotes vasodilation and inhibits platelet aggregation, but TXA2 has opposite effects.
They may have a greater effect on PGI2 endothelial prostacyclin formation than on platelet thromboxane A2. |
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This drug is the only over-the-counter non-anti-inflammatory analgesic commonly available in the US
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Acetaminophen
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This toxic prodrug, that is metabolized to Acetaminophen, is still available in the US
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Phenacetin
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MOA of Acetaminophen
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WEAK COX-1 & 2 inhibitor in peripheral tissues -> lack of anti-inflammatory effect
May inhibit COX-3 in CNS |
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Effects of Acetaminophen
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Analgesic and Antipyretic agent
Lacks anti-inflammatory and antiplatelet effects |
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Acetaminophen is effective for the same indications as what NSAID?
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Intermediate-dose Aspirin
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Therefore Acetaminophen is useful as a substitute for NSAIDs in which situation?
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For children with Viral infection
& anyone with Aspirin intolerance |
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Toxicity of Acetaminophen in therapeutic doses
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Negligible most of the time
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When does acetaminophen cause serious toxicity, and what does it cause?
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In overdose, or pts with Liver impairment
Causes Hepatotoxicity |
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MOA of Acetaminophen toxicity
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Oxidation to cyctotoxic intermediates by Phase I P450 enzymes.
This occurs if substrates for phase II conjugation rxns (acetate and glucuronide) are lacking |
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What do you give a person who has overdosed on Acetaminophen?
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N-Acetyl Cysteine
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What people are at increased risk for acetaminophen-induced hepatotoxicity
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THose who regularly consume 3+ alcoholic drinks per day
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What characteristic of DMARDs make them differ form NSAIDs that give them the name "disease modifying drugs"
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Evidence shows slowing or even reversal of Joint damage, an effect never seen with NSAIDs
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How long does it take for DMARDs to take full effect?
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6 weeks - 6 months
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What is the use of Corticosteroids?
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Too toxic for routine chronic use, so only used for temporary contorl of severe exacerbations and only used long term if nothing else works
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Of the DMARDs, which one is a "cytotoxic drug"?
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Methotrexate
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Which ones interfere with the activity of T Lymphocytes?
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*Sulfasalazine
*Hydroxychloroquine *Cyclosporine Leflunomide Mycophenolate mofetil Abatacept |
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Which ones interfere with B Lymphocytes activitty?
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Rituximab
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Which ones interfere with activity of Macrophages?
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Gold Compounds
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Which ones interfere with TNF-alpha?
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*Infliximab
*Etanercept Adalimumab |
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Which DMARD is usu given early in the course of RA to ameliorate progression?
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Methotrexate
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Toxicities of METHOTREXATE
(also used as anticancer rx) |
Nausea
Mucosal Ulcers Hematotoxicity Teratogenicity |
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Toxicities of CYCLOSPORINE
(also used for Tissue transplantation) |
Nephrotoxicity
Hypertension Liver toxicity |
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Toxicities of Hydroxychloroquine, CHLORIQUINE
(Also an anti-malarial) |
Rash
GI distrub Ocular Toxicity |
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Toxicities of SULFASALAZINE
(also used for IBS) |
Rash
GI distrub Dizziness HA Leukopenia |
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Toxicities of Anti-TNF-alpha drugs
INFLIXIMAB, ETANERCEPT, ADALIMUMAB (also for IBS) |
Macrophage-dependent infection like activ. of latent Tb
Form'n of Ab's to ds-DNA and ANA Vasculitis |
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Toxicities of LEFLUNOMIDE
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Teratogen
Hepatotoxicity GI Disturb Skin Rxns |
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Toxicities of GOLD COMPOUNDS
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Many adverse effects including Diarrhea
Dermatitis Hematologic rxns (Aplastic Anemia) |
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Toxicities of PENICILLAMINE
(also a chelating agent) |
Many SE:
Proteinuria Dermatitis GI disturb Hemat. abnorms (Aplastic Anemia) |
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What are the 3 treatment strategies for Gout?
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1.) Reducing inflammation during acute attacks w/: Colchicine, NSAIDs, or Glucocorticoids
2.) Accel. renal excretion of Uric acid w/uricosuric drugs: Probenecid, or sulfinpyrazone 3.) Reducing conversion of Purines to Uric adic by xanthin oxidase: Allopurinol or Febuxostat |
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MOA of indomethacin for Gout
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Decreases prostaglandins
Inhibits crystal phagocytosis by macrophages |
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MOA of Colchicine for Gout
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Colchicine is a selective inhibitor of Microtubule assembly
It reduces leukocyte migration and phagocytosis. May also reduce production of leukotriene B4 and decrease free radical formation |
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Which drug is a mitotic poison and why?
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Colchicine b/c it reacts with Tubulin and interferes with mictrotubule assembly
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Which drug is prefered for the treatment of Acute Gouty Arthritis
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Indomethacin or a Glucocorticoid
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Why not use Colphicine fo racute attacks?
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Causes GI disturb, particularly Diarrhea
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What's another use for colchicine?
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Mediterranean Fever:
Unknown cause Fever, hepatitis, peritonitis, pleuritis, arthritis, amyloidosis |
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Toxicities of indomethacin
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Renal Damage and Bone marrow depression
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Toxicity of Colchicine
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Damage to Liver & Kidney
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How much filtered Uric acid is reabsorbed in the kidney?
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90%
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What are 2 important Uricosuric agents?
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Probenecid
Sulfinpyrazone |
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MOA of Uricosuric agents
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They are weak acids that compete with uric acid reabsorption by the weak acid transport mechanism in the proximal tubules and thus increase uric acid excretion
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What effect do LOW doses of Uricosuric agents have on uric acid secretion?
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At low doses they also compete with uric acid for SECRETION by the tubule, so can ELEVATE serum uric acid levels.
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What drug used with uricosuric agents increases uric acid levels by competing w/its secretion?
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Aspirin
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How do uricosuriric agents affect other drugs?
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They INHIBIT the secretion of a large number of other weak acids: Penicillin, methotrexate
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What is the USE of Uricosuric agents?
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to treat CHRONIC gout.
They are of no value for acute episodes |
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Toxicity of Uricosuric agents
How do you prevent this? |
Can precipitate an attack of acute gout during early phase of their action.
Can be avoided by simultaneous admin. of Colchicine or Indomethacin |
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Allergic potential for uricosuric agents
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Since they are sulfonamides, they share allergenicity w/other sulfonamides: Diuretics, Antimicrobials, oral hypoglycemics
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What is Xanthine oxidase?
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Converts:
- hypoxanthine to xanthine - xanthine to uric acid - Allopurinol to Oxypurinol |
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What is Oxypurinol?
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an irreversible suicide inhibitor of the Xanthine oxidase
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What is Febuxostat?
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A nonpurine inhibitor of xanthine oxidase that is more selective than allopurinol and alloxanthine
More effective in lowering serum uric acid than allopurinol |
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What is the effect of inhibiting Xanthine oxidase?
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Increases conc. of the more soluble Hypoxanthine and Xanthine, and DECR. the concentration of Uric acid (less soluble)
Thus less likelihood of precipitation of uric acid crystals in joints & tissues |
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What is the USE for Xanthine oxidase inhibitors?
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Its withheld for 1-2 weeks after an acute episode of gouty arthritis.
Used as an adjunct to Cancer Chemo, to slow the formation of uric acid from purines released by the death of large #'s of cancer cells |
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Toxicities of Allopurinol
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GI upset
Rash Rarely: Peripheral neuritis Vasculitis BM dysfunction - aplastic anemia |
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Allopurinol affects the metabolism of what 2 drugs?
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Mercaptopurine
Azathioprine Both depend on xanthine oxidase for elimination |
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Toxicities of Febuxostat
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Liver function abnorms
Headache GI upset |
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What is the main SE of Colchicine at the doses required?
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Diarrhea
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* MOA of NSAIDs
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* Inhibit prostaglandin synthesis by inhibiting cyclo-oxygenase (cox)
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* Difference between Aspirin and other NSAIDs
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* Aspirin irreversibly inhibits cyclooxygenase
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* Four main actions of NSAIDs
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* Anti-inflammatory, analgesia, antipyretic and anti-platelet activity
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* Agent used for closure of patent ductus arteriosus
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* Indomethacin
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* Aspirin is contraindicated in children with viral infection
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* Potential for development of Reye's Syndrome
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* SE of salicylates
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* Tinnitus, GI Bleeding
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* NSAID also available as an ophthalmic preparation
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* Diclofenac
Ketoroac |
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* NSAID available orally, IM, & ophthalmically
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* Ketorolac
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* NSAID used for acute condition, such as pre-op anesthesia and has limited duration of use (<5 days) due to nephrotoxicity
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* Ketorolac
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* Newer NSAID that selectively inhibits COX-2
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* Celecoxib
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* COX 2 inhibitors may have reduced risk of
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* Gastric ulcers and GI bleeding
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* COX 2 inhibitors should be used cautiously in patients with
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* Pre-existing cardiac or renal disease
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* Acetaminophen only has
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* Antipyretic and analgesic activity
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* SE of acetaminophen
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* Hepatotoxicity
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* Antidote for acetaminophen toxicity
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* N-acetylcysteine
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* DMARDs are slow acting drugs for
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* Rheumatic Disease
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* Initial DMARD of choice for pts with RA
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* Methotrexate
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* Drug offer used in combination with TNF-alpha inhibitors for RA
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* Methotrexate
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* Causes of bone marrow suppression
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* Methotrexate
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* SE of penicillamine
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* Aplastic anemia & Renal toxicity
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* Interferes with activity of T-lymphocytes
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* Hydroxychloroquine
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* Anti-malarial drug used in RA
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* Hydroxychloroquine
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* SE of Hydroxychloroquine
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* Retinal destruction and dermatitis
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* MOA of Leflunomide (newer agent)
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* Inhibits dihydroorotate dehydrogenase which leads to decreased pyrimidine synthesis, decreased T cell proliferation and decreased antibody production by B cells
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* Proteins that prevent action of TNF-alpha
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* Adalimumab, infliximab, & etanercept
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* Anti-rheumatic agent also used for ulcerative colitis
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* Sulfasalazine
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* Anti-rheumatic agent also used for Crohn's disease
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* Infliximab
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