Nsaids I
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s 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
Lipoxygenase Lipoxygen ase pathway
NSAIDs
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Cyclooxygenases[COX] COX1 •
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Constitutive House keeping functions
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Inhibition leads to ADEs
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Good
COX2 •
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Induced Induces inflammation, pain and fever Inhibition-beneficial effects Bad [Useful in Kidney, Blood vessels]
ARACHIDONIC ACID
Cyclooxygenase-1
Cyclooxygenase-2
[Constitutive-Good???]
[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] inhibition] Beneficial effects
Toxicities
• Anti-inflammatory
• Gastric ulcer
• Analgesic
• GI bleed
• Antipyretic
• Nephropathy
• Antithrombotic
• Delay in labour
• Closure of D.A.-new born
• Hypersensitivity • Premature closure of D.A. • Increase in bleeding time
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Learning objectives •
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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 Pharmacology of Important NSAIDs 7
Classification-NSAIDs Nonselective Irreversible inhibitors of COX Aspirin Nonselective reversible inhibitors of COX Ibuprofen, Diclofenac, Indomethacin, Piroxicam Weak inhibitors of COX1 COX1 Nimesulide Preferential inhibitors of COX-2[>10times] Meloxicam,Nabumetone, Etodolac •
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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 Nefopam, Diacerein 8 •
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Classification of NSAIDs •
1. 2. 3. 4.
Nonselective COX inhibitors -Sal -Salic icyl ylat ates es:: Aspi Aspiri rinn -Acetic -Acetic acid derivativ derivatives: es: Indomethaci Indomethacin, n, Sulindac, Sulindac, Ketorolac, Ketorolac, Diclofenac -Propioni -Propionicc acid derivat derivative: ive: Ibuprofe Ibuprofen, n, Naproxen Naproxen -Fenolic -Fenolic acd derivativ derivatives-P es-Pirox iroxicam icam
Preferential COX-2 inhibitors -Nimesulide, -Nimesulide, Meloxicam Selective COX-2 inhibitors [Coxibs] -Celecoxib, -Celecoxib, Parecoxib, Etoricoxib, Rofecoxib Paraaminophenols -Paracetamol Others -Apazone, Nefopam •
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NSAIDsCommon benefits and ADEs of COX inhibition i nhibition Beneficial effects •
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Analgesic Anti-inflammatory Antipyretic Antithrombotic Closure of D.A.-new born
Toxicities •
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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, Leukotrin Leukotrines, es, 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[ reversible[Except Except by Aspirin] COXIBS-selective COXIBS-se lective 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
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down regulation of IL- 1 production
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↓
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 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] •
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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
Analgesia •
Prevention of PG-mediated sensitization of nerve endings
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Raises threshold to pain perception
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More effective against inflammation induced pain 16
MOA-NSAIDs [Result of PG synthesis[ COX2?3] inhibition & Antipyretic action] •
Fever
-Hypothalamu Hypothalamuss regulates set point
of body
temp. -Elevated in infection & inflammation[Induction inflammatio n[Induction of COX]forma COX]formation tion of pyrogens [IL, TNFα,PGE2] -NSAIDs inhibit PG synthesis 17
MOA-NSAIDs [Result of PG synthesis[ COX2?3] inhibition & Antipyretic action]
• Antipyresis •
Pyrogens stimulate synthesis[COX-2, COX3???] of PGE2 in brain
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NSAIDs inhibit synthesis of PG→Antipyretic
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Do not cause hypothermia
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Mechanism of action
Phospholipid Phospholipase A2
Arachidonic acid
NSAIDs Cyclo-oxygenase Cyclo-oxygena se 1 & 2 Pain, inflammation & fever
Prostaglandin s 19
MOA-NSAIDs [Result of PG synthesis[ COX1&2] inhibition & Action on platelets action, BV] •
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• Antiplatelet 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] •
Inhibit synthesis of pro-aggregatory (Thromboxanes (Prostanoids
•
–
–
TXA2) and antiaggregatory
PGI2) prostanoids
Effect on platelet thromboxane (COX-1 generated) predominates
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Therapeutic doses: inhibit aggregation
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Bleeding time is prolonged 21
MOA-NSAIDs [Result of PG synthesis[ COX1&2] inhibition & Action PDA] •
During fetal circulation: ductus arteriosus is kept patent by local PGE 2 & PGI2
PDA Kept Patent
By PGs
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MOA-NSAIDs [Result of PG synthesis[ COX] inhibition & Action on PDA]
• Ductus arteriosus closure •
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Ductus arteriosus kept open by PGE2 & PGI2 [Fetal circulation] NSAIDs used in non-closure after birth[beneficial-prema birth[benef icial-premature ture births] Use of NSAIDs during late pregnancy[in preterm labor]→premature closure[ADEs closure[ADEs]] NSAIDs CI in late pregnancy 23
MOA-NSAIDs [Result of PG synthesis[ COX2] inhibition & Action on uterus]
• Effect on uterus •
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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[ COX1] inhibition & Action on Stomach]
• GI effects • GIT ulcer and bleeding are the most imp. ADEs of NSAIDs •
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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&2] inhibition & Action on Kidney]
• Nephropathy
1.NSAIDs reduce renal blood flow[COX-1] f low[COX-1] 2.Na and water retention[COX2] 3.Papillary necrosis-Chronic necrosis-Chronic use Significant-CHF, liver disease. Can reduce the effect of antihypertensive antihyperten sive agents •
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MOA-NSAIDs [Result of PG synthesis[ COX1] inhibition & Action on LT synthesis]
• Hypersensitivity •
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Mild rhinitis, rashes, worsening asthma or anaphylactoid reaction[no reaction[nonn immunological] Diversion of AA to LT synthesis LOX inhibitors and LT receptor antagonists reduce symptoms Cross sensitivity among all NSAIDs 27
Cyclo - oxygenase enzyme COX-2
COX-1 •
Constitutively present
•
cells (except those of
in all cell types at a constant level •
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Normally absent from kidney & brain)
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Inducible by bacterial
Involved in tissue
lipopolysaccharides, IL-1
homeostasis
& TNF-α in activated
Physiological
leukocytes & other inflammatory cells •
Usually pathological
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NSAIDs-Common benefits and ADEs Beneficial effects
Toxicities
• Analgesic [COX2]
• Gastric ulcer [COX1]
• Anti-inflammatory [COX2]
• GI bleed [COX1]
• Antipyretic [COX2?3]
• Nephropathy [COX1&2]
• Antithrombotic [COX1&2]
• Delay in labour [COX1]
• Closure of D.A.-new born
• 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]
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Glucocorticoids NSAIDs
5-LOX inhibitors
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ARACHIDONIC ACID
Cyclooxygenase-1
Cyclooxygenase-2
[Constitutive-Good???]
[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
Toxicities
• Analgesic [COX2]
• Gastric ulcer [COX1]
• Anti-inflammatory [COX2]
• GI bleed [COX1]
• Antipyretic [COX2?3]
• Nephropathy [COX1&2]
• Antithrombotic [COX1&2]
• Delay in labour [COX1]
• Closure of D.A.-new born
• Hypersensitivity [LT] • Premature closure of D.A.
[COX1]
34
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 Nefopam, Diacerein 35 •
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