Nsaids I

(1)

Dr.U.P.Rathnakar

MD.DIH.PGDHM MD.DIH.PGDHM

on

teroidal

nti-nti-

nflammatory

rugs (

(2)

NSAIDs

••

Produce beneficial and ADEs

by inhibiting



Cyclooxygenase[COX]

enzymes



Thereby inhibiting the

synthesis of PG

(3)

Cyclooxygenase pathway

Cyclooxygenase pathway _Lipoxygen_Lipoxygen_ase_ase_pathway_pathway

Glucocorticoids

NSAIDs NSAIDs 5-LOX inhibitors 5-LOX inhibitors

Synthesis of PGs

(4)

Cyclooxygenases[COX]

COX1 COX1 • • ConstitutiveConstitutive •

• House keeping functionsHouse keeping functions •

• Inhibition leads to ADEsInhibition leads to ADEs • • GoodGood COX2 COX2 • • InducedInduced •

• Induces inflammation,Induces inflammation,

pain and fever pain and fever

•

• Inhibition-beneficialInhibition-beneficial

effects effects

•

• Bad [Useful in Kidney,Bad [Useful in Kidney,

Blood vessels] Blood vessels]

(5)

ARACHIDONIC ACID

PGs

Cyclooxygenase-1

[Constitutive-Good???] [Constitutive-Good???]

Cyclooxygenase-2

[Induced-Bad???] [Induced-Bad???]

NSAIDs

ADEs

Uses

ADEs

Uses

-Gastro protective -Gastro protective -Platelet function -Platelet function -Renal function -Renal function -Inflammation -Inflammation -Fever -Fever -Pain -Pain

(6)

NSAIDs-Common benefits and ADEs

[Effects of COX

[Effects of COX inhibitio

inhibition]

n]

Beneficial effects Beneficial effects •• Anti-inflammatoryAnti-inflammatory •• AnalgesicAnalgesic •• AntipyreticAntipyretic •• AntithromboticAntithrombotic

•• Closure of D.A.-new bornClosure of D.A.-new born

Toxicities

•• Gastric ulcerGastric ulcer

•• GI bleedGI bleed

•• NephropathyNephropathy

•• Delay in labourDelay in labour

•• HypersensitivityHypersensitivity

•• Premature closure of D.A.Premature closure of D.A.

(7)

Learning objectives

•

Concept of cyclo-oxygenases [COX-1 &

COX-2] [PG G/H synthase] inhibition and

PG synthesis

•

Classification

Classification of

of NSAIDs

NSAIDs based

based on

on these

these

concepts

•

Above concept and MOA of NSAIDs

•

Uses and ADEs of NSAIDs

•

(8)

Classification-NSAIDs

•

• NonselectiveNonselective IrreversibleIrreversible

inhibitors of COX inhibitors of COX Aspirin

Aspirin

•

• Nonselective reversibleNonselective reversible

inhibitors of COX inhibitors of COX Ibuprofen, Diclofenac, Ibuprofen, Diclofenac, Indomethacin, Piroxicam Indomethacin, Piroxicam •

• Weak Weak inhibitors inhibitors of of COXCOX11

Nimesulide

•

• Preferential inhibitors ofPreferential inhibitors of

COX-2[>10times] COX-2[>10times] Meloxicam,Nabumetone, Meloxicam,Nabumetone, Etodolac Etodolac •

• SelectiveSelective reversiblereversible

inhibitors of COX-2[>50 inhibitors of COX-2[>50 times] times] Rofecoxib, Celecoxib, Rofecoxib, Celecoxib, Valdecoxib, Etoricoxib, Valdecoxib, Etoricoxib, Parecoxib Parecoxib •

• Inhibitors of COX-3[?]Inhibitors of COX-3[?]

or hypothalaamic COX-1 or hypothalaamic COX-1 inhibitors inhibitors Paracetamol, Analgin Paracetamol, Analgin •

• NSAIDsNSAIDs ––Not inhibitorsNot inhibitors

of COX of COX

Nefopam, Diacerein

(9)

Classification of NSAIDs

•

• Nonselective COX inhibitorsNonselective COX inhibitors

1.

1. -S-Salalicicylylatateses: : AsAspipiririnn 2.

2. -Acet-Acetic acid deriic acid derivativvatives: Indomees: Indomethacithacin, Sulindan, Sulindac, Ketoroc, Ketorolac,lac, Diclofenac

Diclofenac 3.

3. -Prop-Propioniionic acid dec acid derivatrivative: Ibuive: Ibuprofeprofen, Napron, Naproxenxen 4.

4. -Fen-Fenolic olic acd acd deriderivativvatives-Pes-Piroxiroxicamicam

•

• Preferential COX-2 inhibitorsPreferential COX-2 inhibitors

-Nimesulide

-Nimesulide, , MeloxicamMeloxicam

•

• Selective COX-2 inhibitors [Coxibs]Selective COX-2 inhibitors [Coxibs]

-Celecoxib

-Celecoxib, , Parecoxib, Etoricoxib, RofecoxibParecoxib, Etoricoxib, Rofecoxib

• • ParaaminophenolsParaaminophenols -Paracetamol -Paracetamol • • OthersOthers -Apazone, Nefopam -Apazone, Nefopam

(10)

NSAIDs-Common benefits and ADEs of COX i

Common benefits and ADEs of COX inhibitionnhibition

Beneficial effects Beneficial effects • •

Analgesic

• •

Anti-inflammatory

• •

Antipyretic

• •

Antithrombotic

•

Closure of D.A.-new

born

Toxicities

•

Gastric ulcer

•

GI bleed

•

Nephropathy

•

Delay in labour

•

Hypersensitivity

•

Premature closure of

D.A.

(11)

MOA-NSAIDs

[Result of PG synthesis[ COX2]

inhibition & Anti-inflammatory action]

•

Inflammation

-COX-2 induction [

COX-1, 15%COX-1, 15%

]

→PG E

₂₂

&

PG I

₂₂

→Blood flow, Vascular permeability,

Leukocyte infiltration → Signs of

inflammation

-Other mediators-PAF,

Leukotrin

es,

cytokines, growth factors

(12)

MOA-NSAIDs

[Result of PG synthesis [COX2]inhibition

& Anti-inflammatory action]

•

Antiinflammatory

•

COX2 induced at sites of inflammation

•

NSAIDs inhibit cycloxygenase

pathway[Not lipooxygenase pathway]

•

Inhibition

is

reversible[

Except

by

Aspirin]

•

COXIBS-se

lective inhibition of

COX-2

[Less GI effects-COX-1]-Other

effects may be more!

(13)

Anti-inflammatory

•

General MOA:

–

Inhibits [COX] biosynthesis of PG

•

Additional MOA:

–

inhibition of chemotaxis

–

down regulation of IL- 1 production

–

(14)

MOA-NSAIDs

[Result of PG synthesis[ COX2]

inhibition & Anelgesic action]

•

Pain

•

Peripheral sensitization-

PG E

22

&

PG I

22

•

Central sensitization-They also

increase spinal dorsal horn

cells-Hyperalgesia

Hyperalgesia

•

NSAIDs

R

aise pain threshold of

nociceptors [Inhibit synthesis of PGs]

(15)

••

Analgesia

•

Raise threshold to sensitization-peripheral &

central

•

Only mild to moderate pain

•

Less efficacious than opioid [also

less ADEs]

•

Pain from hollow viscera not

affected[except

dysmenorrhea]

•

Useful in migraine

•

Not effective in neuropathic pain

MOA-NSAIDs

[Result of PG synthesis[ COX2]

inhibition & Analgesic action]

(16)

Analgesia

•

Prevention of PG-mediated

sensitization of nerve endings

•

Raises threshold to pain perception

•

More effective against inflammation

induced pain

(17)

•

Fever

--

Hypothalamu

s regulates set point

of body

temp.

-Elevated in infection &

inflammatio

n[Induction of

COX]forma

tion

of pyrogens [IL, TNF

α

,PGE

₂₂

]

-NSAIDs inhibit PG synthesis

MOA-NSAIDs

[Result of PG synthesis[ COX2?3]

inhibition & Antipyretic action]

(18)

••

Antipyresis

•

Pyrogens stimulate synthesis[COX-2, COX-

Pyrogens stimulate synthesis[2,

COX-3???] of PGE2 in brain

3???] of PGE2 in brain

•

NSAIDs inhibit synthesis of PG

→Antipyretic→Antipyretic

•

Do not cause hypothermia

MOA-NSAIDs

[Result of PG synthesis[ COX2?3]

inhibition & Antipyretic action]

(19)

Pain, Pain, inflammation & inflammation & Phospholipid Phospholipid Phospholipase A Phospholipase A₂₂ Arachidonic acid Arachidonic acid Prostaglandin Prostaglandin s s Cyclo-oxygena

Cyclo-oxygenase 1 & se 1 & 22

NSAIDs

Mechanism of action

(20)

••

Antiplatel

Antiplatelet

et action

action

•

TXA2 is proaggregatory [PGI2

antiaggregatory]

•

NSAIDs inhibit synthesis of both[More

TXA2]

•

Bleeding time is prolonged

•

All NSAIDs except aspirin produce reversible

inhibition

•

Secondary prevention in IHD

•

Also favors gastric bleed

MOA-NSAIDs

[Result of PG synthesis[ COX1&2]

inhibition & Action on platelets action, BV]

(21)

•

Inhibit synthesis of pro-aggregatory

(Thromboxanes

––

TXA

2

) and antiaggregatory

(Prostanoids

––

PGI

2

) prostanoids

•

Effect on platelet thromboxane (COX-1

generated) predominates

•

Therapeutic doses: inhibit aggregation

•

Bleeding time is prolonged

MOA-NSAIDs

[Result of PG synthesis[ COX1&2]

inhibition & Action on platelets]

(22)

•

During fetal circulation: ductus arteriosus

is kept patent by local PGE

₂₂

& PGI

₂₂

P

PDA

DA

Kept

P Patentatent

By

P

PGs

Gs

MOA-NSAIDs

[Result of PG synthesis[ COX1&2]

inhibition & Action PDA]

(23)

••

Ductus arteriosus closure

•

Ductus arteriosus kept open by PGE2 &

PGI2 [Fetal circulation]

•

NSAIDs used in non-closure after

birth[benef

icial-prema

ture

births]

•

Use of NSAIDs during

late pregnancy[in

preterm labor]

→

premature

closure[ADEs

]

•

NSAIDs CI in late

pregnancy

MOA-NSAIDs

[Result of PG synthesis[ COX]

inhibition & Action on PDA]

(24)

••

Effect on uterus

•

PG synthesis during term initiates and

maintains labour

•

NSAIDs can delay labour[ Can be used

to delay pre term labour-Closure of

D.Arteriosus]

•

Selective COX2

inhibitors-Tocolytic??

MOA-NSAIDs

[Result of PG synthesis[ COX2]

inhibition & Action on uterus]

(25)

••

GI effects

••

GIT ulcer and bleeding are the most imp.

ADEs of NSAIDs

•

COX-1 mediated PGE2 & PGI2

––

gastro

protective

[[↑↑

Mucus and HCO3,

↓HCL↓HCL _]_]

•

Selective COX-2 inhibitors are safer

•

PG analogues can be co-administered

MOA-NSAIDs

[Result of PG synthesis[ COX1]

inhibition & Action on Stomach]

(26)

••

Nephropathy

1.NSAIDs reduce renal blood f

low[COX-1]

2.Na and water retention[COX2]

3.Papillary necrosis-Chron

ic

use

•

Significant-CHF, liver disease.

•

Can reduce the effect of

antihyperten

sive

agents

MOA-NSAIDs

[Result of PG synthesis[ COX1&2]

inhibition & Action on Kidney]

(27)

••

Hypersensitivity

•

Mild rhinitis, rashes,

worsening asthma

or anaphylactoid

reaction[no

n

immunological]

•

Diversion of AA to LT synthesis

•

LOX inhibitors and LT

receptor

antagonists reduce symptoms

•

Cross sensitivity among all NSAIDs

MOA-NSAIDs

[Result of PG synthesis[ COX1]

inhibition & Action on LT synthesis]

(28)

Cyclo - oxygenase enzyme

COX-1

•

Constitutively present

in all cell types at a

constant level

•

Involved in tissue

homeostasis

• •

Physiological

COX-2

•

• Normally absent fromNormally absent from

cells (except those of cells (except those of kidney & brain)

kidney & brain)

•

• Inducible by bacterialInducible by bacterial

lipopolysaccharides, IL-1 lipopolysaccharides, IL-1 &

TNF-& TNF-αα in activatedin activated

leukocytes & other leukocytes & other inflammatory cells inflammatory cells

•

(29)

NSAIDs-Common benefits and

ADEs

Beneficial effects Beneficial effects

•• Analgesic [COX2]Analgesic [COX2]

•• Anti-inflammatory [COX2]Anti-inflammatory [COX2]

•• Antipyretic [COX2?3]Antipyretic [COX2?3]

•• Antithrombotic [COX1&2]Antithrombotic [COX1&2]

Toxicities Toxicities

•• Gastric ulcer [COX1]Gastric ulcer [COX1]

•• GI bleed [COX1]GI bleed [COX1]

•• Nephropathy [COX1&2]Nephropathy [COX1&2]

•• Delay in labour [COX1]Delay in labour [COX1]

•• Hypersensitivity [LT]Hypersensitivity [LT]

•• Premature closure of D.A.Premature closure of D.A. [COX1]

(30)

Drug interactions-NSAIDs



Reduce action of ACEIs-[ACEIs Block kinin

break down

→ ↑

Vasodilator PGs]



NSAIDs+Corticosteroids or SSRIs

↑ GI

bleed



NSAIDs+ Warfarin-Bleeding



NSAIDs+ Sulfonylurea or methotrexate-

NSAIDs+ Sulfonylurea or

methotrexate-displacement reaction

displacement reaction



Li-Reduce excretion[Piroxicam] or

decrease Li levels[Sulindac]

(31)

(32)

Glucocorticoids Glucocorticoids NSAIDs NSAIDs 32 32 5-LOX inhibitors 5-LOX inhibitors

(33)

ARACHIDONIC ACID

PGs

Cyclooxygenase-1

[Constitutive-Good???] [Constitutive-Good???]

Cyclooxygenase-2

[Induced-Bad???] [Induced-Bad???]

NSAIDs

ADEs

Uses

ADEs

Uses

-Gastro protective -Gastro protective -Platelet function -Platelet function -Renal function -Renal function -Inflammation -Inflammation -Fever -Fever -Pain -Pain

(34)

NSAIDs-Common benefits and

ADEs

Beneficial effects Beneficial effects

•• Analgesic [COX2]Analgesic [COX2]

•• Anti-inflammatory [COX2]Anti-inflammatory [COX2]

•• Antipyretic [COX2?3]Antipyretic [COX2?3]

•• Antithrombotic [COX1&2]Antithrombotic [COX1&2]

Toxicities Toxicities

•• Gastric ulcer [COX1]Gastric ulcer [COX1]

•• GI bleed [COX1]GI bleed [COX1]

•• Nephropathy [COX1&2]Nephropathy [COX1&2]

•• Delay in labour [COX1]Delay in labour [COX1]

•• Hypersensitivity [LT]Hypersensitivity [LT]

•• Premature closure of D.A.Premature closure of D.A. [COX1]

(35)

Classification-NSAIDs

•

• Nonselective IrreversibleNonselective Irreversible

inhibitors of COX inhibitors of COX Aspirin

Aspirin

•

• Nonselective reversibleNonselective reversible

inhibitors of COX inhibitors of COX Ibuprofen, Diclofenac, Ibuprofen, Diclofenac, Indomethacin, Piroxicam Indomethacin, Piroxicam •

• Weak Weak inhibitors inhibitors of of COX1COX1

Nimesulide

•

• Preferential inhibitors ofPreferential inhibitors of

COX-2[>10times] COX-2[>10times] Meloxicam,Nabumetone, Meloxicam,Nabumetone, Etodolac Etodolac •

• Selective reversibleSelective reversible

inhibitors of COX-2[>50 inhibitors of COX-2[>50 times] times] Rofecoxib, Celecoxib, Rofecoxib, Celecoxib, Valdecoxib, Etoricoxib, Valdecoxib, Etoricoxib, Parecoxib Parecoxib •

• Inhibitors of COX-3[?]Inhibitors of COX-3[?]

or hypothalaamic COX-1 or hypothalaamic COX-1 inhibitors inhibitors Paracetamol, Analgin Paracetamol, Analgin •

• NSAIDsNSAIDs ––Not inhibitorsNot inhibitors

of COX of COX