NSAIDS 2024.pdf

Pharmacology of NSAIDS Mary Erclik PhD March 22nd 2024  Outline - Pathophysiology of Inflammation, Pain and Fever NSAIDS: General Characteristics - Pharmacokinetics - Adverse Effects - Mechanism of Action - Therapeutic Uses Specific NSAIDS -...

Pharmacology of NSAIDS Mary Erclik PhD March 22nd 2024  Outline - Pathophysiology of Inflammation, Pain and Fever NSAIDS: General Characteristics - Pharmacokinetics - Adverse Effects - Mechanism of Action - Therapeutic Uses Specific NSAIDS - Aspirin - Diclofenac - Indomethacin - Ibuprofen - Naproxen and Fenoprofen - Ketorolac - COX1 vs COX2; Celecoxib - Acetaminophen  Learning Objectives Students will be able to: Recall the names, mechanism of action and primary adverse effects of commonly used NSAIDS Apply their understanding of the pharmacology of NSAIDS to their use as antipyretics, anti-inflammatory and analgesic drugs Apply knowledge of NSAID pharmacology to anticipating adverse effects and drug interactions  NSAIDS: Effects NSAIDS Anti- Analgesic Anti-pyretic Cardiovascular Inflammatory - Osteoarthritis - Headache -fever - Antiplatelet - Gout - Dental pain (ibuprofen, (aspirin) - RA - Joint pain naproxen) - Combination with opioids  What is inflammation? A response by living, vascularized tissue designed to remove some injurious agent (including mechanical, chemical, thermal, radioactive etc.) A mechanism to restore tissue to normal Inflammation involves a reaction of the vasculature that is characterized by the movement of leukocytes and fluid from the blood into tissue The Inflammatory Response  Characteristics of Inflammation Redness: Caused by increased blood flow Swelling: Caused by fluid retention/edema Heat: Caused by increased blood flow Pain: Caused by impingement/pressure on local nerves Loss of function: excess of all of the above  Mediators of the Inflammation Histamine Released by mast cells in tissue and platelets in blood Prostaglandins The initial cause of the injury is thought to increase arachidonic acid availability with a subsequent increase in prostaglandin production Prostaglandins cause peripheral vasodilation with redness and edema (partly due to bradykinin activation) Bradykinin Serotonin  Consequences of Inflammation Inflammation OFTEN SOMETIMES PAIN FEVER  Pain Modulators Due to activation of nociceptors (pain receptors) Either mechanical or chemical induction Inflammatory mediators can directly induce pain (histamine, kinins) or can decrease pain threshold (histamine, PGE2 and PGI2)  Mechanism of Fever Exogenous Pyrogens: Lymphokines/ Phagocytic Cells Micro-organisms TNFα Hypothalamus Leukocytes Prostaglandin E2 IL-1 Raise set point of the temperature regulating centre - cutaneous vasoconstriction - decreased heat loss - increased heat generation - increased body temperature  Treatment of Inflammation TWO MAJOR GOALS OF ANTI-INFLAMMATORY THERAPY: 1. Relief of pain and other symptoms 2. Slowing or arrest of tissue damaging process (especially in chronic inflammatory condition (Key is to avoid side effects)  NSAIDs Pharmacology Non-steroidal Anti- Inflammatory Drugs Often exert antipyretic and analgesic effects as secondary benefit to anti-inflammatory effects Aspirin (ASA) the original drug; numerous molecular modifications to refine efficacy, safety and efficiency  Classes of NSAIDS General Consideration: NSAIDS are chemically diverse They share very similar mechanisms of action (very similar to ASA) Due to their different chemical structures their P.Kinetics are different  NSAIDS-General Kinetics Pharmacokinetics - Very high oral bioavailability - Well absorbed - Highly metabolized; phase I +phase II - Primarily renally eliminated - Some biliary excretion/enterohepatic circulation - Very highly protein-bound (principally albumin)  NSAIDS-PDynamics Mechanism of Action-NSAIDS Competitive inhibitors of the binding of cyclooxygenase to AA (in contrast to ASA which acts irreversibly) Inhibit the production of prostaglandins Coxibs selectively inhibit COX2 Mechanism of anti-inflammation: - COX inhibition, reduction of pro-inflammatory prostaglandins - Decrease vessel sensitivity to bradykinin and histamine - Influence T lymphocytes lymphokine production - Reversal of vasodilatation Biosynthesis of Prostaglandins  NSAIDS-Therapeutic Uses Anti-Inflammatory Drugs - Arthritis, Gout Antipyretics - inhibit effect of PGs in hypothalamus Analgesics - very effective for low to moderate pain (dental pain) - when used in combination may reduce the concentration of opioids Fetal Circulation - used to close patent ductus Cardioprotection - aspirin is an antiplatelet drug and offers protection from cardiovascular disease Niacin Tolerability - niacin is an effective LDL- and triglyceride-lowering medication but its use is associated with a flushing reaction; NSAIDS reduce the flushing Cancer Prevention - aspirin significantly reduces risk of colon cancer  Aspirin, A Unique NSAID Antiplatelet Effect From: European Society for Cardiology: Vol 8 Feb. 10th 2010  NSAIDs Adverse Effects Due to Reduced Prostaglandins Adverse Effects Reversible erosive gastritis (gastric and duodenal ulcers) - due to inhibition of protective prostaglandins (sometime misoprostol is given) - Anorexia - Nausea - Dyspepsia - Abdominal pain - Diarrhea  NSAIDs Adverse Effects Cardiovascular Adverse Effects - Hypertension and fluid retention - Use of COX2 selective drugs associated with increased risk of thrombotic events Renal Adverse Effects and Hypertension - PGs have an important role in controlling renal perfusion and ion reabsorption - In patients with CHF, hypovolemia, chronic kidney disease inhibition of PGs may result in altered renal blood flow and salt retention Lippincott; Pharmacology 7th Edition, 2019 Wolters Kluwer  Common NSAID Adverse Effects Tissue Common Adverse Effect GI Abdominal pain, nausea, diarrhea, anorexia, ulcers Platelets Inhibited platelet activation, increased bruising, increase hemorrhage Renal Salt and water retention, edema, decrease effectiveness of antihypertensive drugs including diuretics and ACE inhibitors, Hyperkalemia, decreased urate excretion CV Closure of ductus arteriosus, (MI, stroke, thrombosis for COX2 selective) CNS Headache, vertigo, dizziness, confusion, hyperventilation Uterus Prolongation of gestation, inhibition of labor From: Adapted from Goodman and Gilman; Pharmacological Basis of Therapeutics. 12th Ed.  NSAIDs-Contraindications Contraindications/ Drug Interactions - due to anti-platelet effects ASA should not be used in hemophiliacs - All NSAIDS may enhance the anticoagulant effect of Warfarin - NSAIDS may reduce antihypertensive effects of ACE inhibitors/ caution with hypertensive individuals particularly if individual is being maintained on ACE inhibitors, ARBs and diuretics - not to be used during pregnancy - aspirin should not be used in children after viral infection (due to danger of Reye’s) - High protein binding may result in the displacement of other drugs and therefore toxicity Individual NSAIDS: Specific Properties  ASPIRIN Pharmacokinetics of Aspirin - organic acid; pKa 3.5 - Rapidly absorbed from stomach and upper small intestine - Peak plasma salicylate levels are reached in 1-2 hours - Rapidly hydrolyzed to acetic acid and salicylate (half-life 15 minutes) - Highly bound (saturable) to albumin (may displace other drugs) - Metabolic pathways for salicylate disposition saturate at 600 mg; beyond this, dosage increases increase salicylate concentration Anti-inflammatory Drugs NSAIDs  NSAIDS- Phenylacetic Acid Derivatives Diclofenac Very potent anti-inflammatory agent , also has analgesic, antipyretic action Used in the treatment of acute gout, severe osteoarthritis and rheumatoid arthritis COX-2 selective Very short half-life Due to selective COX-2 targeting diclofenac offers some GI protection compared to non-selective NSAIDS Associated with reversible increase in liver transaminase levels  NSAIDS- Indols Indomethacin Very potent anti-inflammatory drug Well absorbed (oral route) Substantial plasma protein binding Hepatic metabolism Causes serious gastrointestinal complications therefore should only be used for rheumatoid arthritis, ankylosing spondylitis and acute bouts of gout Headache common: frequency = 15%-25% (including dizziness, depression, confusion)  NSAIDS-Phenylpropionic Acid Derivatives Ibuprofen Very well tolerated for long-term use in individuals who can't tolerate ASA because it causes gastrointestinal irritation/bleeding much less frequently than with aspirin Used often in children (flavoured chewable tablets, suspensions) Very high oral bioavailability Extensive protein binding Serum half-life: 2 hours Adverse Effects: Headache GI irritability Tinnitus  NSAIDS-Phenylpropionic Acid Derivatives Naproxen Naproxen is generally safe but it can cause GI disturbances (20-30%) Naproxen can compete with ASA for albumin binding sites Antacids containing Magnesium oxide or aluminum hydroxide can reduce rate of absorption Extensive plasma protein binding, excellent bioavailability and longer half-life than most other NSAIDS Available as both a topical and ophthalmic solution  Acetic Acid Derivatives- Ketorolac Ketorolac - Potent analgesic with moderate anti-inflammatory effects - Rapid onset and short duration of action - Often used post-operatively Adverse Effects - Risk of serious GI irritation, renal complications and bleeding NSAID: Adverse Effects Lippincott; Pharmacology 7th Edition, 2019 Wolters Kluwer  COX2 Selective Drugs COX 1 vs COX 2 COX 1 COX 2 Housekeeping function Induced at site of inflammation in GI tract, kidneys and platelets  COX 2 Selective Inhibitors Developed to inhibit prostaglandin synthesis by the COX 2 isozyme at sites of inflammation without affecting COX 1 (especially in GI tract) Prototype is celecoxib (15-20X more selective for COX 2) COX2 Selective- Mechanism of Increased Cardiovascular Risk  COX2 Selective: Celecoxib Celecoxib As effective as other NSAIDS in treating rheumatoid arthritis Causes fewer endoscopic ulcers compared to other NSAIDS Reduction of Prostacyclin (PGI2) synthesis in endothelium increases risk of thrombosis Significant drug interaction with warfarin (CYP2C9) Although has fewer GI side effects than other NSAIDS they have a number of other adverse effects including increased risk of cardiovascular events  Acetaminophen Acetaminophen A non anti-inflammatory analgesic; Predominantly antipyretic and analgesic Not useful as anti-rheumatic therapy Mechanism of action is unclear No anti-platelet effects Ideal analgesic for individuals who are susceptible to the gastric irritation of NSAIDS Analgesic and Antipyretic of choice for children and infants Very well tolerated at therapeutic doses  Acetaminophen Pharmacokinetics Oral administration Peak plasma levels: 30-60 minutes At large toxic doses may deplete glutathione in the liver which results in hepatotoxicity (antidote is N- acetylcysteine if delivered within 10 hrs of overdose) Lippincott; Pharmacology 7th Edition, 2019 Wolters Kluwer Pharmacology of Anti-Gout Medications  Gout “Screw up the vise as tightly as possible - you have rheumatism; give it another turn, and it is gout” - Anonymous Gout: - Familial metabolic disease - Deposits of monosodium urate in joints and cartilage - Attacks the big toe - Correlates with high serum levels of uric acid (purine metabolite with low solubility) Dietary considerations: Increasing unsaturated fatty acids such as eicosopentanoic acid (marine fish) can compete with arachadonic acid and alter the metabolites (good for other inflammatory diseases too) Avoid alcohol (wine and beer) and foods high in purines: meat, fish, dry beans, mushrooms, spinach, cured or pickled products Gout- Pathophysiology Lippincott; Pharmacology 7th Edition, 2019 Wolters Kluwer  Gout- Pharmacotherapy Acute and Chronic ACUTE TREATMENT NSAIDS (indomethacin) Corticosteroids If more than two attacks a year, chronic treatments should be considered CHRONIC TREATMENT Uricosuric agents - e.g. probenecid, sulfinpyrazone - inhibit proximal tubular reabsorption of uric acid - secretion of other weak acid drugs may be affected www.abcam.com/index. html?datasheet=616  Gout- Pharmacotherapy Chronic Chronic Treatment: Colchicine - natural compound derived from the autumn crocus - decreases the mobilization of granulocytes and leukocytes by inhibiting microtubule polymerization Allopurinol Inhibits xanthine oxidase to decrease uric acid synthesis  S UMMARY NSAIDS are effective in treating inflammation, pain and fever NSAIDS differ in their pharmacokinetics NSAIDS are therapeutically important drugs but are associated with a number of adverse effects resulting from prostaglandin synthesis inhibition The COX-2 selective drug celecoxib displays less GI complications but increased risk of cardiovascular events Acetaminophen is an effective analgesic and antipyretic but does not have anti-inflammatory properties The treatment of gout involves reducing inflammation from an acute attack and or administering prophylactic drugs that either reduce the production of uric acid (Allopurinol), uricosuric drugs (probenecid) that increase uric acid elimination or colchicine, which reduces the recruitment of leukocytes to the gouty joint