NSAIDS

Dr.B.M.PUROHIT
Assistant Professor (Pharmacology)
P.D.U.MEDICAL COLLEGE,
Rajkot (GUJARAT). 360001
purohitbhargav@rediffmail.com
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Objective is not to bombard information but
to develop concepts.
So.. Get ready to chat !!
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 INTRODUCTION
NSAIDs means.. Non Steroidal Anti Inflammatory Drugs
If you want to study ANTI INFLAMMATORY drugs , you should know
What is inflammation ?...
Response of the body to injurious stimuli
So it is beneficial.
Than why it is required to be suppressed ?
Because at times it can be in EXAGGERATED form and can be.
Harmful to body
Extremely disturbing to the patient

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 Which are the features of
inflammation ?
1. Heat/fever
2. Swelling
3. Pain
4. Redness
5. Loss of function

NSAIDS addresses mainly FEVER, PAIN AND SWELLING.

Redness is not a problem from functional point of view.
Loss of function is usually restored when FEVER , PAIN and SWELLING are
taken care of if it is due to those features..
Loss of function because of permanent fibrosis can not be reversed.

IN ONE WAY, fever and pain are beneficial .. HOW ?

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So both phenomenon
are beneficial

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 But when these reflexes are EXAGGERATED it is
required to be suppressed because
RAISED TEMPERATURE .
May make a person incapable for doing his job.
May inactivate several enzymes required to
maintain normal metabolism.
In extreme casesinterfere with the state of
consciousness.
EXCESSIVE PAIN
May interfere with the quality of life.
May frighten the patient.
In extreme cases may produce shock
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 We will study both pathways
Now get ready for a LONG CHAIN OF
CHEMICAL REACTIONS
This chemical reactions are IMPORTANT..
Products of this pathway PRODUCE
NUMEROUS ACTIONS.
They are the sites of pharmacological
intervention.
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 MEMBRANE PHOSPHOLIPID
PHOSPHOLIPASE

ARACHIDONIC ACID CHEMICAL AND

CYCLOXYGENASE MECHANICAL
PATHWAY LIPOXYGENASE STIMULIE
PATHWAY

PGG2 12-HPETE 15-HPETE 5-HPETE

LTA4
PGH2

LTB4 LTC4
ISOMERASE THROMBOXANE PROSTACYCLINE
SYNTHEASE SYNTHEASE LTD4

TXA2 PGI2
PGD2 PGE2 PGF2 LTF4 LTE4
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TXB2
 Was it frightening. ?
DEFINATETLY NEED A REVISION.. RIGHT ?

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 MEMBRANE PHOSPHOLIPID
PHOSPHOLIPASE

ARACHIDONIC ACID CHEMICAL AND

CYCLOXYGENASE MECHANICAL
PATHWAY LIPOXYGENASE STIMULIE
PATHWAY

PGG2 12-HPETE 15-HPETE 5-HPETE

LTA4
PGH2

LTB4 LTC4
ISOMERASE THROMBOXANE PROSTACYCLINE
SYNTHEASE SYNTHEASE LTD4

TXA2 PGI2
PGD2 PGE2 PGF2 LTF4 LTE4
13
TXB2
 Summary of the chart
Cycloxygenase pathway generates
TXA2.
PGD2
PGE2
PGF2
PGI2.
How to remember it ?
Alphabetical order is DEFGH
Here first G & H and then D E F.
Lipoxygenase pathway generates
12 HPETE through 12-lipoxygenase
15 HPETE through 15-lipoxygenase
5-HETE through 5-Lipoxygenase
5-HETE subsequently produces
LTA4 LTB4
LTA4 LTC4 LTD4 LTE4

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 So that was CHEMISTRY part of
inflammation
Now their FUNCTIONAL part.
There are so many mediators of
inflammation..
Which causes numerous effects.

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They are
Opposite !!!
Store it in
your mind !!!

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 It is not
possible to
remember
everything !!
Dont worry !!

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 Its not possible to remember ALL THE EFFECTS
of ALL THE MEDIATORS.
Just try to remember the NAMES OF
MEDIATORS and
MAJOR EFFECT produced by it.

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 PAIN
Unpleasant experience
Protective reflex
Warning bell of tissue damage !!
Interferes with Quality Of Life.
Two components
Sensations peripheral component
Perception central component

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 CLASSIFICATION
Superficial or cutaneus pain
Deep pain from muscle,joints,ligaments and
bones.
Visceral pain-(spasm,infla.,ischemia,stim. Of
nerve endings)
Deafferentiation pain /neuropathic pain-
(damage to axons or nerve membranes)
Psychological/Functional
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 Now move ahead for PAIN PATHWAY
1ST Slide shows afferent pathway. ( periphery to
centre).
2nd Slide shows efferent pathway.(centre to
periphery).
Again you are not expected to remember it, but you
should have an idea about nuts and bolts of pain
circuits.

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 SOMATIC SENSORY
CORTEX
`

Amygdala Hypothalamus

Anterolateral
Midbrain periaqueductal gray matter
System

Parabrachial Medullary
nucleus Locus
Reticular Raphe nuclei
cerulous
formation

Dorsal horn of the spinal cord

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 Prostaglandins (PGS) sensitize the nerve
endings.
To the nociceptive stimuli .
Caused by .
Histamine and
Bradykinin.

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Pharmacological/Physiological Effects
I. Cardiovascular System

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II. PLATELETS

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NSAIDS
NORMALLY IN GIT So PGS have
PROTECTIVE
blocks effect on GIT
this

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RESPIRATORY SYSTEM

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GI TRACT

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V. Reproductive Organs

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 Pharmacological/Physiological Effects

VI. Pain and Inflammation

1. PGE2, PGI2, LTB4: sensitize nerve endings to painful
stimuli.
2. Hyperemia, Edema, Hotness due to increased
eicosanoids at inflammation sites.
3. LTB4: chemotactic factor for neutrophils and
mononuclear cells. Promotes aggregation and
degranulation of PMNs, adhesion to vessel wall and
migration

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PGS produce PAIN how ?

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 PGS produces FEVER.. How ?
Hypothalamus contains thermoregulatory centre
Maintains balance between heat production and heat

loss
It regulates heat dissipating mechanisms

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34
PGs PRODUCES INFLAMMATION
HOW ?

INFLAMMATION

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Mechanism Of Action : NSAIDS
MOST
IMPORTANT
MECHANISM

Efficacy of these
mechanisms is
doubtful..
So you are not
required to
remember
everything!! Just
keep in mind that
such mechanisms
exist !!

36
 COX-1 COX-2
Physiologically expressed Induced in pathological
Maintains the normal states (mostly)
(house keeping) function. Physiologically expressed in
Expressed in .. kidney.
Platelets
GIT So NON SPECIFIC
NSAIDS
produces
bleeding
tendency and
peptiuc ulcer

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SALICYLATES

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 Analgesic activity

No impairment of mental activity. No hypnosis

Major component peripheral action

Minor component central action

Can be combined with opioids

ONLY NSAID THAT BLOCKS THE COX ENZYME IRRERVERSIBLY

NSAIDS suppresses the pain arising out of bones and joints

exception DYSMENORRHEA 41
 REDUCES THE
INTENSITY OF
PAIN

NSAIDS
blocks..

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 ANTIPYRETIC ACTIVITY
Hypothalamus contains thermoregulatory centre
Maintains balance between heat production and heat

loss
It regulates heat dissipating mechanisms

Reduces fever due to inflammation. But not due to

1.Heat stroke NSAIDS inhibits
2.Exercise induced/Physiological diurnal variation in PGE2 synthesis and
temperature reduces fever 43
 GIT

So Use aspirin with

Plenty of water or after food
Milk
Alkali
Soluble of buffered aspirin
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 ANTIINFLAMMATORY ACTIVITY
Decrease PG in peripheral tissue
Reduce capillary permeability
Inhibition of neutrophil aggregation and
activation
Inhibition of activated kallikrein from inactive
plasma and leucocyte kallikrein.
Inhibite mucopolysaccheride biosynthesis
reduce edema.
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 BLOOD AND PLATELETS
Antiplatelet action
Irreversibe COX inhibition
75-150 mg OD
Platelet activity starts after 7-10 days when
new platelets are synthesized.
IN RHEU. FEVER aspirin reduces WBC count
and ESR.
Decrease fibrinogen level
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 URICOSURIC ACTION
Urate present in glomerular filtrate is reabsorbed by proximal
tubule
Excretion occurs because of tubular secretion.

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 PHARMACOKINETICS
ABSORPTION :
Skin
GIT
Particle size
pH
Solubility of salicylate preparation
Presence of food
DISTRIBUTION:
80% Albumin
Achieves significant concentration in saliva,milk,spinal,synovial fluid, peritoneal fluid
and in RBCs.
HIGH AMOUNT liver, heart and muscle So little central action.
SMALL AMOUNT brain.

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 PHARMACOKINETICS
Metabolism
Aspirin Deacetyl Salicylate
ation

Salicylic acid

300-600 mg dose : 1st order kinetics

1-2 gm dose : zero order kinetics toxicity

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 PHARMACOKINETICS
EXCRETION :
Salicylate

Glycine Oxidized to
Glucuronic
conjugation Gentisic acid
acid
conjugation

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 ADVERSE REACTION
INTOLERANCE :
HS reaction.
Angioedema & anaphylactic symptoms adrenalin
G6PD deficiency hemolytic anaemia

Cell Membrane Phospholipids

Phospholipase A2
NSAIDS

Arachidonic Acid

Cyclooxygenase I&II

Leucotriens
Prostaglandin H2

Inflammation Bronchospasm 51
52
GIT

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KIDNEY

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REYES SYNDROME

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Aspirin Toxicity - Salicylism

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 MANAGEMENT OF SALICYLISM
Hospitalization
Gastric lavage
Rx of
Hyperthermia
Dehydration
Hypokalamia
Acid base disturbances
Ketosis
Alkalization
Vit,K, BLOOD TRANSFUSION
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 USES
LOCAL APPLICATION
Keratolytic
Fungistatic
Antiseptic
Counter irritant
IBS

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 ANALGESIC
Musculoskeletal pain
Dysmenorrhea
ANTIPYRETIC
Remember, it reduces fever due to inflammation but
not due to .?????
ANTIINFLAMMATORY
Arthritis
Fibromyositis
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ANTIRHEUMATIC

Antirheumatic action

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61
 ANTIPLATELET ACTION
Platelets aggregates and provides the nidus for thrombus formation.

prevented by PGI2 in circulation and

Platelet aggregation is

promoted by TXA2.
Inhibition of TXA2 by Aspirin at LOWER DOSES
(75-150 mg) reduce platelet aggregation.
Platelet TXA2 remains irreversibly inhibited
Only when new platelets are synthesized , platelet activity restarts
(approx. 7-10 days)
Stop aspirin one week prior to surgery.
Useful in ..thromboembolic disorders ( MI, TIA, Ischemic stroke, atherosclerotic PVDs)
Avoid aspirin in ..Liver damage Hypo prothombinemia Vit. K deficiency Haemophilia

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 PDA :
PG mediadted
IV administration of 0.1 to 0.2 mg/kg every 12 hours for three doses.
70% success..
Primarily in premature infants who weigh between 500 and 1750 g,
Who have a hemodynamically significant patent ductus arteriosus, and
In whom other supportive maneuvers have been attempted.
Several food allergy
PG mediadted
Radiation induced diarrhoea
PGmediadted
Local application in sunburn PG mediadted

Systemic mastocytosis
Use with antihistaminics
C0lon carcinoma
Familial adenomatous polyposis (fap)
Pgs involved in carcinogenesis
Inhibits angiogenesis
Dysmenorrhoea :
Increase d PG in menstrual blood uterine cramps.
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 NOW ITS TIME TO REVISE
What is inflammation ?
Why it is required to be suppressed >?
How PAIN and FEVER and beneficial and how they are harmful ?
Following injury which chemical reactions are set off ?
What are the effects of PGD2,PGE2,PGF2, PGI2, TXA2, LTA4 ?
How will you classify pain ?
Do your remember pain pathway ? If yes good if no its ok.
What is the effect of different mediators on I.blood vessels, II. platelets, III. GIT, IV. respiratory system
and V. reproductive system ?
How PGS produces PAIN, FEVER and INFLAMMATION ?
Which are the mechanisms of action of NSAIDS ?
Which are the local actions of NSAIDS ?
How NSAIDS produces ANALGESIC, ANTIPYRETIC and ANTIINFLAMMATORY actions ?
How it produces anti platelet action ?
What is the effect of aspirin on urate levels ?
Which are the main ADRs of NSAIDS ? What are the pharmacological basis of the same ?
How they produces reye s syndrome ?
What is salicylism ? How will you treat it ?
Which are the uses of aspirin ? Which are the pharmacological basis of the same ?

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 Diflunisal
Cancer pain with bone metastases
For pain control in dental (third molar)
surgery.
2% diflunisal oral ointment is a clinically useful
analgesic for painful oral lesions.

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 PARACETAMOL
Analgesic
Antipyretic
Central action> Peripheral action
1015 mg/kg every 4 hours (maximum of 5 doses/24 hours)
NO
GI disturbances Acid-base imbalance Electrolyte imbalance
Impairment of clotting
ADR :
Extremely safe drug. But rarely produces . Hepatic toxicity

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Paracetamol overdose
Ingestion of >10g of paracetamol may be fatal
May be lower in chronic alcoholics or subjects with
underlying liver disease.
Clinical features
In severe poisoning
Up to 24 hours - none or nausea and vomiting
> 24 hours - nausea and vomiting, right upper
quadrant pain, jaundice, encephalopathy

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 NAC SUPPLIES MAY BE NAC
NAC MAYdirectly GLUTATHIONES has additional
conjugates with so detoxifies antioxidant and
quinones/epoxide. toxic antiinflammato
metabolites !! ry activity
 PARACETAMOL
(acetaminophen)
Management
Repeat blood paracetamol estimatations.

69
 Now we will discuss all the remaining NSAIDs..
Their
MOA,
ADR,
USES
are more or less same.
So we will only discuss differentiating points.
Or something UNIQUE about that particular drug.
You are not required to remember ALL THE DETAILS of ALL THE DRUGS.
This list has been added only so that . Presentation does not look
incomplete !!!! ????

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 PHENYLBUTAZONE & OXYPHENBUTAZONE
Now almost obsolated
ANALGIN :
Fatal blood dyscrasias
DICLOFENAC SODIUM:
Neutrophil chomotaxis and superoxide production is reduced
Hepatotoxicity more common than other NSAIDS.
Eye drops/Gel for solar keratosis (3%)/Rectal suppository for post op.
analgesia/Oral mouthwash/IM injection
ACECLOFENAC
More GI friendly
Some what selective on COX-2.
Enhancement of glycosaminoglycan synthesis chondroprotective
property.
MELOXICAM
Preferential COX-2 inhibitor

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 ETODOLAC
Postoperative pain relief after coronary artery bypass operations
IBUPROFEN
Oral
Topical cream preparation -primary knee osteoarthritis
Patent ductus arteriosus in preterm infants
FENOPROFEN
The NSAID most closely associated with interstitial nephritis
FLURBIPROFEN
Also affect TNF-a and nitric oxide synthesis??
200-400 mg/d
Ophthalmic formulation for inhibition of intraoperative miosis
Flurbiprofen intravenously has been found to be effective for perioperative
analgesia in minor ear, neck, and nose surgery and in lozenge form for sore throat.

Rarely with cogwheel rigidity, ataxia, tremor, and myoclonus

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 PIROXICAM
A nonselective COX inhibitor that at high concentrations also inhibits polymorphonuclear leukocyte
migration, decreases oxygen radical production, and inhibits lymphocyte function.
Decreases the production of IgM rheumatoid factor.
USES :
Same
TENOXICAM
SAME .
INDOMETHACIN
PDA 0.1-0.2 mg/kg /12 hr X 3 times.
Ophthalmic preparation -- conjunctival inflammation reduce pain after traumatic corneal
abrasion
Gingival inflammation is reduced after administration of indomethacin oral rinse.
Malignancy induced fever.
frontal headache & other CNS side effects. C/I in psychiatric illness or epilepsy.
HYPERKALAMIA
KETOROLAC
Replace morphine in some situations involving mild to moderate postsurgical pain.
ORAL/IM/IV/EYE DROP

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 NABUMETONE
Pseudoporphyria and photosensitivity
NAPROXEN
Oral suspension/SR preperation/Eye drops
SULINDAC :
Suppresses familial intestinal polyposis
It may inhibit the development of colon, breast, and prostate cancer
Sulfa like reaction
NIMESULIDE
Weak PG synthesis inhibitor. Relative COX-2 inhibitor
Other mechanisms like
inhibition of neutrophil activation
Reduced generation of superoxide
Inhibition of PAF synthesis & TNF release.
Free radicle scavanging
Inhibition of metalloproteinase activity.
possibly activation of glucocorticoid receptors???
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 SELECTIVE COX-2 INHIBITORS
CELECOXIB
ROFECOXIB BANNED BECAUSE OF
CARDIOVASCULAR MORATLITY
VALDECOXIB
ETOROCOXIB
LUMERACOXIB
PARACOXIB only selective COX-2 inhibitor for
parental use.

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 Advantages Disadvantage
Increases cardio vascular
No ADR like mortality because of
GI ulceration inhibition of endothelial PGI2
Bleeding tendency production without effect on
platelet TXA2 synthesis.
??Incomplete suppression of
inflammation.
COX-2 is constitutively
expressed in kidney so
nephrotoxicity can not be
avoided. Na+ and Water
retention,edema,HT,CHF may
be ppted.

76
 CELECOXIB
GI friendly
Sulfalike reaction
Edema and HT
ETOROCOXIB
Maximum COX2: COX 1 activity ration
OA 60 mg OD
RA - 90 mg OD
Acute gouty arthritis 120 mg OD
Acute musculoskeletal pain- 60 mg OD
ADR :
Dry mouth
Aphthous ulcer
Taste disturbnaces
Paraesthesia
Lumiracoxib :
Its acidic nature allows it to penetrate well into areas of inflammation
The half-life in synovial fluid is considerably longer than in plasma.
Once-daily dosing.
900-mg dose.
Cardiovascular safety questionable.
Gi safety promised

77
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 TOPICAL NSAIDS
Used for RA,OA,musculoskeletal pain,Soft Tissue Injury etc.
Advantage (???):
??? High local levels????? may be better therapeutic efficacy.
Low systemic levels GI safety.
DILEMMA , whether the effect is .
Due to drug ?
Due to placebo ?
Due to irritant present in ointments ?
Due to concomitant oral NSAID?
EVIDENCES AVAILABLE SO FAR .
Slow topical absorption (~10 times than oral)
Highest blood levels remains 15% below the same dose given orally.
Upto 4-6 mm( Dermis) high concentraion.
At 25 mm (muscle ) concentration is low and same as blood.
MARKED INTERINDIVIDUAL VARIATION( 18-92%)
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Selection of NSAID

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