Non-steroidal anti-inflammatory drugs

Ms. Khushnuma Rasheed

Department of Pharmacology
 Non-steroidal anti-inflammatory
drugs (NSAIDs)
 NSAIDs are heterogeneous group of drugs having
analgesic, anti-inflammatory and antipyretic effect.
 Unlike morphine they do not depress CNS, do not
produce physical dependence, have no abuse liability
and are weaker analgesics.
 They are also called non-narcotic, non-opioid or aspirin
like analgesics.
 They act primarily on peripheral pain mechanism, but
also in the CNS to raise pain threshold.
 History
• White Willow bark (Salix alba) had been used for
many centuries.
• Salicylic acid was prepared by hydrolysis of the
bitter glycosides obtained from White Willow
plant.
• Sodium salicylate – 1875 (pain and fever).
• Acetylsalicylic acid (aspirin)– 1899 (Also
phenacetin and antipyrine).
• Phenylbutazone – 1949 (anti-inflammatory
activity almost similar to corticosteroids), The
term NSAIDs coined to designate such drugs.
• Indomethacin - 1963
 Classification
Classification of NSAIDs based on selectivity of COX Inhibition:
 Non-selective COX Inhibitors (Conventional NSAIDs):
 Salicylates: Aspirin.
 Pyrazolone derivatives: Phenylbutazone, Oxyphenbutazone.
 Indole derivatives: Indomethacin.
 Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen.
 Anthranilic acid derivatives: Mefenamic acid.
 Aryl acetic acid derivatives: Diclofenac.
 Oxicam derivatives: Piroxicam, Tenoxicam.
 Pyrrolo-pyrrole derivatives: Ketorolac.
 Preferential COX-2 Inhibitors: Nimesulide, Meloxicam, Nabumetone.
 Selective COX-2 Inhibitors: Celecoxib, Rofecoxib, Valdecoxib.
Analgesic-antipyretic with poor anti-
inflammatory action:

 p-aminophenol derivatives: Paracetamol

(Acetaminophen).
 Pyrazolone derivatives: Metamizol.
 Benzoxacine derivatives: Nefopam.
 Arachidonic acid

COX-1 COX-2 COX-3

(normal constituent) (inducible)) (normal constituent)
CNS, Heart, Aorta

Nonselective Selective
NSAID COX-2 inhibitor
Body homeostasis Inflammatory Site
• Stomach • Macrophages Pain
• Intestine • Synoviocytes Fever
• Platelet • Endothelial cell
• Kidney
Mechanism: COX-1, COX-2 & COX-3 inhibition
Beneficial effects (inhibition of PG
synthesis)
 Analgesia
 Antipyresis
 Anti-inflammatory
 Antithrombotic
 Closure of ductus arteriosus in newborn
 Antipyresis
 Normal body temperature is maintained by thermoregulatory
centre (thermostat) in hypothalamus, which ensures a balance
between heat production and heat loss.
 Fever occurs due to disturbance in the hypothalamic
thermostat, which is set at a high temperature.
 The antipyretics act by resetting the thermostat to normal set-
point and then the body temperature regulating mechanisms
(dilatation of superficial blood vessels, sweating and increased
respiration, promoting heat loss) operate to lower the elevated
body temperature to normal level.
 Normal body temperature is not affected by NSAIDS or
antipyretics (at therapeutic doses).
 During infections and inflammatory reactions the pathogenic
microbial endotoxins cause release of pyrogen interleukin-I from
macrophages, which stimulates the generation of prostaglandins
(E series) in hypothalamus, which set the thermostat at a higher
level resulting in pyrexia.
 The NSAIDs exert antipyretic effect by irreversibly inhibiting the
enzyme cyclo-oxygenase 1 or cyclo-oxygenase 2 or both which
catalyze the initial reaction of prostaglandin formation from
arachidonic acid in the hypothalamus or through inhibition of a
specific COX isoenzyme in the CNS.
 COX-1 is a constitutive enzyme responsible for physiological
synthesis of prostaglandins for tissue homeostasis (including
protection on gastric mucosa; PGI2 and PGE2). Whereas, COX-2 is
an inducible enzyme responsible for synthesis of prostaglandins
which have a role in fever, pain and inflammation.
 Anti-inflammatory
 The inflammatory reactions such as vasodilatation,
increased vascular permeability, cell proliferation,
pain etc are mediated by the release of a multitude of
chemical mediators having varied mechanisms of
action.
 The inflammatory stimuli in the inflammatory cells
induce synthesis of prostaglandins through COX2.
 The NSAIDS exert anti-inflammatory effect by
inhibition of prostaglandin synthesis by irreversible
inhibition of this enzyme.
 Analgesics

 The NSAIDS are mainly effective against pain

associated with arthritis, muscular pain, vascular
pain, toothache, dysmenorrhoea and bone pain,
in all the conditions there is increased synthesis
of pain inducers and prostaglandins.
 The prostaglandins sensitize nociceptors to pain
inhibiting prostaglangin synthesis through
irreversible inactivation of COX-1 or COX-2 or
both.
 Antiplatelet aggregator

 TXA2 is pro-aggregator (COX-1)

 PGI2 is anti-aggregator
 Most NSAIDs - effects on TXA2 predominates and
inhibits aggregation – prolonged bleeding time
 Aspirin is highly active and acetylates COX in circulation
– before hepatic 1st pass metabolism
 Even small dose Antithrombotic effect – Myocardial
Infarction and other cardiac conditions
Ductus arteriosus closure
• It is a shunt connecting the pulmonary artery to the
aortic arch
• Maintained by local PGE2 and PGI2
• Closes at birth
• Failure to close – small doses of NSAIDs (aspirin or
indomethacin) – closes).
• NSAIDs is not used in late pregnancy – (premature
closure)
Other action of NSAIDs:
Aspirin can reduce diarrhea that occur after radiation
therapy.
 Relative Potency of NSAIDs

 Antipyretic Effect: Aspirin = Paracetamol >

Phenacetin > Phenylbutazone
 Analgesic Effect: Aspirin > Phenacetin & Paracetamol
> Phenylbutazone
 Anti-inflammatory Effect: Phenylbutazone > Aspirin
 ADVERSE EFFECTS OF NSAIDS
Gastrointestinal:
Abdominal pain
Nausea
Diarrhea
Anorexia
Gastric erosions/ulcers
Anemia
GI hemorrhage
Platelets:
Inhibited platelet activation
Increased risk of hemorrhage
 ADVERSE EFFECTS OF NSAIDS
Renal:
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
Stroke*
exception
Thrombosis* of low-dose
aspirin
 ADVERSE EFFECTS OF NSAIDS
CNS:
Headache
Vertigo
Dizziness
Confusion
Hyperventilation (salicylates)

Uterus:
Prolongation of gestation
Inhibition of labuor
 ADVERSE EFFECTS OF NSAIDS

Hypersensitivity:

Vasomotor rhinitis
Angioneurotic edema
Asthma
Urticaria
Flushing
Hypotension
Shock
ASPRIN & SOME OTHER
IMPORTANT NSAIDS
 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.
 USES
1. As analgesic
2. As antipyretic
3. Acute rheumatic fever
4. Rheumatoid arthritis
5. Osteoarthritis
USES
• By inhibiting platelet aggregation aspirin lowers the
incidence of Postmyocardial infarction and poststroke
patients.
• Aspirin 6–1000 mg/day reduces the incidence of
myocardial infarction (MI)
• Aspirin reduces ‘transient ischaemic attacks’ and
lowers
incidence of stroke in such patients
 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.

 PRECAUTIONS AND CONTRAINDICATIONS
• Aspirin 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 CHF and in juvenile rheumatoid
arthritis.
• Aspirin should be stopped 1 week before elective
surgery.
• Pregnancy & lactation
• G-6PD deficiency
 ASPIRIN 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…
 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.
Adverse Effects:
o Hepatotoxicity due to NPAQ
o Antidote of choice is N - acetylcysteine
 DICLOFENAC
• 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.
Diclofenac is used for:
• musculoskeletal complaints:
arthritis
rheumatoid arthritis
polymyositis,
osteoarthritis,
dental pain
gout attacks
• Pain management in kidney stones and gallstones.
• Additional indication is: acute migraines.
• Used commonly to treat : mild to moderate post-operative or
posttraumatic pain, particularly when inflammation is also
present.
• Is effective against: menstrual pain.
 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.
 IBUPROFEN

• Ibuprofen is a NSAID 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.
• 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.
 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.
• 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
 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.
Clinical Uses:
• Gout and ankylosing spondylitis ( inflammatory
arthritis affecting the spine and large joints).
• An ophthalmic preparation for conjunctival
inflammation to reduce pain after traumatic corneal
abrasion.
• Gingival inflammation is reduced after
administration of indomethacin oral rinse.
 KETOROLAC
• Ketorolac is an NSAID promoted for systemic use mainly as an 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.
• 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.
 PIROXICAM
• Piroxicam, an oxicam is a 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 antiinflammatory drug in

rheumatoid and osteo-arthritis, ankylosing spondylitis.

• Toxicity includes gastrointestinal symptoms (20% of patients),

dizziness, tinnitus, headache, and rash.

• When piroxicam is used in dosages higher than 20 mg/d, an

increased incidence of peptic ulcer and bleeding is encountered.
 INDOMETHACIN
• Inhibits PLPA2 and possesses immunouppressive property
• 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,
post-operative 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.
• 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 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.
THANK
YOU