Non-Steroidal Anti-inflammatory Drugs 1 PDF

Non-Steroid Anti-inflammatory Drugs- 1 (NSAIDs 1) Dr Khin Thane Oo, Professor, Department of Pharmacology Learning Outcomes 1. List the non-selective COX inhibitors, selective COX-2 inhibitors, preferential COX-2 inhibitors and NSAIDs with poor anti-inflammatory activity. *** 2. Explain the mechanis...

Non-Steroid Anti-inflammatory Drugs- 1 (NSAIDs 1) Dr Khin Thane Oo, Professor, Department of Pharmacology Learning Outcomes 1. List the non-selective COX inhibitors, selective COX-2 inhibitors, preferential COX-2 inhibitors and NSAIDs with poor anti-inflammatory activity. *** 2. Explain the mechanism of action of NSAIDS. *** 3. Explain the pharmacological actions (antipyretic/anti-inflammatory/ analgesic/ antiplatelet) of NSAIDs. *** 4. Apply concepts of pharmacological actions of NSAIDs to provide the basis for the current therapeutic uses of aspirin, ibuprofen, diclofenac, indomethacin, ketorolac, piroxicam, mefenamic acid *** 5. Apply concepts of pharmacological actions of NSAIDs to provide the basis for the adverse effects of NSAIDs. *** Manipal University College Malaysia 2 Learning Outcomes 6. Apply the concepts of pharmacological actions of NSAIDs and physiology/pathophysiology to provide basis for the contraindications of non-selective COX inhibitors in the following: *** a) Patients with peptic ulcer b) Bleeding disorders c) Children below 12 years of age d) Pregnancy 7. Choose an appropriate NSAID for a given clinical condition by comparing their pharmacological properties. *** 8. Explain the manifestations of paracetamol poisoning. *** 9. Apply the toxicokinetics of paracetamol and pathology of paracetamol poisoning to derive principles of management of paracetamol poisoning. *** 10. List topical NSAIDs and analgesic combinations used in pain management. *** 11. List preferred NSAID(s) for the following: *** a) Mild musculoskeletal pain b) Acute musculoskeletal pain c) Dysmenorrhoea d) Patent ductus arteriosus (PDA) e) Rheumatoid arthritis f) Ankylosing spondylitis/ psoriatic arthritis Acute gout Manipalg) University College Malaysia 3 Pain ❖ An unpleasant sensation that can range from mild, localized discomfort to agony. ❖ Pain has both physical and emotional components. ❖ The physical part of pain results from nerve stimulation. ❖Pain may be contained to a discrete area, as in an injury, or it can be more diffuse, as in disorders like fibromyalgia 4 PAIN CLASSIFICATION Classified into two types: Nociceptive (somatic, visceral) Neuropathic Nociceptive: due to direct stimulation of peripheral nerve endings by a noxious stimulus such as trauma, burns or ischaemia. Neuropathic: due to dysfunction of the pain perception system within the peripheral or central nervous system as a result of injury, disease or surgical damage KTO OPIOID ANALGESICS 6 KTO OPIOID ANALGESICS 7 ❖ Two main sites of pain: The integumental pain i.e., the superficial pain arising from skin, muscles, bones and joints The visceral pain which is deep seated and arises from internal viscera The peripheral pain receptors are the free nerve endings which get sensitized by different proinflammatory mediators like bradykinin, prostaglandins, histamine, 5-HT and interleukins The Non-Steroidal Anti-inflammatory Drugs (NSAIDs) are more effective against integumental pain whereas the Narcotic or Opioid analgesics are effective against visceral pain NSAIDs ❖ Also called non-narcotic, non-opioid and aspirin like analgesic ❖Common mechanism of action - inhibit synthesis of prostaglandins by inhibiting the enzyme cyclooxygenase (COX) ❖ required for maintenance of integrity of gastric mucosa, renal function, platelet aggregation etc. ❖ also formed at the site of tissue injury due to any noxious stimuli (thermal, mechanical, toxins etc.). ❖ Cytokines released from the inflammatory cells lead to the formation of prostaglandins by inducing an enzyme known as ‘Cyclooxygenase’ (COX). ❖ Do not produce CNS depression and no physical dependence & abuse liability ❖ Weaker analgesic than morphine except inflammatory pain, most prescribed drugs 9 Mechanism of action of NSAIDs ❖ NSAIDs prevent synthesis of prostaglandins by inhibiting COX enzyme. 10 Types of COX Enzymes 12 Classification of NSAIDs 1. Nonselective irreversible Inhibitors of COX (COX-1>COX-2): Aspirin, diflunisal 2. Nonselective reversible Inhibitors of COX (COX-1=COX-2): Ibuprofen, Ketoprofen, Naproxen, Indomethacin, Diclofenac, Aceclofenac, Ketorolac, Mefenamic acid, Piroxicam 3. Preferential COX-2 Inhibitors: Meloxicam (10 to 20 fold), Nimesulide (5 to 10-fold), Diclofenac, Aceclofenac (50-fold): Celecoxib, etoricoxib, parecoxib, lumiracoxib 5. Analgesic and Antipyretic with least Anti-inflammatory action (COX-3 Inhibitor): Paracetamol 6. NSAIDs which do not Inhibit Prostaglandin Synthesis: Nefopam 1 3 Pharmacological Actions of NSAIDs 1. Analgesic Effect ❖Analgesic effect is mainly due to peripheral inhibition of PG production. ❖PGs formed during tissue injury, sensitize pain receptors to inflammatory mediators such as bradykinin etc. ❖ NSAIDs ↓ PG formation & ↓ the sensitivity of pain receptors. ❖ Increase pain threshold by acting at subcortical level. ❖Effective in mild to moderate integumental pain e.g., myalgia, tooth ache, arthritis, headache, dysmenorrhea etc. ❖ Effective in mild post operative pain. ❖relieve pain without causing sedation, respiratory depression, tolerance or dependence. ❖Analgesic efficacy less than that of opioids, but, NSAIDs are having synergistic action with opioids. 14 Pharmacological Actions of NSAIDs 2. Antipyretic Effects ❖The thermoregulatory centre (thermostat) is situated in hypothalamus and fever occurs when there is disturbance in the hypothalamic thermostat. ❖PGs released due to tissue damage, infection, malignancy, graft rejection etc. ❖set the hypothalamic heat regulating centre (thermostat) high causing hyperpyrexia ❖ NSAIDs – inhibit production of PG & reset the thermostat. ❖Excess heat is lost by sweating & the raised body temperature is lowered to normal ❖ Do not decrease normal body temperature 15 Pharmacological Actions of NDAIDs 3. Anti-inflammatory Effect ❖ NSAIDs ↓ PG formation at the site of injury and inflammation. ❖In acute inflammation – provide relief by reversing vasodilatation, increased vascular permeability, oedema, pain ❖In chronic inflammation – symptomatic relief such as pain, tenderness, swelling, vasodilatation and leucocyte infiltration ❖They also affect other mediators of inflammation and inhibit granulocyte adherence to the damaged vasculature ❖NSAIDs also cause modulation of T cell function, stabilization of lysosomal membrane and inhibition of chemotaxis ❖ Anti-inflammatory dose is higher than analgesic and antipyretic doses. 16 Pharmacological Actions of NSAIDs 4. Antithrombotic (antiplatelet) effects ❖Aspirin in low doses (75-325mg/day) irreversibly inhibits platelet TXA2 synthesis and produces antiplatelet effect which lasts for 8-10 days, i.e., lifetime of platelets. This is because platelets lack nuclei and cannot synthesize COX. ❖In high doses i.e., in analgesic and anti- inflammatory doses inhibits both PGI2 and TXA2 synthesis, hence antiplatelet effect is lost because PGI2 is vasodilatory and inhibits platelet aggregation. ❖In low doses, PGI2 synthesis is not affected as it is synthesized by the widely distributed vascular endothelium. ❖Aspirin should be withdrawn I week before the elective surgery because of risk of 17 bleeding. Pharmacokinetics of NSAIDs ❖ Rapidly & completely absorbed from GI tract through passive diffusion. ❖ Peak occurring within 1-4hrs ❖ Some can be used as parenteral preparation, drops, gel, spray ❖ Distributed throughout most body tissues, 80-90% is bound to plasma proteins, mainly albumin ❖ Can displace several other drugs from plasma protein resulting in higher effective plasma concentrations of those drugs ❖ Aspirin undergoes zero order kinetics at higher doses. ❖ Inactivation occurs mainly in the hepatic ER (endoplasmic reticulum) and mitochondria and is mainly through the formation of conjugates that are excreted in the urine. 19 Therapeutic Uses of NSAIDs 1. As analgesic: Painful conditions like headache, toothache, backache, muscle pain, bursitis, dysmenorrhoea, neuralgias, bone pain, joint pain etc. 2. As antipyretic: To reduce elevated body temperature in fever. Paracetamol is preferred as it does not cause GI symptoms and doesn’t cause Reye’s syndrome in children. 3. Osteoarthritis: In mild cases – paracetamol and in severe cases other NSAIDs are used. Topical agents like methyl salicylate, diclofenac gel etc. can be used. 4. Rheumatoid arthritis: NSAIDs produce only symptomatic effects but they do not alter the progression of the disease. DMARDs (Disease Modifying Antirheumatic Drugs are drugs of choice. 5. Acute rheumatic fever: Aspirin is the preferred drug. It reduces fever, swelling and joint pain. But does not affect the normal course of the disease. Longacting penicillin can prevent cardiac complications 20 Therapeutic uses of NSAIDs 6.Thromboembolic disorders: Low dose aspirin is the drug of choice in i) Transient ischaemic attack ii)Myocardial infarction (MI) to reduce incidence of recurrent MI and to decrease mortality in post MI patients 7.Medical closure of patent ductus arteriosus (PDA): Ductus arteriosus is a shunt between pulmonary artery and arch of aorta. This is maintained by PGs during intrauterine life and closes at birth. If it is still patent after birth, indomethacin or ibuprofen can be given for the closure. 21 Therapeutic uses of NSAIDs 8. Other uses Colon and rectal cancer: Regular uses of aspirin can prevent according to some studies. Pre-eclampsia: Aspirin is beneficial by selectively reducing TXA2 production. Alzheimer’s disease: Regular use of small dose of aspirin can prevent the risk Niacin induced cutaneous flush and pruritus is mediated through PGs and low dose of aspirin can prevent. To slow down cataract progression 22 ASPIRIN Adverse Effects of NSAIDs 1. Gastric mucosal damage Nausea, vomiting, dyspepsia, gastric erosion especially in chronic users, hematemesis (blood vomiting), melena (blood in the stool), necrosis and ulceration. PGs (PGE2 and PGI2) act as cytoprotective agents by reducing gastric acid production, stimulating mucous and bicarbonate formation and dilating mucosal blood vessels. Inhibition of PG synthesis will lead to loss of cytoprotective action and mucosal damage. Local ‘ion trapping’ of aspirin also plays a significant role in mucosal damage. This can be prevented or minimized by taking a) NSAIDs after food b) buffered aspirin (preparation of aspirin with antacid) c) proton pump inhibitors/H2 blockers/misoprostol with NSAIDs d) selective COX2 inhibitors and Paracetamol for mild inflammation 17 Adverse effects of NSAIDs 2. Renal Effects NSAIDs can cause acute, but reversible renal insufficiency particularly in patients with congestive heart failure, cirrhosis, hypovolemia and renal disease, and in patients taking antihypertensives and diuretics. This may be due to inhibition of PG mediated compensatory vasodilatation and salt and water excretion. Chronic aspirin and other NSAID consumption in such cases may cause analgesic nephropathy characterized by chronic nephritis and renal papillary necrosis leading to irreversible renal damage. 25 Adverse effects of NSAIDs 3. Hypersensitivity and asthma Bronchospasm (aspirin induced asthma) is due to increased production of leukotrienes as more arachidonic acid is diverted to lipoxygenase pathway due to inhibition of COX. So NSAIDs should be avoided in asthmatics, with nasal polyps, recurrent rhinitis or urticaria 26 NSAIDs Induced Adverse Effects 27 Adverse effects of NSAIDs 4. Delay labour if given near term, there is increase chances of post-partum hemorrhage 5.Premature closure of ductus arteriosus: NSAID given in late pregnancy can cause premature closure of ductus arteriosus leading to hemodynamic abnormality. 6.Increase in bleeding tendency: long term use of aspirin decreases prothrombin levels by decreasing proconvertin (factor V) and hence prolongs prothrombin time and increases bleeding. Aspirin should be stopped one week before surgery and is contraindicated in hemophilia. 7. Effect on uric acid excretion: Aspirin in therapeutic doses decreases uric acid excretion and antagonise the uricosuric action of probenecid in gout. Contraindicated in gout. Adverse effects of NSAIDs 8. Reye’s syndrome Use of aspirin (salicylates)in children with viral infection may cause hepatic damage with fatty infiltration and encephalopathy – Reye’s syndrome. Hence salicylates are contraindicated in children below 15 years with viral fever. Paracetamol is preferred in children. 9. Effect on Respiration and Acid-Base Balance Therapeutic dose aspirin – stimulates respiration and produces hyperventilation (cause respiratory alkalosis) Salicylism characterized by headache, vertigo, tinnitus (ringing in the ear), hyperventilation, nausea, vomiting. 30 Adverse Effects of NSAIDs ❖Effects on Respiration and Acid-Base Balance At plasma level of 500microgram to 1 mg of aspirin, there will be respiratory acidosis due to medullary depression and respiratory depression and increased PCO2 level Plasma level above 1mg/ml causes severe and lethal toxicity in the form of metabolic acidosis characterized by hyperpyrexia, vasomotor collapse, renal and respiratory failure, dehydration, convulsion, coma and death. 31