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66 Cards in this Set
- Front
- Back
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Non-steroidal anti-inflammatory drugs
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NSAID
antipyretic analgesic anti-inflammatory activities act primarily by inhibiting the cyclooxygenase enzymes (NOT lipoxygenase enzymes) |
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What is the prototype NSAID?
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Aspirin
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Pharmacological Actions of NSAIDS
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1. inhibition of COX, which then inhibits production of prostaglandins and thromboxanes
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COX Types
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1. COX-1
2. COX-2 |
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COX-1
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constitutive enzyme expressed in most tissues, including blood platelets
involved in cell-to cell signaling, tissue homeostasis, generates prostanoids for housekeeping : gastric epithelial cytoprotection |
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COX-2
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inducible
early-response gene product upregulated by shear stress, growth factors, tumor promoters, cytokines major source of prostanoid in inflammation and cancer |
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Where is COX-2 constitutive in the body?
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Kidney and Brain
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What is the primary source of vascular prostacyclin?
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Endothelial COX-2
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What are kidney COX-2 derived prostanoids important for?
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normal renal development and function
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Do NSAIDs block both COX isozymes?
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Most Yes
anti-inflammatory action is mostly due to blocking of COX-2 adverse affects causing gastric damage is due to inhibition of COX-1 |
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Celecoxib
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selective COX-2 inhibitor
minimizes GI adverse effects |
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Aspirin and the Salicylates
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Irreversibly acetylating and inactivating cyclooxygenase
all other NSAIDs are all reversible inhibitors of cyclooxygenase aspirin is rapidly deacetylated by esterases in the body, producing salicylate----> antiinflammatory, antipyretic and analgesic effects |
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Does salicylate inhibit COX?
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Not very well
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MOA of Aspirin and Salicylate
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Antipyretic and anti-inflammatory effects: primarily due to blockade of prostaglandin synthesis at the thermoregulatory centers of hypothalamus and at peripheral sites.
Salicylates also prevents sensitization of pain receptors to both mechanical and chemical stimuli. Aspirin may also depress pain stimuli at subcortical sites (thalamus and hypothalamus) |
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Uses/Actions of Aspirin
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1. Reduce Inflammation
2. Reduce Pain 3. Reduce Fever |
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Anti-Inflammatory Actions
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diminishes synthesis of prostaglandins and thus modulates those aspects of inflammation in which prostaglandins act as mediators
NSAIDs are more effective than opiods in treating pain in which inflammation |
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Analgesic Actions
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PGE2 is thought to sensitize nerve endings to action of bradykinin, histamine, and other chemical mediators released by inflammatory process
decreasing PGE2 synthesis, aspirin and other NSAIDs repress sensation of pain salicylates are used for managment of pain low to moderate intensity arising from integumental structures rather than arising from viscera |
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How do NSAIDs relieve headaches?
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Abrogation of the vasodilatory effect of prostaglandins in the cerebral vasculature
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Antipyretic Actions
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reduce elevated temperatures but has no real effect on normal body temperature
Aspirin blocks both pyrogen induced production of prostaglandins and the CNS repsonse to interleukin-1 and so may reset the temperature control in the hypothalamus |
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How is fever produced in infection?
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1. production of prostaglandins in the CNS in response to bacterial pyogenes
2. Effect of interleukin-1 on hypothalamus. IL-1 is produced by macrophages and released during inflammatory responses |
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Respiratory Actions
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@ therapeutic doses it increases alveolar ventilation
salicylates uncouple oxidative phosphorylation----> elevated CO2 and increased respiration Higher doses work directly on the respiratory center in the medulla, resulting in hyperventilation and respiratory alkalosis (but is compensated via kidneys) Toxic Levels: centeral respiratory paralysis occurs and respiratory acidosis ensues |
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GI Effects
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Normally:
PGI2 inhibits gastric acid secretion PGE2 and PGF2alpha stimulate synthesis of protective mucus in stomach and small intestine Presence of aspirin, prostanoids are not formed resulting in increase in gastric secretion and decrease in protective mucus |
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how much blood loss may occur through GI at normal doses of aspirin?
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3-8ml lost in feces per day due to ulcerations and hemorrhage
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What can be used in response to damage by NSAIDs?
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Misoprostol
Proton pump inhibitors H2 blockers |
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Misoprostol
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PGE1 derivative
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Effect on Platelets
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TXA2 is generated by platelets: vasoconstrictor and inducer of platelet aggregation
PGI2 is generated by endothelium: vasodilator and inhibitor of platelet aggregation Aspirin irreversibly inhibits TXA2 production in platelets Aspirin does not affect the production of PGI2 at pharmacological low doses because endothelial cells are able to synthesize more PGI2 |
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What does the decrease in TXA2 levels accomplish?
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inhibition of platelet aggregation and prolonged bleeding time
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Actions on the Kidney
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Decrease in Renal Blood Flow with persons with compromised renal hemodynamics.
Kidney's normally synthesize vasodilating prostaglandins PGE2 and PGI2 to offset the effects of vasoconstricting mediators and maintain renal perfusion----maintain GFR NSAID-induced decreases in PGE2 can increase sodium and water retention and can produce peripheral edema, weight gain, inc. blood pressure, etc. NSAID induced decrease in PGI2 may lead to Hyperkalemia and acute renal failure |
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Actions of the Kidney (II)
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type I hypersensitivity can cause ACUTE Interstitial Nephritis
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Actions of Kidney (III)
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Chronic interstitial nephritis is caused by prolonged and excessive consumption of analgesics
renal papillary necrosis results and a response to the necrosis, a chronic interstitial nephritis develops leading to progressive chronic renal failure |
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Other Effects
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long term use of aspirin at low dosage is associated with a lower incidence of colon cancer
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USES of NSAIDS
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antipyretics and analgesics:headache, arthralgia, myalgia, gout, rheumatic fever, rheumatoid arthritis
Cardiovascular applications: inhibit platelet aggregation low doses used prophylactically to decrease incidence of transient ischemic attack and unstable angina in men as well as that of coronary artery thrombosis |
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USES of NSAIDS (Cont)
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facilitates closure of patent ductus arteriousus
PGE2 keeps it open Colon Cancer prevention External Applications: topically for corns, calluses and epidermophytosis |
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Low Dosage
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analgesic
325-mg aspirin tablets taken 4 times a day prophylactic for 1st MI reduce incidence of recurrent MI and reduce mortality in post MI patients |
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Higher Dosage
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anti-inflammatory
45mg/kg/d in divided doses |
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Aspirin Fate
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hydrolyzed to salicylate and acetic acid by esterase in tissues and blood
low doses--->salicylate is mainly converted by liver to hydrosoluble conjugates (glycine and glucuronate)----->excreted by kidney low dose---> first order kinetics and half life of 3.5 |
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Aspirin PK with dose 1g or greater
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conjugation of enzymes become saturated and zero-order kinetics is observed
first order is observed afters salicylate drops to 300mg of aspirin in the body |
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Aspirin and Uric Acid secretion
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secreted into urine and can affect excretion of uric acid
salicylate uses the same transport system as uric acid low concentrations compete with uric acid for secretion into tubular fluid and reduce uric acid secretion high concentrations compete with uric acid for reabsorption and thus increase uric acid secretion in the urine |
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NSAID AE
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mild intoxication= salicylism
severe intoxication=restlessness, delirium, hallucinations, convulsions, coma, respiratory and metabolic acidosis, and death from respiratory failure |
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GI AE
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epigastric distress
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Blood AE
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prolonged bleeding time
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Hypersensitivity AE
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15% of patients experience hypersensitivity reactions
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Reye's Syndrome
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hepatic encephalopathy and liver steatosis in young children
aspirin therapy during the course of febrile viral infection has been implicated as a potential etiology of liver damage use acetaminophen instead in children |
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Repiratory and Metabolism AE
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hyperventilation and respiratory alkalosis. This causes renal excretion of bicarbonate, as a compensatory response, resulting in a mild decrease in buffering capacity
Metabolic acidosis caused by accumulation of acids as a result of: 1. salicylates are weak acids 2. salicylates impair renal function leading to accumulation of sulfuric and phosphoric acid 3. increased synthesis of ketone bodies 4. salicylates also inhibit key dehydrogenases in kreb cycle resulting in increased pyruvate and lactate |
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Acute Salicylate Overdose
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patients present with mixed respiratory alkalosis and metabolic acidosis
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High Dose or Prolonged Exposure Respiratory and Metabolism
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depressant effect of salicylates on the medulla appears
toxic doses cause central respiratory paralysis as well as circulatory collapse secondary to vasmotor depression death usually occurs from respiratory failure after a period of unconsciousness |
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Other AE
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elevation of liver enzymes
hepatitis decreased renal function bleeding rashes asthma daily dose of 2g or less---> increases serum uric acid levels daily dose exceding 4g decrease urate levels below 2.5mg/kL |
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COX-2 Selective Inhibitors
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CELECOXIB
ETORICOXIB MELOXICAM |
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COX-2 Selective Inhibitors General
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block active site of COX-2 isoenzyme
have analgesic, antipyretic and antiinflammatory effects with fewer GI side effects have NO impact on platelet aggregation---> don't offer cardioprotective actions of non-selective NSAIDs |
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COX-2 Renal
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constitutively active in kidney so same AE as nonselective
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COX-2 Inhibitor
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associated with cardiovascular thrombotic events due to balance of COX-1 to COX-2
there is more COX-1 than COX-2 COX-1 promotes platelet aggregation |
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Celecoxib
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only selective COX-2 inhibitor available in the US
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Etericoxib
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second generation COX-2 inhibitor with the highest selectivity ratio
not approved in US |
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Meloxicam
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inhibits COX-2 but not as selective as coxibs
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CLINICAL USES OF NSAIDS
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1. treatment of mild to moderate pain due to inflammation: arthritis and gout
2. COX-2 inhibitors are primarily used in inflammatory disorders 3. Selected NSAIDS are used for conditions including dysmenorrhea, headache, patent ductus arteriousus 4. Long term- reduces risk of colon cancer |
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Other AE
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Renal Damage
hematologic reactions: indomethacin and ibuprofen Celecoxib is a sulfanomide and can cause hypersensitivity reaction (rashes) Phenylbutazone can cause hematologic AE (aplastic anemia) |
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Acetaminophen
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mild to moderate pain when anti-inflammatory effect is NOT necessary
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Phenacetin
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toxic prodrug that is metabolized to acetaminophen
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Acetaminophen is not an NSAID but is sometimes grouped with them
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1. weak COX-1 and COX-2 inhibitor
2. No significant anti-inflammatory effect 3. MOA is unclear 4. COX-3 inhibitor (key in CNS) 5. No antiplatelet effects 6. Does not affect uric acid levels |
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Acetaminiphen AE
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overdose or renal impairment: is a dangerous hepatotoxin
prompt acetylcysteine maybe lifesaving after an overdose |
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Go over relative risk of GI adverse effects pg. 8 in notes
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ok
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Other AE
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Renal Damage
hematologic reactions: indomethacin and ibuprofen Celecoxib is a sulfanomide and can cause hypersensitivity reaction (rashes) Phenylbutazone can cause hematologic AE (aplastic anemia) |
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Acetaminophen
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mild to moderate pain when anti-inflammatory effect is NOT necessary
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Phenacetin
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toxic prodrug that is metabolized to acetaminophen
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Acetaminophen is not an NSAID but is sometimes grouped with them
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1. weak COX-1 and COX-2 inhibitor
2. No significant anti-inflammatory effect 3. MOA is unclear 4. COX-3 inhibitor (key in CNS) 5. No antiplatelet effects 6. Does not affect uric acid levels |
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Acetaminiphen AE
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overdose or renal impairment: is a dangerous hepatotoxin
prompt acetylcysteine maybe lifesaving after an overdose |
