Isoniazid Paracetamol

Other drugs are metabolised by Phase II synthetic reactions, catalysed typically by non-microsomal enzymes. Processes include acetylation, sulphation, glycine conjugation and methylation. Phase II reactions may be affected less frequently by ageing. Thus according to some studies, the elimination of isoniazid, rifampicin (rifampin), paracetamol (acetaminophen), valproic acid, salicylate, indomethacin, lorazepam, oxazepam, and temazepam is not altered with age. However, other studies have demonstrated a reduction in metabolism of lorazepam, paracetamol (acetaminophen), ketoprofen, naproxen, morphine, free valproic acid, and salicylate, indicating that the effect of age on conjugation reactions is variable. 

Following the development of the test, an in-house validation was conducted to evaluate the performance of FETAX compared to the results in the rat and/or rabbit. Thirteen reference chemicals were tested including eight compounds known to be teratogenic in rats and/or rabbits (caffeine, retinoic acid, hydroxyurea, ethanol, cyclophosphamide, nicotine, acetylsalicylic acid, dexametha-sone) and five non-teratogens (isoniazid, saccharin, paracetamol, penicillin G, sildenafil). The estimation of teratogenicity in rats and rabbits was based on published data (9). 

Chemicals which can damage (a) the liver include carbon tetrachloride, paracetamol, bromobenzene, isoniazid, vinyl chloride, ethionine, galactosamine, halothane, dimethyl-nitrosamine (b) the kidney include hexachlorobutadiene, cadmium and mercuric salts, chloroform, ethylene glycol, aminoglycosides, phenacetin (c) the lung include paraquat, ipomeanol, asbestos, monocrotaline, sulfur dioxide, ozone, naphthalene (d) the nervous system include MPTP, hexane, organophosphoms compounds, 6-hydroxydopamine, isoniazid (e) the testes include cadmium, cyclophosphamide, phthalates, ethanemethane sulfonate, 1,3-dinitrobenzene (f) the heart include allylamine, adriamycin, cobalt, hydralazine, carbon disulfide (g) the blood include nitrobenzene, aniline, phenyl-hydrazine, dapsone. 

As with alcohol, there is a complex interaction between isoniazid and paracetamol, affecting the risk of hepatotoxicity [5]. 

PARACETAMOL ISONIAZID Risk of paracetamol toxicity at regular, therapeutic doses when co administered with isoniazid Uncertain it seems that formation of toxic metabolites is t in fast acetylators when isoniazid levels i (i.e. at the end of a dosing period) There have been cases of hepatic pathology regular paracetamol should be avoided in patients taking isoniazid... 

Three forms of drug-induced liver failure are distinguished (1.) obligate, dose-dependent toxicity (e. g. paracetamol, (s. fig. 20.3), (2.) unpredictable, idiosyncratic liver insufficiency (e.g. isoniazid), and (3.) immunoaller-gic idiosyncrasy (e.g. halothane) (s. fig. 29.2). 

The binding of drug to tissue is usually reversible. In some cases, however, there is covalent binding, which by definition is not reversible. This applies to drug or metabolite and could be important because it could be related to toxicity. " A good correlation has been reported in animals between the degree of covalent binding to hepatic protein and the severity of hepatic necrosis of paracetamol, isoniazid, adriamycin, and furosemide. " ... 

Drugs that induce liver microsomal enzymes, such as phenobarbital, phenytoin, carbamazepine, rifampicin, and isoniazid, can make paracetamol poisoning more severe (104,105). In patients taking such drugs the serum paracetamol concentration should be doubled before consulting the usual treatment nomogram. 

Hepafotoxicity from chronic paracetamol (acetaminophen) therapy in adults have been reported in the literature, but compared to the acute toxicity seen with deliberate or accidental overdoses, these are very few. The majorify of fhese are associafed wifh chronic efhanol intake, smoking, isoniazid, rifampin, phenobarbifal and phenyfoin (inducers of the cytochrome P450 system). Short-term fasting and... 

CYP2E1 chlorzoxazone, ethanol, paracetamol ethanol, isoniazid diethyldithiocarbamate... 

A number of reports surest that the toxicity of paracetamol may be increased by isoniazid so that normal analgesic dosages (4 g daily) may not be safe in some individuals. Pharmacokinetic studies surest that isoniazid usually inhibits the metabolism of paracetamol, but that metabolism to toxic metaboUtes may be induced shortly after stopping isoniazid, or late in the isoniazid dose-interval in fast acetylators of isoniazid. 

A 21 -year-old woman who had heen taking isoniazid 300 mg for 6 months took 3.25 g of paracetamol for abdominal cramping. Within about 6 hours she developed marked evidence of liver damage (prolonged prothrombin time, elevated ammonia, transaminases, hyperbilirubinaemia). ... 

A young woman taking isoniazid who had taken up to 11.5 g of paracetamol in a suicide gesture, developed life-threatening hepatic and renal toxicity despite the fact that her serum paracetamol levels 13 hours later were only 15 micromol/L (toxicity normally associated with levels above 26 micromol/L). ... 

Three other similar eases were reported in patients taking isoniazid, ri-fampiein and pyrazinamide who had taken only 2 to 6 g of paracetamol daily. Three other possible eases of this toxic interaction have been described. ... 

However, in a pharmacokinetic study in 10 healthy subjects of both slow and fast acetylator status, isoniazid 300 mg daily for 7 days modestly decreased the total clearance of a single 500-mg dose of paracetamol by 15%. Moreover, the clearance of paracetamol to oxidative metabolites was decreased Similarly, in a further study in 10 healthy slow acetylators of isoniazid, the formation of paracetamol thioether metabolites and oxidative metabolites was reduced by 63% and 49%, respectively, by isoniazid 300 mg daily. However, one day after stopping isoniazid, the formation of thioether metabolites was increased by 56%, and this returned to pretreatment values 3 days after the discontinuation of isoniazid. In yet another study in 10 healthy subjects taking isoniazid prophylaxis, the formation clearance of paracetamol to A -acetyl-p-benzo-quinone imine (NAPQI) was inhibited by 56% when the paracetamol was given simultaneously with the daily isoniazid dose, but when the paracetamol was taken 12 hours after the isoniazid, there was no difference in NAPQI formation clearance, compared with the control phase (1 to 2 weeks after isoniazid had been discontinued). However, when the results were analysed by acetylator status, it appeared that the NAPQI formation clearance was increased in fast acetylators taking paracetamol 12 hours after the isoniazid dose. ... 

Not established. A possible reason is that isoniazid induces the cytochrome P450 isoenzyme CYP2E1 by stabilisation. This means that while the isoniazid is still present, the metabolism of substrates such as paracetamol is inhibited. However, when isoniazid levels drop sufficiently (as may be the case late in the dosing interval in fast acetylators), metabolism may be induced resulting in a greater proportion of the paracetamol being converted into toxic metabolites than would normally occur. ... 

Information is limited, but it would now seem prudent to consider warning patients taking isoniazid to limit their use of paracetamol because it seems that some individuals risk possible paracetamol-induced liver toxicity, even with normal reeommended doses. Pharmacokinetic studies suggest that it is possible that the risk is greatest shortly after stopping isoniazid. The risk may also be higher if paracetamol is taken late in the isoniazid dosing interval, partieularly in fast acetylators of isoniazid. More study is needed to elarify the situation. 

Epstein MM, Nelson SD, Slattery JT, KaUiom TF, Wall RA, Wright JM Inhibition of the metabolism of paracetamol by isoniazid. BrJ Clin Pharmacol (1991) 31,139-42. 

An example of a simple oxidatiim reaction is the craiver-sion of Fe " into Fe. Examples of active substances that are prone to oxidation are acetylcystein, adrenaline, apomorphine, clioquinol, dithranol, dobutamine, ergotamine, hydroquinone, isoniazid, mesalazine, naloxone, neomycin, oxycodone, paracetamol, peptides, salbutamol, phenothiazine derivatives (promazine, promethazine, chlorpromazine), phenylephrine, physostigmine, tetracycline, tretinoin, the vitamins A and D, and the excipients flavouring agents, fragrances and unsaturated fats (vegetable oils, suppository bases). 

Since the pioneering work of the Millers (1) and Magee and Barnes (2), it has become increasingly evident that many stable chemicals are metabolized to electrophilic intermediates that alkylate and arylate tissue macromolecules. This laboratory (3 -5) has shown that drugs, such as acetaminophen (paracetamol), phenacetin, furosemide (frusemide), isoniazid, and iproniazid, also are oxidatively activated by microsomal enzymes to electrophilic intermediates that covalently bind to tissue macromolecules and cause massive tissue necrosis. 

Hepatomegaly with mild disturbance of liver function was reported in a 49-year-old man taking paracetamol, an analgesic powder containing phenacetin and anti-pyrine and multiple antituberculous therapy including isoniazid. Liver biopsies showed marked accumulation of lipofuscin (190 ). Although attributed to phenacetin, hepatomegaly and abnormal liver function were more likely to be due to paracetamol and isoniazid. 

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