1. Nonsteroidal Anti-inflammatory Drugs (NSAIDs) General Pharmacology M212
Dr. Laila M. Matalqah
Ph.D. Pharmacology

2. 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

3. 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

5. Cell Membrane Phospholipids
Steroids
Phospholipase A2
Arachidonic Acid
NSAIDs
Lipooxygenase
COX) ) Cyclooxygenase
Leukotrienes
Prostaglandins (PG)
Thromboxanes (TXN)

6. Pharmacological/Physiological Effects Platelets
Arachidonic Acid
COX -1
COX -2 _ _
Platelet
TXA2
Endothelial
PGI2
ASPIRIN
Vasoconstriction
Platelet Aggregation
Vasodilation
Anti-Platelet Aggregation

7. cyclooxygenase 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.

8. Mechanism of Action
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)

9. Common Pharmacological Effects
Analgesic (CNS and peripheral effect) may involve non-PG related effects
Antipyretic (CNS effect)
Anti-inflammatory (except acetaminophen) due mainly to PG inhibition.
Some shown to inhibit activation, aggregation, adhesion of neutrophils & release of lysosomal enzymes
Some are Uricosuric

10. 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 10

11. Common Adverse Effects
Gastritis and peptic ulceration with bleeding (inhibition of PG + other effects)
Acute Renal Failure in susceptible patients
Sodium + water retention and edema formation
Prolongation of gestation and inhibition of labor
GIT bleeding and perforation
Hypersensitivity
(not immunologic but due to PG inhibition)

12. 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%.

14. The Salicylates - Aspirin
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.

15. Pharmacokinetics of Aspirin

16. Aspirin - Therapeutic Uses
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)

17. Pharmacological/Physiological Effects Platelets
ARACHIDONIC ACID
COX -1
COX -2 _ _
Platelet
TXA2
Endothelial
PGI2
ASPIRIN
Vasoconstriction
Platelet Aggregation
Vasodilation
Anti-Platelet Aggregation

18. Aspirin Toxicity - Salicylism
tinnitus , dizziness , hearing impairment ( mg/l)
Hyperpyrexia (>750mg/l)
Confusion and drowsiness
Sweating and hyperventilation
Nausea, vomiting
Marked acid-base disturbances
Cardiovascular and respiratory collapse, coma convulsions and death

19. Other NSAID’s 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

20. 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

21. Selective COX-2 Inhibitors
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

22. ACETAMINOPHEN
“Paracetamol”

23. Acetaminophen
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)

24. Actions of 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
Peripheral action is blockade of Pain Impulse generation
Less effect on peripheral enzyme
Studies have shown that both apap and asa have equal effects on pain when given in equiv. Doses when the pain in non inflammatory in origin
For inflammatory pain, salicylates are superior.
They also inhibit prostaglandin synthetase peripherally, resulting in anti inflammatory activity.

25. Pharmacokinetics of Acetaminophen T1/2 = 2 hrs

26. Thank You