Non Steroidal Anti-inflammatory drugs (NSAIDs)-I

Dr.U.P.Rathnakar
MD.DIH.PGDHM
1

NSAIDs

Produce beneficial and ADEs by inhibiting Cyclooxygenase[COX] enzymes Thereby inhibiting the synthesis of PG

Synthesis of PGs
Glucocorticoids
5-LOX inhibitors Cyclooxygenase pathway NSAIDs Lipoxygenase pathway

Cyclooxygenases[COX]
COX1 Constitutive House keeping functions Inhibition leads to ADEs COX2 Induced Induces inflammation, pain and fever Inhibition-beneficial effects Bad [Useful in Kidney, Blood vessels]

Good

ARACHIDONIC ACID

Cyclooxygenase-1
[Constitutive-Good???]

Cyclooxygenase-2
[Induced-Bad???]

ADEs

NSAIDs

Uses

PGs
-Gastro protective -Platelet function -Renal function -Uterine contractions -Inflammation -Fever -Pain 5

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

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 COX Ibuprofen, Diclofenac, Indomethacin, Piroxicam Weak inhibitors of COX1 Nimesulide 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 COX 8 Nefopam, Diacerein

Classification of NSAIDs
Nonselective COX inhibitors 1. -Salicylates: Aspirin 2. -Acetic acid derivatives: Indomethacin, Sulindac, Ketorolac, Diclofenac 3. -Propionic acid derivative: Ibuprofen, Naproxen 4. -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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NSAIDsCommon benefits and ADEs of COX inhibition Beneficial effects Toxicities

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

Gastric ulcer GI bleed Nephropathy Delay in labour Hypersensitivity Premature closure of D.A.
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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 cellsHyperalgesia NSAIDs Raise pain threshold of nociceptors [Inhibit synthesis of PGs]
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MOA-NSAIDs
[Result of PG synthesis[ COX2] inhibition & Analgesic action]

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
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Analgesia
Prevention of PG-mediated
sensitization of nerve endings

Raises threshold to pain perception

More effective against inflammation induced pain
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MOA-NSAIDs
[Result of PG synthesis[ COX2?3] inhibition & Antipyretic action]

Fever

-Hypothalamus

temp. -Elevated in infection & inflammation[Induction of COX]formation of pyrogens [IL, TNF,PGE2] -NSAIDs inhibit PG synthesis

regulates set point of body

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MOA-NSAIDs
[Result of PG synthesis[ COX2?3] inhibition & Antipyretic action]

Antipyresis
Pyrogens stimulate synthesis[COX-2, COX3???] of PGE2 in brain

NSAIDs inhibit synthesis of PGAntipyretic

Do not cause hypothermia

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Mechanism of action

Phospholipid
Phospholipase A2

Arachidonic acid

NSAIDs
Cyclo-oxygenase 1 & 2
Pain, inflammation & fever

Prostaglandin s
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MOA-NSAIDs
[Result of PG synthesis[ COX1&2] inhibition & Action on platelets action, BV]

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]
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 PDA]

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

PDA Kept
Patent

By PGs

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

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[ COX1] inhibition & Action on Stomach]

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&2] inhibition & Action on Kidney]

Nephropathy 1.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 agents
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MOA-NSAIDs
[Result of PG synthesis[ COX1] inhibition & Action on LT synthesis]

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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Cyclo - oxygenase enzyme

COX-1
Constitutively present in all cell types at a constant level Involved in tissue homeostasis

COX-2
Normally absent from

cells (except those of

kidney & brain) Inducible by bacterial lipopolysaccharides, IL-1 & TNF- in activated

Physiological

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 methotrexatedisplacement reaction Li-Reduce excretion[Piroxicam] or decrease Li levels[Sulindac] 30

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Glucocorticoids
NSAIDs 5-LOX inhibitors

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ARACHIDONIC ACID

Cyclooxygenase-1
[Constitutive-Good???]

Cyclooxygenase-2
[Induced-Bad???]

ADEs

NSAIDs

Uses

PGs
-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 COX Ibuprofen, Diclofenac, Indomethacin, Piroxicam Weak inhibitors of COX1 Nimesulide 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 COX 35 Nefopam, Diacerein