NSAID's
NSAID's
drugs
Presented by,
Dr Mirunalini Sundaravadivelu
Post Graduate in Public Health Dentistry
Contents
• Introduction
• Actions of NSAID’s
• NSAID’S selectivity
• Prostaglandins
• Classification
• Topical NSAID’s
Introduction
• NSAIDs are a group of chemically dissimilar agents that differ in their antipyretic,
analgesic, and anti-inflammatory activities.
• They act primarily by inhibiting the cyclooxygenase enzymes that catalyze the
first step in prostanoid biosynthesis.
• This leads to decreased prostaglandin synthesis with both beneficial and
unwanted effects.
• Differences in safety and efficacy of the NSAIDs may be explained by relative
selectivity for the COX-1 or COX-2 enzyme.
• Inhibition of COX-2 is thought to lead to the anti-inflammatory and analgesic
actions of NSAIDs, whereas inhibition of COX-1 is responsible for prevention of
cardiovascular events and most adverse events.
Basic Properties
• Weak organic acid
• Binds to serum proteins (albumin)
• Generally have low ionization constant
• Causing binding to sites of inflammation
• Main anti-inflammatory properties due to inhibition of prostaglandin
synthesis by blocking the enzyme prostaglandin G/H synthase (PGHS)
also called cyclooxygenase (COX)2
Actions
• Analgesia
• Antiinflammatory
• Antipyresis
• Antiplatelet
• Inhibit COX-1 thus preventing thromboxane A2 (TXA2) production to
decrease platelet aggregation
Role of prostaglandins as local mediators
• Prostaglandins and related compounds are produced in minute
quantities by virtually all tissues.
• They generally act locally on the tissues in which they are synthesized
and are rapidly metabolized to inactive products at their sites of
action.
• Therefore, prostaglandins do not circulate in the blood in significant
concentrations.
• Thromboxanes and leukotrienes are related compounds that are
synthesized from the same precursors as the prostaglandins
Synthesis of prostaglandins
Anti- not depress the production of other Mediators like LTs, PAF, cytokines, etc.
• Inflammation is the result of concerted participation of a large number of
inflammatory vasoactive, chemotactic and proliferative factors at different stages, and there
are many targets for antiinflammatory action.
• Activated endothelial cells express adhesion molecules (ELAM-1, ICAM-1) on
their surface and play a key role in directing circulating leucocytes to the site of
inflammation (chemotaxis).
• Similarly, inflammatory cells express selectins and integrins. Certain NSAIDs may
act by additional mechanisms including inhibition of expression/activity of some
of these molecules and generation of superoxide/other free radicals.
• Growth factors like GM-CSF, IL-6 as well as lymphocyte transformation factors
and TNFα may also be affected.
• Stabilization of lysosomal membrane of leukocytes and antagonism of certain
actions of kinins may be contributing to antiinflammatory action of NSAIDs.
• Level of PGs in menstrual flow, endometrial biopsy
and that of PGF2α metabolite in circulation are
raised in dysmenorrhoeic women.
• Intermittent ischaemia of the myometrium is
probably responsible for menstrual cramps.
Dysmenorrhoea • NSAIDs lower uterine PG levels—afford excellent
relief in 60–70% and partial relief in the remaining.
• Axcillary symptoms of headache, muscle ache and
nausea are also relieved.
• Excess flow may be normalized
• NSAIDs inhibit synthesis of both proaggregatory
(TXA2) and Antiaggregatory (PGI2) prostanoids, but
effect on platelet TXA2 (COX-1 generated)
predominates.
• Therapeutic doses of most NSAIDs inhibit platelet
aggregation and prolong bleeding time.
Antiplatelet • Aspirin is highly active, because it acetylates
aggregatory platelet COX irreversibly in the portal circulation
before getting deacetylated by first pass
metabolism in liver.
• Small doses of aspirin are therefore able to exert
antithrombotic effect for several days.
• Risk of surgical and anticoagulant associated
bleeding is enhanced.
• During foetal circulation ductus arteriosus is kept
patent by local elaboration of PGE2 by COX-2.
• Unknown mechanisms switch off this synthesis at
birth and the ductus closes.
Pharmacological Anti‐inflammatory actions: Higher doses; 3‐6 g/day, OA , RA, Rh fever, Inhibits prostaglandin synthesis, Blocks action of kinins which are
actions mediated through prostaglandin synthesis, Inhibits granulocyte adherence to damaged vasculature, Stabilizes lysosomes, Inhibits migration
of PMN leukocytes & macrophages into the site of inflammation, Analgesia: inhib of PG :300‐600mg ,6‐8 hrly, Antipyretic axn.: inhib of PG:
resets the “hypothalamic thermostat”, Inhibition of platelet aggregation: low doses: irreversibly inhibit platelet COX , antiplatelet effect lasts
8‐10 days.(acts on TXA2 ,no effect on PGI2)
Pharmacokinetics Well absorbed from the stomach, more from upper small intestine, Distributed all over the body, 50‐80% bound to plasma protein
(albumin), Metabolized to acetic acid and salicylates (activemetabolite), Excreted by the kidney
Adverse effects CNS: Headache, Tinnitus, dizziness, blurred vision, irritability, hyperventilation (Salicylism) CVS.: fluid retention, HT, edema, CHF(rarely) GIT
upset: abdominal pain, nausea, vomiting, peptic ulceration & bleeding Hypersensitivity: bronchial asthma, angioedema & rashes,
Thrombocytopenia, Hypoprothrombinemia and bleeding tendency as aspirin competes with vitamin K, so decreasing prothrombin synthesis
Adverse drug reactions Renal effects: renal insufficiency, renal failure, hyperkalemia, proteinuria. Analgesic nephropathy on chronic use, Hepatic: Liver function
abnormalities, rarely liver failure,
Contraindications Peptic ulcer, esophageal varices, bronchial asthma, idiosyncrasy, allergy, viral infection in children, bleeding tendency and small dose in gout
(competes with uric acid excretion).
Interactions Aspirin displaces oral anticoagulants and oral hypoglycemics from their plasma protein binding sites, so increasing their activities and may
lead to toxicity, Barbiturates increase the analgesic effect of aspirin.
Acute aspirin poisoning
• Restlessness, tremors, convulsion, vomiting, dehydration, hypotension,
hyperventilation, hyper reflexia, hyperpyrexia & coma.
Treatment:
• Activated charcoal 50g to adsorb salicylates and prevents its absorption.
• Alkalinization of urine (to enhance excretion) by i.v Na HCO3 which also corrects
acidosis.
• Anticonvulsant e.g. i.v diazepam.
• Cold fomentation and ice bags.
• Correct dehydration by i.v fluids (5% dextrose).
• Correct acid / base balance (alkalosis or mixed alkalosis/acidosis need no specific
treatment).
• Correct hypoprothrombinemia by i.v vitamin K.
• Hemodialysis may be needed
Locally acting salicylates
• Salicylic acid: keratolytic, antiseptic & fungistatic.
• Methyl salicylate (wintergreen oil): used as counterirritant for muscle
and joint pain.
• Sulfasalazine : it is a combination of sulfapyridine and 5‐aminosalicylic
acid (5‐ASA). Sulfasalazine liberates 5‐ASA in the colon where it blocks
the synthesis of leukotriene B4 locally and used in ulcerative colitis
PROPIONIC ACID DERIVATIVES
• Ibuprofen was the first member of this class to be introduced in 1969
as a better tolerated alternative to aspirin.
• All have similar pharmacodynamic properties but differ considerably
in potency and to some extent in duration of action
• The analgesic, antipyretic and antiinflammatory efficacy is rated
somewhat lower than high dose of aspirin.
• All members inhibit PG synthesis, naproxen being the most potent;
but their in vitro potency to inhibit COX does not closely parallel in
vivo anti-inflammatory potency.
• Inhibition of platelet aggregation is short-lasting with ibuprofen, but
longer lasting with naproxen.
• All are well absorbed orally, highly bound to plasma
proteins (90–99%), but displacement interactions
are not clinically significant—dose of oral
anticoagulants and oral hypoglycaemics need not
be altered.
• Because they inhibit platelet function, use with
anticoagulants should, nevertheless, be avoided.
Pharmacokinetics • Similar to other NSAIDs, they are likely to decrease
and interactions diuretic and antihypertensive action of thiazides,
furosemide and β blockers.
• All propionic acid derivatives enter brain, synovial
fluid and cross placenta.
• They are largely metabolized in liver by
hydroxylation and glucuronide conjugation and
excreted in urine as well as bile
• Ibuprofen is used as a simple analgesic and
antipyretic in the same way as low dose of aspirin.
It is particularly effective in dysmenorrhoea in
which the action is clearly due to PG synthesis
inhibition. It is available as an ‘over-the-counter’
drug.
Adverse • Gastric erosion and occult blood loss are rare. CNS
side effects include headache, dizziness, blurring of
effects vision, tinnitus and depression. Rashes, itching and
other hypersensitivity phenomena are infrequent.
However, these drugs precipitate aspirin-induced
asthma.
• Fluid retention is less marked.
• They are not to be prescribed to pregnant women
and should be avoided in peptic ulcer patient
Ibuprofen
• It has been rated as the safest traditional NSAID by the spontaneous
adverse drug reaction reporting system in U.K. Ibuprofen (400 mg) has
been found equally or more efficacious than a combination of aspirin
(650 mg) + codeine (60 mg) in relieving dental surgery pain, but is a
weaker antiinflammatory; not suitable for acute gout and other
similar conditions
Naproxen
• The anti-inflammatory activity is stronger and it is particularly potent
in inhibiting leucocyte migration—may be more valuable in acute
gout
• It is also recommended for rheumatoid arthritis and ankylosing
spondylitis.
• Because of longer t½ regular use can effectively suppress platelet
function.
• Naproxen carries lower thrombotic risk than diclofenac, etoricoxib,
etc.
Ketoprofen
• An additional action to stabilize lysosomes and inhibit LOX has been
demonstrated with ketoprofen; though antiinflammatory efficacy is
similar to ibuprofen, and side effects are more
Flurbiprofen
• More effective than ibuprofen, but gastric side effects are also more.
It is used as an ocular antiinflammatory action
ACETIC ACID DERIVATIVES - Ketorolac
• This arylacetic acid NSAID has potent analgesic but modest antiinflammatory
activity.
• In postoperative pain it has equalled the efficacy of morphine, but does not
interact with opioid receptors and is free of opioid side effects.
• Like other NSAIDs, it inhibits PG synthesis and relieves pain primarily by a
peripheral mechanism.
• In short-lasting pain, it has compared favourably with aspirin.
• Ketorolac is rapidly absorbed after oral and i.m. administration.
• It is highly plasma protein bound and 60% excreted unchanged in urine.
• Major metabolic pathway is glucuronidation; plasma t½ is 5–7 hours
• Nausea, abdominal pain, dyspepsia, ulceration,
loose stools, drowsiness, headache, dizziness,
Adverse nervousness, pruritus, pain at injection site, rise in
serum transaminase and fluid retention have been
effects noted.
• Ketorolac has been used concurrently with
morphine to keep its dose low.
• Ketorolac is frequently used in postoperative,
dental and acute musculoskeletal pain: 15– 30 mg
i.m. or i.v. every 4–6 hours (max. 90 mg/ day).
• It may also be used for renal colic, migraine and
pain due to bony metastasis.
• Orally it is used in a dose of 10–20 mg 6 hourly for
short-term management of moderate pain.
Use • Ketorolac has been rated superior to aspirin (650
mg), paracetamol (600 mg) and equivalent to
ibuprofen (400 mg).
• Continuous use for more than 5 days is not
recommended.
• Topical ketorolac is quite popular for noninfective
ocular conditions
• This indole acetic acid derivative is a potent
antiinflammatory drug with prompt antipyretic
action.
Indomethacin • Indomethacin relieves only inflammatory or tissue
injury related pain.
• It is a highly potent inhibitor of PG synthesis and
suppresses neutrophil motility.
• Indomethacin is well absorbed orally, rectal
absorption is slow but dependable.
• It is 90% bound to plasma proteins, partly
Pharmacokinetics metabolized in liver to inactive products and
excreted by kidney.
• Plasma t½ is 2–5 hours.
• A high incidence (up to 50%) of gastrointestinal and
CNS side effects is produced.
• Gastric irritation, nausea, anorexia, gastric bleeding
and diarrhoea are prominent.
• Frontal headache (very common), dizziness, ataxia,
Adverse mental confusion, hallucination, depression and
psychosis can occur.
effects • Leukopenia, rashes and other hypersensitivity
reactions are also reported. Increased risk of
bleeding due to decreased platelet aggregability.
• It is contraindicated in machinery operators,
drivers, psychiatric patients, epileptics, kidney
disease, pregnant women and in children
• Because of prominent adverse effects, indomethacin is
used as a reserve drug in conditions requiring potent
antiinflammatory action like ankylosing spondylitis, acute
exacerbations of destructive arthropathies, psoriatic
arthritis and acute gout or rheumatoid arthritis that are
not responding to better tolerated NSAIDs.
• Malignancy associated fever refractory to other
Uses antipyretics may respond to indomethacin.
• It has been the most common drug used for medical
closure of patent ductus arteriosus: three 12 hourly i.v.
injections of 0.1–0.2 mg/kg achieve closure in majority of
cases.
• Bartter’s syndrome responds dramatically, as it does to
other PG synthesis inhibitors
Nabumetone
• It is a prodrug—generates an active metabolite (6-MNA) which inhibits both COX-
1 and COX-2.
• It possesses analgesic, antipyretic and antiinflammatory activities; effective in the
treatment of rheumatoid and osteo-arthritis as well as in soft tissue injury.
• Nabumetone has caused a lower incidence of gastric erosions, ulcers and
bleeding, probably because the active COX inhibitor is produced in the tissues
after absorption.
• However, abdominal cramps and diarrhoea can occur
• The plasma t½ is 24 hours.
PYRAZOLONES
• Antipyrine (phenazone) and amidopyrine (aminopyrine) were introduced in 1884 as antipyretic
and analgesic.
• Their use was associated with high incidence of agranulocytosis: are banned globally.
• Phenylbutazone was introduced in 1949 and soon its active metabolite oxyphenbutazone was
also marketed.
• These two are potent antiinflammatory drugs, inhibit COX, but have slow onset, weak analgesic
and antipyretic action.
• Their gastric toxicity is high; edema due to Na+ and water retention is frequent and CNS side
effects, hypersensitivity reactions, hypothyroidism are reported.
• They have gone out of use due to residual risk of bone marrow depression and other toxicity.
• Two other pyrazolones available in India—metamizol and propiphenazone are primarily used as
analgesic and antipyretic.
Metamizol (Dipyrone)
• In contrast to phenylbutazone, this derivative of amidopyrine is a potent and promptly
acting analgesic and antipyretic but poor antiinflammatory and not uricosuric.
• It can be given orally, i.m. as well as i.v, but gastric irritation, pain at injection site occurs.
• Occasionally, i.v. injection produces precipitous fall in BP.
• Few cases of agranulocytosis were reported and metamizol is banned in the USA and
some European countries.However, it has been extensively used in India and other
European countries.
• Adverse reaction shows that risk of serious toxicity with this drug is lower than with
aspirin or many other NSAIDs.
• Its fixed dose combination with antispasmodics is banned in India
Propiphenazone
• Another pyrazolone, similar in properties to metamizol; found to be
better tolerated.
PREFERENTIAL COX-2 INHIBITORS
Nimesulide
• This NSAID is a relatively weak inhibitor of PG synthesis and moderately COX2 selective.
• Antiinflammatory action may be exerted by other mechanisms as well, e.g. reduced
generation of superoxide by neutrophils, inhibition of PAF synthesis and TNFa release,
free radical scavanging, inhibition of metalloproteinase activity in cartilage.
• The analgesic, antipyretic and antiinflammatory activity of nimesulide has been rated
comparable to other NSAIDs.
• It has been used primarily for short-lasting painful inflammatory conditions like sports
injuries, sinusitis and other ear-nose-throat disorders, dental surgery, bursitis, low
backache, dysmenorrhoea, postoperative pain, osteoarthritis and for fever.
• Nimesulide is almost completely absorbed orally, 99% plasma protein bound, extensively
metabolized and excreted mainly in urine with a t½ of 2–5 hours.
• Gastrointestinal (epigastralgia, heart burn, nausea, loose
motions), dermatological (rash, pruritus) and central
(somnolence, dizziness).
Adverse • Gastric tolerability of nimesulide is better, though ulcer
complications are as prevalent as with other NSAIDs.
effects • Instances of fulminant hepatic failure have been associated
with nimesulide and it has been withdrawn in Spain, Ireland,
Singapore and Turkey; use in children is banned in Portugal,
Israel and now in India as well.
Diclofenac sodium
• An analgesic-antipyretic antiinflammatory drug, similar in efficacy to naproxen.
• It inhibits PG synthesis and is somewhat COX-2 selective.
• Neutrophil chemotaxis and superoxide production at the inflammatory site are
reduced.
• It is well absorbed orally, 99% protein bound, metabolized and excreted both in
urine and bile.
• The plasma t½ is ~2 hours.
• Has good tissue penetrability and concentration in synovial fluid is maintained for
3 times longer period than in plasma, exerting extended therapeutic action in
joints.
• Diclofenac is among the most extensively used
NSAID; employed in rheumatoid and osteoarthritis,
Use bursitis, ankylosing spondylitis, toothache,
dysmenorrhoea, renal colic, posttraumatic and
postoperative inflammatory conditions—affords
quick relief of pain and wound edema.
• Generally mild: epigastric pain, nausea, headache,
dizziness, rashes. Gastric ulceration and bleeding
Adverse are less common.
• Some comparative trials have found its gastric
effects toxicity to be similar to celecoxib and etoricoxib.
• Like many NSAIDs, diclofenac can increase the risk
of heart attack and stroke.
Aceclofenac
• A moderately COX-2 selective congener of diclofenac having similar
properties.
• Enhancement of glycosaminoglycan synthesis may confer
chondroprotective property to aceclofenac.
Meloxicam
Srinivas SM, Shekar R, Gnanamurthy N. Fixed drug eruption to paracetamol in a child. Indian J Paediatr Dermatol
2018;19:386-8
• Many NSAIDs have been marketed in topical
formulations (mostly as gels) for application over
painful muscles or joints.
• These preparations are being used for
osteoarthritis, sprains, sports injuries, tenosinovitis,
Topical backache, spondylitis and other forms of soft tissue
rheumatism.
NSAIDs • It is presumed that the drug would penetrate to
the subjacent tissues attaining high concentrations
in the affected muscles/joints, while maintaining
low blood levels.
• Diclofenac 1% gel : VOLINI GEL, RELAXYL GEL,
DICLONAC GEL
• Ibuprofen 10% gel : RIBUFEN GEL
• Naproxen 10% gel : NAPROSYN GEL
• Ketoprofen 2.5% gel : RHOFENID GEL
Preparations • Flurbiprofen 5% gel : FROBEN GEL
• Nimesulide 1% gel : NIMULID TRANS GEL,
ZOLANDIN GEL, NIMEGESIC-T-GEL
• Piroxicam 0.5% gel : DOLONEX GEL, MOVON GEL,
PIROX GEL, MINICAM GEL
Choice of nonsteroidal antiinflammatory drug
• Mild-to-moderate pain with little inflammation: paracetamol or low-dose ibuprofen.
• Postoperative or similar acute but short lasting pain: ketorolac, a propionic acid derivative, diclofenac or
nimesulide.
• Acute musculoskeletal, osteoarthritic, injury associated pain: paracetamol, a propionic acid derivative or
diclofenac.
• Exacerbation of rheumatoid arthritis, ankylosing spondylitis, acute gout, acute rheumatic fever:
naproxen, piroxicam, indomethacin, high dose aspirin.
• Gastric intolerance to traditional NSAIDs or predisposed patients: a selective COX-2 inhibitor or
paracetamol. Arthritis patients who are dependent on NSAIDs and have developed peptic ulcer must
receive concurrent proton pump inhibitor as gastroprotective.
• Patients with history of asthma or anaphylactoid reaction to aspirin/other NSAIDs: nimesulide, COX-2
inhibitor
• Patients with hypertension or other risk factor for heart attack/stroke: avoid selective COX-2 inhibitor; a
propionic acid derivative or aspirin may be used at the lowest dose for the shortest period.
• Paediatric patients: only paracetamol, aspirin, ibuprofen and naproxen have been adequately evaluated in
children — should be preferred in them. Due to risk of Reye’s syndrome, aspirin should be avoided.
• Elderly patients: use lower dose of the chosen NSAID.
• Fast acting drug formulation is suitable for fever, headache and other short lasting pain, while longer
acting drugs/sustained release formulations are appropriate for chronic arthritic pain.
• Pregnancy: paracetamol is the safest; lowdose aspirin is probably the second best.
• Hypertensive, diabetic, ischaemic heart disease, epileptic and other patients receiving long-term regular
medication: possibility of drug interaction with NSAIDs should be considered.
Referrences
• Goodman & Gilman’s The Pharmacological basis of Therapeutics- 12th
Edition
• Essentials of Medical Pharmacology – 7th Edition, KD TRIPATHI MD
• Lippincott® Illustrated Reviews: Pharmacology - South Asian Edition