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103 Cards in this Set

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