Salicylate pharmacology

The salicylates include aspirin (acetylsalicylic acid) and related drugp, such as magnesium salicylate and sodium salicylate. The salicylates have analgesic (relieves pain), antipyretic (reduces elevated body temperature), and anti-inflammatory effects. All the salicylates are similar in pharmacologic activity however, aspirin has a greater anti-inflammatory effect than the other salicylates. Specific salicylates are listed in the Summary Drug Table Nonnarcotic Analgesics Salicylates and Nonsalicylates. 

In addition to their beneficial effects, some medications may actually cause cellular injury and disease. An example of this phenomenon involves nonsteroidal anti-inflammatory drugs (NSAIDS). These drugs include aspirin (a derivative of salicylic acid), ibuprofen (arylpropionic acid, Advil ), and acetaminophen (para-aminophenol derivative, Tylenol ). Because of their beneficial pharmacological effects, consumption of these agents has increased significantly in recent years. NSAIDS have the ability to treat fever, pain, acute inflammation, and chronic inflammatory diseases such as arthritis. They are also used prophylactically to prevent heart disease, stroke, and colon cancer. 

In view of the well-known pharmacological action of aspirin, it was thought that the fluorine analogue, O (fluoroacetyl) salicylic acid, might be of considerable interest. The compound was readily made by acylation of salicylic acid by fluoroacetyl chloride in the presence of pyridine. The l.d. 50 for subcutaneous injection into mice was approximately 15 mg./kg. After injection the mice went into a drugged sleep, and died overnight. 

Ester hydrolysis does not invariably lead to inactive metabolites, as exemplified by acetylsalicylic acid. The cleavage product, salicylic acid, retains pharmacological activity. In certain cases, drugs are administered in the form of esters in order to facilitate absorption (enalapril enalaprilate testosterone undecanoate testosterone) or to reduce irritation of the gastrointestinal Lullmann, Color Atlas of Pharmacology... 

Lautermann prepared it synthetically from phenol in 1860. Acetylsalicylic acid was first prepared in 1853 by Gerhardt but remained obscure until Hoffmann discovered its pharmacologic activities in 1899. It was first used in medicine by Dreser, who named it aspirin by taking the a from acetyl and adding it to spirin, the old name for salicylic acid. 

Pharmacology Salicylates have analgesic, antipyretic, anti-inflammatory, and antirheumatic effects. Salicylates lower elevated body temperature through vasodilation of peripheral vessels, thus enhancing dissipation of excess heat. The anti-inflammatory and analgesic activity may be mediated through inhibition of the prostaglandin synthetase enzyme complex. 

Mild sallcylism - Mild salicylism may occur after repeated use of large doses and consists of dizziness, tinnitus, difficulty hearing, nausea, vomiting, diarrhea, mental confusion, CNS depression, headache, sweating, hyperventilation, and lassitude. Salicylate serum concentrations correlate with pharmacological actions and adverse effects observed. 

Pharmacology BSS appears to have antisecretory and antimicrobial effects in vitro and may have some anti-inflammatory effects. The salicylate moiety provides the antisecretory effect, while the bismuth moiety may exert direct antimicrobial effects against bacterial and viral enteropathogens. 

Pharmacology Olsalazine sodium is a sodium salt of a salicylate compound that is effectively bioconverted to 5-aminosalicylic acid (mesalamine 5-ASA), which has anti-inflammatory activity in ulcerative colitis. Approximately 98% to 99% of an oral dose will reach the colon, where each molecule is rapidly converted into 2 molecules of 5-ASA by colonic bacteria. The liberated 5-ASA is absorbed slowly, resulting in very high local concentrations in the colon. 

Deschamps, D. et al. (1991) Inhibition by salicylic acid of the activation and thus oxidation of long chain fatty acids. Possible role in the development of Reye s syndrome. Journal of Pharmacology and Experimental Therapeutics, 259 (2), 894-904. 

Although aspirin itself is pharmacologically active, it is rapidly hydrolyzed to salicylic acid after its absorption, and it is the salicylate anion that accounts for most of the anti-inflammatory activity of the drug. The superior analgesic activity of aspirin compared with sodium salicylate implies that aspirin has an intrinsic activity that is not totally explainable by its conversion to salicylic acid. Aspirin inhibits COX-1 to a much greater extent than COX-2 sodium salicylate is more selective for COX-1. This, combined with the ability of aspirin to acetylate proteins, might account for some of the therapeutic and toxicological differences between aspirin and the other salicylates. 

The present primary mode of therapy for these diseases involves the use 5-amino-salicylate (5-ASA) products. Often patients require additional medications, including corticosteroids, to help induce remission and various immune modulators, such as azathioprine, 6-mercaptopurine or methotrexate, to maintain remission. In Crohn s disease certain antibiotics, such as metronidazole and ciprofloxacin, and infliximab Remi-cade), an anti-tumor necrosis factor-a(TNFa) antibody, also have been used. The pharmacology of antibiotics, immunosuppressive drugs, and corticosteroids is discussed in Chapters 43,57, and 60, respectively. 

Many pharmaceutically and pharmacologically important compounds, either of natural or synthetic origin, belong to this class of compounds, e.g. salicylic acid and quercetin. 

The pharmacological actions of salicylates in humans are well documented and are applicable to willow. In recent clinical studies, willow bark extract had moderate analgesic effects in osteoarthritis and low back pain (93-96). 

Aspirin (acetylsalicylic acid, Figure 7.9) is a derivative of salicyclic acid, which was first used in 1875 as an antipyretic and antirheumatic. The usual dose for mild pain is 300-600 mg orally. In the treatment of rheumatic diseases, larger doses, 5-8 g daily, are often required. Aspirin is rapidly hydrolysed in the plasma, liver and eiythrocytes to salicylate, which is responsible for some, but not all, of the analgesic activity. Both aspirin and salicylate are excreted in the urine. Excretion is facilitated by alkalinisation of the urine. Metabolism is normally very rapid, but the liver enzymes responsible for metabolism are easily saturated and after multiple doses the terminal half-life may increase from the normal 2-3 h to 10 h. A soluble salt, lysine acetylsalicylic acid, with similar pharmacological properties to aspirin, has been used by parenteral administration for postoperative pain. Aspirin in low doses (80-160 mg daily) is widely used in patients with cardiovascular disease to reduce the incidence of myocardial infarction and strokes. The prophylaxis against thromboembolic disease by low-dose aspirin is due to inhibition of COX-1-generated thromboxane A2 production. Because platelets do not form new enzymes, and COX-1 is irreversibly inhibited by aspirin, inhibition of platelet function lasts for the lifetime of a platelet (8-10 days). 

Several natural products contain substances that have coumarin, salicylate, or exhibit antiplatelet properties. Therefore, a theoretical risk for potentiation of the pharmacological activity of warfarin exists when these herbs are taken with warfarin. Herbs thought to contain coumarin or coumarin derivatives include the following ... 

Gleaning from herbal medicine the genesis of pharmacology (digitalis salicylic acid—aspirin morphine quinine artemisinin reserpine taxol). Ancient history-present. 

Pelletier JP, Cloutier JM, Martel-Pelletier J (1989) In vitro effects of tiaprofenic acid, sodium salicylate and hydrocortisone on the proteoglycan metabolism of human osteoarthritic cartilage. J Rheumatol 16 646-655 Steinmeyer J, Daufeldt S, Taiwo YO (1998) Pharmacological effect of tetracyclines on proteoglycanases from interleukin-l-treated articular cartilage. Biochem Pharmacol 55 93-100... 

The pharmacological uses of vitamin K are in the treatment of (rare) vitamin K deficiency prophylaxis in newborn infants (Section 5.4.1), and as an antidote to overcome anticoagulant toxicity. Because of its cytoxic effects, menadione has been used in cancer chemotherapy. It also potentiates the analgesic actions of salicylates and opiates, and has been used to enhance pain relief in cancer patients. 

Many hydroxycarboxylic acids are naturally occurring, and their coordination chemistry is of importance in biological processes. These complexes also have uses in many other areas such as analytical chemistry, electroplating processes, and pharmacology. The most widely studied ahphatic hydroxy acids are the lower members of the 2-hydroxyalkanoic acids, while studies of aromatic hydroxy acids have often centered on salicylic acid. A number of these acids contain one or more chiral carbon centers, and hence complexes of these acids have been useful in studying chiroptical properties such as the Cotton Effect see Cotton Effect). 

Inconclusive evidence suggests that salicylic acid can potentiate valproate toxicity (mechanism unclear). Sulfafurazole, sulfamethoxypyridazine, possibly other sulfonamides, and sulfinpyrazone displace phenytoin from plasma protein binding sites with different affinities total phenytoin concentrations may underestimate the concentration of unbound (pharmacologically active) drug. 

Plasma protein binding interactions are usually clinically unimportant, but they should be recognized, because they alter the relation between serum drug concentration and the clinical response if displacement occurs, therapeutic and toxic effects are reached at a total drug concentration lower than usual. For example, valproic acid and salicylate displace phenytoin from plasma proteins this usually results in a fall in total phenytoin concentration without any change in the concentration of unbound (pharmacologically active) phenytoin. 

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