Post on 15-Apr-2017
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NSAIDS 1
NSAIDS Lakshmi Ananth
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INTRODUCTION OF PAIN AND NOCICEPTION Nociception is the mechanism whereby noxious peripheral
stimuli are transmitted to the central nervous system. Pain is an unpleasant sensory and emotional experience with
actual or potential tissue damage. Superficial:
Stimulation of skin & mucous membranes.Fast response
Deep:Arises from muscles, joints, tendons, heart ..etc.Fast response
When tissues become injured, they release chemicals called prostaglandins and leukotrienes that make the pain receptors more sensitive and thus causing pain.
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ACUTE & CHRONIC PAINAcute Pain Chronic Pain
Sudden onset Persistent – usually lasting more than six months
Temporary (disappears once stimulus is removed)
Cause unknown – may be due to neural stimulation or a decrease in endorphins
Physiological responses to acute pain include increased RR, HR, BP and reduction in gastric motility.
Physiological responses are less obvious especially with adaptation. Psychological responses may include depression.
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PROSTANOIDS AND MOA OF NSAIDS
Prostanoids
Membrane Phospholipids
Arachidonic Acid
Leukotrienes Prostaglandins Prostacyclins Thromboxane
Phospholipase
Cyclooxygenase
Corticosteroids
NSAIDs
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CYCLOOXYGENASE ENZYME AND ITS ISOZYMES
COX 1 COX 2 COX 3
Responsible for the Physiologic production of Prostanoids.
Expressed only in brain, kidney & bone.
COX-3 more effects in CNS
Regulates the normal cellular processes Gastric cytoprotection Vascular homeostasis Platelet aggregation Kidney function.
Responsible for the elevated production of Prostanoids in inflammation & disease.
Expression at sites is increased in inflammation.
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Non selective COX inhibitors eg. Aspirine
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CLASSIFICATION OF NSAIDSNon-Selective COX Inhibitors. Selective COX Inhibitors.
Drugs with Analgesic & Marked Anti-inflammatory
Celecoxib , Etoricoxib, Meloxicam, Nimesulide.
Salicylic Acid Derivatives (Aspirin)Pyrazolon Derivatives (Phenylbutazone)
Acetic Acid Derivatives (Diclofenac, Sulindac)
Oxicams (Piroxicam, Tenoxicam)Drugs with Analgesic & Moderate
Anti-inflammatoryPropionic acid derivatives (Ibuprofen,
Naproxen)Fenamates (Meclofenamic)
Drug with Analgesic & no Anti-inflammatory
Para aminophenol Derivative (Acetaminophen)
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ASPIRIN PROFILE• As anti-inflammatory: Aspirin irreversibly acetylates both isoforms of
cyclooxygenase enzyme. There by inhibits biosynthesis of PG which helps in modulation of inflammation.
Aspirin inhibits inflammation in Rheumatoid Arthritis but it neither arrests the progress of disease.• As analgesic: reduces production of PGE2 (involves in sensitizing nerve
ending) there by repress sensation of pain.Toothache, Dysmenorhoea, used along with opioids in post operative
pain.Inhibit pain stimuli at subcortical sites -Thalamus & Hypothalamus.
• As antipyretic: Aspirin lowers raised body temperature , no effect on normal temperature.
• As antiplatelet: In low doses Inhibit Platelet Aggregation, as TXA2 promotes platelet aggregation.
• Dosage of Aspirin:
1. Low range <300mg - to↓ Platelet Aggregation 2. Intermediate dose 300 -2400mg for Analgesic, Antipyretic. 3. High dose 2400 - 4000mg for Anti-Inflammatory effect.
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ASPIRIN PROFILE• Adverse effects of Aspirin
GI disturbances (Can be prevented if given with misoprostol, enteric coated aspirin)Impaired hemostasisAllergy or Hypersensitivity reactionsHyperuricemia (Retention of uric acid at low doses)Decreased renal functionSalicylism (Vomiting, tinnitus, vertigo)Respiratory depression in toxic doses (by affect on CNS)Increased risk of Reye’s Syndrome (Acetaminophen or Ibuprofen should be used)
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ASPIRIN PROFILE• Contraindications • Peptic ulcer.• Hemophilia. • Aspirin hypersensitivity Children with a viral illness.• Chronic liver disease.• Aspirin should be stopped one week before elective surgery.• Avoid high doses in G-6-PD deficient.• Avoid in pregnancy & lactation.
There is no antidote till date
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ACETAMINOPHEN PROFILE• Rapid absorption from GIT.• Significant First pass metabolism in gut wall & liver.• Used for mild to moderate painToxicity:At therapeutic doses
drug fevermild increase in hepatic enzymes
At over doses(above 15g)Hepatic necrosisRenal tubular necrosis Hypoglycemic coma
N-acetyl Cysteine is antidote
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SELECTIVE COX 2 INHIBITORS
• these are 10-20 times more selective to cox-2 and is reversible.• Celecoxib: chemically sulphonamide having half life of 11hrs.• Meloxicam: Related to Piroxicam. Preferentially selective COX-2 inhibitor.• Etoricoxib: Long half life: 22 hrs, Monitoring of hepatic functions required. • Nimesulide: new compound less gastric irritation. • Valdecoxib & Rofecoxib: Withdrawn due to. higher risk of incidence of Cardiovascular thrombotic events Myocardial Infarction & stroke.
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SELECTIVE COX 2 INHIBITORS
Pharmacologic Effects & advantages: Analgesic, Antipyretic, Anti-inflammatory effects No inhibition of platelet aggregation. Does not prolong bleeding time. No inhibition of protective gastric PGs No gastric irritation.• Adverse effects:
Potential for increasing thrombotic events Myocardial infarction & stroke
Renal toxicities similar to non selective NSAIDsSkin rashes for Celecoxib
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CLINICAL USES OF NSAIDS
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GENERIC NAME TRADE NAME SPECIFIC USES ADVERSE REACTIONS
Celecoxib Celebrex • Rheumatoid arthritis and osteoarthritis.
ophthalmic changes
Diclofenac Sodium
Voltaren* • Rheumatoid arthritis and osteoarthritis.
• Ankylosing spondylitis
Gastric and duodenal ulcers formation.GI bleeding.
Fenoprofen Nalfon • Long term management to mild to moderate pain
Visual disturbancesJaundicePeptic ulcers
Ibuprofen Advil, Genpril • Mild to moderate pain.• Painful dysmenorrhea.• Rheumatoid arthritis.
GI DisturbancesNausea, DizzinessGI Bleeding
Indomethacin Indocin • Rheumatoid arthritis• Ankylosing spondylitis• Acute gouty arthritis
Hematologic changesNausea, ConstipationDuodenal Ulcers
meflofenamate meflofenamate* • mild to moderate pain.• Painful dysmenorrhea.
RashBleedingHeadache, Dizziness, Nausea, Dyspepsia
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GENERIC NAME
TRADE NAME SPECIFIC USES ADVERSE REACTIONS
Naproxen Aleve, Anaprox*
• Management of inflammatory disorders.
• Mild to moderate pain.• Painful dysmenorrhea.
visual changes, nausea, vomitingGI bleeding.
Rofecoxib Vioxx • Signs and symptoms of osteoarthritis.
• Management of acute pain
• Primary dysmenorrhea.
Visual Disturbances
Sulindac Clinoril* • Mild to moderate pain.• Rheumatoid arthritis• Ankylosing spondylitis• gouty arthritis
nausea, vomiting,Diarrhoea, constipation, GI bleeding. Gastric and duodenal ulcers formation.
Valdecoxib Bextra • osteoarthritis.• Rheumatoid arthritis• Primary dysmenorrhea
Anemia, Headache,Dyspepsia,Abdominal pain
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ADVERSE REACTIONS OF NSAIDS
• Gastrointestinal tract: nausea, vomiting, diarrhea, constipation, epigastric pain, indigestion, abdominal distress or discomfort, intestinal ulceration, stomatitis, jaundice, bloating, anorexia, and dry mouth• Central nervous system: dizziness. headache, drowsiness, insomnia.• Cardiovascular: decrease or increase in blood pressure, and cardiac arrhythmias• Renal: hematuria and acute renal failure In those with impaired renal function• Special senses: visual disturbances, blurred or diminished vision.• Hematologic: anemia• Skin: rash, erythema, irritation.
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CONTRAINDICATIONS & INTERACTIONS
• Contraindicated in patients with known hypersensitivity and in third trimester of pregnancy and during lactation.•If a patient is allergic to one NSAID, there is an increased risk of an allergic reaction with any other NSAID (Cross sensitivity)• Cautiously in patients with bleeding disorders, renal disease, cardiovascular disease, or hepatic impairment.• Increased risk of Ulcers in patients of age 65 and above.• Prolong bleeding time and increase the effects of anticoagulants.• May decrease the effects of diuretics or antihypertensive drugs.
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IN BRIEF….Advantagesdi
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