Eicosanoids and NSAIDs PDF

Eicosanoids and NSAIDs PHRM 240 Ramzi Sabra, MD, MHPE EICOSANOIDS Arachidonic Acid Metabolites: Prostaglandins, Prostacyclins, Thromboxanes, Leukotrienes  Cell Membrane Phospholipids Tissue injury (Ca++) Phospholipase A2 Inflammation Hormones, Peptides Cyt...

Eicosanoids and NSAIDs PHRM 240 Ramzi Sabra, MD, MHPE EICOSANOIDS Arachidonic Acid Metabolites: Prostaglandins, Prostacyclins, Thromboxanes, Leukotrienes  Cell Membrane Phospholipids Tissue injury (Ca++) Phospholipase A2 Inflammation Hormones, Peptides Cytokines… Arachidonic Acid Li e po as xy en yg ge n ox as clo e Cy Others Prostaglandins Leukotrienes Thromboxanes Prostacyclins Isoprostanes Cyt. P450 products  Cell Membrane Phospholipids Phospholipase A2 Arachidonic Acid COX I&II (cyclooxygenase and hydroperoxidase activities Prostaglandin G2 &H2 (cyclic endoperoxides) TXA2 synthase PGI2 synthase Thromboxane A2 Prostacyclin (PGI2) red uct ase isomerases Prostaglandin D2 Prostaglandin F2α Prostaglandin E2 Theory 20 years ago - no longer true Endothelium, brain, spinal cord COX-2 also in Kidney (Macula densa), ovaries, uterus  Cell Membrane Phospholipids Phospholipase A2 12-LO 15-LO HETE-12 Arachidonic Acid HPETE-15 5-Lipoxygenase + FLAP Leukotriene B4 5- HPETE Hydrolase Dehydrase Leukotriene A4 5-HETE Glutathione S-transferase Leukotriene C4 Leukotriene D4 Leukotriene E4 Peptidase Peptidase  General Properties of AA Metabolites Multiple cell-surface receptors Multiple complex physiological and pathophysiological roles Synthesized on demand – not stored Metabolized: short t1/2 (seconds/minutes) Act locally where produced – autocrine and paracrine  MODULATORS OF THE PATHWAYS Membrane Phospholipids Corticosteroids - Phospholipase A2 Arachidonic Acid NSAID’s Zileuton - LO - II X I& X CO Cyclic Endoperoxides Leukotrienes - Prostaglandins Thromboxanes Receptor Antagonists Agonist - Prostacyclins Synthesis Inhibitors  Pharmacological/ Physiological Effects I. Cardiovascular/Renal System 1. PGE2 and PGI2: vasodilators. – By vasodilating they protect the kidney against ischemia – They also decrease Na and water absorption in kidney  diuresis If you give a PG synthesis blockers (e.g. NSAID) to a patient who is hypertensive, what would you expect to see? A. Worsening of hypertension B. Improvement of hypertension C. Nothing whatsoever Same if someone has congestive heart failure  more edema and congestion Pharmacological/Physiological Effects II. Platelets ARACHIDONIC ACID COX -1 COX -2 Platelet Endothelial TXA2 PGI2 Vasoconstriction Vasodilation Platelet Aggregation Anti-Platelet Aggregation Pharmacological/Physiological Effects II. Platelets ARACHIDONIC ACID COX -1 _ _ COX -2 Platelet Endothelial TXA2 ASPIRIN PGI2 X Vasoconstriction Vasodilation Platelet Aggregation Anti-Platelet Aggregation Aspirin’s Antiplatelet Effect 1. Aspirin is more selective for COX 1 than COX 2, so at small doses, preferential inhibition of COX 1 2. Irreversible inhibition of COX. Since platelet cannot synthesize COX while vessel wall can, get preferential inhibition of platelet TXA2 production. 3. Net effect: shifts balance between prostacyclin and thromboxane in favor of prostacyclin  antiplatelet aggregation What happens if you give a drug that blocks COX-2 only? Pharmacological/Physiological Effects III. Pulmonary LTC4 and LTD4: Bronchoconstriction + ↑mucus secretion + ↑vascular permeability: major role in symptoms of asthma Blocker of their receptor e.g. montelukast: useful in asthma Pharmacological/Physiological Effects IV. GI Tract PGE2: watery diarrhea, vomiting and cramps (↑cAMP) PGE2+ PGI2: inhibit gastric acid secretion; + have a cytoprotective effect in stomach: ↑ mucosal blood flow; ↑ mucus secretion; ↑ protein synthesis Blockers (NSAIDs) can cause peptic ulcer Analogues e.g. Misoprostol: PGE1 analogue: used to treat peptic ulcers Pharmacological/Physiological Effects V. Reproductive Organs 1. PGE2 and PGF2: contract pregnant uterus. 2. Role in promoting labor; in miscarriages (premature labor); used to induce abortions. 3. Role in maintaining patent ductus arteriosus. Blockers of synthesis (NSAIDs) may porolong gestation and risk closing PDA  fetal death  Pharmacological/ Physiological Effects VI. Pain and Inflammation 1. PGE2, PGI2, LTB4: sensitize nerve endings to painful stimuli. In CNS increase excitability of pain pathways 2. Vasodilation  Hyperemia, Edema, Hotness in inflammation 3. LTB4: chemotactic factor for neutrophils and mononuclear cells. Promotes inflammatory response Blockers (NSAIDs, Corticosteroids):  Which of the following would be the most effective anti-inflammatory drug? A. NSAID’s B. Selective COX-2 inhibitors C. LOX inhibitors D. Steroids E. Leukotriene Antagonists  Therapeutic Uses of Eicosanoids or their Analogues Induction of abortion (PGE’s and PGF’s) Gastric protection/peptic ulcer (PGE analogue - misoprostol) Maintain patency of ductus arteriosus (PGE) Pulmonary Hypertension (PGI2 analog- iloprost)  Therapeutic Uses of Modulators NSAID’s and Corticosteroids: anti- inflammatory, analgesic, antipyretic. Zileuton: ulcerative colitis, asthma, allergic rhinitis: limited success Montelukast: LTC4 & D4 receptor antagonist: asthma NON STEROIDAL ANTI INFLAMMATORY DRUGS Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Common therapeutic indications Common adverse effects Common mechanism of action (cyclooxygenase inhibition) Different pharmacokinetics and potency Different chemical families Similarities more striking than Differences Different selectivity to COX I and II – pharmacological consequences A. Chemical Similarity B. COX isoform selectivity C. Plasma Half-life From Goodman and Gilman  Common Therapeutic Uses Analgesic (CNS and peripheral effect) may involve non-PG related effects Antipyretic (CNS effect) Anti-inflammatory (except acetaminophen) due mainly to PG inhibition. Some are Uricosuric: increase uric acid excretion  Common Adverse Effects Gastritis and peptic ulceration with bleeding Platelet-Endothelial Dysfunction: Bleeding vs. Thrombosis Acute Renal Failure if susceptible individuals (decrease RBF, and GFR) Sodium retention, edema, worsen hypertension and heart failure Hyperkalemia (increase risk if other factors exist)  Aspirin (acetylsalicylic acid) Therapeutic Uses Antipyretic Analgesic (moderate pain: musculoskeletal, post-surgery, inflammatory) Anti-inflammatory: rheumatological diseases. High dose needed (5-8 g/day) Anti-platelet - prophylaxis of diseases due to platelet aggregation (CAD, post- op DVT) Pre-eclampsia and hypertension of pregnancy (?excess TXA )  Aspirin Toxicity - Salicylism Headache - tinnitus - dizziness – hearing impairment – dim vision Confusion and drowsiness Hyperpyrexia and excessive sweating Hyperventilation Nausea, vomiting Marked acid-base disturbances Dehydration Cardiovascular and respiratory collapse, coma convulsions and death Among the following strategies for treatment of aspirin poisoning, which would be the least useful and potentially harmful? A. Gastric lavage B. Acidifying the urine C. Icecold baths D. IV fluid 0% 0% 0% 0% 0% administration sis s n ng e E. Hemodialysis th tio in ly ba iti ur ia ra om od ld he ist co gv m in gt Ice He m cin in ad ify du id id In Ac flu IV  Aspirin Toxicity - Treatment Decrease absorption - activated charcoal, gastric lavage Enhance excretion - alkalinize urine, forced diuresis, hemodialysis Supportive measures - fluids, decrease temperature, bicarbonate, electrolytes, glucose, etc…  Acetaminophen differs from others in many ways: Analgesic and antipyretic but weak anti-inflammatory No GI, renal or cardiovascular adverse effects Main toxicity: hepatitis due to toxic intermediate which depletes glutathione. Treat with N- acetylcysteine.  Hepatotoxicity by Acetaminophen - Toxic Intermediate Treat hepatotoxicity with N-Actylcysteine (binds intermediate and restores glutathione) N-acetyl-p-benzo-quinone imine (NAPQI)  Selective COX-II Inhibitors (e.g. celecoxib) Anti-inflammatory with less adverse GI events. But Toxicities: kidney and platelets: - Na retention, edema, hypertension - Increased risk of thrombotic events (rofecoxib withdrawn from markets by manufacturer) - Therefore, their use is restricted to special patients who do not have these risks Role in Cancer prevention Role in Alzheimer’s disease