NSAIDs – (Non-steroidal Anti-Inflammatory Drugs)

INTRODUCTION of NSAIDs

• NSAIDs (Non-steroidal anti-inflammatory drugs) are the groups of drugs that reduce pain, decrease fever, and, in higher doses, decrease inflammation, they are less potent than a narcotic analgesic.
• These are also called non-narcotic analgesics.
• They reduce dull aching pain but not useful in visceral pain.
• Useful in the treatment of postoperative, dental, menstrual pain, Muscle pain, Joint pain, headaches, and migraine.
• They possess non-narcotic analgesic, antipyretics, and anti-inflammatory action.

Non-narcotic analgesic: Reduced pain without CNS depression.

Antipyretics: Which reduces elevated body temperature.

Anti inflammatory: Useful to produced symptomatic relief from pain.

CLASSIFICATION of NSAIDs

(A) Nonselective COX Inhibitors (Traditional NSAIDs)

1. Salicylates: Aspirin, Methyl Salicylate, Sodium salicylate.

2. Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen.

3. Anthranilic acid derivative: Mefenamic acid, Enfenamic acid, Flufenamic acid.

4. Aryl-acetic acid derivatives: Diclofenac, Aceclofenac.

5. Oxicam derivatives: Piroxicam, Tenoxicam.

6. Pyrrolo-pyrrole derivative: Ketorolac.

7. Indole derivative: Indomethacin, Sulindac.

8. Pyrazolone derivative: Phenylbutazone, Oxyphenbutazon.

(B) Preferential COX-2 Inhibitors:

Nimesulide, Meloxicam, Nabumetone.

(C) Selective COX-2 Inhibitors:

Celecoxib, Etoricoxib, Parecoxib.

(D) Analgesic-antipyretics with Poor Anti-inflammatory Action:

1. Para aminophenol derivatives: Paracetamol, Phenacitn.

2. Pyrazolone derivative: Metamizol, Propiphenazone.

3. Benzoxazocine derivative: Nefopam.

MECHANISM OF ACTION of NSAIDs

• Inhibits Platelets aggregation
• Inhibits pain sensation – Analgesic action.
• Reset hypothalamus at a lower temperature – Antipyretic action.
• Reduced capillary permeability, Decreased tissue edema – Anti-inflammatory action.

COX inhibitors cause inhibition of COX enzyme and inhibit the conversion of Arachidonic acid into PGG₂ later PGG₂ to PGH ₂, PGI ₂, PGE₂, PGF₂α, PGD_2, and Thromboxane A₂.

So result: Inhibits pain sensation – Analgesic action, Reset hypothalamus at a lower temperature – Antipyretic action, reduced capillary permeability, decreased tissue edema – Anti-inflammatory action and inhibits pain sensation – Analgesic action.

PHARMACOLOGICAL ACTIONS of NSAIDs

Analgesic effect:

The analgesic effect by:

• Peripheral inhibition of prostaglandin production.
• May also be due to the inhibition of pain stimuli at a subcortical site.
• It also inhibits the pain sensitizing mechanism induced by TNFα and Bradykinin.
• Prevent the potentiating action of prostaglandins on endogenous mediators of peripheral nerve stimulation.
• Aspirin is a weaker analgesic than morphine-type drugs.
• Effectively relieves inflammation, tissue injury, connective tissue, and integumental pain, but is relatively ineffective in severe visceral and ischaemic pain.
• No sedation, subjective effects, tolerance, or physical dependence.

Antipyretic effect:

• Inhibition of the production of prostaglandins induced by interleukin-1 (IL-1) and interleukin-6 (IL-6) in the hypothalamus.
• “Resetting” of the thermoregulatory system, leading to vasodilatation and increased heat loss.

Anti-inflammatory effect:

• Due to the inhibition of the enzymes that produce prostaglandin (cyclooxygenase, or COX), which converts arachidonic acid to prostaglandins, and TxA₂ and prostacyclin.
• Inhibits accumulation of fluids.
• Reduced capillary permeability.
• Reduced exudation of fluid.
• Reduced tissue swelling.
• Result anti-inflammatory effect.

Metabolic and Endocrine effects:

• Significant only at anti-inflammatory doses (High dose).
• Cellular metabolism is increased, especially in skeletal muscles, due to the uncoupling of oxidative phosphorylation.
• Increased utilization of glucose blood sugar may decrease and liver glycogen is depleted.
• Chronic use of large doses causes negative N₂ balance by increased conversion of protein to carbohydrate.
• Plasma-free fatty acid and cholesterol levels are reduced.
• It stimulates the adrenal medulla and increases adrenaline secretion which intern produced hypoglycemia.

Respiratory System:

• Effects are dose-dependent.
• It increased the consumption of oxygen by skeletal muscles and increased the production of carbon dioxide.
• It stimulates medullar respiratory centers so result increased rate of respiration.
• At anti-inflammatory doses, respiration is stimulated by peripheral (increased CO₂ production) and central (increased sensitivity of respiratory center to CO₂) actions.
• Hyperventilation is prominent in salicylate poisoning.
• Further rise in salicylate level causes respiratory depression; death is due to respiratory failure.

Acid-base and Electrolyte Balance:

• Anti-inflammatory doses produce significant changes in the acid-base and electrolyte composition of body fluids.
• Initially, respiratory stimulation predominates.
• Still higher doses cause respiratory depression with CO₂ retention, leading to respiratory acidosis.

CVS:

• Aspirin has no direct effect in therapeutic doses.
• Larger doses increase cardiac output to meet increased peripheral O₂ demand and cause direct vasodilatation.
• Toxic doses depress vasomotor center: BP may fall.
• Because of increased cardiac work as well as Na⁺ and water retention, CHF may be precipitated.
• Decreased prothrombin levels and inhibits platelet aggregation.

Blood:

• Aspirin irreversibly inhibits TxA₂ synthesis by platelets, bleeding time is prolonged to twice.
• Long-term intake of large dose decreases synthesis of clotting factors in liver and predisposes to bleeding; can be prevented by prophylactic Vit. K therapy.

GIT:

• Aspirin and released salicylic acid irritate gastric mucosa, cause epigastric distress, nausea, and vomiting.
• It also stimulates CTZ.
• Prolonged use may lead to ulcer formation as it inhibits PGE₂, PGF₂α synthesis, which intern inhibits gastric mucosa production.

Kidney:

• It inhibits PGE₂, PGF₂α results in decreased glomerular filtration and decreased urine outputs.
• It also increases Na⁺ and Water retention, which leads to increased BP and edema formation.

Local Action:

• It produced fungistatic, keratolytic and antiseptic action.
• It caused irritation of GIT which leads to nausea and vomiting.

Pharmacokinetics:

• Absorbed from the stomach and small intestines.
• Poor water solubility is the limiting factor in absorption: micro fining the drug particles and inclusion of an alkali enhances absorption.
• 50-60% binds to plasma protein.
• Rapidly deacetylated in the gut wall, liver, plasma, and other tissues to release salicylic acid which is the major circulating and active form.
• Slowly enters the brain but freely crosses the placenta.
• The metabolites are excreted by glomerular filtration as well as tubular secretion.

Therapeutic Uses:

• Analgesic.
• Antipyretic.
• Acute rheumatic fever.
• Rheumatoid arthritis.
• As antiplatelet agents.
• Local application for Fungistatics, Antiseptics, and Keratolytics.

Adverse Effects:

• GIT – Nausea, vomiting, Diarrhoea, Ulceration, perforation, and hemorrhage.
• Intolerance – Skin rashes, urticaria, pruritis, bronchial asthma, anaphylactic shock.
• Bone marrow depression – Agranulocytosis, Thrombocytopenia, Aplastic anemia.

Precautions to be taken while using Aspirin:

• It should not be taken on an empty stomach.
• Patients suffering from ulceration.
• During delivery as it increases bleeding time.
• Allergic or sensitive to salicylates.

Salicylism:

• Headache, Tinnitus, Giddiness, Difficulty in hearing, Mental confusion, vomiting, diarrhea, respiratory alkalosis.

Acute poisoning:

• Hyperglycemia, acidosis, dehydration, GIT irritation, hemorrhage, restlessness, excitement, delirium, tremors, euphoria, convulsion, hallucination.

Treatment:

• Gastric lavage.
• Correction of dehydration, acid-base balance.
• Administration of alkalies and fluids (0.9% saline with 2% NaHCO3) prevents metabolic acidosis and increased excretion of salicylates.

PARACETAMOL

• Most commonly used as antipyretics and analgesics effects.
• Analgesic – one of the most commonly used non-narcotic antipyretic agents.
• Weak anti-inflammatory activity.
• Effects of does not share the gastric or platelet side the other NSAIDs.

• Inhibits Prostaglandins synthesis.
• Inhibition of the production of prostaglandins induced by interleukin-1 (IL-1) and interleukin-6 (IL-6) in the hypothalamus.
• Reset hypothalamus at a lower temperature – Antipyretic action.

Pharmacokinetics:

• Well absorbed when given orally, with min. 30-60 in reaching concentrations plasma peak.
• The plasma half-life of therapeutic doses is 2-4 h.
• Paracetamol is metabolized to N-Acetyl P-benzoquinone imine and inactivated in the liver, being conjugated to give glucuronide.
• Excreted in urine.

Therapeutic Uses:

• Analgesics
• Anti-pyretic

Adverse Effects:

• With therapeutic doses, side effects are few and uncommon.
• Allergic skin reactions.
• Regular intake of large doses over a long period causes kidney damage.
• Toxic doses cause potentially fatal hepatotoxicity.

SELECTIVE COX-2 INHIBITORS

Celecoxib and Etoricoxib

• Symptomatic relief in the treatment of osteoarthritis and rheumatoid arthritis.
• Extensively metabolized in the liver.
• High plasma protein binding.
• Dizziness, skin. Common adverse effects are headaches, rashes, and peripheral edema caused by fluid retention.

Parecoxib:

• Prodrug of valdecoxib.
• Short-term treatment of postoperative pain.
• Plasma protein binding is high.
• The drug should also be given with caution to patients with impaired renal function, and renal failure has been reported.
• Postoperative anemia may also occur.

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