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

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