Nsaids I

Dr.U.P.RathnakarMD.DIH.PGDHM

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NSAIDs

• Produce beneficial and ADEs by inhibiting

Cyclooxygenase[COX] enzymes

Thereby inhibiting the synthesis of PG

3

Cyclooxygenase pathway Lipoxygenase pathway

Glucocorticoids

NSAIDs

5-LOX inhibitors

Synthesis of PGs

Cyclooxygenases[COX]

COX1• Constitutive• House keeping

functions

• Inhibition leads to ADEs

• Good

COX2• Induced• Induces inflammation,

pain and fever• Inhibition-beneficial

effects• Bad [Useful in Kidney,

Blood vessels]

ARACHIDONIC ACID

PGs

Cyclooxygenase-1

[Constitutive-Good???]

Cyclooxygenase-2

[Induced-Bad???]NSAIDsADEs Uses

-Gastro protective-Platelet function-Renal function-Uterine contractions

-Inflammation-Fever-Pain

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NSAIDs-Common benefits and ADEs[Effects of COX inhibition]

Beneficial effects• Anti-inflammatory• Analgesic• Antipyretic• Antithrombotic• Closure of D.A.-new born

Toxicities• Gastric ulcer• GI bleed• Nephropathy• Delay in labour• Hypersensitivity• Premature closure of D.A.• Increase in bleeding time

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Learning objectives• Concept of cyclo-oxygenases [COX-1

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

• Classification of NSAIDs based on these concepts

• Above concept and MOA of NSAIDs• Uses and ADEs of NSAIDs• Pharmacology of Important NSAIDs

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Classification-NSAIDs

• Nonselective Irreversible inhibitors of COX

Aspirin• Nonselective reversible

inhibitors of COXIbuprofen, Diclofenac,

Indomethacin, Piroxicam• Weak inhibitors of COX1Nimesulide• Preferential inhibitors of

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

Etodolac

• Selective reversible inhibitors of COX-2[>50 times]

Rofecoxib, Celecoxib, Valdecoxib, Etoricoxib, Parecoxib

• Inhibitors of COX-3[?] or hypothalaamic COX-1 inhibitors

Paracetamol, Analgin• NSAIDs –Not inhibitors

of COXNefopam, Diacerein 8

Classification of NSAIDs• Nonselective COX inhibitors1. -Salicylates: Aspirin2. -Acetic acid derivatives: Indomethacin, Sulindac,

Ketorolac, Diclofenac3. -Propionic acid derivative: Ibuprofen, Naproxen4. -Fenolic acd derivatives-Piroxicam

• Preferential COX-2 inhibitors-Nimesulide, Meloxicam• Selective COX-2 inhibitors [Coxibs]-Celecoxib, Parecoxib, Etoricoxib, Rofecoxib• Paraaminophenols-Paracetamol• Others-Apazone, Nefopam

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NSAIDs-Common benefits and ADEs of COX inhibition

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.

10

MOA-NSAIDs[Result of PG synthesis[ COX2]

inhibition & Anti-inflammatory action]

•Inflammation-COX-2 induction [COX-1, 15%]→PG E2 & PG I2

→Blood flow, Vascular permeability, Leukocyte infiltration → Signs of inflammation

-Other mediators-PAF, Leukotrines, cytokines, growth factors

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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-selective inhibition of COX-2

[Less GI effects-COX-1]-Other effects may be more!

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Anti-inflammatory • General MOA:

– Inhibits [COX] biosynthesis of PG

• Additional MOA:– inhibition of chemotaxis

– down regulation of IL- 1 production

– ↓ production of free radicals & superoxide

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MOA-NSAIDs[Result of PG synthesis[ COX2] inhibition & Anelgesic action]

• Pain•Peripheral sensitization- PG E2 & PG I2

•Central sensitization-They also increase spinal dorsal horn cells-Hyperalgesia

•NSAIDs Raise pain threshold of nociceptors [Inhibit synthesis of PGs]

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• 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 15

MOA-NSAIDs[Result of PG synthesis[ COX2] inhibition & Analgesic action]

Analgesia

•Prevention of PG-mediated sensitization of nerve endings

•Raises threshold to pain perception•More effective against

inflammation induced pain

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•Fever-Hypothalamus regulates set point of

body temp.-Elevated in infection &

inflammation[Induction of COX]formation of pyrogens [IL, TNFα,PGE2]

-NSAIDs inhibit PG synthesis17

MOA-NSAIDs[Result of PG synthesis[ COX2?3]

inhibition & Antipyretic action]

• Antipyresis

• Pyrogens stimulate synthesis[COX-2, COX-3???] of PGE2 in brain

• NSAIDs inhibit synthesis of PG→Antipyretic

• Do not cause hypothermia

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MOA-NSAIDs[Result of PG synthesis[ COX2?3]

inhibition & Antipyretic action]

Pain, inflammation

& fever

Phospholipid

Phospholipase A2

Arachidonic acid

Prostaglandins

Cyclo-oxygenase 1 & 2NSAIDs

Mechanism of action

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• Antiplatelet 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

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MOA-NSAIDs[Result of PG synthesis[ COX1&2]

inhibition & Action on platelets action, BV]

• Inhibit synthesis of pro-aggregatory (Thromboxanes – TXA2) and antiaggregatory (Prostanoids – PGI2) prostanoids

• Effect on platelet thromboxane (COX-1 generated) predominates

• Therapeutic doses: inhibit aggregation • Bleeding time is prolonged

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MOA-NSAIDs[Result of PG synthesis[ COX1&2]

inhibition & Action on platelets]

• During fetal circulation: ductus arteriosus is kept patent by local PGE2 & PGI2

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PDAKeptPatentBy

PGs

MOA-NSAIDs[Result of PG synthesis[ COX1&2]

inhibition & Action PDA]

• Ductus arteriosus closure• Ductus arteriosus kept open by PGE2 &

PGI2 [Fetal circulation]• NSAIDs used in non-closure after

birth[beneficial-premature births] • Use of NSAIDs during late pregnancy[in

preterm labor]→premature closure[ADEs]

• NSAIDs CI in late pregnancy23

MOA-NSAIDs[Result of PG synthesis[ COX]

inhibition & Action on PDA]

• 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??

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MOA-NSAIDs[Result of PG synthesis[ COX2] inhibition & Action on uterus]

• GI effects• GIT ulcer and bleeding are the most imp. ADEs

of NSAIDs • COX-1 mediated PGE2 & PGI2 –gastro

protective[↑Mucus and HCO3,↓HCL ]• Selective COX-2 inhibitors are safer• PG analogues can be co-administered

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MOA-NSAIDs[Result of PG synthesis[ COX1] inhibition & Action on Stomach]

• Nephropathy1.NSAIDs reduce renal blood

flow[COX-1]2.Na and water retention[COX2]3.Papillary necrosis-Chronic use• Significant-CHF, liver disease.• Can reduce the effect of

antihypertensive agents26

MOA-NSAIDs[Result of PG synthesis[ COX1&2]

inhibition & Action on Kidney]

• Hypersensitivity• Mild rhinitis, rashes, worsening

asthma or anaphylactoid reaction[non immunological]

• Diversion of AA to LT synthesis• LOX inhibitors and LT receptor

antagonists reduce symptoms• Cross sensitivity among all NSAIDs

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MOA-NSAIDs[Result of PG synthesis[ COX1]

inhibition & Action on LT synthesis]

Cyclo - oxygenase enzymeCOX-1

• Constitutively present in all cell types at a constant level

• Involved in tissue homeostasis

• Physiological

COX-2• Normally absent from

cells (except those of kidney & brain)

• Inducible by bacterial lipopolysaccharides, IL-1 & TNF-α in activated leukocytes & other inflammatory cells

• Usually pathological

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NSAIDs-Common benefits and ADEs

Beneficial effects• Analgesic [COX2]• Anti-inflammatory [COX2]• Antipyretic [COX2?3]• Antithrombotic [COX1&2]• Closure of D.A.-new born

Toxicities• Gastric ulcer [COX1]• GI bleed [COX1]• Nephropathy [COX1&2]• Delay in labour [COX1]• Hypersensitivity [LT]• Premature closure of D.A.[COX1]

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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-

displacement reaction Li-Reduce excretion[Piroxicam] or

decrease Li levels[Sulindac] 30

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Glucocorticoids

NSAIDs

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5-LOX inhibitors

ARACHIDONIC ACID

PGs

Cyclooxygenase-1

[Constitutive-Good???]

Cyclooxygenase-2

[Induced-Bad???]NSAIDsADEs Uses

-Gastro protective-Platelet function-Renal function-Uterine contractions

-Inflammation-Fever-Pain

33

NSAIDs-Common benefits and ADEs

Beneficial effects• Analgesic [COX2]• Anti-inflammatory [COX2]• Antipyretic [COX2?3]• Antithrombotic [COX1&2]• Closure of D.A.-new born

Toxicities• Gastric ulcer [COX1]• GI bleed [COX1]• Nephropathy [COX1&2]• Delay in labour [COX1]• Hypersensitivity [LT]• Premature closure of D.A.[COX1]

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Classification-NSAIDs

• Nonselective Irreversible inhibitors of COX

Aspirin• Nonselective reversible

inhibitors of COXIbuprofen, Diclofenac,

Indomethacin, Piroxicam• Weak inhibitors of COX1Nimesulide• Preferential inhibitors of

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

Etodolac

• Selective reversible inhibitors of COX-2[>50 times]

Rofecoxib, Celecoxib, Valdecoxib, Etoricoxib, Parecoxib

• Inhibitors of COX-3[?] or hypothalaamic COX-1 inhibitors

Paracetamol, Analgin• NSAIDs –Not inhibitors

of COXNefopam, Diacerein 35