NSAID Analgesics (finished) Flashcards
Discuss the proposed mechanism of action of NSAIDs
Arachidonic acid is liberated from membrane phospholipids by phospholipase
Stimuli include:
- Inflammation
- Trauma
- Bacterial invasion
- Allergic reaction
Arachidonic acid is acted upon by one of two enzymes:
1. Lipoxygenase to generate leukotrienes OR 2. Cyclooxygenase to generate: - Prostaglandins - Thromboxane - Prostacyclin
Explain why NSAIDs have limited utility in treating arthritis or other inflammatory disease conditions
be able to do this
Describe aspirin’s chief pharmacokinetic parameters and its implications in treatment of pain, fever or inflammation
Fever
Headache
Dysmenorrhea
Osteoarthritis
Rheumatoid arthritis
Prophylaxis against heart attack
Low dose (81mg) preferentially synthesis of thromboxane
Thromboxane promotes platelet aggregation
Prostacyclin decreases platelet aggregation
Avoid concurrent use of other NSAIDs
Nsaids vs opioids
NSAIDs Pros Pain due to inflammation Fewer adverse effects Cons: Only mild/moderate pain
Opioids Pros: Low to high intensity pain Helps sharp, intense pain Cons: Drowsiness Tolerance Physical dependence Abuse potential Respiratory depression
Cyclooxygenase (COX)
Target of NSAIDS
Two isoforms COX1: normal physiology Gastric cytoprotection, vasodilation, platelet aggregation COX2: inducible Induced by acute inflammation Inhibited by glucocorticoids
NSAIDs inhibit both COX1 and COX2
Aspirin irreversibly inhibits both COX1 and COX2
Other NSAIDs reversibly inhibit cyclooxygenase
COX metabolism generates
Prostaglandins
PGE2, PGD2, PGF2a
Modify nociception thresholds
Thromboxane (TXA2)
Increases platelet aggregation
Prostacyclin (PCI2)
Decreases platelet aggregation
All NSAIDs are
Analgesic
Antipyretic
Anti-inflammatory
Pharmacological Effects
Analgesic:
Prostaglandins (PGE2 and PGI2) cause peripheral sensitization of nociceptors
Decrease threshold for nociceptor stimulation
NSAIDs decrease prostaglandin synthesis = reversal of peripheral sensitization
Prostaglandins may also contribute to sensitization in CNS
Antipyretic:
Hypothalamus sets body temperature
Temperature elevated in infection
Mediated by cytokines
Mediated by COX2 induction, and PGE2 synthesis, in epithelial cells of brain vasculature
PGE2 crosses BBB, promotes elevation of body temperature by hypothalamus
NSAIDs decrease prostaglandin synthesis (PGE2) = decrease body temperature
Adverse Effects
Gastrointestinal distress
Varies by individual
NOT hypersensitivity
Nausea, etc.
gastric bleeding
Aspirin has significant impact on clotting time
up to 2x increase for 7 days after single 650 mg dose (fever dose)
Due to irreversible inhibition of COX, and therefore thromboxane (TXA2) synthesis, in platelets
Other NSAIDs have reversible effect on clotting
Use caution with patients on anticoagulants
Impact on elective surgery
Terminate aspirin use 1 week prior
Terminate other NSAID use 2 days prior
Respiratory and electrolyte disturbances
Gastric bleeding
Prostaglandins and prostacyclins have cytoprotective role in gastric mucosa
Inhibit secretion of gastric acid, promote secretion of mucus
Capillary damage can lead to necrosis and bleeding
Could lead to iron deficiency anemia
Respiratory and electrolyte disturbances
Hyperventilation: high doses stimulate respiratory center in medulla (dose dependent)
Respiratory alkalosis – hyperventilation increases blood pH
Metabolic acidosis
At toxic doses aspirin can uncouple oxidative phosphorylation (primarily in skeletal muscle)
Lactic acid accumulates in serum, decreased blood pH
Compensatory mechanisms overwhelmed – serum bicarbonate consumed – pH continues to drop
Aspirin overdose
Mild toxicity Tinnitus Headache Nausea, vomiting Sweating, thirst, hyperventilation Hearing loss (reversible)
Severe toxicity (overdose) Hyperventilation Acid-base imbalance Dehydration Agitation, hyperactivity, slurred speech, tremor, seizures, coma Fever (especially in children)
Treatment of overdose
Gastric decontamination
Induce vomiting, gastric lavage, activated charcoal
Correct acid-base imbalance
Increase systemic pH (sodium bicarbonate)
Additional measures:
Transfusion
Dialysis
Full recovery is possible if treated
Aspirin Hypersensitivity
5-6% of US population
~50% of hypersensitive patients have nasal polyps
~10-20% of asthmatics are hypersensitive
Allergy- or anaphylaxis-like symptoms
Rhinitis, profuse watery secretions, bronchial asthma, bronchoconstriction, hypotension, vasomotor collapse, coma
Not immune (immunoglobulin) mediated
Likely due to shunting of arachidonic acid into leukotriene pathway
Treat with epinephrine
Avoid NSAIDS
Avoid other salicilates
Pepto Bismol
Reye’s Syndrome
Rare, often fatal
Children at highest risk
Associated with aspirin use in presence of viral infection (varicella, others)
Exact mechanism unknown
Epidemiology demonstrated aspirin/viral connection
No animal models of syndrome
Salicylates contraindicated in children/adolescents with chicken pox
