Nonsteroidal anti-

inflammatory drugs (NSAID)

Ali Jaber, Ph.D.

MS in Pharmacy

MS in Pharmaceutical Chemistry

The inflammatory response

occurs in vascularised tissues in

response to injury.

It is part of the innate nonspecific immune

response.

Inflammatory responses require activation of

leukocytes: neutrophils, eosinophils,

basophils,mast cells, monocytes, and

lymphocytes,

(+)

Phospholipase A2 Phospholipids

Arachidonic acid

5-lipoxygenase

Leucotrienes

Cyclooxy genase (COX)

Endoperoxides

PGs TxA2

15-lipoxygenase

Lipoxins

Inflammatory stimulus

Ex

In

PGI2 (prostacyclin) is located

predominantly in vascular

endothelium. Main effects:

•vasodilatation

•inhibition of platelet aggregation

TxA2 is found in the platelets.

Main effects:

•platelet aggregation

•vasoconstriction

PROSTANOIDS (PGs & Txs)

PGE2 causes:

• inhibition of gastric acid secretion

•contraction of pregnant uterus

•contraction of GI smooth muscles

PGF2α – main effects:

•contraction of bronchi

•contraction of miometrium

Cyclooxygenase (COX) is found

bound to the endoplasmatic

reticulum. It exists in 3 isoforms:

• COX-1 (constitutive) acts

in physiological conditions.

• COX-2 (inducible) is

induced in inflammatory cells

by pathological stimulus.

• COX-3 (in brain).

Essential of Medical Pharmacology – 5st Ed. (2003)

COX-2

inhibitors • Selective (coxibs)

• Preferential

COX-3

inhibitors •Antipyretic

analgesics

Nonselective

COX-1/COX-2

inhibitors NSAIDs

COX inhibitors

Nonselective

COX-1/COX-2

inhibitors

(Classical NSAIDs) •Salicylates

•Phenylacetates

•Indolacetates

•Enolates

•Fenamates

•Propionates

•Butylpyrazolidindiones

•Pyrazolones

De rivatives

of acid

Acetylsalicylic acid (Aspirin®)

Paracetamol (Panadol)

Diclofenac (Voltaren)

Indometacin

Piroxicam (Brexin)

Meloxicam (Mobic)

Ibuprofen (Brufen)

Ketoprofen (Profenid)

Nonselective COX-1/COX-2 inhibitors

Beneficial actions of NSAIDs due

to prostanoid synthesis inhibition

1. Analgesia

prevention of pain nerve ending sensitization

2. Antipyresis

connected with influence of thermoregulatory

centre in the hypothalamus

3. Antiinflammatory action

mainly antiexudative effect

4. Antithrombotic action

in very low daily doses

5. Closure of ductus arteriosus

Shared toxicities of NSAIDs due

to prostanoid synthesis inhibition

1. Gastric mucosal damage

connected with PGE inhibition

2. Bleeding: inhibition of platelet

function (TxA2 synthesis)

3. Limitation of renal blood flow

Na+ and water retention

4. Delay / prolongation of labour

connected with PGF2α inhibition

5. Asthma and anaphylactoid reactions

connected with PGF2α inhibition

Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)

Aspirin® (Bayer, 1899) As analgesic for headache,pulled muscle, neuralgias.

As antipyretic in fever of any origin.

However, paracetamol is preferred

Acute rheumatic fever. Aspirin is the first drug of

choice. Other drugs substitute Aspirin only when it

fails or in severe cases.

Rheumatoid arthritis. Aspirin a dose of 3 to 5 g/24 h

after meal is effective in most cases. Since large

doses of Aspirin are poorly tolerated for a long time, the

new NSAIDs (diclofenac, ibuprofen, etc.) in depot

form are preferred.

Aspirin therapy in children with rheumatoid arthritis

has been found to raise serum concentration trans-

aminases, indicating liver damage. Most cases are

asymptomatic but it is potentially dangerous.

An association between salicylate therapy and

“Reye’s syndrome”, a rare form of hepatic

encephalopathy seen in children, having viral infection

(varicella, influenza), has been noted.

Aspirin should not be given to children under 15

years unless specifically indicated, e.g. for juvenile

arthritis (paracetamol is preferred).

Postmyocardial infarction and poststroke patients.

By inhibiting platelet aggregation in low doses (100 mg

daily) Aspirin decreases the incidence of reinfarction.

Arachidonic acid

Cyclooxygenase (COX)

Endoperoxides

PGs TxA2

(-)

Aspirin

Thromboxane A2 synthase

(-) 100 mg/24 h

>1 g/24 h

Drugs Result

Diuretics Decrease diuresis

Beta-blockers Decrease antihypertensive effect

ACE inhibitors Decrease antihypertensive effect

Anticoagulants Increase of GI bleeding

Sulfonylurea Increase hypoglycemic risk

Cyclosporine Increase nephrotoxicity

GCS Increase of GI bleeding

Alcohol Increase of GI bleeding

Drug interactions with NSAIDs

Ibuprofen (Brufen) Oral ibuprofen is often prescribed in lower doses at

which it has analgesic but not antiinflammatory

efficacy.

A topical cream preparation is absorbed into fascia

and muscle.

A liquid gel preparation of ibuprofen provides

prompt relief in postsurgical dental pain.

Ketoprofen (Profenid)

The effectiveness of ketoprofen at dosages of

100–300 mg/d is equivalent to that of other NSAIDs

in the treatment of rheumatoid arthritis, osteoarthritis,

gout, dysmenorrhea, and other painful conditions.

In spite of its dual effect on prostaglandins and

leukotrienes, ketoprofen is not superior to other

NSAIDs. Its major adverse effects are on the GIT

and the CNS.

Indometacin

Is a potent nonselective COX inhibitor and may also

inhibit phospholipase, reduce neutrophil migration,

and decrease T cell and B cell proliferation.

Indications:

juvenile rheumatoid arthritis, gout and post episiotomy

pain.

Side effects: A high incidence (up to 50%)

of GI and CNS side effects is produced: GI bleeding,

diarrhoea, frontal headache, mental confusion, etc.

Diclofenac (Voltaren)

Diclofenac in rectal suppository form can be

considered a drug of choice for

analgesia and postoperative nausea.

It is also available for intramuscular and oral

administration

Indications: All moderate pain

Side effects occur in approximately 20%: GI distress

and occult bleeding, gastric ulceration. A preparation

combining diclofenac and misoprostol (PGE1)

decrea-

ses upper GI ulceration but may result in diarrhoea.

Piroxicam, (Feldene) Its long half-life permits once-daily dosing.

Piroxicam can be used for the usual rheumatic

indications.

Side effects: Toxicity includes GI symptoms (20%

of patients), dizziness, tinnitus, headache, rash.

When piroxicam is used in dosages higher than

20 mg/d, an increased incidence of peptic ulcer

and bleeding is encountered. This risk is as much as

10 times higher with piroxicam than with other NSAIDs.

COX-2

inhibitors

(1) Selective COX-2

inhibitors (Coxibs)

• Celecoxib (celebrex)

• Etoricoxib (Arcoxia)

(2) Preferential

COX-2 inhibitors

• Meloxicam(Mobic)

• Nimesulide(Aulin)

Inhibiting activity rate

(COX-2/COX-1)

•Aspirin

•Indometacin

•Meloxicam

155

60

0,8

(Preferential COX-2 inhibitor)

Classical

NSAIDs

Coxibs are selective COX-2 inhibitors. They exert

antiinflammatory, analgesic, and antipyretic action

with low ulcerogenic potential. Coxibs can cause

infertility. They have prothrombotic cardiovascular

risk. The ulcerogenic potential of preferential

COX-2 inhibitors Meloxicam (Mobic), and

Nimesulide (Aulin®) is significant.

Celecoxib (Celebrex)is as effective as other

NSAIDs in the

treatment of rheumatoid arthritis and

osteoarthritis,

Side effects: celecoxib may cause rashes.

It does not affect platelet aggregation at usual

doses.

Etoricoxib (Arcoxia)

is a second-generation COX-2-selective inhibitor

Indications: treatment of the symptoms of

osteoarthritis, rheumatoid arthritis

and for the relief of acute musculoskeletal pain

Etoricoxib has similar efficacy to traditional NSAIDs

for osteoarthritis, acute gouty arthritis, and primary

dysmenorrhea and has a GI safety profile similar to

other coxibs.

Meloxicam (Mobic)

It has been shown to preferentially inhibit COX-2

over COX-1

It is not as selective as the other coxibs and may

be considered “

preferentially" selective rather than

“highly” selective.

Indications: treatment of osteoarthritis and

rheumatoid arthritis.

Side effects: are similar to those of other NSAIDs.

Comparative action between

COX inhibitors

COX-1/COX-2

inhibitors

COX-2

inhibitors

1. Analgesic action (+) (+) (+)

2. Antipyretic action (+) (+)

3. Antiinflammatory action (+) (+) (+)

4. Antiplatelet aggregatory (+) (-)

5. Gastric mucosal damage (+) (+) (+) (+)

6. Renal salt / water retention (+) (+)

7. Delay/prolongation of labor

8. Infertility

(+) (+)

(-)

(+)

(+) (+)

9. Ductus arteriosus closure (+) ?

10. Aspirin-like asthma

11. Cardiotoxicity

(+)

(-)

?

(+) (+)

Many severe side effects •Infertility (> PGF2α)

•Thrombosis (< PGI2; > TxA2)

Bextra® (Valdecoxib): Pfizer (penalty!)

COX-3

inhibitors

(antipyretic

analgesics)

NSAIDs in

low doses

NONOPIOID ANALGESICS

(1) Anilides

Paracetamol – tabl. 500 mg

(Acetaminophen – USAN)

Propacetamol (prodrug)

(2) Pyrazolones

Metamizole

(Analgin® – tabl. 500 mg)

(3) COX-1/COX-2 inhibitors

Aspirin®, Diclofenac,

Ibuprofen, Naproxen etc.

(4) COX-2 inhibitors

Pathogenesis

of pain

Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)

Acetaminophen (USAN)

(Paracetamol – INN)

•Efferalgan®

•Panadol®

•ParacetaMAX®

Propacetamol is a prodrug.

It converts into paracetamol.

Acetylsalicylic acid

•Aspirin®

•Aspegic® lisinate

(Metamizole – INN)

•Analgin®

•Proalgin®

Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)

Paracetamol (Panadol, Efferelgan)

paracetamol lacks antiinflammatory properties.

Indications: mild to moderate pain: headache,

myalgia,postpartum pain.

paracetamol is the preferred drug in children as

antipyretic and analgesic

Side effects: hepatotoxcity most of all

Acute paracetamol poisoning occurs especially in

small children who have low hepatic glucuronide conjugating

ability. If a large dose (> 150 mg/kg or > 10 g in adult)

is taken, serious toxicity can occur. The letal dose is 250 mg/kg