2 NSAIDs.pdf

1 2. NON-STEROIDAL ANTI- INFLAMMATORY DRUGS Dr. Racha KARAKY Pharmacology Faculty of Pharmacy L3 – S6 2  Eicosanoids 3 Mediators of inflammation  Some excellent youtube videos 4  Inflammation  https://www.youtube.com/watch?v=LaG3nKGotZs...

1 2. NON-STEROIDAL ANTI- INFLAMMATORY DRUGS Dr. Racha KARAKY Pharmacology Faculty of Pharmacy L3 – S6 2  Eicosanoids 3 Mediators of inflammation  Some excellent youtube videos 4  Inflammation  https://www.youtube.com/watch?v=LaG3nKGotZs  https://www.youtube.com/watch?v=uc6IV85mf3s  Fever  https://www.youtube.com/watch?v=QV7j-XQ7wv8  Eicosanoids  https://www.youtube.com/watch?v=-JOn8g8LvwE  This course … 5  Eicosanoids  NSAIDs  Analgesics : paracetamol = acetaminophen 6 Eicosanoids  Eicosanoids : Introduction 7  Eicos = 20 (Greek ; 20 carbon fatty acids)  Lipid-membrane derived compounds  Include prostaglandins (PGs), prostacyclin (PGI2), thromboxane A2 (TxA2), leukotrienes (LTs), lipoxins, and hepoxilins  Highly potent with a wide spectrum of activity  Have very short t1/2 (seconds – minutes)  Low blood concentrations  Produced de novo (by all cells except RBC) : not stored !  Prostanoids are released from cells predominantly by facilitated transport through the PG transporter  Synthesis, release, action and inactivation occur locally in the same tissue  Eicosanoids contribute to inflammation, smooth muscle tone, hemostasis, thrombosis, parturition, and GI secretion.  Eicosanoids biosynthesis 8 Eicosanoids production is initiated by the release of C20-polyunsaturated fatty acids, such as arachidonic acid Rate-limiting step Liberated fatty acids are then stereospecifically oxygenated either through the cyclic prostaglandin synthase pathway (prostaglandin H2 synthase (PGH2S), including cyclooxygenase (COX) activity) or through the linear lipoxygenase- dependent pathway (5-lipoxygenase; 5-LO), and are thus converted into one of four families of eicosanoids: the prostaglandins (PGs), prostacyclins, thromboxanes (TXs) and leukotrienes. Platelet- activating factor  EETs CYPs Isoprostanes Free radical attack 9 Cysteinyl leukotrienes  Prostaglandin / thromboxane pathway 10  PLA2 : membrane phospholipids → arachidonic acid (AA)  Can be constitutive  Can be induced by chemical and physical (thermal, mechanical) or biological (immune complexes, thrombin, bradylkinin, …) stimuli  COX = cyclooxygenase : AA → Intermediates (PGG2 /PGH2)  COX1 is constitutive → prostanoids with housekeeping functions  COX2 is inducible → upregulated by cytokines, shear stress, and growth factors → prostanoid involved in inflammation and cancer.  Others : intermediates → prostanoids  Enzymes = isomerases and synthases expressed in a relatively cell- specific fashion ◼ Platelets (COX1) → TxA2 ◼ Activated macrophages (COX-2) → PGE2 and TxA2 ◼ Vascular endothelium → PGI2 ◼ Mast cells → PGD2 ◼ GI tract, lung, other tissues → PGE  COX1 & COX2 structural difference : COX2 has a wider channel COX2 has a side pocket 11  Vasoconstriction Inh Plt aggregation /GI Vasoconstriction  Vessel Permeability Bronchodilation 12 Cytoprotection = Increase in gastric mucous secretion In kidney : modulation of blood flow and glomerular filtration+  Na/H2O excretion  Therapeutic uses 13 14 NSAIDs Mechanisms of action PK  Physiological Inflammatory Stimulus Stimulus COX-1 COX-2 Other inflammatory constitutive Induced mediators PGE2 PGE2 PGI2 TXA2 15  Eicosanoids in inflammation 16 Damaged membrane ▪ Trauma (mechanical, Corticosteroids chemical, thermal) ▪ Immune complexes PLA2 EP2 & IP → local BF, vascular permeability NSAIDs and leucocyte Arachidonic Acid infiltration LOX-5 COX -1&2 COX-1 Initial phase of acute inflammation Prostaglandins Leukotrienes PGE2, PGD2, PGF2α COX_2 Upregulated in few hours Prostacyclin (PGI2) PGD2 contributes to Major source of pro- inflammation in inflammatory Thromboxane A2 allergic response prostanoid TXA2  Eicosanoids in pain 17 Central analgesics : ▪ Opioids ▪ NMDA antagonists ▪ 2 agonists Peripheral analgesics : ▪ NSAIDs ▪ Local anesthetics PG, Bradykinin, 5HT, histamine, ATP, H+, endotheline, interleukins, …  Eicosanoids in pain 18 PGE2 (EP1/EP4) and PGI2 reduce the threshold to stimulation of nociceptors → peripheral sensitization 5HT , Sub P Reversal of peripheral sensitization is the mechanistic basis of the peripheral analgesic activity of NSAIDs. NSAIDs also have important central actions Centrally PGE2 ,PGD2, PGI2 & PGF2α → central sensitization COX-1 and COX-2 are expressed in the spinal cord and release PGs to peripheral pain stimuli  Pain levels 19 Pharmacologic Therapy for Acute Pain https://www.aafp.org/afp/2013/0601/p766.html  Pain levels 20  Eicosanoids in fever 21  Body temperature regulation = balance between production and loss of energy Infection, or tissue damage, inflammation, graft rejection, or malignancy Formation of endogenous pyrogens = cytokines such as IL-1, IL-6, TNF-, and interferons Late response of hypothalamus = induction of COX-2 endothelium of blood vessels in the preoptic hypothalamic area → PGE2 PGE2 → EP3 and perhaps EP1 receptors on thermosensitive neurons → hypothalamus elevates body temperature by promoting an increase in heat generation and a decrease in heat loss  NSAIDs classification 22  Selectivity of NSAIDs 23 IC50Cox − 1 Ratio = = 10 IC50Cox − 2 100% Enzyme activity inhibition COX2 COX1 0.3 3 (µg/mL) IC50, COX-2 IC50, COX-1  Selectivity of NSAIDs 24 RATIO COX1 COX2 Non selective tNSAIDs NSAIDs Preferential Preferential COX1 COX2 Selective COX2 COXIBS  Mechanism of action : COXi 25  NSAIDs : competitive & reversible inhibitors of COX  Enter channel  Block channel by binding with H-bonds to an arg half of the way in  Prevent AA from gaining access  Duration of action is related to the time course of drug disposition  Aspirin: irreversible inhibitor of COX1  Acetylates serine 529 of COX-1, located high up in the hydrophobic channel  Mechanism of action : COXi 26  Mechanism of action : COXi 27 Selective COX-2 inhibitors are generally more bulky molecules, can enter and block the channel of COX-2, but “not” that of COX-1.  Rationale for COX2 selective inhibitors 28  COX-2 = bad enzyme  COX-1 = good enzyme Rationale for COX-2 selective inhibitors Coxibs would provide  Overly simplistic perception ❖ Similar efficacy to tNSAIDs  COX-2 may be constitutive ❖ Less GI adverse effects ◼ In kidney, brain, ovary, uterus, …  Studies showed that COX-1 is involved in inflammation  COX-2 can generate anti-inflammatory PG (PGJ2) and promote healing  CV risk ??  Mechanism of action : extra COXi 29 MISCONCEPTION : all NSAIDs are equally therapeutically effective & any one of them could be used for a given indication  Additional possible anti-inflammatory mechanisms  Inhibition of leukocyte movement & chemotaxis  Inhibition of other enzymes : 5LOX, PLA2, iNOS  Down-regulation of IL-1 production  Inhibition of actions of other mediators of inflammation/ bradykinin  Inhibition of neutrophil activation thereby preventing ◼ Release of free radicals and superoxide ◼ Release of lysosomal & nonlysosomal enzymes  Inhibition of breakdown of cartilage matrix  Additional actions of some drugs Examples Inhibition COX2 transcription Salicylates Inhibition 5LOX Ketoprofen Inhibition other phospholipases Indomethacin, Inhibition NFKB Aspirin, salicylates, Ibuprofen, flurbiprofen, sulindac, indomethacin, L-selectin shedding Aspirin, salicylates, ketoprofen, flurbiprofen, diclofenac, indomethacin, aceclofenac, meclofenamic acid, mefenamic acid Inhibition of iNOS Aspirin, salicylates Inhibition of neutrophil chemotactic pathways Naproxen, oxaprozin Inhibition of VLA-4 activation Diclofenac, indomethacin, aceclofenac Cleavage of epithelial cell adhesion molecule Sulindac Inhibition of 2 integrin activation Piroxicam, meloxicam Antagonize bradykinin Ketoprofen 30 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5065088/  PK 31  Good oral absorption ❑ Food intake delays absorption ❑ Antacids delay but do not reduce absorption  High Pp binding  Wide distribution (including CNS)  Hepatic metabolism & renal excretion  Enterohepatic circulation  Variable t1/2  Short t1/2 → rapid effect and clearance ◼ Diclofenac , ibuprofen, indomethacine, …  Longer t1/2 → slower onset and slower clearance ◼ Naproxen, meloxicam, piroxicam, … 32 NSAIDs Adverse effects  ❖ CV : hypertension, MI & CHF ❖ CNS : Headaches, tinnitus, dizziness, and rarely, aseptic meningitis. ❖ Hepatic : Abnormal liver function test results and rare liver failure ❖ Delayed healing ❖ Skin : Rashes, all types, pruritus 33 ❖ Hematologic : Rare thrombocytopenia, neutropenia, or even aplastic anemia.  GI toxicity 34 GI erosion and ulceration Mild gastritis and vomiting Full-thickness perforation of the muscularis mucosa Blood loss Gradual, leading to anemia over Acute and life-threatening time Infections Organisms may gain access to the Endotoxic shock circulation  GI toxicity 35  Irritation of the GI mucosa can be  Direct: Acidic NSAIDs diffuse into the gastric mucosa where they cause injury  Systemic :  PG (PGI2 and PGE2) synthesis ◼ Decreased cytoprotection ◼ Diminished blood flow ◼ Inhibition of mucosal cell turnover and repair  Symptoms : Abdominal pain, dyspepsia, nausea, vomiting, and, less frequently, ulcers  Prevention  Administration of NSAIDs with food and water / gastro-resistant formulations  Co-administration of the PGE1 analog, misoprostol, or proton pump inhibitors (PPIs) or anti-H2 drugs  Drug selection : coxibs or COX2 preferential drug  Systemic effects Systemic effects 36  Renal toxicity 37 Minor role in healthy individuals Role when renal perfusion  COX1 & COX2 expressed  Renal toxicity 38  PG are involved in maintaining renal blood flow and GFR in cases of reduced renal perfusion or fluid/sodium depletion  Dehydration, electrolyte depletion  Congestive heart failure, hepatic diseases, chronic kidney disease  Anesthesia  Shock  Renal toxicity associated with NSAIDs is characterized by  Decreased renal perfusion, reduced GFR and decreased tubular function  Sodium and fluid retention  Systemic hypertension  Reported cases of toxicity occurred when high doses were used or when there were other complicating factors/drugs  Cardiovascular toxicity of Coxibs 39 Effects of NSAIDs on platelets and vascular endothelial cells. Balance between thromboxane and prostacyclin is important in thrombosis. COX-1 inhibitors decrease thromboxane production more effectively than prostacyclin production, tipping the balance away from thrombosis. In contrast, COX-2 inhibitors inhibit only prostacyclin production, decreasing inflammation but tipping the balance toward thrombosis. ASA indicates aspirin; Coxibs, COX inhibitors. 40 NSAIDs Clinical uses  Therapeutic uses 41  Inflammation - pain – fever  Arthritic disorders : Rheumatoid arthritis, osteoarthritis, spondylarthopathies  Acute/ chronic musculoskeletal pain  Gout  Cardioprotection → aspirin  Others  Closure of patent ductus arteriosus : Indomethacin, Ibuprofen  Dysmenorrhea : Naproxen , Meclofenamic acid  Cancer Chemoprevention: ◼ Aspirin use (> 5 years) is associated with as much as a 50% decrease in the risk of colon cancer ◼ Effect observed with other NSAIDs  Chemical classification 42 Carboxylic ac Enolic ac COXIB salicylate Propionic ac Fenamic ac Acetic ac Celecoxib CELEBREX Etoricoxib ARCOXIA Aspirine Ibuprofen Mefenamic ac Indomethacin OXICAMS Diflunisal ADVIL PONSTAN INDOCIN Piroxicam Naproxen Meclofenamic ac Sulindac FELDENE PROXEN Flufenamic ac Etodolac Meloxicam Ketoprofen ETODINE Nicotinic ac MOBIC PROFENID Diclofenac Tenoxicam Tiaprofenic ac VOLTARENE TILCOTIL SURGAM Ketorolac Lornoxicam Loxoprofen ALGIKEY XEFO Lysine ROXONIN Aceclofenac clonixinate AIRTAL DORIXINA 43 NSAIDs Aspirin Salicylates  Aspirin : mechanism of action 44  Aspirin acetylates COX1 (ser 529) & COX2 (ser 516)  COX1 → Interposition of the bulky acetyl residue prevents the binding of AA to the active site of the enzyme → impedes the ability of the enzyme to make PGs  Aspirin : mechanism of action 45 Irreversible inhibition Acetylated COX2 → of COX1 Unique ability to generate an endogenous mimetic of natural lipoxin A4, namely aspirin triggered lipoxins ATL  Pharmacological effects 46 Main use  Aspirin anti-aggregant effect 47  Doses : 75 – 325 mg  Used for secondary prophylaxis of MI & stroke  Aspirin acetylates platelet COX1 within minutes of reaching the circulation  Platelet COX1 irreversibly blocked for the entire lifetime of the platelet  8 days  Inhibition of platelet COX1 is cumulative with repeated doses of aspirin  After aspirin discontinuation → 5 days required for the full recovery of platelets  PK : Aspirin 48  Weak organic acid Irreversible COX  Absorbed in the stomach and blocker the upper small intestine  Metabolized to acetic acid Reversible and salicylate by esterases in COX tissues and blood blocker  The free salicylate is then excreted unchanged, or converted to other water- soluble compounds that are then excreted by the kidney  Aspirin adverse effects 49  GI :  Epigastralgia, nausea, and vomiting (irritation + central effect)  Ototoxic effect :  High-dose of salicylate therapy → Hearing impairment, alterations of perceived sounds, and tinnitus ❑ Hepatic effects: ❑ Dose-dependent hepatic damage (reversible after drug D/C ) ❑ Asymptomatic, with elevated plasma transaminase levels ❑ May be more severe and associated with encephalopathy seen in Reye’s syndrome. ❑ Use of salicylates in children with chickenpox or influenzae is contraindicated  Aspirin adverse effects 50  Urate excretion: effects of salicylates on uric acid excretion are dose dependent Low doses  urate excretion &  plasma urate concentrations Large doses induce uricosuria and  plasma urate levels  Interference with aspirin antiplatelet 51 activity 52 NSAIDs Acetic acid derivatives  Indomethacin INDOCIN 53  Nonselective & potent inhibitor of the COXs  Highly effective : Several extra-COX activities  Therapeutic uses  A high rate of intolerance limits its long-term analgesic use  Used for closure of persistent patent ductus arteriosus in premature infants  Treatment of moderate to severe rheumatoid arthritis, osteoarthritis, and acute gouty arthritis; ankylosing spondylitis; and acute painful shoulder  Adverse effects : Cause of D/C in 20% of patients  GI adverse events are common and can be very severe/fatal ◼ Diarrhea, acute pancreatitis, fatal hepatitis  CNS effects ◼ Severe frontal headache (25-50%) ◼ Dizziness, vertigo, mental confusion, severe depression, psychosis, hallucinations, and suicide  Hematopoietic effects : leukopenia, hemolytic anemia, …  Possibility of cross-sensitivity with aspirin  Others … 54  Diclofenac VOLTARENE  Analgesic, antipyretic and anti inflammatory agent  Accumulates in synovial fluids  ↑ hepatic transaminases in 5-15 % of patients (transaminases should be measured during the first 8 weeks of therapy)  Ketorolac ALGIKEY, KETOLAC  Potent analgesic & moderate anti inflammatory agent  Mainly used for short term management of pain mainly in postsurgical pain  Used per os , IM, IV , eye drops ACULAR  Rapid onset of action & Short duration of action (4 – 6 h)  Adverse effects: somnolence, headache, GI pain & bleeding  Causes ulcers more frequently than other NSAID → not used for more than five days !  Renal toxicity is more common than NSAIDs with chronic use & in patients with renal/hepatic dysfunction  Aspirin sensitivity is a contraindication 55 NSAIDs Propionic acid derivatives  Propionic acid derivatives 56  Among the most widely used NSAIDs for pain & inflammation  Low doses : mild pain & inflammation  High doses : arthritic disorders  Non selective COX inhibitors  Short term use → very few adverse effects  Dose-dependent gastric irritation, nausea, dyspepsia & bleeding  Long term use → associated with peptic ulcer disease  Possible cross-sensitivity to aspirin  Agents 57  Ibuprofen ADVIL  Analgesic doses ( 20 mg/d →  (9.5 x) incidence of peptic ulcer & bleeding  Meloxicam MOBIC  Preferential COX2 inhibitor (7.5 mg dose)  Fewer clinical GI symptoms and complications than piroxicam, diclofenac, and naproxen  Used for OA, RA and other rheumatic conditions 61 NSAIDs Coxibs  Properties 62  Highly COX2 selective  Compared to non selective NSAIDs  Less ulcerogenic  Same nephrotoxicity risk  Increased risk of CV events  Do not interfere with aspirin antiaggregant effect  CV risk  with dose and duration of therapy → use for the shortest duration possible and the lowest effective daily dose  Should be avoided in patients with CV disease or with significant risk factors for CV events : hypertension, hyperlipidemia, diabetes mellitus, smoking  PK of oral coxibs  Extensive metabolism by CYP2C9 (celecoxib), CYP3A4 (etoricoxib) → DDI  Long t1/2 (QD/BID)  Coxibs Timeline 63  Coxibs 64  Celecoxib CELEBREX  May cause rash (sulfonamide)  Etoricoxib ARCOXIA  Associated with more frequent and severe hypertension than other NSAIDs → Hypertension should be controlled before treatment & regular BP monitoring during treatment  Parecoxib DYNASTAT  Only coxib administered by injection.  Prodrug converted to valdecoxib the active drug  Valdecoxib (T½=7 – 8 h) is metabolized by CYP2C9 & 3A4 ❑ Adverse effects : possibility of life threatening skin reactions : stevens Johnson syndrome (valdecoxib) ❑ Must be discontinued at the first sign of rash, mucosal lesion, or any other sign of hypersensitivity https://www.dovepress.com/the-safety-profile-of-parecoxib-for-the-treatment-of-postoperative-pai- peer-reviewed-fulltext-article-JPR#T4 65 Analgesics Paracetamol = Acetaminophen  Acetaminophen = paracetamol = 66 PANADOL  Analgesic & antipyretic effect  Mild to moderate pain such as headache, myalgia, postpartum pain,…  Preferred drug in pregnancy, in patients allergic to aspirin, with hemophilia, in those with a history of peptic ulcer, and in those in whom bronchospasm is precipitated by aspirin when NSAIDs are poorly tolerated  Weak anti-inflammatory effects :  ex vivo →1000 mg results in 50% inhibition of both COX-1 and COX-2 in whole blood assays  in vivo → Poor ability to inhibit COX in the presence of high concentrations of peroxides, as are found at sites of inflammation  Not a suitable substitute for NSAIDs in chronic inflammatory conditions such as rheumatoid arthritis  Advantage : well tolerated and low incidence of GI side effects.  Hypothesis of mechanism of action : crosses BBB → central effect  Inhibits selectively COX3 (canine COX1 splice variant)  Acetaminophen = paracetamol = 67 PANADOL  PK  Excellent bioavailability  Uniform distribution throughout most body fluids  Pp binding < other NSAIDs  Metabolism ◼ Mainly conjugation to glucuronide (60%) ◼ Minor CYP metabolism → NAPQI, a highly reactive intermediate → conjugated with sulfhydryl groups in glutathione (GSH)  Children have less capacity for glucuronidation of the drug than do adults  35% 60% 68  Acetaminophen = paracetamol = 69 PANADOL  Adverse effects  Therapeutic doses ◼ No effect on the GI , CV and respiratory systems, platelets, or coagulation ◼ Rash and other allergic reactions occur occasionally ◼ Patients who show hypersensitivity reactions to the salicylates only rarely exhibit sensitivity to acetaminophen  Main toxicity → liver damage ◼ Therapeutic concentrations → mild reversible increase in hepatic enzymes ◼ Doses > 4g/d : not recommended Early symptoms of hepatic damage : nausea, vomiting, diarrhea, ◼ and abdominal pain ◼ Conditions of CYP induction (e.g., heavy alcohol consumption) or GSH depletion (e.g., fasting or malnutrition) increase the susceptibility to hepatic injury  Acetaminophen = paracetamol = 70 PANADOL  Overdosage  Acute ingestion of > 7.5 g or repeat use of supratherapeutic doses  Hepatotoxicity, renal necrosis, myocardial damage, Hemolytic anemia and methemoglobinemia  Doses > 15 g are potentially fatal  Intoxication  Saturation of glucuronide and sulfate conjugation pathways →  NAPQI → binds covalently to cell macromolecules, leading to dysfunction of enzymatic systems and structural and metabolic disarray → necrosis (liver + renal cells)  Treatment : medical emergency ! ◼ Gastric decontamination : activated charcoal if ingestion < 4h ◼ N-acetylcysteine : repletes GSH stores and may conjugate directly with NAPQI by serving as a GSH substitute