NONSTEROIDAL ANTI-

INFLAMMATORY DRUGS
(NSAIDS)
Lt Col Jackson Yamvwa
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 O X inhibitors (traditional NSAIDs)

S alicylates Propionic Fenamate Enolic acid Acetic acid Pyrazolone

acid derivatives derivatives derivatives
derivatives
Ibuprofen Piroxicam Ketorolac Phenylbutazone,
Aspirin Naproxen Mefenamic acid. Tenoxicam Indomethacin Oxyphenbutazone
K etoprofen Nabumetone
Flurbiprofen

Preferential Selective Analgesic-antipyretics with poor

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

• 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 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 by various mediators
*COX-1 products (PGE2, PGI2) are involved in normal of inflammation, interleukin, superoxide radicals,
cellular processes in stomach, platelets and kidney 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.
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• Inhibition of platelet COX-1–dependent TxA2 formation is cumulative with
 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.

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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 + – 9
 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

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set
point for temperature causing fever.
 THERAPEUTIC USES OF NSAIDS
• Three main therapeutic effects of all NSAIDs, including selective COX-2
inhibitors are:
1. Anti-inflammatory effect:
• Modification of the inflammatory reaction
• Paracetamol is antipyretic and analgesic but largely devoid of

anti-inflammatory activity.
2. Analgesic effect
• Reduction of certain types of (especially inflammatory) pain
3. Antipyretic effect
• Lowering of body temperature when this is raised in disease (i.e.
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fever).
 THERAPEUTIC USES
4. Fetal Circulatory System
• Indomethacin and ibuprofen have been used in neonates to close the
inappropriately patent ductus arteriosus.
5. Antiplatelet:
• 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 NSAIDS
 Pyrexia
 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

 PDA (Patent Ductus Arteriosus) 13

 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. 14

• Treatment with indomethacin, combined with potassium repletion and spironolactone,

 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 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 exception
 Stroke* of low-dose aspirin
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 Thrombosis*
 ADVERSE EFFECTS OF NSAIDS
CNS: Hypersensitivity:
Headache
  Vasomotor rhinitis

 Vertigo  Angioneurotic edema

 Dizziness  Asthma

 Confusion  Urticaria

 Hyperventilation (salicylates)  Flushing

Uterus:  Hypotension

 Prolongation of gestation  Shock

 Inhibition of labuor

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ASPRIN & SOME OTHER IMPORTANT
NSAIDS

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 ASPIRIN
Actions-
⚫ reduces inflammation
⚫ antiinflammatory action is exerted at high doses (3–6 g/day or100 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.
 CLINICAL USES
1. As analgesic

2. As antipyretic

3. Acute rheumatic fever

4. Rheumatoid arthritis

5. Osteoarthritis

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 CLINICAL 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

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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. 23

 PRECAUTIONS AND CONTRAINDICATIONS
• Aspirin is 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
 A S P I R I N T O X I C I T Y - T R E AT M E N T

 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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 PARACETAM
Actions:
OL
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 paraaminobenzoqunonimine (NAPQ) by microsomal enzyme.
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 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

 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.

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 Diclofenac is used for:

Musculoskeletal complaints:
Arthritis
Rheumatoid arthritis
Polymyositis
Osteoarthritis
Gout attacks
 Dental pain
 Ankylosing spondylitis
• 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 andendometriosis. 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.
 IBUPROF
EN
• 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.
 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.
• 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.
 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.
 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.
 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.

 T 1/2 is 5-7 hours. 37

 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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 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 antiinflammatorydrug 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, an39 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-op

and musculoskeletal pain.

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 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.
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 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, 2 selective COX-2 inhibitors (also called coxibs) Celecoxib,
Etoricoxib are available in Zambia.
• Rofecoxib and valdecoxib were withdrawn due to increased risk of
thrombotic disorders like myocardial infarction.