Analgésiques Paracetamol AINS 2024.pptx

ANALGESIQUES: PARACETAMOL ET ANTI-INFLAMMATOIRES NON-STEROIDIENS Turgay TUNA Mogil JS. The genetic mediation of individual differences in sensitivity to pain and its inhibition. Proc Natl Acad Sci U S A 1999;96(14):7744– 51 [review]. PARACETAMOL ▪ Acetaminophen At A Glance...

ANALGESIQUES: PARACETAMOL ET ANTI-INFLAMMATOIRES NON-STEROIDIENS Turgay TUNA Mogil JS. The genetic mediation of individual differences in sensitivity to pain and its inhibition. Proc Natl Acad Sci U S A 1999;96(14):7744– 51 [review]. PARACETAMOL ▪ Acetaminophen At A Glance ▪ AKA: N-(4-hydroxyphenyl)acetamide, paracetamol, APAP ▪ U.S. brand name: Tylenol ▪ First synthesized: 1878 ▪ Over-the-counter debut: 1960 ▪ Sales: 27 billion doses in 2009 ▪ SOURCES: Tylenol.com, ProPublica, Merck Index ▪ Analgesic ; - Mechanism : elusive. ▪ Antipyretic ; ▪ Complex metabolism : - Hepatotoxic compounds : p-benzoquinone and N-acetyl-p-benzoquinone imine. NEW METABOLIC PATHWAY ▪ Paracetamol -> p-aminophenol -> via fatty acid amide hydrolase (FAAH) -> N-(4-hydroxyphenyl)- 5Z,8Z,11Z,14Z-eicosatraenamide (AM404) -> induction of analgesia ; ▪ Structurally related to the lipoamino acids, signalling molecules involved in pain modulation : anandamide ; ▪ Anandamide : cannabinoid and TRPV1 receptors and inhibition of T-type calcium channels (Ca,3,2 subtype).  PARACETAMOL Dosage chez le sujet adulte: 1 g 3 à 4 fois par jour SAUF si le sujet pèse moins de 50 kg => Il faut utiliser les doses pédiatriques dans ce cas, à savoir 15 mg/kg/prise AINS NSAIDS: MODE OF ACTION ▪ NSAIDS block both COX-1 and COX-2 ▪ This accounts for most of the side effects of NSAIDS ▪ Different types of NSAIDS have different specificities for COX-1 and COX-2 ▪ This contributes to differences in side effects between the NSAIDS.  ACTION OF CYCLO-OXYGENASE Constitutive pathway (stable Induced pathway conc) phospholipid phospholipid Arachidonic acid Arachidonic acid COX – 1 COX-2 enzyme enzyme Prostaglandins associated Inflammatory with normal body functions prostaglandins e.g. prostaglandin E2 (for kidney function), prostaglandin I2 (for stomach protection) ▪ Inhibition of prostaglandin production through blockade of cyclooxygenases (’70ies) ; ▪ COX-1 and COX-2 : -1 constitutively expressed in most tissues, -2 under the control of pro- and anti-inflammatory cytokines ; ▪ Dichotomy not followed in all organs, as in endothelial cells or in the kidney ; ▪ Undesired actions : arterial hypertension, increased cardiovascular risk.  PARACETAMOL / AINS ▪ Action centrale Action centrale et périphérique Inhibition des enzymes ▪ Pic (15-60 min) COX-1 et -2 Excellente absorption ▪ Analgésique PO, liaison protéinique (>90%) ▪ IV, PO, IR Analgésique, anti- inflammatoire IV, PO, IM, IR, topique CLASS SIDE EFFECTS ▪ Ulcers of the upper GI tract ; ▪ Asthma ; ▪ Increases in blood pressure ; ▪ Kidney damage ; ▪ Bleeding ; ▪ Increased cardiovascular risk SAFETY ▪ Bleeding ulcer = 1 in 13 death overall, 1 in 5 if NSAIDs ; ▪ 106000 NSAID-related hospital admissions and 16500 deaths each year in USA ; ▪ 1,9% of NSAIDs users admitted to the hospital each year with upper gastrointestinal emergencies ; ▪ 1 episode of bleeding ulcer in the elderly for each 2823 prescriptions ; SAFETY If oral NSAIDS are taken for at least 2 months, the risk for : - an endoscopicaly confirmed ulcer is 1 in 5 ; - a symptomatic ulcer : 1 in 70 ; - a bleeding ulcer : 1 in 150 ; - 1 death from a bleeding ulcer : 1 in 1300. None of these risks are associated with topical NSAIDS. Ratio for no drug – coxib – NSAID = 1:2:4 OTHER ROUTES OF ADMINISTRATION Topical : - in acute pain : NNT = 3,9 - in chronic pain : NNT = 4,6 ; 1st line treatment of osteoarthritis  NSAIDs with a short elimination half-life and low potency : - Ibuprofen : maximum dose of 2,4 g, close to 100% bioavailability. ▪ NSAIDs with a short elimination half-life and high potency : - Diclofenac : 50% oral bioavailibility - Ketorolac, etc. : high risk for unwanted drug effects. NSAIDs with a long elimination half-life : - Naproxen ; - Oxicams COX-2 ▪ All inhibitors of COX-2, selective and non-selective may increase the risk for myocardial infarction and stroke ; => Lowest dose and shortest period necessary ▪ Celecoxib inhibits CYP2D6 (interactions with cardiovascular and psychotropic drugs). EBM Attention