Pharmacology-1 PHL 211 2nd Term 3rd Lecture By Abdelkader Ashour, Ph.D. Phone: 4677212 Email: aeashour@ksu.edu.sa

Analgesics An analgesic (also known as a painkiller) is any member of the diverse group of drugs used to relieve pain (achieve analgesia). The word analgesic derives from Greek an- ("without") and algos ("pain") Analgesic drugs include: Paracetamol (acetaminophen) The non-steroidal anti-inflammatory drugs (NSAIDs) such as the salicylates Narcotic drugs such as morphine Synthetic drugs with narcotic properties such as tramadol The NSAIDs, sometimes called the aspirin-like drugs, are among the most widely used of all drugs All NSAIDs are anti-inflammatory, analgesic, and antipyretic. Paracetamol, which is antipyretic and analgesic but largely devoid of anti-inflammatory activity, is conventionally segregated from the group despite its sharing NSAID activity with other actions relevant to its clinical action in vivo NSAIDs are a chemically heterogeneous group of compounds, often chemically unrelated (although most of them are organic acids), which nevertheless share certain therapeutic actions and adverse effects

Pharmacological Effects and Uses of NSAIDs The three main therapeutic effects are: Anti-inflammatory effect: NSAIDs reduce mainly those components of the inflammatory and immune response in which prostaglandins (PGs) play a significant part. These include: vasodilatation Oedema (by an indirect action: the vasodilatation facilitates and potentiates the action of mediators such as histamine that increase the permeability of postcapillary venules) Pain, potentiating other mediators, such as bradykinin Analgesic effect: NSAIDs are effective against mild or moderate pain NSAIDs act peripherally by decreasing production of the PGs that sensitise nociceptors to inflammatory mediators such as bradykinin NSAIDs are effective in arthritis, bursitis, pain of muscular and vascular origin, toothache, dysmenorrhoea, the pain of postpartum states NSAIDs also act centrally, possibly in the spinal cord, via inhibiting synthesis of PGs within the cord (PGs facilitate transmission from afferent pain fibres to relay neurons in the cord) The ability of NSAIDs to relieve headache may be related to the abrogation of the vasodilator effect of PGs on the cerebral vasculature

Pharmacological Effects and Uses of NSAIDs, contd. Antipyretic effect: NSAIDs lower body temperature when this is raised in disease (i.e. fever) Normal body temperature in humans is not affected by NSAIDs NSAIDs exert their antipyretic action through inhibition of PGs production in the hypothalamus. During an inflammatory reaction, bacterial endotoxins cause the release of a pyrogen-IL-1 (from macrophages) which stimulates the generation, in the hypothalamus, of E-type prostaglandins that elevate the temperature set point In addition, all the NSAIDs share, to a greater or lesser degree, the same types of mechanism-based side effects. These include: gastric irritation, which may range from simple discomfort to ulcer formation an effect on renal blood flow in the compromised kidney a tendency to prolong bleeding through inhibition of platelet function All these effects are generally related to the primary action of the drugs; inhibition of cyclooxygenase (COX), leading to inhibition of the production of PGs and thromboxanes

Mechanism of Action of NSAIDs, Pathways of Arachidonic Acid (AA) Release - Corticosteroids LOX Inhibitors NSAIDs - -

COX Isoforms Three known isoforms of COX are COX-1, COX-2 and COX-3 COX-1 is a constitutive enzyme expressed in most tissues, including blood platelets. It has a 'housekeeping' role in the body, being involved in tissue homeostasis, and is responsible for the production of prostaglandins involved in gastric cytoprotection, platelet aggregation, renal blood flow autoregulation and the initiation of parturition COX-2 is induced in inflammatory cells when they are activated. Thus the COX-2 isoform is responsible for the production of the prostanoid mediators of inflammation. In addition, there is a considerable pool of 'constitutive' COX-2 present in the CNS, kidney and some other tissues COX-3 (an alternate splice product of COX-1) exist in tissues such as cerebral cortex and aorta. Paracetamol, as well as some other drugs with similar properties (e.g. antipyrine and dipyrone), are selective inhibitors of this enzyme Most 'traditional' NSAIDs are inhibitors of COX-1 and COX-2 The anti-inflammatory action (and probably most analgesic actions) of the NSAIDs is related to their inhibition of COX-2, while their unwanted effects-particularly those affecting the gastrointestinal tract-are largely a result of their inhibition of COX-1 Compounds with a selective inhibitory action on COX-2 such as celecoxib and rofecoxib are now in clinical use, but they may be associated with an increase in cardiovascular risk

COX Isoforms Most NSAIDs are generally 'competitive reversible' inhibitors of COX, but there are differences in their time courses. Generally, these drugs inhibit COX-1 rapidly, but the inhibition of COX-2 is more time-dependent and the inhibition is often irreversible To block the enzymes, NSAIDs enter the hydrophobic channel, forming hydrogen bonds with an arginine residue at position 120, thus preventing substrate fatty acids from entering into the catalytic domain Aspirin is an exception. It enters the active site and acetylates a serine at position 530, irreversibly inactivating COX-1. This is the basis for aspirin's long-lasting effects on platelets