Non-Opioid Analgesics Pharmacology I BMS 242 Non-Opioid Analgesics NSAIDs Dr. Aya M. Serry 2017

Lecture Objectives Defining Inflammation Inflammatory Mediators (Prostaglandins) Mechanism of Action of NSAIDs Therapeutic Uses of Aspirin and side effects Acetaminophen uses and side effects Selective COX 2 inhibitors and their advantages over traditional NSAIDs

What’s Inflammation ? Inflammation is a defense reaction caused by tissue damage or injury Can be elicited by numerous stimuli including: infectious agents antigen-antibody interaction ischemia thermal and physical injury WBCs activation leads to the release of chemicals that are responsible for the inflammatory features

What’s Inflammation ? The chemical mediators of inflammation primarily cause their effects in the localized area where they are released, then some of these chemicals (interleukin-1 and Prostaglandins will then be carried in blood, causing other effects in the body (e.g: fever)

What’s inflammation ? Inflammatory responses are: (All caused due to the release of inflammatory mediators ) Redness: vasodilation of capillaries to increase blood flow Heat: vasodilation Pain: Hyperalgesia, sensitization of pain fibres Swelling: Increased vascular permeability (microvascular structural changes and escape of plasma proteins from the bloodstream) Fever: affect the activity of the TRC (Thermogenic regulatory center in brain) [ prostaglandins will act on hypothalamus causing an increase in Thermostat set point]

Mediators of Inflammation What’s Inflammation ? Mediators of Inflammation Vasoactive amines (Histamine, Serotonin) Platelet activating factor (PAF) Complement system Kinin system Cytokines Nitric oxide Adhesion Molecules Arachidonic acid metabolites: mediated by cyclooxygenases (COX) Prostaglandins (PGs) Thromboxane A2 (TXA2) HETE (hydroxy-eicosatetraenoic acid) Leukotrienes (LTs)

Two main forms of Cyclooxygenases (COX) Cyclooxygenase-1 (COX-1) Produces prostaglandins that mediate homeostatic functions Constitutively expressed Plays an important role in Gastric mucosa Kidney Platelets Vascular endothelium Cyclooxygenase-2 (COX-2) Produces prostaglandins that mediate inflammation, pain, and fever. Induced mainly in sites of inflammation by cytokines

Inflammatory responses occur in three distinct phases: An acute transient phase, characterized by: local vasodilation increased capillary permeability A delayed, subacute phase, most prominently characterized by: infiltration of leukocytes and phagocytic cells A chronic proliferative phase, in which: tissue degeneration and fibrosis occur

Mechanism of action of NSAIDs NSAIDs block injured cells from releasing prostaglandins, so, everything that prostaglandins cause to happen will not happen… Anti-inflammatory effect due to the inhibition of COX1, or COX2, which converts arachidonic acid to prostaglandins, and to TXA2 and prostacyclins. NSAIDs inactivates COX-1 and COX-2 by acetylation of a specific serine residue

Mechanism of action of NSAIDs 2. Analgesic effect NSAIDs are mainly effective against pain associated with inflammation or tissue damage because they decrease production of the prostaglandins that sensitise nociceptors to inflammatory mediators such as Bradykinin Their ability to relief headache may be related to inhibition of the vasodilating effect caused by prostaglandins in the cerebral blood vessels

Mechanism of action of NSAIDs Antipyretic effect Normal body temperature is regulated by a centre in the hypothalamus which ensures a balance between heat loss and heat production Fever occurs when there is a disturbance of this hypothalamus “thermostat” that leads to the set point of body temperature being raised NSAIDs decrease fever by resetting this thermostat by inhibition of production of prostaglandins in the hypothalamus

Therapeutic Uses of NSAIDs NSAIDs are used in the treatment of: Inflammation NSAIDs are first-line drugs used to arrest inflammation and the accompanying pain of rheumatic and non-rheumatic diseases NSAIDs do not significantly reverse the progress of rheumatic disease they slow the destruction of cartilages and bones, allowing patients to increase mobility and use of their joints.

Therapeutic Uses of NSAIDs Treatment of chronic inflammation requires use of these agents at doses well above those used for analgesia and antipyresis the incidence of adverse drug effects is increased.

Therapeutic Uses of NSAIDs Drug selection is generally dictated by the patient's ability to tolerate the adverse effects, and the cost of the drugs. Antiinflammatory effects may develop only after several weeks of treatment.

Therapeutic Uses of NSAIDs Analgesia NSAIDs alleviate mild-to-moderate pain by: decreasing PGE- and PGF-mediated increases in pain receptor sensitivity. They are more effective against pain associated with integument structures (pain of muscular and vascular origin, arthritis) than with pain associated with the viscera.

Therapeutic Uses of NSAIDs Antipyretics NSAIDs reduce elevated body temperature with little effect on normal body temperature.

NSAIDs- Aspirin Aspirin (acetylsalicylic acid) -Prototype

NSAIDs- Aspirin Pharmacologic properties: Salicylates are weak organic acids; aspirin has a pKa of 3.5. These agents are rapidly absorbed from the intestine as well as from the stomach, where the low pH favors absorption.

NSAIDs- Aspirin Salicylates are hydrolyzed rapidly by plasma and tissue esterases to acetic acid and the active metabolite salicylic acid. esterases

NSAIDs- Aspirin Unmetabolized salicylates are excreted by the kidney. If the urine pH is raised above 8, clearance is increased approximately fourfold as a result of decreased reabsorption of the ionized salicylate from the tubules.

Therapeutic uses of Aspirin Aspirin uses: Analgesic Antipyretic Anti-inflammatory [ reliefs Rheumatoid Arthritis] Antiplatelet aggregation (Anticoagulant)

Side effects of Aspirin Gastrointestinal effects most common adverse effects of high-dose aspirin use (70% of patients): nausea vomiting diarrhea or constipation dyspepsia (impaired digestion) epigastric pain bleeding, and ulceration (primarily gastric).

Side effects of Aspirin These gastrointestinal effects are thought to be due to: a direct chemical effect on gastric cells or a decrease in the production and cytoprotective activity of prostaglandins, which leads to gastric tissue susceptibility to damage by hydrochloric acid.

Side effects of Aspirin The gastrointestinal effects may contraindicate aspirin use in patients with an active ulcer. Aspirin may be taken with prostaglandins to reduce gastric damage. Decrease gastric irritation by: Substitution of enteric-coated or timed-release preparations, or the use of other NSAIDs with less effect on GIT

Side effects of Aspirin Reye's syndrome The use of aspirin and other salicylates to control fever during viral infections (influenza and chickenpox) in children and adolescents is associated with an increased incidence of Reye’s syndrome It’s an illness characterized by vomiting, hepatic disturbances, and encephalopathy that has a 35% mortality rate. Acetaminophen is recommended as a substitute for children with fever of unknown etiology.

Side effects of Aspirin In adults, salicylism (tinnitus, hearing loss, vertigo) occurs as initial sign of toxicity after aspirin or salicylate overdose or poisoning. In children, the common signs of toxicity include hyperventilation and acidosis, with accompanying lethargy and hyperventilation.

OTHER NSAIDS

Acetaminophen (Paracetamol) Paracetamol has an analgesic and antipyretic activity It’s possible that its antipyretic action is due to a selective effect on a specific COX enzyme in the CNS it causes minimal gastric irritation has little effect on platelet adhesion and aggregation Acetaminophen has no significant anti-inflammatory activity.

Acetaminophen (Paracetamol) Acetaminophen is administered orally and is rapidly absorbed. Acetaminophen is a substitute for aspirin to treat mild-to-moderate pain for selected patients who are: intolerant to aspirin (Hypersenstivity) have a history of peptic ulcer are using anticoagulants Children who are at risk for Reye's syndrome.

Acetaminophen toxicity accumulation of a minor metabolite, N-acetyl-p-benzoquinone, which is responsible for hepatotoxicity.

COX-2 Selective inhibitors

COX-2 Selective inhibitors Celecoxib [Celebrex] Rofecoxib [Vioxx] Valdecoxib [Bextra] They are drugs that inhibit COX-2 more than COX-1 have been developed and approved for use. The rationale behind development of these drugs was that: inhibition of COX-2 would reduce the inflammatory response and pain not inhibit the cytoprotective action of prostaglandins in the stomach, which is largely mediated by COX-1.

Celecoxib remains on the market and is approved for: Rofecoxib and valdecoxib have been removed from the market due to a doubling in the incidence of heart attack and stroke Celecoxib remains on the market and is approved for: Osteoarthritis and rheumatoid arthritis Pain including bone pain, dental pain, and headache