NSAIDS Flashcards
general properties of NSAIDs
Anti inflammatory: number of chemical mediatiors released at sites of inflammation which release arachidonic acid which is metabolized to Pgs which directly cause vasodilation–>edema
antipyretic: chemical mediations such as IL1 can induce the synthesis of PGs (PGE2) which act within hypothalamus to elevate body temp
analgesic: PGs lower the pain threshold by increasing the sensitivity of pain receptors to chemical mediatiors such as bradykinin and histamine
mechanism of all NSAIDs
Inhibition of cyclooxygenase!
COX catalyzes arachidonic acid to PGs 2 forms (COX1-constitutive and COX2-inducible) traditional NSAIDs inhibit both COX 1 and COX2
there is one thats COX2 selective and aspirin is the irreversible inhibitor of both COX 1 and COX2
Acetylsalicylic acid aka aspirin
MOA and pharmacokinetics
irreversible inhibitor of COX unique to aspirin
acetylates the serine group of COX
Absorption: limited by dissolution rate (buffered vs enteric coat)
Distribution: plasmaprotein binding, crosses BBB and placental barrier
Metabolism: acetylsalicylic acid is metabolized to salicylic acid which is trasformed to a number of less polar metabolites
renal elimination
Therapeutics : fever/low intensity pain- 325 mg
inflammatory disorders- 5-8 g/day
antiplatelet in CV disease- 80 mg/day
closes patent DA, systemic mastocytosis, niacin intolerance, bartter syndrome, cancer
pharmacological effects of all NSAIDs
anti inflammatory in large doses
analgesic: low intesity pain alleviated by aspirin
antipyretic: reduces fever by inhibition of PG production
unique effects of aspirin that are not related to its COX inhibition activity
uric acid excretion
@ low doses: aspirin competes with uric acid for secretion by organic acid transport system into renal tubules –> increase in serum uric acid
@high doses: aspirin competes with uric acid for both REAB and secretion and –> decrease in serum uric acid
CNS high doses: crosses BBB-> delirium/psychoses/nausea/vomiting
respiration: direct stimulation of resp center increases respiratory rate–> respiratory alkalosis compensated by renal excretion of bicarb
indirect effects on resp: increases O2 consumption and production of CO2 in muscles compensated by increased respiration
adverse reactions/toxicity/ contraindications in aspirin
GI, blood
GI: gastric irritation -> gastric ulcers and bleeding MOA: inhibition of COX1 in GI prevents cytoprotective prostaglandins
Blood: increased bleeding time, inhibition of COX-1 in platelets blocks production of platelet thromboxane and decreases platelet aggregation
adverse reactions/toxicity/ contraindications in aspirin
hypersensitivity, renal
hypersensitivity: bronchoconstriction, edema, cross sensitivity with other NSAIDs, more common in pts with asthma and nasal polyps. MOA leukotrienes shunts AA pathway from COX to lipooxygenase
renal: decreased RBF and glomerular filtration rate, salt and water retention
renal perfusion is more dependent on production of vasodilatory PGs in patients with conjestive heart failure, chronic renal disease or liver disease compared to normal individuals bc COX2 is upregulated in these diseases. Analgesic nephropathy–a condition of slowly progressive renal failure, decreased concentratind ability of the renal tubule and sterile pyuria
risk factors are the chronic use of high doses of combos of NSAIDs and frequent UTIs–treat with discontinuation of NSAID
NSAID use in pregnancy
decreased uterine contraction, may prolong labor
MOA- PGs stimulate uterine contraction, production of PGs increase before birth
salicylism
unique to aspirin
aka overdose of aspirin, can be fatal
intial- slight resp stimulation, nausea, vomiting, tinnitus, deafness
increase dose: confusion, fever, dehydration, electrolyte imbalance, metabolic acidosis
saturation of enzymes that convert salicylic acid to inactive metabolites–> builds up
trt: gastric lavage, activated charcoal to prevent absorption, replacepent fluid with electrolytes, alkalinization of urine via IV bicarb)
Reye syndrome
unique to aspirin
illness directly related to viruses can result liver failure and death. in kids viruses + aspirin = bad news
propionic derivatives
MOA
Pharmakokinetics
adverse effects
ibuprofen and naproxen
MOA: reversible inhibition of COX 1 and COX2
Pharmacokinetics: ibuprofen (t.5=2hrs), naproxen (t.5=14hrs) both drugs are highly bound to plasma proteins
Pharmacologic effects: anti inflammatory, analgesic and antipyretic
Adverse effects: GI effects (less than aspirin), hypersensitivity, kidney, blood, drug interactions
therapeutic applications of ibuprofen and naproxen
ibuprofen: inflammatory diseases and rheumatoid disorders (incl juvenile), mild to moderate pain, fever, dysmenorrhea, osteoarthritis
ibuprofen lysin injection: induces closure of a clinically siignificant Patent ductus arteriosus (PDA) in premies
naproxen: management of ankylosing spondylitis, osteoarthritis and rheumatoid arthritis, acute gout, mild to moderate pain, tendonitis, bursitis, dysmenorrhea, fever
acetic acid derivatives (2) MOA Pharmakokinetics adverse effects therapeutic application
indomethacin:
MOA: reversible inhibitor of COX 1 and COX 2
Pharmacokinetics: t.5=3hrs 90% bound to plasma proteins
Adverse effects: frequent, GI toxicity, CNS frontal headache
Therapeutic app: acute gout, acute bursitis/tendonitis, moderate to severe osteoarthritis, rheumatoid arthritis, ank spond, IV closure of PDA, not usually treat for pain and fever, but can be used preterm labor
ketorolac
MOA: reversible inhibitor of COX 1 and COX 2
Pharm: absorbed orally and IM, highly plasma bound
Effects: potent analgesic, and antipyretic, moderate antiinflammatory
Therapy: oral and injection short tem management of moderate to severe pain requiring analgesia at the opiod level
oxicam derivative
MOA
Pharmakokinetics
adverse effects
piroxicam
MOA: reversible inhibitor of COX 1 and COX2
Pharmacokinetics: t.5=50hrs, 99% bound to plasma proteins
Effects: anti inflammatory, antipyretic, analgesic
SE: GI toxicity
therapeutic effects: symptomatic treatment of acute and chronic rheumatoid arthritis and osteoarthritis
Selective COX 2 inhibitor
COX 2 is upregulated via inflammation
does not block cytoprotective prostaglandins in GI
Celecoxib
MOA: inhibits COX2, close proximity to a distinct hydrophilic side pocket (not present in COX1)
pharmacokinetics: oral admin highly bound metabolized by CYP 450– 2C9
Pharm: anti inflammatory, analgesic, antipyretic
SE: hypersensitvity, increased risk of GI irritation ulceration and bleeding, adverse thrombotic events, MI and stroke
ContX: sulfonamide toxicity, prior NSAID hypersensitivity, pre exisiting CV risk, or GI disorders, Hx of CABG surgeery or deficient CYPT 2C9
therapy: rhematoid arthritis, 1’ dysmenorrhea, acute pain managment,reduce # of intestinal polyps
due to CV hasard, use the lowest possible dose for shortest amount of time
