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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

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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.

??

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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