Non-steroidal anti-inflammatory drugs

They have 3 pharmacological actions:

 Antipyretic
 Analgesic
 Antiinflammatory

Antipyretic action:
 Fever raises the set temperature in hypothalamus
 NSAIDs decrease this set temperature
 Pyrogens released by macrophages (for example
IL-1)
 These pyrogens will stimulate prostaglandin PG
production in hypothalamus.
 PG raises the set point in hypothalamus —> fever
 NSAIDs inhibits production of PG
 NSAIDs have no action on normal temperature
(37.2°)

Analgesic action:
 They are effective in pain associated with
inflammation.

Antiinflammatory action:
 They inhibits cyclooxygenase enzyme (COX) —> decrease production of PG
 They decrease production of oxygen radicals (ROS) —> ↓ tissue damage.
 They have no effects on lysosomal enzyme release.
Mechanism of action:
3 types of COX enzyme:
 COX-1: constitutively expressed , widely distributed, maintains the normal
physiological ‘housekeeping’ function.
 COX-2: inducible in inflammatory cells by inflammatory stimuli.
 Expression is stimulated by growth factors, tumor
promotersmers, cytokines, and endotoxins.
 COX-3: implicated in fever, expressed in the brain
 Indomethacin & sulindac primarily inhibit COX-1.
 Meclofenamate & ibuprofen have equally action on COX-1 &COX-2.
 Celecoxib & rofecoxib inhibit COX-2
 Drugs with short half-lives in the plasma remain in the joints for a long time and
vice versa; long half-life acting drugs last longer in the plasma, and have a
proportional level with that of the intrarticular concentration.
 COX-2 inhibitors have no effect on platelet function (thus no cardioprotctive
properties), but of importance, have less effect on the GI system.
 NSAIDs decrease sensitivity of the vessels to bradykinin and histamine and reduce
the incidence of colon cancer by about 50%.
Common adverse effects:
1. Gastrointestinal effects:
 result mainly from inhibition of the COX-1 isoform.
 dyspepsia, diarrhea, nausea, vomiting, gastric bleeding, and ulceration.
2. Adverse renal effects:

This figure illustrates the action of PG on the kidney

 NSAIDs inhibit the action of PG in the kidney thus impeding renal vascular auto-
regulation.
 In susceptible pt. —> acute renal insufficiency.
3. Skin reactions (caused by mefenamic acid and sulindac.)
 Include: mild rash, urticaria, and photosensitivity reactions.
 Classification of NSAIDS

Another Classification of NSAIDs

Nonselective COX inhibitors COX-2 selective inhibitors

 COX-1 inhibition, in general, is instantaneous and competitively reversible.

 COX-2 inhibition is time
dependent, i.e. its effect
increases with time.
 The COX-2-selective
drugs have minimal
gastrointestinal toxicity.
 COX-2 inhibitors no
impact on platelet
aggregation.
 Cardiovascular thrombotic
events seen in COX-2
inhibitors.
 COX-2 is constitutively
active within the kidney.

Salicylates (aspirin)
Mechanism of action:
 Non-selective Inhibitor of both COX isoforms
 Irreversibly inhibits COX and inhibit platelet aggregation
PK:
 Weak acid
 Most of it is protein bound
 T1/2= low dose: 3h high dose: 15h
 Hydrolyzed by plasma and tissue esterases.
  Metabolism:
 25% oxidized
 25% excreted unchanged
 some conjugated to glycine,
glucuronic , & sulfuric acid
 Rate of excretion is higher in
alkaline urine (Henderson-Hasselbalch
equation).

Adverse effects:
 Contraindicated in hemophilic pt.
 GIT side effects: dyspepsia, nausea, vomiting, mucosal
damage —> peptic ulcers.
 Analgesia-associated nephropathy
 Bronchospasm in aspirin-sensitive asthmatics
 Skin reactions
 Impaired homeostasis.
 Reye’s syndrome: occurs in aspirin consumption by children with viral diseases such
as chickenpox. (fatal disease)

Acute toxicity:
 Local effects:
Gastritis with focal erosion
 Systemic effects:
Salicylism: Large therapeutic doses alter acid-base balance —> hyperventilation &
respiratory alkalosis.
In larger doses —> respiratory acidosis.
Also Causes:
 Interference with carbohydrate metabolism —> metabolic acidosis
 Hyperpyrexia
 Dehydration
 CNS effects: initially stimulation with excitement then coma & respiratory
depression.

Treatment of toxicity:
 Correction of acid-base balance
 Rehydration and treat hyperthermia
 Maintenance of kidney function
 Gastric lavage & forced alkaline diuresis
Drug interaction:
 Aspirin increases
concentrations of: warfarin,
phenytoin, valproic acid
 Avoid aspirin use with
probencid & sulfinpyrazone
because they increase uric
acid excretion while aspirin
does the opposite
 Ketorolac + aspirin = ↑ risk of
GI bleeding and platelet inhi-
bition

Clinical uses:
 Minor musculoskeletal disorders → bursitis, synovitis, tendinitis, myositis, and
myalgia
 Fever and headache
 Inflammatory disease, such as acute rheumatic fever, rheumatoid arthritis,
osteoarthritis, and certain rheumatoid variants, such as ankylosing spondylitis
 Prophylaxis of myocardial infarction and ischemic stroke.
 Colon cancer
 Paracetamol (acetaminophen)

Has no significant antiinflammatory effects and is usally

used as an analgesic.
PK:
 Well absorbed orally
 Peak plasma concentration 30-60 m
 Variability in protein binding
 T1/2= 2-4 h
 Drug is inactivated in the liver by conjugation with
gluco
 uronic & sulfuric acid
 T1/2 for toxic dose= 4-8 h

Adverse effects
 Allergic skin reactions
 Toxicity:
 The drug is metabolized to N-acetyl-p- benzoquinone.
 In normal doses the previous compound binds with
glutathione, and is converted to mercaptopuric acid
(nontoxic)
 With high doses N-acetyl-p-benzoquinone will cause
necrosis in the liver and kidney
 Initial symptoms: nausea and vomiting
 Treatment:
1. Gastric lavage, oral activated charcoal.
2. Agents that ↑ glutathione formation e.g. acetylsystine (orally or IV)
3. Agents that ↑ conjugation reaction (methionine & cystamine)
4. After 12 hours these agents are useless and they may precipitate hepatic coma

Clinical uses
 Allergy to aspirin
 When slicylates are poorly tolerated
 Hemophilia
 History of peptic ulcer
 Bronchospasm precipitated by aspirin
 Children with certain viral infection
 Is usually combined with probencid

Ibuprofen
A nonselective COX inhibitor
PK:
 T1/2= 2 h
 Oral, cream preperation, and IV
 Hepatic metabolism and urinary excretion
 Clinical uses:
 As an analgesic, antipyretic, in treatment of rheumatoid arthritis and degenerative joint
disease.
 Closing patent ductus arteriosus in preterm infants
 A liquid gel preparation → postsurgical dental pain.
 Ibuprofen + aspirin = no platelet inhibition

Adverse effect
Nausea, heartburn, epigastric pain, rash, and dizziness, visual changes, prolongation of
bleeding times

Diclofenac Piroxicam Meloxicam

Equal action on COX-1,2 Mechanism of action:

 Nonselective COX Mechanism of action:
PK inhibitor COX-2 selective
 Oral, IM, ophthalmic, topical,  In high concentrations it inhibitor but less
 T1/2= 1.1 h inhibits selective than celecoxib
polymorphonuclear or rofecoxib for COX-2
Clinical uses leukocyte migration,
 Used for rheumatoid arthritis, decreases oxygen radical Clinical uses:
osteoarthritis, ankylosing production, and inhibits Osteoarthritis,
spondylitis, dysmenorrhea. lymphocyte function. rheumatoid arthritis and
 Topical for solar keratosis certain acute conditions
 Usually combined with PK
misoprostol or omeparazole T1/2= 57 h Adverse effects
to prevent upper GI bleeding Low frequency GI
 Ophthalmic preparation → Clinical uses: effects
postoperative ophthalmic Rheumatoid arthritis and
inflammation. osteoarthritis
 Rectal suppository for
preemptive analgesia and Adverse effects:
postoperative nausea GI reactions, edema, dizziness,
headache, rash, and changes in
Adverse effects hematological parameters.
 GI disturbances
 Headache
 Reversible elevation of serum
transaminases.
 Nabumetone Celecoxib

PK:
 The only nonacid NSAID
 T1/2= 26 h A COX-2 Selective inhibitor
 A prodrug metabolized in the liver to 6- PK:
methoxy-2-naphthylacetic acid, a strong  T1/2= 11 h
COX inhibitor, which is chemically simi-  27% urinary excretion
lar to naproxen
 Renal impairment may double its t ½ . Clinical uses
Osteoarthritis and rheumatoid arthritis
Clinical uses
Rheumatoid arthritis, osteoarthritis, and pain Contraindications:
management.  Hypersensitivity to sulfonamides or
other NSAIDs.
Adverse effects:  Used with caution in persons with
 Less damage to the stomach hepatic disease
 Pseudoporphyria and photosensitivity in
some patients Drug interactions:
 lower-bowel complaints, rashes, and with other drugs that induce CYP2C9 (e.g
CNS disturbances. rifampin) or compete for metabolism by this
enzyme (e.g. warfarin, fluconazole,
leflunomide).

Adverse effects:
 Mild to moderate GI effects such as
dyspepsia, diarrhea, and abdominal
pain.
 Serious GI and renal effects have
occurred rarely
 hypertension and edema