NONSTEROIDAL ANTI-INFLAMMATORY

DRUGS (NSAIDS)
 The term "nonsteroidal" is used to distinguish these drugs from
steroids, which have a similar eicosanoid-depressing, anti-
inflammatory action.

 NSAIDs are non-narcotic, non-opioid, aspirin-like analgesics.

 Most currently available NSAIDs act by inhibiting the

prostaglandin (PG) synthase enzymes.

 Most NSAIDs are competitive, reversible, active site inhibitors

of
the COX enzymes. Aspirin inhibits them irreversibly.
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 CLASSIFICATION
Nonselective C OX inhibitors (traditional NSAIDs)
Salicylates Propionic Fenamate Enolic acid Acetic acid Pyrazolone
acid derivatives derivatives derivatives
derivatives

Aspirin Ibuprofen, Mephena- Piroxicam, Ketorolac, Phenylbut-

Naproxen, mic acid. Tenoxicam Indometha- azone,
Ketoprofen, cin, Oxyphenb-
Flurbiprof- Nabumeto- utazone
en ne

Preferential Selective Analgesic-antipyretics with poor

COX- 2 COX - 2 Antiinflammatory action
inhibitors inhibitor
Nimesulide, s
Celecoxib, 1.Paraaminophenol derivative:
Diclofenac, Etoricoxib, Paracetamol(Acetaminophen).
Aceclofenac, Parecoxib. 2.Pyrazolone derivatives: Metamizol
3
Meloxicam, (Dipyrone), Propiphenazone.
Etodolac 3. Benzoxazocine derivative:
Nefopam.
 MECHANISM OF ACTION
(MOA)Inhibition
Cyclooxygenase

Aspirin and NSAIDs inhibit the COX enzymes and PG production.

There are two forms of COX, COX-1 and COX-2.

 COX-1, expressed constitutively in most cells, is the dominant

source of prostanoids for housekeeping functions.

 COX-2 is the more important source of prostanoid formation in

inflammation.

4
 induced by cytokines, shear stress, and tumor promoters.
5
 COX1 COX2
*Expressed in all tissues *Selectively expressed in renal, brain
& endothelium, fetus
*constitutive
• COX-2 products (PG) are induced
*COX-1 products (PGE2, PGI2) are by various mediators of
involved in normal cellular processes inflammation, interleukin,
in stomach, platelets and kidney superoxide radicals, cytokines and
endotoxins mainly in inflammed
areas and cause more pain and
inflammation

• Constitutive in brain and kidney

• Inducible in macula densa in

response to salt restriction

*Does not affect platelet aggregation

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 MOA CONTD…
Irreversible Cyclooxygenase Inhibition by Aspirin
 Aspirin covalently modifies COX-1 and COX-2, irreversibly

inhibiting COX activity.

 The duration of aspirin’s effects is related to the turnover rate of

COXs in different target tissues.

 The importance of enzyme turnover in recovery from aspirin

action is most notable in platelets.

 Platelets being anucleate have a markedly limited capacity for

protein synthesis.
• Inhibition of platelet COX-1–dependent TxA2 formation is 7

cumulative with repeated doses of aspirin.

 MOA CONTD…
Selective Inhibition of Cyclooxygenase-2

 Constitutively expressed COX-1 is the predominant source of

cytoprotective PGs formed by the GI epithelium.

 COX-2 is source of PG formation in inflammation and cancer.

 Selective inhibitors of COX-2 were developed based on the

hypothesis

• they would afford efficacy similar to tNSAIDs with better

GI
tolerability. 8
 Features of nonselective COX inhibitors and
selective COX-2 inhibitors
Action Nonselective COX inhibitors Selective/COX-2 inhibitors
1. Analgesic + +
2. Antipyretic + +
3. Antiinflammatory + +
4. Antiplatelet aggregatory + –
5. Gastric mucosal damage + –
6. Renal salt/water retention + +
7. Delay/prolongation of labour + +
8. Ductus arteriosus closure + ?
9. Aspirin sensitive asthma
precipitation + –
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 MOA CONTD…
An anti-inflammatory action: the decrease in prostaglandin E2 and
prostacyclin reduces vasodilatation and, indirectly, oedema.

An analgesic action: decreased prostaglandin generation means

less sensitisation of nociceptive nerve endings to inflammatory
mediators such as bradykinin and 5-hydroxytryptamine.

An antipyretic action: endogenous pyrogens elevate the

hypothalamic set point for temperature causing fever.

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 THERAPEUTIC USES
Three main therapeutic effects of all NSAIDs, including selective
COX-2 inhibitors are:

 anti-inflammatory effect: modification of the inflammatory

reaction
• Acetaminophen, which is antipyretic and analgesic is
largely devoid of anti-inflammatory activity.

 analgesic effect: reduction of certain types of (especially

inflammatory) pain

 antipyretic effect: lowering of body temperature when this is

raised in disease (i.e. fever). 11
 THERAPEUTIC USES
 Fetal Circulatory System: Indomethacin and ibuprofen
have been used in neonates to close
the inappropriately patent ductus arteriosus.

 Cardioprotection: Aspirin reduces the risk of serious

vascular
events in high risk patients.

• Irreversible acetylation of platelet COX → inhibition of platelet

function until sufficient numbers of newplatelets are released.

• Permanent and complete suppression of platelet COX-1–

dependent TxA2 formation → cardioprotective effect of aspirin.
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 INDICATIONS FOR
 Pyrexia NSAIDS
 Mild to moderate pain

 Rheumatoid arthritis

 Osteoarthritis

 Inflammatory arthropathies (ankylosing spondylitis,

psoriatic arthritis, Reiter’s syndrome)

 Acute gout

 Dysmenorrhoea

 Metastatic bone pain

 Headache & Migraine

 Postoperative pain

 Injury 13
 PDA (Patent Ductus Arteriosus)
 OTHER CLINICAL USES
 Systemic Mastocytosis:
⚫ In patients with systemic mastocytosis, PGD2, released
from mast cells in large amounts is the major mediator of
severe episodes of flushing, vasodilation, and hypotension.
⚫ This PGD2 effect is resistant to antihistamines.
⚫The addition of aspirin or ketoprofen provides relief.
 Niacin Intolerability: Aspin inhibits PGD2 mediated flushing by

niacin.
 Bartter Syndrome:

⚫ Caused by mutations in a Na+-K+-2Cl− co-transporter.

⚫ Treatment with indomethacin, combined with potassium
repletion and spironolactone, is associated with
improvement in the biochemical derangements and 14

symptoms.
 ADVERSE EFFECTS OF
NSAIDS
Gastrointestinal:
 Abdominal pain
 Nausea

 Diarrhea

 Anorexia

 Gastric erosions/ulcers

 Anemia

 GI hemorrhage

Platelets:
 Inhibited platelet activation

 Propensity for bruising

 Increased risk of hemorrhage 15

 ADVERSE EFFECTS OF
Renal: NSAIDS
 Salt and water retention
 Edema, worsening of renal function in renal/cardiac and

cirrhotic patients
 Decreased effectiveness of antihypertensive medications

 Decreased effectiveness of diuretic medications

 Decreased urate excretion (especially with aspirin)

 Hyperkalemia

Cardiovascular:
 Closure of ductus arteriosus

 Myocardial infarction*
* With the exception
 Stroke* of low-dose aspirin
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 Thrombosis*
 ADVERSE EFFECTS OF
CNS: NSAIDS
Headache


 Vertigo

 Dizziness

 Confusion

 Hyperventilation (salicylates)

Uterus:
 Prolongation of gestation

 Inhibition of labuor

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 ADVERSE EFFECTS OF
NSAIDS
Hypersensitivity:
 Vasomotor rhinitis

 Angioneurotic edema

 Asthma

 Urticaria

 Flushing

 Hypotension

 Shock

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 ASPRIN & SOME OTHER
IMPORTANT
NSAIDS
19
 ASPIRIN
Actions-
⚫ reduces inflammation
⚫ antiinflammatory action is exerted at high doses (3–6 g/day or
100 mg/kg/ day).
⚫ analgesic(0.3–1.5 g/day) for inflammatory pain
⚫ antipyretic (i.e. reduces raised temperature)
⚫ At low doses (40-325mg) it acts as antiplatelet drug

MOA- Irreversibly inactivating both cyclo-oxygenase (COX-1

and COX-2).

Abs/Distrb/Elim- Given orally. Half-life only 30min – rapid

hydrolysis to salicylate but effects last longer because the COX
has been inactivated and new enzyme must be produced. 20
 USES
1. As analgesic

2. As antipyretic

3. Acute rheumatic fever

4. Rheumatoid arthritis

5. Osteoarthritis

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 USES
6. By inhibiting platelet aggregation aspirin lowers the incidence of
reinfarction in Postmyocardial infarction and poststroke
patients.

 Aspirin 6–1000 mg/day reduces the incidence of myocardial

infarction (MI)

 ‘New onset’ or ‘sudden worsening’ angina is associated with

high infarction rate & can be reduced to half by 100–150 mg
aspirin per day for 12 weeks.

 Aspirin reduces ‘transient ischaemic attacks’ and lowers

incidence of stroke in such patients 22
 ADVERSE EFFECTS

Gastrointestinal disturbances, especially gastric bleeding.

 In high dosage can cause ‘salicylism’ (tinnitus, vertigo, reduced

hearing); allergic reactions occasionally; renal toxicity rarely.

 Can cause the potentially fatal Reye’s syndrome

(encephalopathy & liver disorder) in children after a viral
infection.

 At therapeutic dose it can cause hyperuricemia.

 Prolongs bleeding time. 23

 PRECAUTIONS AND
 Aspirin is CONTRAINDICATIONS
C/I in patients who are sensitive to it and in peptic ulcer,
bleeding tendencies, in children suffering from chicken pox or
influenza.

 Liver disease: can cause hepatic necrosis.

 It should be avoided in diabetics, in those with low cardiac

reserve or frank CHF and in juvenile rheumatoid arthritis.

 Aspirin should be stopped 1 week before elective surgery.

 Pregnancy & lactation

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 G-6PD deficiency
 AS P I R I N TOXICITY -
TREATMENT
 Decrease absorption - activated charcoal,
emetics, gastric lavage

 Enhance excretion - alkalinize urine, forced

diuresis, hemodialysis

 Supportive measures - fluids, decrease

temperature, bicarbonate, electrolytes, glucose,
etc…

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 PARACETAMOL
Actions:
Paracetamol has potent analgesic and antipyretic actions but
rather weaker anti inflammatory effects than other NSAIDs.

MOA:
Inhibition of COX-1, COX-2 and also the recently identified COX-3
which occurs predominantly in the CNS.

Absorption/Metabolism:
It is given orally and metabolised in the liver (half-life 2-4 hours).
Metabolized to N-acetyl paraaminobenzo qunonimine (NAPQ) by
microsomal enzyme. 26
Adverse Effects:

o Hepatotoxicity due to NPAQ

o Glutathione produced by liver detoxifies NPAQ

o Chronic alcoholics are predisposed to toxicity due to

 Reduced glutathione

 Alcohol induces production of NPAQ from acetaminophen.

o Antidote of choice is N - acetylcysteine 27

 DICLOFEN
AC
 Diclofenac reduces inflammation , acts as an analgesic,
reducing pain in conditions such as arthritis or acute injury.

 The action of one single dose is much longer (6 to 8 hours) than

the very short half-life that the drug indicates.

 This could be partly because it persists for over 11 hours in

synovial fluids.

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Diclofenac is used for:
 musculoskeletal complaints: arthritis
rheumatoid arthritis
polymyositis,
osteoarthritis,
dental pain
ankylosing spondylitis
gout attacks
 Pain management in kidney stones and gallstones.

Additional indication is: acute migraines.

 Used commonly to treat : mild to moderate post-

operative or post-
traumatic pain, particularly when inflammation is
also present.
Is effective against: menstrual pain and
endometriosis. 29
Propionic acid derivatives
• Naproxen, fenoprofen, ketoprofen, flurbiprofen and oxaprozin.

Mechanism of action:
• These drugs are reversible inhibitors of the cyclooxygenases, and
thus, inhibit the synthesis of prostaglandins.

Uses:

•All these drugs possess anti-inflammatory, analgesic,

and antipyretic activity.

• Used in the chronic treatment of rheumatoid arthritis and

osteoarthritis, because their gastrointestinal effects are generally
less intense than that of aspirin.
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 IBUPROFEN

• Ibuprofen is a N SA I D originally marketed as Brufen.

• It is used for relief of symptoms of

Arthritis
Primary dysmenorrhea,
Fever

As an analgesic, especially where there is an

inflammatory component.
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 Ibuprofen is known to have an antiplatelet effect, though it is
relatively mild and short-lived when compared with aspirin
or other better-known antiplatelet drugs.

 Ibuprofen is a core medicine in the World Health Organization's

"Essential Drugs List", which is a list of minimum medical needs
for a basic healthcare system.

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 MEFENAMIC ACID
 Used to treat pain, including menstrual pain. It is typically
prescribed for oral administration.

 Decreases inflammation (swelling) and uterine contractions by

inhibiting prostaglandin synthesis.

 Used for perimenstrual migraine headache prophylaxis, with

treatment starting 2 days prior to the onset of flow or 1 day
prior to the expected onset of the headache and continuing for
the duration of menstruation.

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 Since hepatic metabolism plays a significant role in mefenamic
acid elimination, patients with known liver deficiency may
be prescribed lower doses.

 Kidney deficiency may also cause accumulation of the drug

and its metabolites in the excretory system. Therefore patients
suffering from renal conditions should not be prescribed
mefenamic acid.

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 INDOMETHACIN

 Indomethacin, is a potent nonselective COX inhibitor and

may
also inhibit phospholipase A and C, reduce neutrophil migration,
and decrease T cell and B cell proliferation.

 Probenecid prolongs indomethacin's half-life by inhibiting both

renal and biliary clearance.

Clinical Uses:
 Gout and ankylosing spondylitis. In addition, it has been used
to treat patent ductus arteriosus. 35
Clinical Uses:

 An ophthalmic preparation for conjunctival inflammation

to reduce pain after traumatic corneal abrasion.

 Gingival inflammation is reduced after administration of

indomethacin oral rinse.

 Epidural injections produce a degree of pain relief similar to

that achieved with
methylprednisolone in post laminectomy syndrome.

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 KETOROL
AC for systemic use mainly as an
 Ketorolac is an NSAID promoted

analgesic, not as an antiinflammatory drug (though it has

typical NSAID properties).

 Rapidaly absorbed after oral and i.m. administration.

 It is most often given intramuscularly or intravenously, but an

oral dose formulation is available.

 Higly plasma protien bound and 60% excreted unchanged in

urine.

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 T1/2 is 5-7 hours.
 The drug has been used successfully to replace morphine in
some situations involving mild to moderate postsurgical pain.

 When used with an opioid, it may decrease the opioid

requirement by 25–50%.

 An ophthalmic preparation is available for anti-inflammatory

applications.

 Toxicities are similar to those of other NSAIDs, although renal

toxicity may be more common with chronic use.

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 PIROXICA
 Piroxicam, an oxicam isMa nonselective COX inhibitor but at high
concentrations also inhibits polymorphonuclear leukocyte
migration, decreases IgM rheumatoid factor and inhibits
lymphocyte function.

 Suitable for use as long-term antiinflammatorydrug in

rheumatoid and osteo-arthritis, ankylosing
spondylitis.

 Toxicity includes gastrointestinal symptoms (20% of

patients),
 dizziness,
When tinnitus,
piroxicam is headache, and rash.
used in dosages higher than 20 mg/d, an
increased incidence of peptic ulcer and bleeding is
encountered. 39
INDOMETHACIN
 Inhibits PLPA and possesses immunouppressive property
2
 Indicated in Bartter’s syndrome

MEFANAMIC ACID
 possesses PG receptor antagonistic and PLPA2 inhibitory activity.

 Useful in dysmenorrhoea.

 Piroxicam and Tenoxicam are longest acting NSAIDs due to

enterohepatic circulation.

 Nefopam does not inhibit PG synthesis but relieves traumatic,

40
post-op and musculoskeletal pain.
 COX-2 SELECTIVE
INHIBITORS
 These drugs have advantage of very little GI toxicity.

 Renal toxicity is similar to traditional NSAIDs and chances of

thrombosis (acute MI and stroke) are increased on
prolonged use.

 Celecoxib, rofecoxib and valdecoxib are sulphonamide derivatives

(can cause hypersensitivity reactions)

 Etoricoxib is longest acting and requires hepatic function

monitoring during its use.

41
 Lumiracoxib is a newer cox 2 inhibitor that has more activity in
the acidic medium.
 COX-2 SELECTIVE
INHIBITORS
 COX-2 inhibitors have been recommended mainly for treatment
of osteoarthritis and rheumatoid arthritis.

 Other indications include primary familial adenomatous

polyposis, dysmenorrhea, acute gouty arthritis &
acute musculoskeletal pain.

 Currently, 3 selective COX-2 inhibitors (also called coxibs)

Celecoxib, Etoricoxib and Parecoxib are available in India.

 Rofecoxib and valdecoxib were withdrawn due to increased

risk of thrombotic disorders like myocardial infarction.
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