Lecture 1 NSAIDs PDF

Analgesics & Anaesthetics  Pain refresher (Anatomy, Physiology) and Non-steroidal antiinflammatory drugs (NSAIDs)  Opioids and other analgesic drug classes  Local anaesthetics  General anaesthetics Prof. David Finn Pharmacology and Therapeutics [email protected] Analgesics Lecture...

Analgesics & Anaesthetics  Pain refresher (Anatomy, Physiology) and Non-steroidal antiinflammatory drugs (NSAIDs)  Opioids and other analgesic drug classes  Local anaesthetics  General anaesthetics Prof. David Finn Pharmacology and Therapeutics [email protected] Analgesics Lecture 1: Pain Refresher and NSAIDs Prof. David Finn Pharmacology and Therapeutics [email protected] Lecture objectives + Pain refresher – Physiology, Anatomy + NSAIDs Classification Examples of commonly used NSAIDs Effects Mechanism of action ADRs COX-1 vs COX-2 What is pain? IASP definition (2020) An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage Additional notes: + Pain is always a personal experience that is influenced to varying degrees by biological, psychological, and social factors. + Pain and nociception are different phenomena. Pain cannot be inferred solely from activity in sensory neurons. + Through their life experiences, individuals learn the concept of pain. + A person’s report of an experience as pain should be respected. + Although pain usually serves an adaptive role, it may have adverse effects on function and social and psychological well-being. + Verbal description is only one of several behaviors to express pain; inability to communicate does not negate the possibility that a human or a nonhuman animal experiences pain. What is pain? Dimensions of pain: Sensory (physical) Affective (psychological) Cognitive Pain may be influenced by: Mood/emotion, sex, genetic makeup, environmental context Chronic Pain is a devastating and widespread problem A leading cause of disability globally One in five people in Europe Persistent pain states have a profound social and economic impact Breivik et al., 2006 Eur J Pain Chronic pain is a major unmet clinical need 29% Medication adequate 71% Medication inadequate at times Classifying pain + Two main types of pain Acute (physiological) Chronic (pathophysiological) Hyperalgesia: Increased pain from a stimulus that normally provokes pain Allodynia: Pain due to a stimulus that does not normally provoke pain + Chronic Primary Pain + Chronic Secondary Pain Syndromes Treede et al. (2019) PAIN Ascending pain pathway Rang, Pharmacology NSAIDs – Introduction Non-Steroidal Anti-Inflammatory Drugs Weaker analgesics (versus opioids) WHO Analgesic Ladder Strategy proposed by WHO to provide adequate pain relief for cancer patients Provide pain relief “aroundthe-clock” rather than “ondemand” History of NSAIDs Willow bark – used for centuries as an analgesic Salicylic acid – obtained by hydrolysis of the bitter glycoside extracted from the willow bark (1838) Sodium salicylate – 1875 Acetyl salicylate – “Aspirin” (1899) History of NSAIDs Vane and co-workers demonstrated that aspirin inhibited production of prostaglandin in guinea-pig isolated lungs (1971) Nobel Prize for Medicine in 1982 This is the major mechanism of action of all NSAIDs Prostaglandin synthesis Lipoxygenase (LOX) Leukotrienes (LT) e.g. LT B4, LT C4, LT D4, LT E4 Cyclooxygenase (COX) Prostanoids Prostacyclines (PGI2) Prostaglandins (PGD2, PGE2, PGF2α) Thromboxanes (TxA2) Tissue-specific production Prostanoids PGI2 Vascular endothelium Vasodilation Inhibits platelet aggregation TxA2 Platelets Vasoconstriction Promotes platelet aggregation PGE2 Throughout the body Smooth muscle contraction Inhibits gastric acid secretion Hyperalgesia PGF2α Uterus, airways Contraction of bronchi and myometrium (uterine wall) Mechanism of action of NSAIDs (1) Inhibit NSAIDs Mechanism of action of NSAIDs (2) There are two isoforms of COX enzyme o COX-1 o COX-2 NSAIDs can block o both COX enzymes or o COX-2 enzyme selectively Selective COX-2 NSAIDs Non-selective NSAIDs Inhibition undesirable Inhibition desirable Mechanism of action of NSAIDs (3) Arachidonic acid enters the COX enzyme channel and is converted first to prostaglandin G2, then to Prostaglandin H2, and finally to one of the prostaglandins (example here, E2)​ Mechanism of action of NSAIDs (4) The two isoforms differ at position 523 COX-1 has bulky isoleucine while COX-2 has a smaller valine Classification of NSAIDs Based on chemical structure Classification of NSAIDs Based on COX affinity Non-selective COX inhibitor Aspirin Ibuprofen Diclofenac Naproxen Indomethacin Mephenamic acid Piroxicam Ketorolac Selective COX-2 inhibitor Celecoxib (only COX2 inhibitor in US) Etoricoxib (approved in >70 countries but not US) Rofecoxib* Valdecoxib* *Discontinued from the market Classic actions of NSAIDs Effects of NSAIDs – Beneficial actions (when prostanoid synthesis is inhibited) Analgesia: prevention of nerve ending sensitisation Antipyresis: reduction of body temperature (influence on thermoregulatory centre in the hypothalamus) Anti-inflammatory: reduction in signs of inflammation (pain, tenderness, swelling, vasodilation) Antithrombotic: inhibition of platelet aggregation (in very low dose taken daily) Closure of ductus arteriosus: in the newborn Effects of NSAIDs – Shared toxicities (when prostanoid synthesis is inhibited) Gastric mucosal damage: connected with PGE2 inhibition Prolonged bleeding time: inhibition of platelet function (TxA2 synthesis) Limitation of renal blood flow: Na+ and water retention​ Delay / prolongation of labour: connected with PGF2α inhibition Asthma, hypersensitivity and anaphylactic reactions: connected with PGE2 inhibition ADR – Gastric mucosal damage Deficiency of PGs reduces mucus and HCO3 Tends to enhance acid secretion and promote mucosal ischemia​ All this finally leads to enhancement of aggressive factors and inhibition of defensive factors ulcerogenic effect o Perforation​ o Bleeding​ To counteract the GI mucosal damage by NSAIDs o Acid secretion inhibitors: H2RA, PPI o PG analogues: misoprostol NSAID actions - Analgesia PGs are responsible for pain and symptoms during inflammation​ PG sensitize nociceptive primary afferent fibers and lower their threshold for activation by other pro-nociceptive inflammatory mediators such as serotonin (5-HT), bradykinin, TNFα, interleukins (ILs) NSAID actions - Analgesia NSAIDs: more effective against pain due to inflammation NSAID actions - Antipyresis During infection and tissue injury, fever is produced through the generation of pyrogen ILs, TNFα, interferons Induction of PG synthesis in the hypothalamus  raises body temperature NSAIDs block PG production in the hypothalamus and reduce body temperature in fever o Do not cause hypothermia NSAID actions – Anti-inflammatory At the site of injury – enhanced COX-2 mediated PG synthesis NSAIDs inhibit PG synthesis at the site of injury antiinflammatory effect The anti-inflammatory potency of compounds corresponds to their potency to inhibit COX Aspirin Acetylsalicylic acid Non-selective and irreversibly inhibits both COX enzymes Classic actions: analgesic, antipyretic, and anti-inflammatory Inhibits platelet aggregation Pharmacokinetics: o Oral: rapid absorption, 75% metabolism in liver o Plasma half-life (t1/2) is dose-dependent but not duration of action ADR – Salicylism (mild intoxication) Anti-inflammatory doses of Aspirin cause a syndrome called salicylism Dizziness, tinnitus, vertigo, reversible impairment of hearing Mental confusion and hyperventilation can occur ADR – Acute salicylate poisoning (severe intoxication) More common in children (