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NSAIDs Analgesic (CNS and peripheral effect) MOA: They act by inhibiting the cyclooxygenase enzymes that catalyze the first step in prostaglandin biosynthesis. The NSAIDs are a group of chemically dissimilar agents USES: Analgesic (CNS and peripheral effect) Antipyretic (Inhibit prostaglandin E2 within the area of the brain that controls temperature) Anti-inflammatory
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Nonsteroidal Anti-inflammatory Drugs (NSAIDs)General Pharmacology
M212
Dr. Laila M. MatalqahPh.D. Pharmacology
NSAIDs MOA: They act by inhibiting the cyclooxygenase
enzymes that catalyze the first step in prostaglandin biosynthesis.
The NSAIDs are a group of chemically dissimilar agents USES:◦Analgesic (CNS and peripheral effect)◦Antipyretic (Inhibit prostaglandin E2 within
the area of the brain that controls temperature)
◦Anti-inflammatory
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
Characteristics: Different chemical families Different pharmacokinetics and potency Common mechanism of action (cyclooxygenase inhibition) Different selectivity to COX-1 and COX-2 Common therapeutic indications Common adverse effects
Cell Membrane Phospholipids
Arachidonic Acid
Phospholipase A2
COX) )
Cyclooxyg
enase
Lipooxygenase
NSAIDs
Steroids
Prostaglandins (PG)Thromboxanes (TXN)
Leukotrienes
Arachidonic Acid
Platelet TXA2
EndothelialPGI2
VasoconstrictionPlatelet Aggregation
VasodilationAnti-Platelet Aggregation
COX -1 COX -2
ASPIRIN
_ _
Pharmacological/Physiological Effects Platelets
Exists in the tissue as isoform (COX-1). At site of inflammation, cytokines stimulate the
induction of the 2nd isoform (COX-2). Inhibition of COX-2 is thought to be due to the anti-
inflammatory actions of NSAIDs. Inhibition of COX-1 is responsible for their GIT
toxicity.
cyclooxygenase
inhibit cyclooxygenase: Result in inhibition of endogenous compounds synthesis known as“ PROSTAGLANDINS (PG)
But, inhibition of PG synthase in gastric mucosa cause GIT damage (dyspepsia, gastritis, ulcer)
Mechanism of Action
In what conditions are NSAIDs used?
To treat inflammation, mild to moderate pain, & fever
Specific uses: headaches, arthritis, sports injuries, menstrual cramps (dysmenorrhea)
Included in cold/allergy preparations
1. Gastritis and peptic ulceration with bleeding (inhibition of PG + other effects)
2. Acute Renal Failure in susceptible patients 3. Sodium + water retention and edema formation4. Prolongation of gestation and inhibition of labor5. GIT bleeding and perforation6. Hypersensitivity (not immunologic but due to PG inhibition)
Common Adverse Effects
selective COX-2 inhibitors Celecoxib etoricoxib valdecoxib
Have similar efficacies to that of the non-selective inhibitors, but the GIT side effects are decreased by ~50%.
Aspirin (acetylsalicylic acid ) Hydrolyzed by esterases in tissues and blood to
salicylate (active) and acetic acid. Duration of action ~ 4 hr. Orally taken. Weak acid (pKa ~ 3.5); so, it will be non-ionized
in stomach so, easily absorbed.
The Salicylates - Aspirin
Pharmacokinetics of Aspirin
T h e ra p e u tic E ffe ct
S a lic ylic a c id
1 0 -2 0 % a re fre e p a rtic le sA ce tyla sa lic ylic a c id is h yd ro lyze d in to
8 0 -9 0 % b o u n d to p la sm a p ro te in s(P la sm a p ro te in b ind in g)
A sp irinA b sorb ed in th e S tom a ch /S m a ll In tes tine
antiplatelet aggregation: Prophylaxis of diseases due to (CAD, post myocardial infarction, post stroke patients, post-operation. DVT)
Analgesic : somatic; mild-moderate Antipyretic Anti-inflammatory : rheumatic fever,
rheumatoid arthritis, other rheumatological diseases. High dose needed (5-8 g/day)
Aspirin - Therapeutic Uses
ARACHIDONIC ACID
Platelet TXA2
EndothelialPGI2
VasoconstrictionPlatelet Aggregation
VasodilationAnti-Platelet Aggregation
COX -1 COX -2
ASPIRIN
_ _
Pharmacological/Physiological Effects Platelets
tinnitus , dizziness , hearing impairment (500-750mg/l)
Hyperpyrexia (>750mg/l) Confusion and drowsiness Sweating and hyperventilation Nausea, vomiting Marked acid-base disturbances Cardiovascular and respiratory collapse,
coma convulsions and death
Aspirin Toxicity - Salicylism
Phenylbutazone: Additional uricosuric effect used for treatment of
gout. Indomethacin: - ADR: CNS most common: halucinations,
depression, seizures, contraindicated in children
Ibuprofen : Better tolerated. Fewer side-effects Diclofenac sodium : high conc. in synovial fluid, used for rheumatoid
arithritis
Other NSAID’s
Piroxicam: Long-acting. Meloxicam: COX-2 /COX-1 selectivity ratio of about 10 Ketorolac:equal efficacy to morphine in postoperative pain,
approved for parenteral adminstration. Nabumetone: A prodrug, more potent COX-2 than COX-1
Other NSAID’s
Celecoxib,(Celebrex) Etoricoxib,(Arcoxia) Anti-inflammatory with less adverse effects,
especially GI events
Potential toxicities: increased risk of thrombotic events should not be given to patients with CV disease
Role in Cancer prevention
Role in Alzheimer’s disease
Selective COX-2 Inhibitors
ACETAMINOPHEN“Paracetamol”
Acetaminophen is NOT considered an NSAIDs because it lacks anti-inflammatory properties.
Acetaminophen is similar to aspirin and other NSAIDs because it can reduce pain and fever (analgesic & antipyretic effects)
Acetaminophen
Antipyretics Efficacy similar to salicylates Inhibits prostaglandin synthetase in the
hypothalamus (COX-3)Analgesia
Relieves mild to moderate pain Efficacy equivalent to salicylates Inhibits brain prostaglandin synthetase Blocks pain impulses peripherally
Actions of Acetaminophen
Pharmacokinetics of Acetaminophen T1/2 = 2 hrs
H ig h d o se s ca n lea d to h ep a tic n e cro s is T h e ra p e u tic E ffe ct
M e ta bo lism o ccu rs in the live rW ith o th er sub s tan ce s fro m th e L ive r/K id n ey
2 0 -5 0 % P la sm a P ro te in B in d in g
AcetaminophenA b s o rb e d ra p id ly/co m p le te ly fro m u p pe r G I T ra ct