NSAIDS

Dr. Masoom Akhtar Ph.D

• This is not a LECTURE……………this is a
discussion… sadly … not live !!!
• Objective is not to bombard information but
to develop concepts….
• So.. Get ready to chat !!
 VARIFY THAT
NOW CLICK TO
YOU
READ THINK UNDERSTAND REMEMBER MOVE AHEAD
REMEMBER
TO NEXT STEP
COMPLETELY

!!! GO SLOW !! Best luck !!!

 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

4
 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 ?

5
 So both phenomenon
are beneficial

Infection occurs TISSUE DAMAGE OCCUR

Fever develops
Pain nerve endings are stimulated

Raised temperature kills microbes

Person feels pain
Gets idea about tissue damage and
INFECTION CLEARS !!!! tries to remove the source of injury
which would have otherwise ignored.

6
• 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 cases…interfere with the state of
consciousness.
• EXCESSIVE PAIN …
– May interfere with the quality of life.
– May frighten the patient.
– In extreme cases …may produce shock …
7
 Injury/infection/trauma

Attacks the cell membrane of the cell

Cell membrane contains phospholipids

Activation of phospholipase occurs

It causes formation of arachidonic acid

Arachidonic acid is further metabolized by….

Cycloxygenase pathway Lipoxygenase pathway 8

• 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.
9
 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 PGF2α LTF4 LTE4
10
TXB2
• Was it frightening…. ?
• DEFINATETLY NEED A REVISION…….. RIGHT ?

11
 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 PGF2α LTF4 LTE4
12
TXB2
 Summary of the chart…
• Cycloxygenase pathway generates …
– TXA2.
– PGD2
– PGE2
– PGF2α
– 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 13
• So that was CHEMISTRY part of
inflammation…
• Now their FUNCTIONAL part….
• There are so many mediators of
inflammation..
• Which causes numerous effects….

14
 • vasodilatation
PGD2

• Affect the hypothalamus temperature regulating system produces fever

PGE2 • Increases water electrolytes and mucus secretion in GIT.

• Produces contraction of uterine smooth muscles.

PGF2α

• Vasodilatation and inhibition of platelet aggregation. They are

PGI2
Opposite !!!
Store it in
your mind !!!
• Vasoconstriction and stimulates platelet aggregation
TXA2

• Bronchoconstriction
LTC4 AND • Increased capillary permeability
LTD4

15
 OTHER CHEMICAL
MEDIATORS
PAF Histamine Bradykinin 5-HT Others
• VD • Contraction • Stimulates • Vascular • Kaillidine
• Platelet of venules nociceptors response • Lactic acid
aggregation • Relaxation of • H release • Pain • ATP
• Leucocyte arterioles • Platelet • ADP
infiltration • Increased aggregation
• Degranulation capillary
of leuco. permeability
It is not possible
to remember
everything !!
Don’t worry !!

16
• 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.

17
 PAIN
• Unpleasant experience
• Protective reflex
– Warning bell of tissue damage !!
• Interferes with Quality Of Life.
• Two components
– Sensations  peripheral component
– Perception  central component

18
 CLASSIFICATION
• Superficial or coetaneous pain
• Deep pain from muscle, joints, ligaments and
bones.
• Visceral pain-(spasm, infla., ischemia, stim. Of
nerve endings)
• Defferentiation pain /neuropathic pain-
(damage to axons or nerve membranes)
• Psychological/Functional
19
• 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.

20
 Physical/chemical stimuli

Transmission from Nerve fibres

Tectile sensations from L fibers Pain from S fibers

Reaches spinal cord (DRG)

1st transmission cells Collateral cells in Subst.Gelatinosa

SG inhibits the upwards propagation

When strong stimuli SG cells are inhibited HIGHER Out Put is released

20exons cross over to other site and form spinothalamic tract

Tract ends in thalamus

Relays fibres to
21
Sensory cortex Frontal lobes Hypothalamus Limbic system
 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

22
• Prostaglandins (PGS) sensitize the nerve
endings….
• To the nociceptive stimuli …….
• Caused by …….
• Histamine…… and
• Bradykinin.

23
Pharmacological/Physiological Effects
I. Cardiovascular System

TXA2:
vasoconstrictor.

PGE2 and PGI2:

vasodilators.

24
II. PLATELETS

TXA2 stimulates
platelet
aggregation

PGI2 inhibits
platelet
aggregation
25
 NORMALLY IN GIT… So PGS have
PROTECTIVE
NSAIDS effect on GIT
blocks this
PGI2 & PGE2

Inhibits acid Inhibits leucocyte- Inhibits the

Has cytoprotective
secretion & increase endothelial activation of
action
mucus production. interaction neutorphils

So interaction of
Protease and oxygen
leucocyte with
radicles
endothelial cells

Capillary obstruction Endothelial injury

Ischemic injury

Mucosal
ulceration

26
RESPIRATORY SYSTEM
LTC4 AND LTD4 produces
bronchoconstriction +
increased mucus secretion
+Increased vascular
permeability

PGI2 AND PGE2 produces

bronchodilatation..

27
GI TRACT
PGE2 + LT’s
contract
smooth
muscle

28
V. Reproductive Organs

PGE2: and
PGF2:
Both
contract
pregnant
uterus.

29
 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 PMN’s, adhesion to vessel wall and
migration

30
 PGS produce PAIN… how ?
PERIPHERALLY :
PGS sensitize the nerve
endings to bradykinin and
histamine

PAIN
CENTRALLY :
PGs Lower the threshold
for central pain circuits

31
 PGS produces FEVER….. How ?

• Hypothalamus contains thermoregulatory

centre

• Maintains balance
between heat
production and heat loss
• It regulates heat dissipating
mechanisms
32
 Hypothalamus
Normally
When temperatures activates heat losing
hypothalamus is So temperature is This set point it
is elevated beyond mechanisms like
adjusted to a set normalized elevated in FEVER
level sweating and
point
vasodilatation

PGE2 has two

When there is mechanisms :
tissue 1. Increases
Increased PGE2 Raised body
damage/inflam Neutrophil Stimulates COX- heat
synthesis in temperature 
ation/AG:AB releases IL-1 2 enzymes production.
hypothalamus FEVER
reaction/infecti 2.shuts down
on HEAT LOSING
MECHANISM

33
PGs PRODUCES INFLAMMATION …
HOW ?
Increased
capillary
perameabilit
y

INFLAMMATION

34
 Mechanism Of Action : NSAIDS
MOST
IMPORTANT
Inhibits the cycloxygenase MECHANISM

Enzyme & Reduce prostaglandin biosynthesis

Reduce production of superoxide radicals

Induce apoptosis Efficacy of these

mechanisms is
Inhibit the expression of adhesion molecules
doubtful..
So you are not
Decrease nitric oxide synthase,
required to
Decrease proinflammatory cytokines (e.g., TNF-, interleukin-1) remember
everything!! Just
Modify lymphocyte activity keep in mind that
such mechanisms
Alter cellular membrane functions. exist !!

Stabilize lysosomal enzymes

35
 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

36
 • Aspirin Diflunisal
Salicylates • Na.salicylate salicylamide
• Acetaminophen
Para-aminophenol
• Diclofenac
Phenyl Acetic acid • Ketorolac
• Piroxicam
Oxicams
• Phenylbutazone Oxyphenbutazone
Pyrazolone derivatives • Analgin Azapropazone
Propionic acid • Ibuprofen Ketoprofen Flurbiprofen
derivatives • Naproxen
• Mafenamic acid
Fenamates • Flufenamic acid
Preferential COX-2 • Nimesulide
inhibitors • Meloxicam Nebumatone
Selective COX-2 • Celecoxib Rofecoxib
37
inhibitors • Paracoxib Lumiracoxib Valdecoxib
38
 SALICYLATES

LOCAL ACTIONS

Irritants Keratolytic Antiseptic Fungistatic

39
 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 40
 REDUCES THE
PERIPHERALLY : INTENSITY OF
PGS sensitize PAIN
the nerve
endings to
bradykinin and
histamine

NSAIDS
blocks..
PAIN

CENTRALLY :
PGs Lower the
threshold for
central pain
circuits
41
 ANTIPYRETIC ACTIVITY
• Hypothalamus contains thermoregulatory centre
• Maintains balance between heat production and heat
loss
• It regulates heat dissipating mechanisms
PGE2 has two
mechanisms :
When there is
Increased 1. Increases
tissue Raised body
Neutrophil Stimulates PGE2 synthesis heat
damage/inflamati temperature
releases IL-1 COX-2 enzymes in production.
on/AG:AB  FEVER
hypothalamus 2.shuts down
reaction/infection
HEAT LOSING
MECHANISM

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 42
 GIT
ACIDIC pH keeps Aspirin nonionized
insoluble particles

Increases the contact

Local COX inhibition and decreased of salicylates with
PGs gastric mucosa and GI
irritaion

So Use aspirin with

Plenty of water or after food
Reduces motility of stomach Milk
Alkali
Soluble of buffered aspirin
43
 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.
44
 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
45
 URICOSURIC ACTION
• Urate present in glomerular filtrate is reabsorbed by proximal
tubule
• Excretion occurs because of tubular secretion.

SMALL DOSES (1-2 LARGE DOES

G/DAY) (>5G/DAY)
• Interefere with • Inhibit
urate secretion reabsorption
• Elevate urate level • Uricosuric action
• Blocks the action
of uricosuric drugs
46
 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.

47
 PHARMACOKINETICS
• Metabolism
Aspirin Deacetylation
Salicylate

Salicylic acid

• 300-600 mg dose : 1st order kinetics

• 1-2 gm dose : zero order kinetics  toxicity

48
 PHARMACOKINETICS
• EXCRETION :
Salicylate

Glycine Oxidized to
Glucuronic acid
conjugation Gentisic acid
conjugation

49
 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 50
 So increased
So AA
AA is production of SO… NSAIDS
metabolism is
metabolized NSAIDS blocks LTs which PRODUCES/AGG
channelized
by COX and LO COX pathway produces RAVATES
towards LO
pathways bronchoconstri BRONCHOSPASM
pathway
ction

51
 GIT

Hypopro
Local thrombi
mucosal nemia
irritation
Antiplate
let
action

GI BLEEDING

52
 KIDNEY

Impairment
of RBF and
Na & GFR
H2Oretention

Papillary
necrosis on
long term use

NEPHROTOXICITY
53
 REYE’S SYNDROME
Children < 12 years develops viral infection (influenza & vericella)

Administered aspirin

Anicteric liver dysfunction due to…..

Hepatic mitochondrial injury fatty infiltration of the liver Metabolic encephalopathy

??? Serious and fatal complications ???

So aspirin to be avoided in pts < 12 yrs except juvenile RA.

54
 Aspirin Toxicity - Salicylism

CV
&
H D RS
Headache
y r e
- timmitus
Confusion Sweating Marked p e h
t Collapse
- dizziness
and and Nausea, acid-base i
– hearing e x y Convulsio
drowzines hyperventi vomiting disturbanc o
impairmen r i d
s lation es
t – dim n ns
vision p a r
y a Coma &
Death

55
 MANAGEMENT OF SALICYLISM
• Hospitalization
• Gastric lavage
• Rx of
– Hyperthermia
– Dehydration
– Hypokalamia
– Acid base disturbances
– Ketosis
• Alkalization
• Vit,K, BLOOD TRANSFUSION 56
 USES
• LOCAL APPLICATION
– Keratolytic
– Fungistatic
– Antiseptic
– Counter irritant
– IBS

57
• ANALGESIC
– Musculoskeletal pain
– Dysmenorrhea
• ANTIPYRETIC
– Remember, it reduces fever due to inflammation
but not due to ….?????
• ANTIINFLAMMATORY
– Arthritis
– Fibromyositis
58
 ANTIRHEUMATIC

Decrease
activation
and function
of
neutrophils

Reduce edema, pain Stabilization of lyso.

and inflammation Antirheumatic action Membranes

Inhibits
mucopoly
saccheride
biosynthesis

59
 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

60
 NOW IT’S 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,PGF2α, PGI2, TXA2, LTA4 ?
• How will you classify pain ?
• Do your remember pain pathway ? If yes … good …if no … it’s 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 ?
61
 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.

62
 PARACETAMOL
• Analgesic
• Antipyretic
• Central action> Peripheral action
• 10–15 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

63
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
64
 When normal
dose of
paracetamol is
Minor amount of
taken major
highly reactive They combine Converted to
amount is NO Tissue damage
quinones/epoxide with Glutathione harmless products
metabolized by
s are formed
glucuronid e and
sulfate
conjucation
NAC SUPPLIES MAY BE… NAC
NAC “MAY”directly GLUTATHIONES has additional
conjugates with so detoxifies antioxidant and
quinones/epoxide. toxic antiinflammato
metabolites !! ry activity

Large number of
When large amount Toxic intermediates
highly reactive Glutathione supply
of drug is are formed within Tissue damage
quinones/epoxides falls short.
taken(poisoning) tissue constituents
are formed
 PARACETAMOL
(acetaminophen)
Management
• Repeat blood paracetamol estimatations.

Orally 5% solution of 70 mg/kg /4 hr x

(nasogastric tube) NAC 140 mg/kg 17 doses

150 mg/kg by 50 mg/kg by 100 mg/kg by

intravenous intravenous intravenous
intravenous
infusion in 100 ml infusion in 250 ml infusion in 500 ml
loading dose
of 5% dextrose of 5% dextrose of 5% dextrose
over 15 minutes over 4 hours over 16 hours

66
• 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 !!!! ????

67
• 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

68
• 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

69
• 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

70
• 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 α release.
– Free radicle scavanging
– Inhibition of metalloproteinase activity.
– possibly activation of glucocorticoid receptors???
71
 SELECTIVE COX-2 INHIBITORS
• CELECOXIB
• ROFECOXIB BANNED BECAUSE OF
CARDIOVASCULAR MORATLITY
• VALDECOXIB
• ETOROCOXIB
• LUMERACOXIB
• PARACOXIB– only selective COX-2 inhibitor for
parental use.

72
 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.

73
• 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…
74
 Traditional
NSAIDS like
aspirin produces
GI irritation

It can be
CV mortality can
prevented by
be prevented by
selective COX-2
Aspirin
inhibitors

COX-2 inhibitors
produces CV
mortality
75
 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%) 76
HIGH COST

SO AVOID
TOPICAL
NSAID
PREPERATION
DOUBTFUL
EFFICASY

77
 Selection of NSAID
• Paracetamol
Mild/moderate pain
• Low dose ibuprofen
Post op. or short lasting
• Ketorolac ,diclofenac,
pain
• Paracetamol
Musculoskeletal pain
• Ibuprofen, naproxen,ketoprofen
RA,AS,ACUTE • Naproxen, piroxicam,
GOUT,ACUTE RH.FEVER • Indomethacin, high dose aspirin
• Paracetamol
GI IRRITATION
• Cox-2 inhibitors
H/O HS reaction to
• Paracetamol or COX-2 inhibitors
tNSAIDS

Paediatric pts • Paracetamol, ibuprofen and naproxen

Pregnancy • Paracetamol
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