Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) SZH - student version.pptx

NON-STEROIDAL ANTI- INFLAMMATORY DRUGS (NSAIDS) Siti Zawanah Binti Halim Master in Pharmacology and Toxicology (UPM) Faculty of Dentistry, AIMST University Learning Outcomes Classify NSAIDs based on chemical structure & therapeutic efficacy. Explain pharmacological actions, uses, routes...

NON-STEROIDAL ANTI- INFLAMMATORY DRUGS (NSAIDS) Siti Zawanah Binti Halim Master in Pharmacology and Toxicology (UPM) Faculty of Dentistry, AIMST University Learning Outcomes Classify NSAIDs based on chemical structure & therapeutic efficacy. Explain pharmacological actions, uses, routes of administration, adverse effects, contraindications & treatment of overdosage of NSAIDs. Apply the basic knowledge and relate the use of NSAIDS analgesics in Dentistry. Analgesics classified into: 1. Opioid – act on opioid receptors in the CNS & produce analgesia.  Morphine, Pethidine 2. NSAIDs (Non-opioid analgesics)  act centrally & peripherally.  prostaglandins, produced at the site of inflammation, stimulate pain receptors. NSAIDs act at site of inflammation & inhibit synthesis of prostaglandins.  Aspirin, Ibuprofen, Diclofenac Prostaglandins and Cyclooxygenase Prostaglandins (PGs) present in CNS & most other tissues. PGs synthesised by enzyme known as ‘Cyclooxygenase’ (COX). PGs regulate normal functions in body such as gastric mucosal integrity, platelet activity, kidney function etc. Thermal & mechanical stimuli, toxins etc. lead to PGs synthesis which act as mediators of inflammation, pain & fever. COX has many isozymes, of which COX-1 & COX-2 are clinically important. COX-1 COX-2 Constitutive: enzyme Constitutively: present in kidney & (continuously produced without CNS. Up regulated in certain cancers. need for an inducer). Induced by tissue injury, endotoxins, ‘House-keeping’: cytokines, tumor promoters etc. maintains homeostasis. Mediates Mediates Gastric mucosal integrity PGI synthesis in endothelium 2 Renal function Renal function Platelet aggregation Inflammation Cell to cell signalling Fever production Inflammation Tissue healing & resolution NSAIDs Classification (Effect on COX & Efficacy) 1) Nonselective COX inhibitors  High efficacy: Indomethacin, Piroxicam, Dicofenac  Moderate efficacy: Aspirin, Naproxen, Ibuprofen, Ketoprofen, Mefenamic acid  Moderate anti-inflammatory efficacy with high analgesic activity: Ketorolac  Analgesic & Antipyretic activity with no significant anti- inflammatory activity: Paracetamol 2) Selective COX2 inhibitors  Moderate efficacy: Celecoxib, Etoricoxib MoA of NSAIDs  Used to treat pain, fever & other inflammatory processes.  Main mechanism is inhibiting enzyme COX.  COX required to convert arachidonic acid into thromboxanes, prostaglandins & prostacyclins.  COX-1 constitutively expressed in body & plays a role in maintaining gastrointestinal mucosa lining, kidney function & platelet aggregation.  COX-2 not constitutively expressed in body & instead, its inducibly expresses during an inflammatory response.  MoA of NSAIDs Arachidonic acid Cyclooxygenase NSAIDs (COX) Prostaglandin formation inhibited NSAIDs have four major actions. 1) Anti-inflammatory – ↓ inflammation 2) Analgesic – ↓ pain 3) Antipyretic – ↓ body temperature in fever 4) Antiplatelet action – inhibit COX-1,mainly aspirin 1. Anti-inflammatory action Main MoA: NSAIDs ↓ PGs synthesis at site of inflammation. Other MoA: free radical scavenging, inhibition of lipooxygenase pathway etc.  Acute inflammation – provide relief by decreasing  Vasodilatation  Increased vascular permeability  Edema  Pain  Chronic inflammation – symptomatic relief only & the underlying pathology & progression of causes of the disease are unchanged. Note: Anti-inflammatory activity is higher than analgesic & antipyretic activity. 2. Analgesic action  Analgesia both by central & peripheral (main mechanism) actions.  PGs formed during tissue injury, inflammation etc. sensitize pain receptors.  NSAIDs prevent PGs formation & decrease sensitivity of pain receptors.  Analgesic efficacy of NSAIDs is less than opioids & are synergistic with opioids. Type of pain relieved: Mild to moderate pain from musculo-skeletal disorders involving inflammation & tissue damage. E.g., myalgia, toothache, arthritis, headache, dysmenorrhea, mild post operative pain. 3. Antipyretic action  PGs released during infection, malignancy, tissue damage, graft rejection etc. & set the hypothalamic heat regulating centre (thermostat) high causing hyperpyrexia (condition where body temperature goes above 106.7 degrees Fahrenheit (41.5 degrees Celsius) due to changes in the hypothalamus) COX-2 is predominantly involved in causing pyrexia/ fever.  NSAIDs – inhibit production of PGs & reset thermostat to normal temperature.  Excess heat produced due to fever is lost through sweating, lowering body temperature to normal.  Do not lower the normal body temperature below the range and do not cause hypothermia. 4. Antiplatelet action Platelet Blood vessel Thromboxane Prostacyclin COX-1 inhibition in platelets COX-2 selective NSAIDs results in antiplatelet action. (Coxibs) are found to Aspirin produces increase platelet aggregation irreversible inhibition of & incidence of thrombo- platelets & is the only embolic events by inhibiting NSAIDs used as COX-2 in endothelium antiplatelet drug. lowering prostayclin levels. Other actions of NSAIDs - COX-1 & 2 mediated lead to ADRs 5. GI effects - ↓ synthesis of PGs due to inhibition of COX-1 will decrease mucus production, direct gastric irritation cause gastric erosions, ulceration etc. Long term use of COX-2 selective NSAIDs also has GI toxicity. 6. Renal effects – autoregulation of renal blood flow is through local PGs which are inhibited by NSAIDs leading to salt & water retention, decreasing efficacy of diuretics. Chronic use of NSAIDs causes analgesic nephropathy.  Uses: For analgesia & anti-inflammatory action: toothache, headache, backache, joint sprains, dysmenorrhea, mild postoperative pain. For anti-inflammatory action in chronic or acute inflammatory conditions (e.g., osteoarthritis, rheumatoid arthritis, gout): higher doses & for longer periods & hence, toxicity is common. Antiplatelet action: low dose aspirin in secondary prophylaxis of MI & unstable angina or transient ischaemic attacks. In fever as antipyretic: Paracetamol is preferred. Note: COX-2 selective NSAIDs for patients with peptic ulcer/ gastric irritation to avoid decrease in mucus production. Routes of administration: Oral – cause GI irritation (to minimize GIT irritation give NSAIDs after food). Other routes - IM, IV, topical (drops, gel, spray, ointment etc.). Direct transport through skin from topical application is minimal. Drug reaches tissues via blood stream following absorption.  Drug interactions: Decrease the effect of diuretics & antihypertensives drugs. Cause additive GI toxicity with corticosteroids. Increase activity of warfarin & oral antidiabetic drugs. Contraindications : During pregnancy. Aspirin is contraindicated in children & teens for the treatment of viral acute febrile illness due to risk of Reye’s syndrome (encephalopathy, liver dysfunction & fatty infiltration of viscera with high mortality). ADRs: 1) GIT: nausea, vomiting, dyspepsia, gastric erosion on chronic use, hematemesis. 2) Renal: salt & water retention, edema, ‘analgesic nephropathy’ following chronic & high dose intake. 3) Antiplatelet action with non-selective NSAIDs: increased bleeding time, may potentiate anticoagulants. 4) CVS: closure of patent ductus arteriosus (PDA) in babies if given to mother late in pregnancy; CCF, MI, stroke increased (except with low dose aspirin). 5) Psychiatric reactions: excitement etc. with indomethacin. 6) Hepatotoxicity: with large doses of paracetamol. 7) Hypersensitivity: skin rash, precipitation of asthma. NON-SELECTIVE COX INHIBITORS 1. Ibuprofen  Equipotent to aspirin.  Efficacy - moderate Route: oral, topical ADR: low, tolerated better. It is safe in children. Drug interactions: no interaction with oral anticoagulants & oral antidiabetic agents. Uses: toothache, myalgia, fever, rheumatoid arthritis etc. 2. Aspirin Irreversible inhibitor of COX. MOA: in ‘low doses’ of 7.5 g. Patients with hepatic disease, viral hepatitis, a history of alcoholism are at higher risk of acetaminophen-induced hepatotoxicity. Paracetamol is present in several FDC (fixed-dose combination) (hidden) and if prescribed together or taken in self-medication, fatal toxicity can occur. Paracetamol poisoning: often seen If > 5 -10g is ingested (accidental / suicidal), a reactive metabolite (N-acetyl- p-benzoquinoneimine) (detoxified by conjugation with glutathione) is formed in large quantities & reacts with liver & kidney enzymes causing necrosis. Nausea, vomiting, abdominal pain, coma. Treatment: Supplement glutathione by giving acetyl cysteine (oral or IV) or methionine (oral), Most effective if given within 12 h of ingestion of paracetamol. Basic knowledge and uses of NSAIDS analgesics in Dentistry  NSAIDs analgesics are the mainstay for management of acute dental pain.  While pain during an invasive dental procedure is allayed by a local anesthetic, that before and after it is treated mostly with NSAIDs analgesics.  Cause and nature of pain (mild, moderate or severe; acute or chronic; ratio of pain: inflammation) along with consideration of the risk factors in the patient govern selection of the analgesic. Also, to be considered are the experience of the patient, acceptability and individual preference.  Basic knowledge and uses of NSAIDS analgesics in Dentistry Guidelines:  Mild-to-moderate pain with little inflammation - paracetamol or low-dose ibuprofen.  Post extraction or similar acute but short-lasting pain - ketorolac, a propionic acid derivative, diclofenac or nimesulide.  Gastric intolerance to conventional NSAIDs or predisposed patients - etoricoxib or paracetamol.  Patients with history of asthma or anaphylactoid reaction to aspirin/other NSAIDs - nimesulide, COX-2 inhibitor.  Paediatric patients - only paracetamol, aspirin, ibuprofen and naproxen have been adequately evaluated in children - should be preferred in them. Due to risk of Reye’s syndrome, aspirin should be avoided unless viral infection can be ruled out.  Pregnancy - paracetamol is the safest; low dose aspirin is probably the second best.  Hypertensive, diabetic, ischaemic heart disease, epileptic and other patients receiving long-term regular medication - possibility of drug interaction with NSAIDs should be considered and the physician consulted.  Patients with risk factors for cardiovascular diseases, stroke - avoid etoricoxib/ celecoxib; ibuprofen or low-dose aspirin may be used. Recommended reading  Katzung Bertram G. (2018) Basic & Clinical pharmacology, (14th Edition), Mcgraw Hill.  Whalen,K., Finkel, R. (2019 )Lippincott Illustrated Reviews: Pharmacology (7th Edition), Wolters Kluwer.  Rang HP, (2020)Dale’s Pharmacology, (9th Edition), Elsevier,.  Brunton. L.L., Hilal-Dandan. R., Knollmann. B.C., (2018) Goodman & Gilman's: The Pharmacological Basis of Therapeutics, (13th Edition), Mcgraw Hill.  Tripati, K.D. (2016) Essentials of Pharmacology for Dentistry, (3rd edition) Jaypee Brothers.  Tripati, K.D. (2019) Essentials of Medical Pharmacology, (8th Edition) Jaypee Brothers.  Rang, H.P., M.M and Ritter, J.M.(1999) Pharmacology (4th Edition), Churchill Livingstone.  Katjung B.G. (2000) Basic and Clinical Pharmacology, (8th Edition), Appleton and Lange.  Page, C.P., Curtis, M.J., Sutter, M.C., Walker, M.J.A and Hoffman, B.B. (2002) Integrated Pharmacology. (2nd Edition), Mosby.  Seymour.R, John G. Meechan and Yates. M., Pharmacology and Dental Therapeutics (3rd edition) Oxford publication.