Pharmacology – II [PHL 322]

1. Pharmacology – II [PHL 322] Non Steroidal Anti- Inflammatory Drugs (NSAIDS) Dr. Mohd Nazam Ansari

2. Terminology • Analgesic: A drug given to reduce pain without resulting in loss of consciousness. • Antipyretic: A drug given to reduce or stop fever. • Inflammation: A basic way in which the body reacts to infection, irritation or other injury, the key feature being redness, warmth, swelling and pain. • NSAID’s: Non-Steroidal Anti-inflammatory Drugs. • Narcotic: is an addictive drug that reduces pain, dulls the senses, alters mood and behavior, and usually induces sleep or stupor.

3. Narcotic Analgesics • Opiates: are the alkaloids found in opium, a white liquid extract of unripe seeds of the poppy plant (morphine and codeine). • Opioids: are derivatives of opiates, they bind to opioid receptors in the central nervous system or gastrointestinal tract. • Endogenous opioid peptides produced in the body (endorphins, dynorphins, enkephalins) • Semi-synthetic opioids (heroin, oxycodone, hydrocodone) • Fully synthetic opioids (Demerol, methadone, fentanyl, tramadol)

4. NSAID’s • Have antipyretic, analgesic and anti-inflammatory activities. • Not as effective as narcotic analgesics. • Unlike narcotics, the site of action of NSAID’s is peripheral tissues. • Examples include: • Pyrazolon • Phenylbutazone • Indomethacin • Ibuprofen

5. Inflammation is a defense reaction caused by tissue damage or injury • Characterized by: • Redness: vasodilationof capillaries to increase blood flow • Heat: vasodilation • Pain: Hyperalgesia, sensitization of nociceptors • Swelling: Increased vascular permeability (microvascular structural changes and escape of plasma proteins from the bloodstream) • Loss of function • Inflammatory cell transmigrationthrough endothelium and accumulation at the site of injury

6. Prostaglandins (PGs) are derived from arachidonic acid Lipoxygenase (LOX) Leukotrienes Cell Membrane (phospholipids) phospholipase A2 Arachidonic acid cyclooxygenaseaspirin, indomethacin (COX1 & COX2) Cyclic endoperoxides (PGG2, PGH2) prostacyclin prostaglandin thromboxane synthetase synthetase synthetase prostacyclin PGE2 PGF2 Thromboxane A2 PDX, PGI2 (vasodilator, (erythma (vasodilator (vasoconstriction antiaggregating) edema uterus contractor) platelet aggregation) pain, fever)

7. How do they work? - NSAID v COX2 Arachidonic acid Maintenance Induced COX-1 COX-2 NSAIDs thromboxane / prostaglandins prostaglandins Primarily mediate inflammation, pain & fever Primarily support platelet function Primarily protect GI mucosa

8. Effects of COX Inhibition COX-1 COX-2 Gastric ulcers Reduce inflammation Bleeding Reduce pain Acute renal failure Reduce fever

9. Beneficial actions of NSAIDs due to prostanoid synthesis inhibition 1. Analgesia: prevention of pain 2. Antipyretic: connected with influence of thermoregulatory centre in the hypothalamus 3. Anti-inflammatory action: mainly antiexudative effect 4. Antithrombotic action: in very low daily doses 5. Closure of ductusarteriosus

10. Shared toxicities of NSAIDs due to prostanoid synthesis inhibition • 1. Gastric mucosal damage: • connected with PGE inhibition • 2. Bleeding: inhibition of platelet • function (TxA2 synthesis) • 3. Limitation of renal blood flow • Na+ and water retention • 4. Delay / prolongation of labour • connected with PGF2α inhibition • 5. Asthma and anaphylactic reactions • connected with PGF2α inhibition

11. NSAIDs: Classifications based on chemistry • Salicylic acid derivatives • Aspirin • Para-aminophenol derivatives • Acetaminophen • Indole and indene acetic acids • Indomethacin • Pyranocarboxylic acids • Etodolac • Ketorolac • Propionic acids • Ibuprofen • Naproxen • Ketoprofen • Carprofen • Vedaprofen • Fenamates • Meclofenamic acid • Tolfenamic acid • Pyrazolones or enolic acids • Phenylbutazone • Dipyrone • Oxicams • Piroxicam,Meloxicam • Nicotinic acid derivatives • Flunixin meglumine • Hydroxamic acid derivatives • Tepoxalin • Coxib-class NSAIDs • Deracoxib, Firocoxib

12. Acetaminophen: Paracetamol • Acetaminophen (Paracetamol) is the most commonly used over-the-counter (OTC), non-narcotic analgesic. • Used as an analgesic and antipyretic. • No clinically significant anti-inflammatory effect. • Paracetamol is found in more than 600 over-the-counter drugs. • It can be found in combination with other active ingredients in many cold, sinus, and cough medications • Rapidly and completely absorbed from the GI tract.

13. Drug Interactions / Adverse Effects Paracetamol is remarkably free of drug interactions at its usual therapeutic doses. It exerts little or no pharmacologic effect on the cardiovascular, respiratory, or gastrointestinal systems, on acid-base regulation, or on platelet function. With large doses (>4g/day), an intermediate metabolite is produced that is thought to be hepatotoxic and possibly nephrotoxic. Alcohol induces drug-metabolizing enzymes in liver, resulting rapid metabolism of acetaminophen produces and accumulation of toxic metabolites.

14. The Salicylates: Aspirin • Has antipyretic, analgesic and anti-inflamatory activities. • It is useful as analgesics for certain categories of pain, such as headache and arthritis. • It remains the standard, first-line drug in the therapy of rheumatoid arthritis, and can provide relief of symptoms in acute rheumatic fever. • Some clinicians recommend small daily doses of aspirin for stroke or myocardial infarction because of its antiplatelet activity.

15. Pharmacologic effects Analgesic effects: Aspirin is as effective as Acetaminophen for low- to moderate-intensity pain treatment Antipyretic action: is rapidly effective in febrile patients, yet has little effect on normal body temperature. Anti-inflammatory effects: the primary clinical application is in the treatment of musculoskeletal disorders, such as rheumatoid arthritis Respiratory effects: high doses result in medullary stimulation, leading to hyperventilation and respiratory alkalosis

16. Pharmacologic effects Cardiovascular effects: high doses may cause peripheral vasodilation by exerting a direct effect on smooth muscle and Toxic doses depress circulation. Hepatic effects: aspirin can cause dose-dependent hepatic damage. Hematologic effects: It can inhibits platelet aggregation and reduce plasma prothrombin levels. Gastrointestinal effects: It can cause nausea and vomiting by irritating the gastric mucosal lining. It may also cause a dose-related gastric ulceration, bleeding.

17. Pharmacologic effects Renal effects: It can result in salt and water retention because of decreasing renal blood flow. Metabolic effects: It can produce hyperglycemia and glycosuria in large doses. Endocrine effects: In very large doses, it can stimulate steroid secretion

18. Uses of Aspirin • As analgesic(300 to 600 mg during 6 to 8 h) for headache, backache, pulled muscle, toothache, neuralgias. • As antipyretic in fever of any origin in the same doses as for analglesia. However, paracetamol and metamizole are safer, and generally preferred. • Acute rheumatic fever. Aspirin is the drug of choice. Antirheumatic doses are 75 to 100 mg/kg/day. • Rheumatoid arthritis. 3-5 g/day after meal is effective in most cases. Since large doses of Aspirin are poorly tolerated for a long time, the new NSAIDs (diclofenac, ibuprofen, etc.) in depot form are preferred. • Salicylicacid is used topically to treat: plantar warts , fungal infections, corns

19. Aspirin Toxicity • In adults, salicylism(tinnitus, hearing loss, vertigo) occurs as initial sign of toxicity after aspirin or salicylate overdose or poisoning. • In children, the common signs of toxicity include hyperventilation and acidosis, with accompanying lethargy and hyperventilation.

20. Drug interactions with NSAIDs

21. COX-2 inhibitors • (1) Selective COX-2 • inhibitors (Coxibs) • Celecoxib, Rofecoxib • Etoricoxib, Valdecoxib • Parecoxib • (2) Preferential • COX-2inhibitors • Meloxicam • Nimesulide • Nabumetone

22. Coxibs are selective COX-2 inhibitors. • They exert Anti-inflammatory, analgesic, and antipyretic action with low ulcerogenic potential. • Coxibs can cause infertility. • The ulcerogenic potential of preferential COX-2 inhibitors (Meloxicam, and Nimesulide) is significant. • Celecoxib is as effective as other NSAIDs in the treatment of rheumatoid arthritis and osteoarthritis, and in trials it has caused fewer endoscopic ulcers than most other NSAIDs. • Probably because it is a sulfonamide, celecoxib may cause rashes. • It does not affect platelet aggregation at usual doses. It interacts occasionally with warfarin – would be expected of a drug metabolized via CYP 2C9.

23. Rofecoxib and valdecoxib have been removed from the market due to a doubling in the incidence of heart attack and stroke • Celecoxib remains on the market and is approved for: • Osteoarthritis and rheumatoid arthritis • Pain including bone pain, dental pain, and headache • Ankylosing spondylitis.