Acetylsalicylic acid toxicity

Acetyls alley lie acid was shown to prevent cirrhosis under certain experimental conditions [125]. Naproxen and indomethacin partially protected against LPS and D-galactosamine-in-duced hepatotoxicity [126] Acetylsalicylic acid and ibuprofen were also protective in endo-toxic shock [127]. Endotoxaemia is one of the complications in cirrhotic patients [128] and is probably caused by an impaired ability of the liver to take up and detoxify gut-derived LPS [116]. The presence of portosystemic shunts in cirrhotic patients may also contribute to this spill-over of LPS into the systemic circulation [129]. NSAIDs, however, are also reported to provoke deleterious effects on renal function in cirrhosis [130], and can therefore not be used in cirrhotic patients. Cell-specific delivery of NSAIDs to SECs and/or KCs may make application of these drugs in cirrhosis feasible by circumventing the renal side-effects. 

Salicin is an (9-glycoside of a phenol, namely salicyl alcohol. Salicin is a natural antipyretic and analgesic found in willow bark, and is the template from which aspirin (acetylsalicylic acid, see Box 7.13) was developed. Prunasin from cherry laurel is an example of a cyanogenic glycoside, hydrolysis of which leads to release of toxic HCN (see Box 7.7). It is the (9-glucoside of the alcohol mandelonitrile, the trivial name for the cyanohydrin of benzaldehyde. It is the further hydrolysis of mandelonitrile that liberates HCN. 

Regarding the positive compounds, six out of eight compounds showed a developmental toxicity both in mammalian embryo-fetal studies and in FETAX. Concerning the negative compounds, four out of five chemicals were found negative in both models. There were two false negative compounds, acetylsalicylic acid and dexame-... 

Acetylsalicylic acid, phenytoin, phenothiazines Competition for binding to glycoprotein TCA toxicity (cardiac effects, delirium, sedation) due to increased amount of free TCA Lower TCA dose Baldessarini, 1996... 

Protein or calcium deficiency impairs drug metabolism in animals, due to decreased activity of the microsomal enzymes of the liver. The sleeping time by hexobarbitone is increased as a result of prolonged protein malnutrition. Acetylsalicylic acid has been shown to be more toxic to animals on a diet deficient in protein and magnesium. 

Goulden KJ, Dooley JM, Camfield PR, et al. Clinical valproate toxicity induced by acetylsalicylic acid. Neurology 1987 37 1392-1394. 

Aspirin (acetylsalicylic acid) and other salicylates are still a common cause of human poisoning, both therapeutic and suicidal, and account for a significant number of deaths each year. Although the toxic effects have a biochemical basis, some of the effects caused are clearly physiological, and consequently, it has been used as an example in this category. 

Blood and various organs of humans and other animals contain esterases capable of acetylsalicylic acid hydrolysis. A comparative study has shown that the liver is the most active tissue in all animal species studied except for the guinea pig, in which the kidney is more than twice as active as the liver. Human liver is least active the enzyme in guinea pig liver is the most active. The relatively low toxicity of some of the new synthetic pyrethroid insecticides appears to be related to the ability of mammals to hydrolyze their carboxyester linkages. Thus mouse liver microsomes catalyzing (+)-/runs-resin e 111ri n hydrolysis are more than 30-fold more active than insect microsomal preparations. The relative rates of hydrolysis of this substrate in enzyme preparations from various species are mouse > > milkweed bug > > cockroach > > cabbage looper > housefly. 

The pH of the toxic substance can greatly influence its absorption and therefore its toxicity. An example of this phenomenon is provided by aspirin, one of the most common causes of poisoning in humans. The chemical name of aspirin is sodium acetylsalicylate, the acidic form of which is acetylsalicylic acid (HAsc), a weak acid that ionizes as follows ... 

The Ka expression is expressed in molar concentrations (denoted by brackets) of the neutral and ionized species involved in the ionization of the acetylsalicylic acid. The pKa (negative log of Ka) of HAsc is 3.2, and at a pH substantially below 3.2, most of this acid is in the neutral HAsc form. This neutral form is easily absorbed by the body, especially in the stomach, where the contents have a low pH of about 1. Many other toxic substances exhibit acid-base behavior and pH is a factor in their uptake. 

Mild and transient abnormalities in serum transaminase and alkaline phosphatase activities have been reported during therapy with auranofin (0.4%). This is noteworthy, since almost all patients were taking acetylsalicylic acid or other non-steroidal anti-inflammatory drugs, which also can cause increases in transaminases. There has been a report of two cases of toxic hepatosis in patients taking auranofin (52). 

Absorption kinetics are an Important consideration for drugs which produce toxicity at the absorption site. Decrease in gastrointestinal irritations of acetylsalicylic acid was accomplished via an analog diflusinal, which is 2, 4 -difluoro-4-hydroxy-3-biphenylcarboxylic acid. This compound apparently emerged after pharmacologic screening... 

The traditional method of drag development, at least in this century, has been to develop leads by first using, and then by isolating and identifying, the active chemical constituents from natural products, some of which may have been medicinally in use since antiquity. With the advent of modem organic chemistry some of these purified compounds were used directly (e.g., morphine, cocaine, atropine, quinine), and, once their chemical structures were ascertained, they became leads for hoped-for chemical modifications to achieve improved efficacy, less toxicity, or, at least, higher potency (e.g., dihydromorphinone, homatropine, acetylsalicylic acid). 

Paraamino salicylic acid has bacteriostatic activity against Mycobacterium tuberculosis. Methyl salicylate (oil of wintergreen) has been used in the past as a counterirritant. Salicylic acid (20% solution) has keratolytic properties and is used to remove comified epidermis (com). Because salicylic acid itself is too toxic for systemic use, the various salts of salicylate, including acetylsalicylic acid (aspirin), are used instead (see also Table 3). 

McKinney and Lish found that aminophylline is active in oral doses of 200 or 400 mg/kg in oedema of the rat-foot produced by carrageenan, dextran and formalin, but only slightly in that induced by 5-hydroxytryp-tamine. On the basis of the carrageenan results, it has a potency about half that of acetylsalicylic acid. It is about one-third as active as acetysalicylic acid in delaying ultra-violet erythema in the guinea-pig, but a toxic effect in this species cannot be excluded in making this assessment. The authors speculate on the extent to which the smooth muscle relaxant or vasodilator properties of aminophylline contribute to these results, and also whether the anti-inflammatory properties contribute to the therapeutic value of the drug in bronchoconstriction. 

Carboxylesterases include cholinesterase (pseudocholinesterase), arylcarboxyesterases, liver microsomal carboxylesterases, and other unclassified liver carboxylesterases. Cholinesterase hydrolyzes oholihe-like esters (succinylcholine) and procaine as well as acetylsalicylic acid. Genetic variant forms of cholinesterase have beeh idehtified in human serum (e.g., succinylcholine toxicity when administered as ganglionic blocker for muscle relaxation). Meperidine is hydrolyzed only by liver microsomal carboxylesterases (Fig. 10.19). Diphenoxylate is hydrolyzed to its active metabolite, diphenoxylic acid, within 1 hour (Fig. 10.19). Presumably, the peripheral pharmacological action of diphenoxylate is attributed to zwitterionic diphenoxylic acid, which is readily eliminated in the urine. 

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