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09 Non-Steroidal Anti-Inflammatory Drugs (Nsaids)

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09 Non-Steroidal Anti-Inflammatory Drugs (Nsaids) Part I Anaesthesia Refresher Course – 2017 09 University of Cape Town Non-steroidal anti-inflammatory drugs (NSAIDs) Dr Ernest Welch Private Practice Honorary lecturer- Wits University Non-steroidal anti-inflammatory drugs (NSAIDs) are a group of unrelated chemical compounds that have analgesic, anti-inflammatory and antipyretic effects. The similarity in therapeutic actions and side effects is due to common mechanisms of action and as a result they can be studied as a single class of drugs. The understanding of the NSAIDs, their effects and controversies is dependent on knowledge of the COX (cyclo-oxygenase) enzyme system. Mechanism of action Basic physiology of the COX pathway: 1. Fatty acid metabolism results in the production of prostaglandins (PG) via the COX pathway. 2. PGs mediate: inflammation, pain, pyrexia, cell mitosis and neuromuscular function. 3. All NSAIDs inhibit cyclo-oxygenase (COX). Formation of prostaglandin Arachidonic acid (AA) is a phospholipid fatty acid found in cell membranes that is released by a variety of stimuli particularly membrane damage. Cyclo-oxygenase (COX) and lipoxygenase (LOX) enzymes convert Arachidonic acid (AA) to lipid mediator’s PG and leukotrienes (also known as the eicosanoids) The two COX isoforms (COX-1 and COX-2) catalyse AA to PG and thromboxane (TxA) Initially COX converts AA to prostaglandin G2 (PGG2), and then converts PGG2 to prostaglandin H2 (PGH2) PGH2 is converted to 5 active forms of PG prostaglandin D2 (PGD2), prostaglandin E2 (PGE2) prostaglandin F2α (PGF2α) prostacyclin (PGI2) thromboxane A2 (TxA2) These 5 prostanoids act as secondary messengers mainly on G protein-coupled receptors. THE SYNTHESIS OF PROSTOGLANDINS USING CYCLO-OXYGENASE S. Bacchi, P. Palumbo, A. Sponta and M.F. Coppolino. Clinical Pharmacology of Non-Steroidal Anti- Inflammatory Drugs: A Review, Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2012, 11, 52-64 Non-steroidal Anti-Inflammatory Drugs Dr E Welch COX has 2 main isoforms. The gene for COX-1 is located on chromosome 9 and COX-2 on chromosome 1. COX-1 is constitutively expressed in most tissue types and the prostanoids produced by this isoform generally mediate ‘housekeeping’ functions: protection of the gastric mucosa, regulation of renal blood flow and platelet aggregation. It can be induced during cell differentiation and angiogenesis Platelets only express COX-1. COX-2 is highly inducible (but constitutively expressed in the brain, spinal cord and kidneys.) COX-2 is induced by: inflammatory conditions in response to cytokines (interferon, TNF, IL1), hormones, growth factors and hypoxia, and is found in tumour endothelium. COX-3 has been described and is a variant of COX-1 that appears to have no prostaglandin producing activity. Pharmacology of NSAIDS NSAIDs act by blocking COX and reducing the synthesis of PG resulting in a decrease in inflammation, pain and fever. The anti-inflammatory action is due to the decrease in vasodilation and oedema (PGE2, PGI2). PGE2 and PGI2 inhibition results in central and peripheral analgesic effects. The antipyretic effect results from blocking production of PGE2 modulated hypothalamic thermoregulation. COX-2 inhibitors (COXIBs) were developed to maintain the desirable NSAID effects of analgesia, anti- inflammation and antipyretic without inhibiting the homeostatic effects of COX-1 on the GIT, kidneys and platelets. Unfortunately, it’s now known that these 2 enzyme systems are not exclusive and the COXIBS still have effects on the homeostatic systems and the side effects remain. In addition, following long term studies the COXIBs have demonstrated cardiovascular risks that have resulted in the withdrawal of rofecoxib and warnings about their use in patients at risk of cardiovascular disease. Classification of NSAIDs As a group of different chemical compounds, logically it’s easy to classify the NSAIDs according to their drugs class; but this is of little clinical relevance and classification by means of their clinical and side effect profiles as a result of the varying amounts of COX inhibition is far more practical. CLASSIFICATION OF NSAIDs BY CYCLO-OXYGENASE (COX) INHIBITION Group COX inhibition Example Group Poorly selective. Ibuprofen, diclofenac, aspirin, piroxicam, 1 Fully inhibit both COX-1 and COX- naproxen 2 Less than 5 times COX-2 selectivity Group Preferential COX-2 selective Celecoxib, meloxicam, nimesulide, etodolac 2 Inhibit both COX-1 and COX-2 5 to 50 times COX-2 selectivity Group Predominantly COX-2 selective Rofecoxib 3 Weak COX-1 inhibition Greater than 50 times COX-2 selectivity Group Weak inhibitors of both COX-1 and Sodium salicylate, nabumetone 4 COX-2 09-2 Non-steroidal Anti-Inflammatory Drugs Dr E Welch CLASSIFICATION OF NSAIDs BY CHEMICAL COMPOUND / DRUG CLASS Drug class Example Comments Salicylic acid derivates aspirin Indole and indene acetic indomethacin, etodolac, sulindac acids Hetero-aryl acetic acids diclofenac, ketorolac, tolmetin Aryl-propionic acids ibuprofen, ketoprofen, flurbiprofen, naproxen, fenoprofen, oxaprozin, aceclofenac, fenclofenac Anthranilic acids mefenamic acid, meclofenanic acid Also called fenamates Enolic acids piroxicam, tenoxicam, meloxicam Also called oxicams Alkanones nabumetone Not available is SA (Relafen®) Pyrazolidinediones pheynylbutazone, oxyphenylbutazone Diarylheterocycles lumiracoxib > rofecoxib > etoricoxib > Selective COX-2 inhibitors valdecoxib > parecoxib > celecoxib In rank order of COX-2 inhibition Para-aminophenol paracetamol (acetaminophen) Paracetamol is classified as derivates a NSAID despite having little anti-inflammatory activity Meta-analysis has shown that there is no significant analgesic difference between the classes of NSAIDs or between the selective COX-2 inhibitors and poorly-selective agents in all forms of arthritis and orthopaedic pain. RANKING OF CYCLO-OXYGENASE (COX) SELECTIVITY Morten Schmidt, Morten Lamberts, Anne-Marie Schjerning Olsen et al. Cardiovascular safety of non- aspirin non-steroidal anti-inflammatory drugs: review and position paper by the working group for Cardiovascular Pharmacotherapy of the European Society of Cardiology. European Heart Journal – Cardiovascular Pharmacotherapy (2016) 2, 108–118 Pharmacokinetics of all NSAIDs are generally very similar: Lipid-soluble weak acids. Most are completely absorbed from the GIT. Have little first-pass hepatic metabolism. Highly protein bound with a small volume of distribution. Metabolised by CYP3A and CYP2C and /or glucuronidation Half-lives vary from less than 2 to 8 hours. 09-3 Non-steroidal Anti-Inflammatory Drugs Dr E Welch Adverse effects Gastro Intestinal Tract effects 1-3% of patients on chronic NSAIDs develop gastrointestinal bleeding. PGs inhibit H+ secretion and promote mucous production. NSAIDs block this promoting gastric erosion, ulceration and bleeding. COX-2 selective inhibitors theoretically have less GIT complications than non-selective NSAIDs, but this has not been conclusively shown in large trials with chronic use. The risk of GIT symptoms increases if patients are on concomitant aspirin. (CLASS, TARGET and VIGOR trials) Cardiovascular Long term trials on the COX-2 specific inhibitors showed an increased risk of 1.5 to 5 times of cardiovascular complications when compared to placebo. Non- selective NSAIDs except aspirin also have an increased risk. The safest drug in this setting appears to be naproxen. Myocardial infarction, cerebrovascular accident and thrombo-emboli: COX-2 inhibition causes suppression of prostacyclin (PCI2), which is a potent vasodilator and prevents platelet aggregation helping protect endothelial cells during shear stress and inhibiting smooth muscle cell proliferation. Platelets contain only COX-1, which produces thromboxane A2—a potent vasoconstrictor, platelet aggregator and pro-thrombotic. Selective COX-2 inhibition therefore results in unopposed COX-1 effects - promoting thrombosis. COX-2 inhibitors also accelerate atherosclerosis and raise blood pressure. COX-2 inhibition is associated with increased infarct size, myocardial wall thinning and myocardial rupture post myocardial infarction. Patients with cardiovascular disease or risk factors (such as hypertension, hyperlipidaemia, diabetes mellitus, or smoking) have an increased risk of thromboembolic events and NSAIDs should be avoided. Arrhythmias COX-2 produced prostacyclin acts as an endogenous antiarrhythmic agent via inhibition of epicardial sympathetic nerve activity. NSAIDs also elicit proarrhythmic effects through fluid retention and electrolyte disturbances. Cardiac failure NSAIDs can cause fluid retention and elevate blood pressure doubling the risk of heart failure. Renal NSAIDs are associated with renal toxicity PGs are involved in controlling renin release, regulating vascular tone, and controlling tubular function. COX inhibition produces changes in fluid and electrolyte control COX-1 controls renal blood flow and perfusion. COX-2 is involved in diuresis and electrolyte balance. COX-2 inhibition is associated with increased potassium levels Inhibition of these enzyme systems can have profound effects on renal function. Hepatic Liver toxicity from paracetamol is well known. It is the result of decreased glutathione required for metabolism of paracetamol. Diclofenac, nimesulide and sulindac, lumiracoxib have all been associated with liver dysfunction and failure. Bleeding By inhibiting the formation of TxA2 NSAIDS and aspirin decrease platelet function. 09-4 Non-steroidal
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