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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
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
6
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
7
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
9
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
11
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!
12
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
13
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]
14
• 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
16
•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
18
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
19
• 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
20
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
21
MOA-NSAIDs[Result of PG synthesis[ COX1&2]
inhibition & Action on platelets]
• During fetal circulation: ductus arteriosus is kept patent by local PGE2 & PGI2
22
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??
24
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
25
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
27
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
28
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]
29
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
31
Glucocorticoids
NSAIDs
32
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]
34
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