Cyclooxygenase-2 Inhibitors and Non Spesific Non Steroidal Anti Inflammatory Drugs

NUR HAJRIYA BRAHMI

Cyclooxygenase (COX)

An enzyme that catalyzes the synthesis of prostaglandins from arachnoid acid

It’s activity associated with 2 iso-enzymes expressed as COX-1 and COX-2

COX -1 essential in homeostatic process such as platelet aggregation, gastrointestinal mucosal integrity and renal fuction

COX 2 is inducible, expressed in mainly at sites of injury (brain and kidneys),mediates inflammation, fever, pain , and carcinogenesis

Cyclooxygenase (COX)

Non Steroidal Anti Inflammatory Drugs A varied group of drugs processing

analgesic, antiinflammatory, and antipyretic effects.

Inhibited both COX-1 and COX-2 enzymes.

Non Steroidal Anti Inflammatory Drugs

Characteristic Potensial Adverse Effect

Decrease activation and sensitization of peripheral nociceptors

Inhibition of platelet aggregation

Attenuate the inflammatory response Gastric ulceration

Absence of dependence or addictional potential

Renal dysfunction

Synergistic effect with opioids Hepatocellular injury

Preemptive Analgesia (decrease neuronal sesitization)

Asthma Exacerbation

Absence of depression of breathing Allergic reaction

Less nausea and vomiting compared with opioids

Tinnitus

Long duration of action Urticaria

Less dose variability compared with opioids

No pupillary changes

Absence of cognitive effects

Cyclooxygenase-2 Spesific Inhibitors

Examples of Drugs Characteristic Dosage

Celecoxib Pain and inflammation related to Osteorthritis and Rheumatoid Arthritis

OA : 1x 200 mg dailyRA : 2 x 100 – 200 mg daily

RofecoxibWithdrawn since double the risk of myocardial infarction and CVA

Acute surgical painAcute menstrual pain

Loading 50 mg then 25 mg daily

Valdecoxib Relief post operative pain

40 mg : 1 hour before surgery , and additional 40 mg after surgery if needed

Parecoxib The only available with parenteral formPost operative pain relief

40 mg : 1 hour before surgery , and additional 40 mg after surgery if needed

Cyclooxygenase-2 Spesific InhibitorsClinical Use Description

Analgesic efficacy Suitable for : pain due to osteoarthritis, rheumtoid arthritis, acute gout, dental pain, dysmenorrhea, musculoskeletal conditon. Acute post operative pain : orthopaedic surgery and arthroscopy

Post operative Pain Management

Reduce post operative pain by suppressing COX mediated production of prostaglandin E minimize sensitivity of peripheral nociceptor of pain. Lack of effect on platelet function and bleedingTolerable for patient with gastritis or gastric ulcer, asthma

Protection Against Colorectal Cancer

Inhibit colon tumor growth, adenomatous polyps

Protection Against Dementia Decrease inflammatory process of neural destruction

Cyclooxygenase-2 Spesific InhibitorsSide Effect Description

Gastrointestinal Toxicity

Nonselective NSAID inhibition of COX-1 minimize PG that protect gastrointestinal mucose by maintaining mucosal blood flow and increase secretion mucous and bicarbonate50% decrease in COX-2 spesific inhibitor

Coagulation Effects Platelet aggregitation and homeostasis depend on the ability of platelets to generate thromboxane mediated by COX-1. COX-2 inhibitor have no effect on platelet aggregation, bleeding time or post operative blood loss.

Cardiac effect COX-2 inhibitor selective suppression of PG I2 (vasoprotective) without affecting thromboxane A2 (procoagulant), increasing the risk of myocrdial infarction.

Hypertensive effect PG modulate systemic blood pressure by virtue effect on vascular tone arterial smooth muscle and control of extracellular fluid volume (natriuretic effect).

Cyclooxygenase-2 Spesific InhibitorsSide Effect Description

Renal Effect PG participate autoregulation on renal blood flow and glomerular filtration. Nephrotoxic potential increase in elderly that had NSAID. Prerenal azotemia reflecting decrease renal perfusion is the most frequent pattern of renal injury, hipercloremic metabolic acidosis in association hyperkalemia mostly occur with patient with preexisting renal disease.

Hepatic Effect Increase in plasma concentration of liver transaminase

Allergy Contraindication to treatment with celecoxib and valdecoxib is sulfonamide hypersensitivity. Should not be administer to patient who have asthma, urticaria or allergic type reaction to aspirin.

Asthma May trigger bronchoconstriction by blocking COX mediated conversion of arachdonic acid to prostaglandin esp PG E2 (a poten antiinflammatory substance).

Selectivity of COX-2 inhibitors and non-steroidal anti-inflammatory drugs given as log inhibitory concentration (IC80) ratio. The `0' line indicates equipotency.

Chemical Classification Example of drugs

Carboxylic Acid Acetylated Nonacetylated

AspirinSalicylamide

Acetic Acid Indometacin, tolmetin

Propionic Acid Ibuprofen, Naproxen, Ketoprofen

Enolic acid Phenylbutazone, piroxicam

Pyrrolopyrrole Ketorolac

CHEMICAL CLASSIFICATION NONSPESIFIC CYCLOOXIGENASE INHIBITORS

NONSPESIFIC CYCLOOXIGENASE INHIBITORSDrugs Description

Aspirin Acetylsalicylic Acid

Produce analgesia through irreversible acetylate COX enzyme decrease synthesis and release of PG. Leukotrients pathway remain intake, does not interact with opioid receptor, little effect on release histamin/serotonin. Rapidly absorb from small intestine , the rate of absorption influenced by administer tablet and gastric emptying time : more acid the rate is increased, food delay absorption. Metabolism in hepar, excreted in the urine . Clinical Use : analgesic symptomatic relief of low intensity pain associated with headache and musculoskeletal disorders ; antipyretic, antiplatelet drugs for myocardial infarct.Major side effects of aspirin teraphy related to gastrointestinal tract dysfunction (gastric irritation and ulceration) and inhibition of platelet function (prolongation of bleeding time). The other side effect will be CNS Simulation (hyperventilation – direct effect to medullary ventilatory centre), tinnitus, hepatic dysfunction, aspirin induced asthma.

Drugs Description

Acetaminophen

Widely used as analgesic and antipyretic , an over the counter drugAlternate to aspirin if given 325 to 650 mg every 4 – 6 hours, esp for pediatric patient and patients whom salicylates not recommended. Unlike aspirin, acetaminophen does not gastric irritation, alter aggregation of platelet. Weak antiinflammatory effect. Oral route administrationIt’s metabolit (p-aminophenol) concentrated in the hypertonic renal papillae (nephrotoxic : it’s oxidize and binds convalently to sulfhidryl containing tissue-macromolecule and deplete stores of reduce gluthation, leading to cell necrosis.

NONSPESIFIC CYCLOOXIGENASE INHIBITORS

Drugs Description

Ketorolac Exhibit potent analgesic (for post op analesia : less painful ambulatory procedur or for supplement to opioids, moderate anti inflamatory effect). Exhibit a ceiling effect to post operative analgesia30 mg ketorolac IM similar potency of analgesia as 10 mg morphin or 100 mg meperidine. Absence of ventilatory or cardiovascular depressionLittle or no effect on biliary tract : useful analgesic when spasm of the biliry tract is undesirable. IM : max plasma concentration achieved 45 – 60 mins elimination time is 5 hours. Clearance is decrease in elderly , the dose should be less Inhibit platelet aggregation by reversible inhibition of prostaglandin synthetaseLife threatening bronchospasm may follow in nasal polyp patient, asthma, and aspirin sensitiviy. Gastro intestinal irritation and perforation, nausea may accompany

NONSPESIFIC CYCLOOXIGENASE INHIBITORS