Naslov
Treatment of Inflamation. Biotransformation of NSAIDs. Common adverse effects. Overdoses and pharmacist's role in ADR prevention

Autori
Jadrijević-Mladar Takač, Milena ; Takač, Vedran

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, stručni

Izvornik
9th CEEPUS - Biomedicine Students' Council Summer University. Abstract Book. Inflamation - Multidisciplinary approach / D. Juretć, V. Takač, M. Vasung, S. Crnković, M. Pletikos - Zagreb : Student's Council, Faculty of Pharmacy and Biochemistry , University of Zagreb, 2006, 22-24

Skup
9th CEEPUS - Biomedicine Student's Council Summer School

Mjesto i datum
Zadar, Hrvatska, 24.07.2006. - 31.07.2006

Vrsta sudjelovanja
Pozvano predavanje

Vrsta recenzije
Domaća recenzija

Ključne riječi
Nonsteroidal antiinflammatory drugs; NSAID; Adverse drug reaction; ADR; biotransformation; COX izoenzyme inhibittion

Sažetak
The nonsteroidal anti-inflammatory drugs (NSAIDs) comprise a large family of weakly acidic drugs whose pharmacological effect results primarily from the inhibition of cyclooxygenase (COX) an enzyme that catalyzes the first step in the syntheses of prostaglandins from arachidonic acid (AA). AA is released from cell membranes by the action of phospholypase A2, an enzyme that is activated by physical trauma and various chemical stimuli. Since the demonstration that prostaglandin synthase (cyclooxygenase, COX) was inhibited by aspirin in 1971, COX inhibition has long been the target for pharmacologic intervention given its rate-limiting production of prostaglandins in vivo. This understanding of the mechanism of action of aspirin led to development of the newer NSAIDs. As predicted, more than one isoform of the COX enzyme exists, and they are COX-1, COX-2 and COX-3. COX-1 is a constitutive enzyme that is found in relatively constant levels in various tissues. COX-1 participates in the synthesis of prostaglandins that have a cytoprotective effect on the gastrointestinal tract. The non-inducible COX-1 isozyme functions to produce prostaglandins involved in homeostasis (gastric cytoprotection, renal function). It catalyzes the formation of tromboxane A2 in platelets, leading to platelet aggregation and haemostasis. COX-2 is an inducible enzyme. Its levels are normally quite low in most tissues but are rapidly up-regulated during the inflammatory process by proinflammatory substances, such as cytokines, endotoxins, and tumor promoters. Both, COX-1 and COX-2 appears to participate in renal homeostasis. COX-3 exists solely within the blood brain barrier, therefore acts centrally and mediates only central analgesia and antipyretic activity. Most of the NSAIDs available today are nonselective inhibitors of COX-1 and COX-2. The discovery of COX isoenzymes recently led to the development of COX-2 inhibitors, such as celecoxib. These selective inhibitors are effective anti-inflammatory drugs, and they have a lower tendency to cause gastrointestinal bleeding and peptic ulcer disease than do the nonselective COX inhibitors. Nonselective NSAIDs such as ibuprofen and naproxen inhibit all three isoforms. Selective COX-2 agents (celecoxib) inhibit COX-2 and COX-3. Acetaminophen inhibits only COX-3 explaining why it lacks peripheral anti-inflammatory activity. NSAIDs also appear to inhibit B and T cell proliferation by mechanisms that do not involve inhibition of COX enzyme and prostaglandin formation. These drugs may exert their anti-inflammatory effects by inhibiting G protein signal transduction and phospholipase C activation in leukocytes and thereby decreasing the adhesiveness of cells in inflamed tissue. Acetylsalicylic acid (ASA, Aspirin) has long been used as an anti-inflammatory agent, sometimes in very large doses. This drug decreases prostaglandin synthesis at the site of inflammation, reducing the inflammatory response. As well, ASA reduces pain (analgesic) and fever (antipyretic), which may be helpful in many cases. However it is not recommended for children with viral infections because the combination of ASA and a viral infection is believed to contribute to the development of Reye's syndrome, a serious complication involving the brain and liver. This is rare syndrome in which encephalopathy occurs and if not diagnosed early can lead to death. Many individuals are allergic to ASA, and the drug may cause irritation and ulcer in stomach. This medication interferes with blood clotting by reducing platelet adhesion, and therefore it cannot be used in all conditions. Therapeutic doses of aspirin can cause gastric irritation and contribute to gastrointestinal bleeding and peptic ulcer. Moderately high therapeutic doses can cause tinnitus, which is described as an abnormal auditory sensation or noise. Excessive doses of aspirin produce the toxic effects. Hyperventilation is due to direct and indirect stimulation of the respiratory centre in the medulla, and is often leads to increased exhalation of carbon dioxide and respiratory alkalosis. High plasma salicylate concentrations may cause fever, dehydratation, and severe metabolic acidosis. If not treated promptly, these events may cumulate in shock, coma, organ system failure, and death. Excessive doses of aspirin may also cause a hypoprothrombinemic effect that impairs haemostasis and cause bleeding. Aspirin hypersensitivity is an uncommon but serious condition that may result in severe and potentially fatal anaphylactic reactions. Metabolism of ASA involves hydrolysis to salicylic acid and their metabolites (gentisamide, salycyluric acid, two glucuronides and sulfo-conjugate). Symptoms of ASA intolerance include vasomotor rhinitis, angioedema, and urticaria (hives). ASA sensitivity occurs most frequently in persons with asthma, nasal polyps, or chronic urticaria. Persons who have had a severe hypersensitivity reaction to aspirin or another salycilate should not be treated with another type of NSAIDs, because there is a 5% risk of cross-sensitivity between salycilates and other NSAIDs. The treatment of salycilate poisoning may include the following: (1) induction of vomiting and gastric lavage to remove unabsorbed drug ; (2) intravenous administration of sodium bicarbonate to counteract metabolic acidosis, increase the ionisation of salycilate in the kidneys, and thereby enhance the rate of excretion of salycilate ; and (3) administration of fluids, electrolytes, and other supportive care as needed. NSAIDs, such as ibuprofen, ketoprofen and naproxen are propionic acid derivatives that are among the most widely used NSAIDs for pain and inflammation due to trauma, infection, autoimmune disorders, neoplasms, joint degradation, and other causes. Piroxicam and diclofenac sodium are now used extensively to treat many types of inflammatory conditions. Ibuprofen has been recommended for many disorders, including menstrual pain and headache. The side effects are similar to those of ASA, but they are less severe. These drugs are available as oral medications and some in small doses are available as ASA without prescription (OTC). Ibuprofen and related drugs produce dose-dependant gastric irritation, nausea, dyspepsia, and bleeding. Long-term administration of high doses has been associated with peptic ulcer disease, but short-term use of low doses causes very few serious adverse effects. Among the serious effects that have been reported are hepatic toxicity and renal toxicity. In some cases, acute renal failure occurred following short-term use of therapeutic doses by patients who failed to ingest adequate fluids and became dehydrated. Metabolism of ibuprofen involves primarily  -,  -1 and  -2 oxidation of the p-isobutyl side chain, followed by alcohol oxidation of  -OH to the corresponding carboxylic acid. All metabolites are inactive. Ketoprofen is metabolized by glucuronidation of the carboxylic acid, hydroxylation of the benzene ring, and reduction of the keto function. Approximately 70% of an administered dose of naproxen is eliminated as either unchanged drug or as conjugates of parent drug. The metabolism of piroxicam occurs via hydroxylation of pyridine or benzene ring. Ketoralac is an arylacetic acid derivative. It is available for parenteral use as well as oral and topical ophthalmic use. Ketoralac may cause fewer adverse gastrointestinal and central nervous system effects than do opioid analgesics, but it poses a significant risk of haematologic toxicity. For this reasons oral and parenteral therapy with the drug must be limited to five or fewer days. Ketorolac is metabolised to the p-hydroxy derivative and to conjugates that are excreted primarily in the urine. The selective cyclooxygenase-2 (COX-2) inhibitors are a new group of drugs that appear to provide potent anti-inflammatory activity without causing significant gastrointestinal toxicity. Celecoxib, a diarl-substituted pyrazole, is the first selective COX-2 inhibitor to be marketed, and several other compounds with similar activity are being developed. Celecoxib appears to cause a low incidence of adverse reactions, the most common of which are diarrhoea, dyspepsia, and abdominal pain. The drug is associated with much lower incidence of gastroduodenal ulcers than are nonselective NSAIDs such as ibuprofen and naproxen. Because celexoxib is metabolised by CYP2C9, which involves hydroxylation of the 4-methyl group to the primary alcohol and further to the corresponding carboxylic acid, drugs such as flucunazole, fluvastatin my inhibit its metabolism and increase its serum concentration. Other selective COX-2 inhibitor, rofecoxib, was used in the treatment of osteoarthritis, acute pain conditions, and dysmenorrhoea. Formerly marketed by Merck & Co. under the trade names Vioxx, Ceoxx and Ceeoxx, it was voluntarily withdrawn from the market in 2004 because of concerns about increased risk of heart attack and stroke. Although, the metabolism of rofecoxib has not been fully determined, the microsomal CYP450 system appears to play only a minor role – a major difference in the metabolic routes of rofecoxib and celecoxib. The major metabolic route appears to lead to the cis and trans  -lactone. Rofecoxib was available on prescription as tablets and as an oral suspension. Rofecoxib was one of the most widely used drugs ever to be withdrawn from the market. Worldwide, over 80 million people were prescribed rofecoxib at some time. In the year before withdrawal, Merck had sales revenue of US$2.5 billion from Vioxx. Demand on healthcare professionals to deliver high quality patient care has never been greater. A multitude of factors impinge on healthcare deliver today, including aging population, more sophisticated medicines, high patient expectations, health service infrastructure as well as adequate and appropriate staffing levels. Probably of greatest impact to community pharmacy practice is the continued de-regulation of medicines. The global market for over-the-counter medicines is considerable, and rising. A combination of factors has fuelled this worldwide increase in OTC sales: including government healthcare policies that have encouraged self-care and self-medication ; a greater emphasis on cost containment by healthcare organisations ; an unprecedented rise in the number of medicines deregulated from prescription-only control to OTC status ; and the profit interests of pharmaceutical companies. In these circumstances, pharmacists have to demonstrate that they are competent practitioners to be trusted with this additional responsibility. References: 1. D. A. Willoughbv, A. R. More, P. R. Colville-Nash, COX-1, COX-2, and COX-3 and the future treatment of chronic inflammatory disease ; Lancet. 2000, 355(9204):646-8. 2. D. A. Williams, T. L. Lemke, Foye's Principles of Medicinal Chemistry, 5th Ed. Lippincott Williams & Wilkins, Philadelphia 2002. 3. B. E. Gould, Pathophysiology for the health professions, 2nd Ed., W.B. Saunders company, Elsevier Science, London 1997. 4. G. M. Brenner, Pharmacology, Saunders, Phyladelphia, 2000. 5. P. Rutter, Community pharmacy. Symptoms, Diagnosis and Treatment, Churchill Linvingstone, Edinburgh, 2004.

Izvorni jezik
Engleski

Znanstvena područja
Farmacija

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