NSAIDs

Non Steroidal Anti Inflammatory Drugs

 INFLAMMATION

• Inflammation (Latin, inflamatio, to set on fire) is

the complex biological response of vascular tissues
to harmful stimuli, such as pathogens, damaged
cells, or irritants.

• It is a protective attempt by the organism to

remove the injurious stimuli as well as initiate the
healing process for the tissue.
 CAUSES
• Burns
• Chemical irritants
• Frostbite
• Toxins
• Infection by pathogens
• Physical injury
• Immune reactions due to hypersensitivity
• Radiation
• Foreign bodies
The classic signs and symptoms of acute
inflammation

English Latin
Redness Rubor*
Swelling Tumor/Turgor*
Heat Calor*
Pain Dolor*
Loss of function Functio laesa**
 Process of Inflammation
• Inflammation can be classified as either acute or chronic.
• The initial phase of cell injury is known as the acute
phase and is mediated by several autacoids like :
– Histamine
– 5-HT
– Bradykinin
– Prostaglandins

• When a tissue is injured, from any cause, prostaglandin

synthesis in that tissue increases.
 Synthesis of Prostaglandins
Cyclo-oxygenase (COX) pathway
Membrane Phospholipids
Phospholipase A2

Arachidonic Acid

COX

Prostaglandins
Thromboxanes
Prostacyclin
 NSAIDs
• Among the most widely used all therapeutic agents
world wide

• They are frequently prescribed for ‘rheumatic’

musculo-skeletal complaints and are often taken
without prescription for minor aches and pains

• More than 50 different NSAIDs on the market and

none of these is ideal in controlling or modifying the
signs and symptoms of inflammation
 NSAIDs Cont..

• Analgesic
• Antipyretic
• Anti-inflammatory actions
• Compared to Morphine:
– Weaker analgesics
– Do not depress CNS
– Do not produce physical dependence
– No abuse liability
 NSAIDs Cont..
• They are also called:
– Non norcotic
– Non opioid
– Aspirin like analgesics
• They act primarily on peripheral pain
mechanisms but also in CNS to raise pain
threshold
• These drugs are chemically diverse, but most
are organic acids.
 Common characteristics of all NSAIDs
Cont..

• Non of these steroid

• All are analgesic, antipyretic, anti-inflammatory
(expect paracetamol)
• Do not produce CNS, RS depression.
• Dose dependent uricosuric action.
• Act by inhibition of PGs except Nimesulide,
Nefopam
 Classification
Non selective COX inhibitors:
Salicylates Aspirin, Diflunisal

Pyrazolone derivatives Phenylbutazone,

Oxyphenbutazone
Indole derivatives Indomethacin, Sulindac

Propianic acid derivatives Ibuprofen, Naproxen,

Ketoprofen, Flurbiprofen
Anthranilic acid derivatives Mephenamic acid

Aryl-acetic acid derivatives Diclofenac

Pyrrolo-pyrrolo derivative ketorolac

 Classification cont..

Preferential COX-2 inhibitors:

Nimesulide, Meloxicam, Nabumatone

Selective COX-2 inhibitors

Celecoxib, Rofecoxib, Valdecoxib

Analgesic –Antipyretics with poor Anti inflammatory action

Para amino phenol derivatives Paracetamol (Acetaminophen)
Pyrazolone derivatives Metamizol (Dypirone),
Propifenazone
Benzoxazocine derivative Nefopam
 Non selective COX inhibitors:
Salicylates Aspirin, Diflunisal

Pyrazolone derivatives Phenylbutazone,

Oxyphenbutazone
Indole derivatives Indomethacin, Sulindac

Propianic acid derivatives Ibuprofen, Naproxen,

Ketoprofen, Flurbiprofen
Anthranilic acid derivatives Mephenamic acid

Aryl-acetic acid derivatives Dicofenac

Pyrrolo-pyrrolo derivative ketorolac

 Mechanism of action

• When a tissue is injured, from any cause, prostaglandin

synthesis in that tissue increases.

• PGs have TWO major actions:

• They are mediators of inflammation

• They also sensitize pain receptors at the nerve
endings, lowering their threshold of response to
stimuli and allowing the other mediators of
inflammation
 Mechanism of action Cont..

• Naturally, a drug that prevents the synthesis of PGs is

likely to be effective in relieving pain due to inflammation
of any kind

• In 1971 Vane and coworkers made the landmark

observation that aspirin and some NSAIDs blocked PG
generation.

• This is they do by inhibiting cyclo –oxygenase (COX)

enzyme in the pathway for PGs synthesis
 Synthesis of Prostaglandins
Cyclo-oxygenase (COX) pathway

Membrane Phospholipids
Phospholipase A2

Arachidonic Acid

NSAIDs COX

Prostaglandins
Thromboxanes
Prostacyclin
 COX

• Exists in two isoforms:

1. COX-1 (constitutive)
2. COX-2 (inducible)
– Oxidative stress
– Injury
– Ischemia
– Neurodegenerative diseases
Beneficial actions due to PG synthesis
inhibition

• Analgesia
• Antipyresis
• Antiinflammatory
• Antithrombotic
• Closure of ductus arteriosus
 Shared toxicities due to PG synthesis
inhibition

• Gastric mucosal damage

• Bleeding
• Limitation of renal blood flow/Na+ & water
retention
• Delay/prolongation of labour
• Asthma and anaphylactoid reactions in
susceptible individuals
 Salicylates - Aspirin
• Prototype

• Acetylsalicylic acid

• It was obtained from „willow bark‟ (Salicaceae) but

is now synthesized

• Methyl salicylate is a volatile liqiud derivate. (Counter irritant)

• Irreversible inhibitor of COX

• Nonselective inhibitor of COX

 Aspirin – Pharmacological actions

1. Antiinflammatory action:
 Potent
 Exerted at high doses (3-6g/day or
100mg/kg/day)
 Signs of inflammation are suppressed
 Acts mainly by inhibiting PG synthesis
 Aspirin – Pharmacological actions

2. Analgesic action:

• Mild analgesic effect

≤ codeine
• Effective in non -
visceral pain
• Inhibition of
peripheral PG
synthesis
 Aspirin – Pharmacological actions
3. Antipyretic action:
• Reduces body temperature in fever
• Resets the hypothalamic thermostat
• Rapidly reduces fever by heat loss
• But does not decrease heat production
4. Metabolic effects:
• These are significant at only at antiinflammatory
doses
• ↑ Cellular metabolism
• increased heat production
• ↑ Utilization of glucose
 Aspirin – Pharmacological actions
3. Respiration:
• Stimulated at therapeutic doses by peripheral and
central actions
• Hyperventilation is prominent in salicylate poisoning
• Further raise causes respiratory depression and death
due to respiratory failure
4. Acid -base and electrolyte balance:
• Significant changes at antiinflammatory doses
• Hypokalemia, Respiratory alkalosis(400µg-
500µgstimulation of respiratory centre inc. pO2),
compensated respiratory alkalosis(most pts), respiratory
acidosis(higher doses500µg to 1mg medullary
depress,inc.pCO2 ), uncompensated metabolic
acidosis(poisoning) and dehydration(poisoning).
 Aspirin – Pharmacological actions
5. CVS:
• No direct effect in therapeutic doses
• Larger doses increase Cardiac Output (3g)
• Toxic doses depress VMC

6. GIT:
• Irritate gastric mucosa and cause epigastric distress,
nausea and vomiting pH 7.1
• Also stimulates CTZ pH 1.5
A
Gastric
mucosal cell
• “Ion trapping” s
p Asp
• Heart burn, dyspepsia, gers.astritis, erosion,
Acid
Gastric ulcers.
 Aspirin – Pharmacological actions

7. Effect on platelets/coagulation:
• TXA2 enhances platelet aggregation
• PGI2 decreases it
• Low doses(80-100mg/day) An anticoagulant effect with
a prolonged BT
 Aspirin – Pharmacological actions

8. Urate excretion:
• Dose related effect is seen
• <2gm/day- urate retention and antagonism of all other
uricosuric drugs
• 2-5gm/day- variable effects, often no change
• >5gm/day- increased urate excretion
• Not suitable in chronic gout- high doses are not
tolerated
 Aspirin – Pharmacological actions

9. Local irritant effect:

• Cause irritating to the skin & mucosa and destroys
epithelical cells
• Keratolytic effects

10. Endocrine effect:

• Large dose stimulate adrenal cortex by hypothalamus
inc adrenocortico steroid production
• L.Dose dec. thyroid uptake of iron cause goitre.
 Aspirin – Pharmacokinetics

• Well absorbed
• Poor water solubility is the limiting factor
• Solubility is more at higher pH
• Rapidly deacetylated in the gut wall, liver, plasma and
other tissues to salicylic acid
• 80% bound to proteins
• Vd=0.17L/kg
• Slowly enters the brain but freely crosses placenta
 Aspirin – Pharmacokinetics
• Conjugated in the liver by glycine and glucuronic acid
• Excreted by glomerular filtration as well as tubular
secretion
• t1/2 of aspirin as such is 15-20min
• Together that released salicylic acid is 3-5hrs
• Metabolic processes get saturated over therapeutic
range
• t1/2 of antiinflammatory doses may be 8-12hrs
• While that during poisoning may be upto 30hrs
• Thus elimination is dose dependant
 Aspirin – Adverse effects
a) Gastrointestinal:
• Most common
• Epigastric distress, Nausea, Vomiting
• Increased occult blood loss in stools
• Gastric mucosal damage and peptic ulcer
b) Rey‟s syndrome
• Occurs in infants and children
• Occurs when aspirin given during viral infections
• Characterized by liver damage and encephalopathy
• Replaced by acetaminophen in such condition to
reduce fever
 Aspirin – Adverse effects
c) Hypersensitivity:
• Though infrequent, these can be serious
• Reactions include; rashes, urticaria, angioedema,
rhinorrhoea, asthma and anaphylactoid shock

d) Salicylism
• High doses(at antiinflammatory doses) or chronic use
of aspirin may induce a syndrome characterised by
tinnitus, hearing defects, blurring of vision, dizziness,
headache and mental confusion
• Effects are reversible
Aspirin – Adverse effects
 Aspirin – Adverse effects
e) Acute salicylate poisonig:
• More common in children
• Fatal dose in adults estimated to be 15-30gm, but
considerably low in children
• Serious toxicities seen at serum levels >50mg/dl
Manifestations are:
 vomiting, dehydration, electrolyte imbalance, acidotic breathing,
hyper/hypoglycemia, petecheal hemorrhages, restlessness,
delirium, hallucinations, hyperpyrexia, convulsions, coma and
death due to respiratory and cardiovascular failure
 Aspirin – Adverse effects

Treatment:

• Symptomatic and supportive

• Gastric lavage
• i.v. infusion of Na+, K+, HCO3 and glucose(dextrose-5%)
• Vitamin K 10mg i.v.
• Peritoneal dialysis or hemodialysis
contraindications
Aspirin – Contraindications

• Peptic ulcer

• Ulcerative colitis

• Gout

• Renal failure

• Patients hypersensitive to salicylates

• Hemophilias
DrugAspirin – Drug interactions
interactions
Uses Aspirin – Uses

1. As analgesic
2. As antipyretic
3. Antiinflammatory
i. Acute rheumatic fever
ii. Rheumatoid arthritis
iii. Osteoarthritis
4. Cardio protective
 Aspirin – Doses(oral)

• As analgesic and antipyretic:

 0.3-0.6gm, 6-8 hourly
• Acute rheumatic fever:
 75-100mg/kg/day in divided doses/4-6 days
 50mg/kg/day/2-3wks- maintenance dose
• Rheumatoid arthritis:
 3-5gm/day
• Cardio protective:
 80-100mg/day
 Other clinically used Salicylates
a) Sodium salicylate:
• Aspirin alternative in rheumatic fever
• But now is obsolete
b) Methylsalicylate (Topical):
• Used topically as a counterirritant in muscle and joint
pain, in the form of liniments and ointments
• Systemic absorption can lead to toxicity
c) Salicylic acid (Topical):
• Used as keratolytic and corn remover
• Combined with benzoic acid (Whitefield ointment) for
local use in epidermophytosis
 Pyrazolone Derivatives
These are:
• Aminopyrine and antipyrine
• Phenylbutazone and oxyphenbutazone
• Analgin (dipyrone)
Phenylbutazone:
• Potent antiinflammatory drug
• Poorly tolerated by many patients
• Causes GI, hepatic, renal and fatal hematologic,
agranulocytosis toxic effects
• Gives rise to various drug interactions
• Hence now it is rarely used
 Pyrazolone Derivatives Cont…

Oxyphenbutazone:
• Metabolic degradation product of phenylbutazone
• Less gastric irritation than phenylbutazone
• It shares all toxic effects of phenylbutazone
Analgin (Dipyrone, Novalgin):
• Has potent analgesic antipyretic but no antiinflammatory
actions
• Has no advantage over aspirin
• Toxic effects are similar to phenylbutazone
 Indole Derivatives
Indomethacin:
• Potent antiinflammatory agent
• Has antipyretic, analgesic and anti-inflammatory actions
• Effective in gout, rheumatoid arthritis, ankylosing spondylitis
and osteoarthritis.
• Given orally, absorbed well
• Mainly metabolized by liver and excreted by kidneys
• Its action is more prolonged than its t1/2
• Headache is the most common adverse effect, followed by giddiness,
mental confusion, blurring of vision, depression and psychotic
disturbances.
• Total daily dose is 50-150mg in divided doses (Indomethacin 25mg cap)
after food.
 Indole Derivatives Cont..

Tocolytic agent: As effective as MgSo4

It dec. preterm birth significantly by arresting
premature uterine contractions
Dose; 25mg 2-3 times a day.
Sulindac:

• Fluorinated derivative of indomethacin

• It is a prodrug and has a longer duration of action
• Given orally in the dose of 100-200mg twice a day
 Propionic acid Derivatives
These are:
Ibuprofen, naproxen, flurbiprofen and ketoprofen
• Analgesic, antipyretic and anti-inflammatory properties
similar to Aspirin
• Better tolerated orally
• Adverse effects are lower than aspirin and indomethacin
• Highly bound to plasma proteins (92-99%)
• ADR: cause GI disturbances such as epigastric
pain, nausea, sensation of fullness in the stomach and
heartburn
• Less frequently they may cause CNS symptoms
 Anthranilic acid Derivatives (Fenamates)
Mefenamic acid:
• Useful in chronic and dull aching pains
• No advantages over other NSAIDs
• Weaker analgesic than aspirin
• Adverse reactions include gastric upset, diarrhoea,
dizziness, headache, skin rashes, hemolytic anemia
• Dose is 500mg 2-3 times a day
• Used in Dysmenorrhoea
 Arylacetic acid Derivatives
Diclofenac:

• Probably has greater activity than other NSAIDs

• Extensively bound to plasma proteins, t1/2 is 1-2hrs
• Accumulates in the synovial fluid- probably responsible
for its longer duration of action than its t1/2
• Incidence of adverse reactions is 20%
• Adverse effects similar to propionic acid
derivatives+elevation of liver enzymes
 Oxicam Derivatives

Piroxicam:

• Structurally different from other NSAIDs

• Given orally, well absorbed, has long t1/2 (38-45hrs) –
administered OD
• Commonly causes GI and CNS disturbances
• Has been used to treat rheumatoid arthritis, ankylosing
spondylitis, osteoarthritis and acute gout
• Has no advantages except a longer duration of action
 Pyrollo pyrollo Derivatives
Ketorolac:
• Has less antiinflammatory activity
• IM. 20-30mg (single dose) is a moderately effective
analgesic in patients with moderate to severe
postoperative pain
• IV ketorolac has been as effective as, and have fewer
side effects than morphine in surgical and chronic cancer
pain
• Has longer duration of action (t1/2 5hrs)
• Metabolised in liver and excreted by kidneys
 Para aminophenol Derivatives
• The commonly used drug is Paracetamol
(Acetaminophen)
• Potent antipyretic and equianalgesic with aspirin in
therapeutic doses but devoid of significant
antiinflammatory effect
• Does not produce gastric irritation, acid –base
imbalance, electrolyte disturbances nor does it affect
blood clotting
• Hence is preferred to aspirin as an analgesic antipyretic
• Absorption, fate and excretion:
• Rapidly absorbed on oral administration
• Peak plasma levels are reached within ½ an hour to
1hour
 Para aminophenol Derivatives Cont..

• Metabolised in the liver and excreted in urine as

conjugation products of glucuronic and sulfuric acids
• Poor metabolism in infants- enhanced toxicity

Adverse effects:
• At recommended therapeutic doses (500-1000mg) in
healthy subjects is well tolerated
Hepatic and renal toxicity:
• Larger doses (7-10gm) produce extensive hepatocellular
damage and renal tubular necrosis, and may cause
death
 Para aminophenol Derivatives Cont..

• This is a major problem in paracetamol poisoning

• Liver toxicity is due to N-acetyl-P- benzoquinone imine
which normally turns harmless by conjugation with
glutathione
• Early manifestations are just nausea, vomiting,
abdominal pain and live tenderness with no impairment
of consciousness
• After 12-18hrs centrilobular hepatic necrosis occurs
which may be accompanied by renal tubular necrosis
and hypoglycemia that may progress to coma
 Para aminophenol Derivatives Cont..

paracetamol

Glutathione N-acetyl benzoquinone imine

In toxic doses
For normal Oxidation of SH group
therapeutic doses Of hepatic and renal
Treatment
Cell proteins
Glutathione
Glutathione conjugate Methionine or Cell proteins get covalently
of toxic metabolite N-acetylcysteine Bound to toxic metabolite
(non toxic, excreted) Conjugates of toxic →cell death
metabolite
 Para aminophenol Derivatives Cont..

Treatment:
• Patient is brought early (within 16hrs of ingestion)
• Vomiting should be induced or gastric lavage done
• Activated charcoal is given orally or through tube to
prevent further absorption
• Other supportive measures, as needed, should be taken

Specific:
• N- acetylcysteine 150mg/kg should be infused i.v. over
15min, followed by the same dose i.v. over next 20hrs
 Benzoxazocine Derivatives
Nefopam:
• Different from other NSAIDs since it has atropin like
actions
• Effective in traumatic and post operative pain, and in
musculoskeletal pain not responding to other NSAIDs
• Atropine like adverse effects
• Contraindicated in epilepsy
 Pref COX-2 inhibitors
These are:
Nimesulide, Meloxicam, Nabumatone
Nimesulide:
• Relative weak PGs inhibitor with COX-2 selective action
• Other mechanisms implicated are reduced superoxide
generation by neutrophils, inhibition of PAF synthesis
and free radical scavenging action
• Gastric and other adverse effects are similar to other
NSAIDs
 Has been reported to cause nephrotoxicity and hepatotoxicity
 Not licensed in some developed countries
 And it has been withdrawn from others
 Use should be avoided especially in children and old persons
 Selective COX-2 Inhibitors
• Selectively block COX-2 activity more than COX-1
activity
• Less action on stomach, blood vessels and kidneys
This group includes:
Celecoxib, Rofecoxib and Valdecoxib
• Given orally, absorption is complete
• Established analgesic- antiinflammatory NSAIDs
• They have to be shown effective in treatment of
osteoarthritis and rheumatoid arthritis
• Their major advantage is that they cause fewer gastric
ulcers and do not inhibit platelet aggregation
• Stomach friendly
 Selective COX-2 Inhibitors Cont..

Adverse effects:
• The most common adverse effects are nausea, vomiting,
dyspepsia, abdominal pain, diarrhoea and edema of the
lower extremities
• Share some of the renal adverse effects of non selective
COX inhibitors and renal toxicity
• Hence their use should be restricted to patients who do
not tolerate other NSAIDs
 Selective COX-2 Inhibitors Cont..

 Recently, the use of rofecoxib and valdecoxib has

been reported to be associated with increased incidence
of MI and stroke
 Hence, they have been withdrawn by the original
manufacturers
 Currently all the selective COX -2 inhibitors are under
suspicion regarding their long term toxicity
 They have been described as drugs with “marginal
efficacy, heighted risk and excessive cost compared with
traditional NSAIDs”
 Topical NSAIDs
• Diclofenac 1% gel
• Ibuprofen 10% gel
• Naproxen 10% gel
• Ketoprofen 2.5% gel
• Flurbiprofen 5% gel
• Nimesulide 1% gel
• Piroxicam 0.5% gel
Thank you