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103 Cards in this Set
- Front
- Back
- 3rd side (hint)
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What is inflammation
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The reaction of vascularized living tissue to injury
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How is inflammation mediated by the body
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Inflammation is initiated and sustained through chemical mediators such as prostaglandins, prostacyclins, bradykinin, histamine, interleukin-1, and leukotrienes
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What exactly are prostaglandins
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Prostaglandins are local mediators (they do not circulate in the blood) that have a variety of physiologic actions. They are a member of a group of compounds known as eicosanoids
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None
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What is an eicosanoid
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An eicosanoid is any biologically active compound derived from arachidonic acid, including prostaglandins, leukotrienes, prostacyclin, and thromboxane
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What is arachidonic acid
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Arachidonic acid is a 20-carbon fatty acid that serves as the precursor for prostaglandin and structurally similar compounds. Arachidonic acid is found in the phospholipids of cell membranes and is liberated by phospholipase A2
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What are the two major enzymes that use arachidonic acid as a substrate
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Cyclooxygenase and lipoxygenase
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Give some examples of prostaglandins and leukotrienes and state their role in inflammation
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PGE2—erythema
PGI2—vasodilation LTC4—edema LTD4—vasodilation PGE2, PGI2, LTB4—pain/tenderness |
None
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What are NSAIDs
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These drugs are a class of chemically dissimilar agents that act by inhibiting the enzyme cyclooxygenase and, subsequently, prostaglandin synthesis.
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Name six groups of NSAIDS
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Salicylates; Pyrazolones; Indoleacetic Acids; Propionic Acids; Oxicams; Fenamates
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Give three examples of Salicylates
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Aspirin; Diflunisal—poor antipyretic properties; Salsalate
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Give an example of a Pyrazolone
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Phenylbutazone—very toxic; can cause agranulocytosis and aplastic anemia
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Given four examples of Indoleacetic acids
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Indomethacin—used in acute gouty arthritis, ankylosing spondylitis, and to close a patent ductus arteriosus; Sulindac; Etodolac; Ketorolac—excellent analgesic properties; commonly use as an alternative to opioids
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Give three examples of propionic acids
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Naproxen; Ketoprofen; Ibuprofen
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Give an example of an oxicam
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Piroxicam—long half-life permits once-daily dosing
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Given two examples of fenamates
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Mefenamic acid; Meclofenamic acid
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How do NSAIDs work
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By acetylating cyclooxygenase
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How does aspirin differ in its action from the other NSAIDs
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Aspirin is unique among NSAIDs by acetylating cyclooxygenase irreversibly. All the other NSAIDs inhibit cyclooxygenase in a reversible manner
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What are the four main therapeutic uses of NSAIDs
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Anti-inflammatory—frequently used for osteoarthritis, gout, rheumatoid arthritis, ankylosing spondylitis, and dysmenorrhea; Analgesia—alleviates mild to moderate pain; Antpyretic; Anti-platelet activity—due to the decreased production of thromboxane. Aspirin’s antiplatelet activity lasts 7 days (life span of the platelet); it is often used in the treatment of MI
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How do NSAIDs decrease a patient’s fever or pain
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The antipyretic and anti-inflammatory effects of NSAIDs are accomplished by inhibition of prostaglandin synthesis at thermoregulatory centers in the hypothalamus
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How are the NSAIDs metabolized
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They are converted to water-soluble conjugates in the liver and cleared by the kidney. If the hepatic system is over-whelmed, the half-life of the drug will increase dramatically.
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What are the adverse effects of NSAIDs
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Epigastric distress, nausea, and vomiting; Coagulation disorders; Metabolic abnormalities; Hypersensivity; Reye’s syndrome
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What is salicylism
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when plasma levels of NSAIDs go beyond maximum therapeutic range, patients develop salicylate toxicity, or salicylism. Features include: Tinnitus; Vertigo; Respiratory stimulation; Coma; Metabolic acidosis; Delirium; Hallucinations; Respiratory and Renal depression
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What is the treatment for salicylate toxicity
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Maintaining respiration and circulation, minimizing drug absorption (via gastric lavage), and maximizing elimination (alkalinizing the urine enhances elimination)
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What other agents are used to treat inflammation
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Corticosteroids, such as prednisone.
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Eicosanoids (inflammatory mediators) are synthesized from what chemical compound
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Arachidonic acid
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Give two examples of eicosanoids
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Leukotrienes; Prostaglandins
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How is arachidonic acid formed
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Phospholipase A2 acting on cell membrane phospholipids
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How many carbons does arachidonic acid have
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20
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Corticosteroids block what part of the inflammatory pathway
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Inhibition of phospholipase A2
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Angiotensin and bradykinin have what effect on the inflammatory pathway
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Stimulation of phospholipase A2
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What enzyme acts on arachidonic acid to form LTs
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5-lipoxygenase
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Which LT is involved in neutrophil chemotaxis
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LTB4
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Which LTs are involved in anaphylaxis and bronchoconstriction
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LTA4, LTC4, LTD4
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What drug inhibits 5-lipoxygenase thereby inhibiting LT synthesis
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Zileuton
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What is zileuton used for
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Asthma, allergies
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What two drugs act as LT receptor antagonists and are used in the treatment of asthma and allergy
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Montelukast; Zafirlukast
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What are the adverse effects of zileuton and the LT receptor antagonists
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Increased liver function tests; headache; Churg-Strauss syndrome
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5-lipoxygenase is found in which cell types
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Neutrophils, eosinophils, basophils, mast cells
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Which LTs are considered the slow-releasing substances of anaphylaxis
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LTA2, LTC4, LTD4
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What enzyme acts on arachidonic acid to form PGs and thromboxanes
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Cyclooxygenase (COX)
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Where is COX 1 found
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Platelets; gastrointestinal mucosa; vasculature
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Where is COX 2 found
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Sites on inflammation; brain; kidney; GI tract (low amounts vs. COX 1)
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Is COX 1 a constitutive or inducible enzyme
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Constitutive
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Is COX 2 a constitutive or inducible enzyme
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Inducible
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PGE1 does what to patent ductus arteriosus
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Maintains patency
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PGE1 does what to uterine smooth muscle
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Increases contraction; used as an abortifacient during pregnancy
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PGE1 does what to blood vessels
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Vasodilation
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PGE1 does what to gastric mucosa
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Cytoprotective effect (inhibition of HCl secretion and stimulation of mucus and bicarbonate secretion)
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What two PGF2α analogs promote bronchiolar and uterine smooth muscle contraction
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Carboprost; dinoprost
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Why are NSAIDs effective in the treatment of dysmenorrhea
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Inhibition of PGE2 and PGF2α synthesis
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What PGE1 analog is used for impotence due to its vasodilatory effects
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Alprostadil
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What is another name for PGI2
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Prostacyclin
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What does the subscript of PGI2 signify
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The number of bonds in the side chain
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What are the actions of prostacyclin
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Inhibits platelet aggregation; vasodilation
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What is the name of a prostacyclin analog and what is it used for
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Epoprostenol; pulmonary hypertension
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What are the actions of TXA2
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Promotes platelet aggregation; bronchoconstriction; vasoconstriction
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Increasing cyclic adenosine monophosphate (cAMP) will do what to platelet aggregation
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Decrease platelet aggregation (mechanism of action of PGI2)
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What is the mechanism of action of the nonselective NSAIDs
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Inhibit both COX 1 and COX 2 thereby inhibiting synthesis of PGs and TXAs
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Name the three COX 2 specific inhibitors
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Celecoxib; Rofecoxib; Valdecoxib
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Do COX 2 inhibitors inhibit platelet aggregation
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No
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Which adverse effects of celecoxib have sparked debates about whether it should be pulled from the market or not
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Increased risk of cardiovascular events (MI, stroke, and worsening of preexisting HTN)
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What are the main therapeutic effects of NSAIDs
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Anti-inflammatory; analgesic; antipyretic; antiplatelet
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What is the prototype NSAID
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Acetylsalicyclic acid
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Does ASA act as a reversible or irreversible inhibitor of COX 1
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Irreversible
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How does ASA irreversibly inhibit COX
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Acetylates serine hydroxyl group near active site of COX thereby forming an irreversible covalent bond
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What is the half-life of a platelet
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5-7 days
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What can’t platelets produce more COX after ASA therapy
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Nonnucleated cells, therefore, lacking the capability of protein synthesis
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What lab test is prolonged after ASA therapy
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Bleeding time
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How does ASA work as an antipyretic
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Inhibits IL-1 stimulated synthesis of PGE2 in the hypothalamus thereby inhibiting alteration of the temperature set-point
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Low dose ASA does what to uric acid elimination
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Decreases tubular secretion (increases serum uric acid levels)
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High dose ASA does what to uric acid elimination
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Decreases tubular reabsorption (decreases serum uric acid levels)
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What type of acid-base disturbance is seen in ASA overdose
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Mixed respiratory alkalosis with metabolic acidosis
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Does ASA overdose cause an anion gap or nonanion gap metabolic acidosis
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Anion gap metabolic acidosis
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None
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What are the signs/symptoms of salicylism
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Decreased hearing; tinnitus; vertigo; nausea; vomiting; headache; hyperventilation; confusion; dizziness
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None
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Why is ASA not given to children especially during times of viral (varicella and influenza) infections
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Reye syndrome
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What characterizes Reye syndrome
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Encephalopathy; hepatotoxicity
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How can excretion of ASA from the urine be expedited
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Alkalinization of urine with NaHCO3
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What should be given instead of ASA to children with fever
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Acetaminophen (APAP)
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What is the mechanism of action of APAP
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Inhibits synthesis of PGs (via COX 3 inhibition) in the central nervous system; block pain impulse generation peripherally; antipyresis via inhibition of the hypothalamic heat regulating center
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ASA can do what to asthmatics
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Exacerbate symptoms via bronchoconstriction
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What is the triad of ASA hypersensitivity
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Asthma; nasal polyps; rhinitis
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What is the mechanism of ASA-induced hyperthermia at toxic doses
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Uncoupling of oxidative phosphorylation
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What are the GI adverse effects of NSAIDs
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Ulcers; Gastritis; GI bleeding (via decreased PGs which act as GI mucosal protectants); nausea; abdominal cramping
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If a patient is taking ASA and warfarin concomitantly, what should the dose of ASA be
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81 mg daily
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ASA can do what to blood glucose
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Decrease blood glucose
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What type of kinetics does ASA follow
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Zero order
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Antiplatelet and analgesic effects of ASA occur at lower or higher doses than those required for anti-inflammatory effects
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Lower
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What is the drug of choice for closing a patent ductus arteriosus
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Indomethacin
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What is the mechanism of NSAID-induced renal failure
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Inhibition of PGE2 and PGI2 synthesis which are responsible for maintaining renal blood flow
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Give examples of nonselective NSAIDs other than ASA
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Ibuprofen; Naproxen; Diclofenac; Indomethacin; Ketorolac; Piroxicam; Oxaprozin; Nabumetone; Sulindac
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What are the major differences between nonselective NSAIDs and selective COX 2 inhibitors
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COX 2 inhibitors have less antiplatelet action and less GI adverse effects
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Which COX 2 inhibitors are potentially cross-reactive in patients with sulfonamide allergy
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Celecoxib; valdecoxib
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Name two drugs that have antipyretic and analgesic effects yet lack anti-inflammatory and antiplatelet effects
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APAP; phenacetin
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APAP inhibits COX centrally, peripherally, or both
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Centrally (inhibits PG synthesis in the CNS)
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Overdose of APAP can potentially cause what life-threatening condition
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Hepatic necrosis
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How is APAP predominantly metabolized
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Glucuronidation; sulfation
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Cytochrome P-450 2E1 metabolizes APAP to which compound (this is a minor metabolic pathway)
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N-acetyl-benzoquinoneimine (NAPQI)
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Which metabolite of APAP is hepatotoxic
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NAPQI
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Which compound binds to NAPQI and ultimately leads to its excretion
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Glutathione
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What happens to patients taking APAP when glutathione stores run out
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Accumulation of NAPQI with subsequent hepatotoxicity
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What drug is used to replenish reduced glutathione during times of APAP overdose
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N-acetylcysteine
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What is the maximum daily dose of APAP in patients with normal hepatic function
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4 g per 24 hours
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What is the maximum daily dose of APAP in patients with abnormal hepatic function
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2 g per 24 hours
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