Exam 2: Lecture 2, NSAIDs Flashcards
What is inflammation?
Protective response of the body to tissue injury
What can cause tissue injury?
Trauma, chemicals or microbiologic agents
inflammation may cause progressive tissue injury
Inflammation is the first step in….
a big number of pathophysiological processes
and
in a variety of immunological disorders
NSAID’s are…
Analgesic = mild/moderate pain
Antipyretic (fever reducer) in fever pt, little effect on normal people
Anti-inflammatory = arthritis, osteoarthritis, musculoskeletal disorders
NSAId’s used for self treatment for….
Headaches, Dental Pain, and Muscle Pain
NSAID common properties
weak organic acids (except nabumetone = keto prodrug)
Well absorbed
Highly metabolized phase I and II
Biliary excretion and reabsorption through the enterohepatic circulation
GI irritation correlate with the amount in enterohepatic circulation
After repeated doses, NSAIDs found in synovial fluid
NSAID’s primary mech of action
COX inhibition
act indirectly, don’t block PG receptors, no effect on previously formed PG’s
Cox-1
Found in many tissues, important under normal conditions
Cox-2
Found in inflammatory tissue, expressed during inflammation
Renal tissue - exception, found in normal tissue
Cox-1 vs Cox-2
Channel in Cox 2 wider than in Cox 1
some drugs can get into Cox 2, not Cox 1
How do NSAID’s block Cox?
Enter channel, and block it. (Except aspirin)
Bind to arginine via H-bonds
Cause reversible inhibition of Cox
How does aspirin work?
Acetylates the enzyme (Cox) at serine and causes irreversible inhibition of Cox
Which prostaglandins do NSAID’s suppress?
PGE2
PGD2
PGF2a
PGI
TXA2
Aspirin Clinical I
inhibit platelet aggregation
produces anticoagulant effect + prevent thrombosis
reduce inflammation
reduce pain via reduce PGE2 synthesis
Peripherally inhibit PGs in inflamed tissue
Aspirin Clinical II
Antipyretic effect mediated though the hypothalamus (CNS)
No effect on temp in healthy individuals, but effect with those that have fever (by reducing PGE2 synthesis)
Aspirin Absorption
Oral + stomach absorption = rapid
Upper portion of Small intestine = major site of absorption
Rectal = slow and unpredictable absorption
Aspirin Excretion
Alkalization of urine increases salicylates excretion
via increase ionization and decreased reabsorption in the renal tube.
Aspirin Effect on Blood I
decrease platelet aggregation
recommended in individual with 1 or more MIs
prevents incidence of first MI and Transient ischemic attacks
Aspirin Effect on Blood II
TXA2 synthesis in platelets reduced, recovers only when new platelets formed
takes 7 days to recover from single dose
increase bleeding time, shouldn’t be taken 1 week before surgery
Aspirin effect on Cardiovascular system
therapeutic dose = no effect
High dose = effect smooth muscle
Toxic dose = cause central vasomotor paralysis
Aspirin effect on Respiratory System
directly effects respiratory center
Toxic doses can depress respiratory center, cause metabolic acidosis
indirectly increases O2 consumption in skeletal muscle
Indirectly increases CO2 production in skeletal muscles
Aspirin effect on GI system
decrease PGE2/PGE2a = decrease mucus protection
Dose related gastric ulceration, bleeding, erosive gastritis
worsening of peptic ulcer, gastric bleeding leading to iron-deficiency
Epigrastic distress, nausea and vomiting by irritating mucosa lining
Stimulate CTZ in CNS
Should be taken with food + significant act water
Aspirin effects on Urinary System
determine effect on urinary system
Decreased PGI2 production = decrease kidney blood flow = increase Na/H20 retention = edema and hyperkalimia
may increase circulating plasma volume by 20%
Aspirin decrease inflammation by…
decreasing PGs, PGI2, and TXA2
Aspirin decrease platelet aggregation by…
Decrease TXA2
Aspirin increase ulcer formation by…
Decrease PGE2, PGE2a = Decrease Mucous
Aspirin increasing edema by…
decrease PGI2 = decrease blood flow = decrease filtration = increase NA/H20 = increase edema
effects of Large and toxic Aspirin doses
uncouple oxidative phosphorylation
deplete glycogen in liver/skeletal muscle = hyperglycemia/glycosuria
reduce lipogenesis by blocking incorporating of acetates into FA
cause sig nitrogen loss through aminoaciduria
Low Doses aspirin?
<300mg/day = antipyretic and analgesic effects
Moderate doses Aspirin?
300-2400 mg/day = antipyretic and analgesic effects
High doses Aspirin?
2400 - 4000mg/day = anti-inflammatory effects
Major adverse effects moderate dose aspirin?
Epigastic pain nausea vomiting skin rashes asthma vertigo tinnitus hyperventilation = Respiratory alkalosis
Major adverse effects high dose aspirin?
Metabolic acidosis dehydration hyperthermia collapse Coma Death
Aspirin serious Warning
Children with viral infection at greater risk of developing Reyes Syndrome if given aspirin
20-40% mortality, dialysis used to remove salicylates
Children should be given acetaminophen instead of aspirin
New NSAIDs
treatment of arthritis and osteoarthritis
cause GI disturbances similar to aspirin but lower incidence
removed through kidney, sig risk of renal damage in patient with preexisting renal disease
Ibuprofen and Naproxen better tolerated than Indomethacin
Ibuprofen
Reversibly inhibit thromboxane synthesis by blocking COX-1
Short duration (2hr)
should not be used during pregnancy or nursing
more effective analgesic than aspirin, same anti-inflammatory
used in arthritis, dysmenorrhea, muscle inflammation, peptic ulcer, and renal damage. used to accelerate closure of patent ductus arteriousus
Naproxen
bind to plasma proteins, does not cross placenta
half life = 14hr, 2 doses per day
isolated case of renal dysfunction/thrombocytopenia/agranulocytosis
Indomethacin
potent
Reversibly inhibit thromboxane synthesis by blocking COX-1
used to accelerate closure of patent ductus arteriousus
more effective anti-inflame than aspirin or other NSAIDs
Inhibits PLA,PLC
reduces neutrophil migration, T-Cell and B-Cell proliferation
Serious toxicity = limiting factor
Percentage of Adverse effects indomethacin?
50% of patients
20% of patients adverse effects = intolerable
Acetaminophen
inhibits prostaglandin synthesis in CNS
Weak cyclooxyrgenase inhibitor in peripheral tissue
** No anti-inflammatory effect **
No anti-platelet effect
No effect on Cardiovascular, respiratory, GI, acid-base regualtion
** OD = hepatic necrosis **
Acetaminophen Clinical
one of most important drugs in treatment of mild/moderate pain
used in patient that don’t req anti-inflam effects
substitute for aspirin in patients with increased rick of Reye’s syndrome, gastric complains
low toxicity - used in all headache products
Acetaminophen Adverse effects
in small doses = no sig side effect
Dangerous in OD = serious hepatic necrosis
Antidote = N-acetylcystein I.V (bind to toxic metabolites) if given within 10 hrs or methionine given orally
Renal tubular necrosis and hypoglycemic coma can also occur
