Nsaids I

May 10, 2018 | Author: Dr.U.P.Rathnakar.MD.DIH.PGDHM | Category: Nonsteroidal Anti Inflammatory Drug, Analgesic, Drugs, Organic Compounds, Clinical Medicine
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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

3

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

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

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 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 •







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 •





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 •









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, 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! •









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







14

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 15

Analgesia •

Prevention of PG-mediated sensitization of nerve endings



Raises threshold to pain perception



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



NSAIDs inhibit synthesis of PG→Antipyretic



Do not cause hypothermia

18

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] •











• 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



Therapeutic doses: inhibit aggregation



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

22

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-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 •





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 •





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 •



26

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

• Hypersensitivity •







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 •



Normally absent from kidney & brain)



Inducible by bacterial

Involved in tissue

lipopolysaccharides, IL-1

homeostasis

& TNF-α in activated

Physiological

leukocytes & other inflammatory cells •

Usually pathological

28

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]

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

30

31

Glucocorticoids NSAIDs

5-LOX inhibitors

32

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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