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Analgesics

 Drugs that used clinically for controlling pain

with out significant change on patient
consciousness
◦ Act through central or peripheral pain mechanisms

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 Have anti-inflammatory, analgesic, and antipyretic effects

 As antipyretics

◦ Reduce body temperature in febrile states

 As analgesics

◦ Relieve mild to moderate pain such as dental pain,

dysmenorrhea, and headache

◦ Do not cause neurological depression or dependence

 As anti-inflammatory agents

◦ Used to treat conditions such as musculo-skeletal

inflammatory condition

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Mechanism of Action

 Inhibition of biosynthesis of prostaglandins by

blocking the enzyme COX

PGs don’t produce pain but sensitize nociceptores to

inflammatory mediators such as bradykinin and 5-HT

 Various NSAIDs have also additional possible

mechanisms

 Down-regulation of interleukin-1 production

 Decrease production of free radicals and

superoxide

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Mechanism of action continued…
 COX-1 is a primarily constitutive in most normal cells and
tissues

 Serve “housekeeping” functions such as cytoprotection of

the gastric epithelium

 COX-2 is induced isoform but is also constitutively

expressed in certain areas of kidney and brain

 All NSAIDs, with the exception of aspirin, are competitive

reversible inhibitors of COX; aspirin, however, irreversibly
acetylates the enzyme

 They do not inhibit the lipoxygenase pathways of AA

metabolism and hence do not suppress LT formation
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Classification of NSAIDs
Salicylates: e.g. Aspirin, diflunisal, salsalate,
olsalazine, sulfasalazine, methyl salicylate

Acetic acid derivatives: e.g. indomethacin,

sulindac

 Phenylacetic acid derivative: e.g diclofenac

The fenamates: mefenamic, meclofenamic, and

flufenamic acids

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Propionic acid derivatives: ibuprofen, naproxen,
ketoprofen, flurbiprofen, fenoprofen…

Enolic acids (oxicams): piroxicam, tenoxicam,

menoxicam

Pyrazolon derivatives: phenylbutazone,

oxyphenbutazone, dipyrone

Selective COX-2 inhibitors: celecoxib, etoricoxib,

rofecoxib,valdecoxib

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Therapeutic Effects
 All NSAIDs are antipyretic, analgesic, and anti-

inflammatory,

 with the exception of acetaminophen which is devoid of anti-

inflammatory activity

Analgesics (e.g. for headache, dysmenorrhoea, backache,

postoperative pain):

◦ Effective only against pain of low-to-moderate intensity,

such as dental pain

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Antipyretic

◦ NSAIDs reduce fever in most situations

Anti-inflammatory
◦ Used as anti-inflammatory agents in the treatment of
musculoskeletal disorders, such as
 rheumatoid arthritis and osteoarthritis

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Miscelaneous uses
Cardiovascular Effects

 Closure of ductus arteriosus

 Prostaglandins also have been implicated in the maintenance of

patency of the ductus arteriosus

 In delayed closure of the ductus arteriosus, COX inhibitors

(especially, indomethacin) are used to inhibit synthesis of PGE2

 Antithrombotic

 Low doses of aspirin (<100 mg daily) used widely for their

cardioprotective effects for patients at high risk of arterial
thrombosis (e.g. following MI)

 Prophylactic therapy against cardiac and cerebral ischemic

vascular disease

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Adverse Effects of NSAID Therapy

 Gastrointestinal

 The most common symptoms include: anorexia, nausea,

dyspepsia, abdominal pain, and diarrhea

o which are related to the induction of gastric or

intestinal ulcers

 Gastric damage due to at least two distinct MSM

Inhibition of COX-1 in gastric epithelial cells depresses

mucosal cytoprotective prostaglandins, especially PGI2
and PGE2

Direct local irritation of the gastric mucosa following oral

admin. e.g. aspirin
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 Gastrointestinal continued…

 COX-2-selective inhibitors are associated with a

decreased incidence of GI adverse events

 Ibuprofen better tolerated than aspirin and

indomethacin

– may be used in patients with a history of GI

intolerance to other NSAIDs

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 Cardiovascular

Owing to long half life, (irreversible inhibitor)

aspirin, can afford cardio-protection.

Use of COX-2-selective inhibitors is associated with

increased CV hazards

 Depress PGI2 formation by endothelial cells

without concomitant inhibition of platelet TXs

o PGI2 seems to restrain the CVS effects of TXA2

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Renal, and Renovascular Adverse Events

Associated with loss of the prostaglandin-induced inhibition of

both the reabsorption of Cl- and the action of antidiuretic
hormone – leading to the retention of salt and water

 Worsen CHF, hepatic cirrhosis, chronic kidney disease …

COX-2 inhibition in kidney attributed for ed generation of

vasodilator PGs (PGE2 and PGI2) – raise the likelihood of
hypertensive complications

Others

Hepatotoxicity, asthma, rash, and renal toxicity occur

less frequently

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 The salicylates (aspirin – prototype)
Pharmacological Actions

 Analgesia, anti-pyresis and anti-inflammatory

Cardiovascular Effects

 Aspirin irreversibly inhibits platelet COX, so its anti-platelet

effect lasts 8–10 days

 Low doses of aspirin (<100 mg daily) used widely for their

cardioprotective effects

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Therapeutic Uses

 Systemic Uses

◦ Analgesia, antipyresis, and Rheumatoid Arthritis

 Local Uses

◦ For treatment of Inflammatory Bowel Disease

 Mesalamine (5-aminosalicylic acid), olsalazine,
sulfasalazine– commonly used

 Other uses

◦ Aspirin decreases the incidence of transient ischemic

attacks, unstable angina, coronary artery thrombosis with
myocardial infarction

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Adverse Effects
 GI disturbance (most common)

◦ Occult blood loss from the GI tract, peptic ulceration, and

rarely, severe GI hemorrhage

 In large doses vomiting, tinnitus, hearing impairment, blurred

vision, and light-headedness, dizziness = salicylism

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 Acetaminophen
 Acetaminophen (paracetamol; N-acetyl-p-aminophenol) is
the active metabolite of phenacetin

 Well tolerated and has a low incidence of GI side effects

Pharmacological Properties

 Has analgesic and antipyretic effects similar to those of

aspirin

 It is a weak COX-1 and COX-2 inhibitor in peripheral

tissues and possesses no significant anti-inflammatory
effects

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Therapeutic Uses

 Acetaminophen is a suitable substitute for aspirin for

analgesic or antipyretic uses;
 particularly valuable for patients in whom aspirin is contraindicated
(e.g., those with peptic ulcer, aspirin hypersensitivity, children with
a febrile illness)

Adverse Effects

 Well tolerated at therapeutic doses

 Rash and other allergic reactions occur occasionally

 Neutropenia, thrombocytopenia

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 Over-dosage causes a potentially fatal hepatic
necrosis (~10 – 15g); 20 to 25 g is fatal
◦ Treatment: N- acetylcysteine, IV or methionine orally – to ↑
glutathione formation in the liver

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 ACETIC ACID DERIVATIVES
Indomethacin

 Prominent anti-inflammatory and analgesic-

antipyretic properties like salicylates

 More potent inhibitor of the COXs than aspirin,

◦ but patient intolerance generally limits its use to short-term

dosing

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Indomethacin continued…

 Excellent oral bioavailability

 90% bound to plasma proteins and tissues

Therapeutic Uses

 A high rate of intolerance limits its long-term use

 In the treatment of acute gouty arthritis, rheumatoid

arthritis, and osteoarthritis

 For closure of persistent patent ductus arteriosus

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Diclofenac

 Potency against COX-2 is substantially greater than

several other NSAIDs

 Rapid absorption, extensive protein binding, and a

short half-life

 Substantial first-pass effect = only 50% available

systemically

Therapeutic Uses

 Long-term symptomatic treatment of rheumatoid

arthritis, osteoarthritis,

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Adverse Effects: GI, modest, usually reversible,

elevation of hepatic transaminases

 CNS effects, rashes, allergic reactions, fluid retention,

and edema, and rarely impairment of renal function

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 Propionic acid derivatives
 Approved for use in the symptomatic

treatment of

◦ Rheumatoid arthritis, osteoarthritis, and

acute gouty arthritis

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Ibuprofen
 Absorbed rapidly, bound avidly to protein, and
undergoes hepatic metabolism and renal excretion

Adverse Effects

◦ Better tolerated than aspirin and indomethacin – may

be used in patients with a history of GI intolerance to
other NSAIDs

◦ Patients who develop ocular disturbances should

discontinue the use of ibuprofen

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COX-2 selective NSAIDs
 Non-selective COX inhibitors

◦ Cause frequent GI side effects due to significant

inhibition of cytoprotective PGs synthesized by the
COX-1 enzyme

 Selective COX-2 inhibitors/coxibs

◦ Do not affect the house keeping activity of COX-1

found in GI, kidneys, and platelets

◦ Inhibits COX-2 which is believed to be dominant in

inflammatory sites and cancers

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Selective COX-2 inhibitors continued…

◦ Hence, cause inhibition of PG synthesis in

inflammatory sites while the gastric cytoprotective
function of PG is left intact (produce half of GI adverse
effects)

◦ Higher incidence of cardiovascular thrombotic events

associated with COX-2 inhibitors

 Depress PGI2 formation by endothelial cells without

concomitant inhibition of platelet thromboxane

o Other NSAIDs such as nimesulide, diclofenac, and

meloxicam exhibit relative selectivity for COX-2 inhibition

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Include:
 Parecoxib,

 Etoricoxib,

 Lumiracoxib ,

 Celecoxib

 They are selective for COX-2 enzyme

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 Celecoxib

 The bioavailability of oral celecoxib is not

known,
◦ but peak plasma levels at 2 to 4 hrs

 Little drug is excreted unchanged;

◦ most is excreted as metabolites in the urine and
feces;

◦ half-life is approximately 11 hours

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Pharmacological Properties and Adverse Effects

 Hypertension and edema are attributed to the

inhibition of PG production in the kidney occur

with nonselective COX inhibitors and also with

celecoxib

 Coxibs should be avoided in patients prone to

CV or cerebrovascular disease

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Therapeutic Uses
 Treatment of osteoarthritis and rheumatoid arthritis

 Use the lowest possible dose for the shortest possible

time

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Fig: summary of nonsteroidal anti-inflammatory agents
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THANK YOU…!!!

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