Paracetamol Alcohol

Typically, funding to embark on information and/or knowledge management initiatives within the life sciences only occurs after a serious failure within the business, such as a project failure or a withdrawal of a medicine from the market. Recently, COX-2 programs across the industry are under close scrutiny since the highly publicized withdrawal of Vioxx [10]. Of course, there has been no withdrawal of aspirin, paracetamol, alcohol, or tobacco products, which are well known as toxic. 

The paracetamol-alcohol interaction is complex acute and chronic ethanol intake has opposite effects. 

Prescott LF Paracetamol, alcohol and the liver. BrJ Clin Pharmacol (2000) 49,291-301. 

Hydroxyacetanilide. This derivative (21), also known as 4-acetamidophenol, acetaminophen, or paracetamol, forms large white monoclinic prisms from water. The compound is odorless and has a bitter taste. 4-Hydroxyacetani1 ide is insoluble in petroleum ether, pentane, and ben2ene slightly soluble in diethyl ether and cold water and soluble in hot water, alcohols, dimethylformamide, 1,2-dichloroethane, acetone, and ethyl acetate. The dissociation constant, pfC, is 9.5 (25°C). 

N-(2-Hydroxypropyl)carbamates (8.139, Fig. 8.13,b) are prodrugs that resemble the A-(2-hydroxyphenyl)carbamates discussed above. Here, activation yielded the tranquilizer mephenoxalone (8.140, Fig. 8.13,b) and an alcohol or a phenol such as paracetamol. Other active oxazolidinones could be obtained by replacing the MeO group in 8.139 (Fig. 8.13, b) with another substituent. For this series, the mechanism of activation is not an intramolecular nucleophilic attack, but, rather, decomposition of the deprotonated carbamate group as shown in Fig. 8.7,b, Reaction b, with the intermediate isocyanate being trapped to form the oxazolidinone ring. 

Buckley, N.A. and Srinivasan, J. (2002) Should a lower treatment line be used when treating paracetamol poisoning in patients with chronic alcoholism a case for. Drug Safety, 25 (9), 619-624. 

Bioactivation is a classic toxicity mechanism where the functional group or the chemical structure of the drug molecule is altered by enzymatic reactions. For example, the enzymatic breakdown of the analgesic acetaminophen (paracetamol), where the aromatic nature and the hydroxyl functionality in paracetamol are lost, yields A -acetyl-p-benzoquinone imine, a hepatotoxic agent. Paracetamol can cause liver damage and even liver failure, especially when combined with alcohol. 

This is known as Michaelis-Menten or saturation kinetics. The processes that involve specific interactions between chemicals and proteins such as plasma protein binding, active excretion from the kidney or liver via transporters, and metabolism catalyzed by enzymes can be saturated. This is because there are a specific number of binding sites that can be fully occupied at higher doses. In some cases, cofactors are required, and their concentration may be limiting (see chap. 7 for salicylate, paracetamol toxicity). These all lead to an increase in the free concentration of the chemical. Some drugs, such as phenytoin, exhibit saturation of metabolism and therefore nonlinear kinetics at therapeutic doses. Alcohol metabolism is also saturated at even normal levels of intake. Under these circumstances, the rate of... 

Alcohol is an inducer of CYP2E1, which can lead to situations of enhanced drug toxicity in alcoholics or heavy drinkers (e.g., from paracetamol overdose). 

Zimmerman HJ, Maddrey WC. Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol analysis of instances of therapeutic misadventure. Hepatology 1995 22 762-777. 

Lauterburg BH, Velez ME. Glutathione deficiency in alcoholics risk factor for paracetamol hepatotoxicity. Gut 1988 29 1153-1157. 

Overdoses of paracetamol can be very dangerous, as the drug has a narrow therapeutic index and may cause hepatic and renal necrosis. Nausea, vomiting, lethargy, and sweating are the early overdose symptoms. Paracetamol must be given with caution in alcoholics and patients with liver and kidney damage. 

Dextropropoxyphene Dextropropoxyphene, a drug of abuse, and any misuse or overdose of which causes intoxication if taken along with paracetamol or alcohol. The individual develops serious CNS depression leading to death.40-42 Adverse effects can be treated by gastric lavage and administration of activated charcoal and naloxone 43... 

A 34-year-old alcoholic man with acute pancreatitis was given continuous intravenous infusion of haloperidol (2 mg/hour) for agitation after 7 hours he received a bolus dose of haloperidol 10 mg for worsening agitation and 20 minutes later, QT interval was 560 ms (420 ms before treatment) (131). He developed torsade de pointes and ventricular fibrillation, which resolved with electric defibrillation. He was a smoker and was also taking tiapride and alprazolam for depression, in addition to pantoprazole, piperazilline + tazobactam, paracetamol, and vitamins Bi, B6, and B 12-... 

There is a theoretical concern that chronic alcoholics are at an increased risk of paracetamol hepatotoxicity. However, from the shortterm data available in controlled situations, there seems to be no increased risk of hepatotoxicity when these patients are administered therapeutic doses of paracetamol. Some evidence suggests that the potential increased risk of hepatotoxicity may be related more to poor diet and fasting than to the effects of the alcohol. Longer-term controlled studies are still needed to assess the risks of chronic therapeutic dosing in alcoholics. 

Hepatotoxicity from paracetamol overdose can occur with single doses as low as 10-15 g. The risk factors for hepatotoxicity in excessive doses include induction of cytochrome P450 enzymes malnutrition or fasting, due to reduced glutathione stores and reduced glucuronidation chronic alcohol use and age over five years [8, 13]. 

There is no good evidence that alcoholics are more susceptible to hepatotoxicity as a result of their alcohol intake. Several large retrospective studies examining hundreds of paracetamol overdoses have shown no difference in hepatotoxicity/survival rate in those who chronically consume alcohol compared to moderate or non-drinkers [14,17]. However, alcoholics are more likely to present later and to be malnourished, and thus may appear to be more susceptible to paracetamol hepatotoxicity [14]. 

When administered acutely, ethanol competes with paracetamol for CYP2E1 and blocks the active site, theoretically resulting in less formation of NAPQI. The protective, competitive influence of ethanol is thought to be present for as long as alcohol is present in the body [14, 18]. 

Owing to the theoretical risk of greater NAPQI formation when paracetamol is taken in overdose by alcoholics, they are administered N-acetylcysteine at a reduced threshold. 

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

If this patient was alcoholic or malnourished it might raise additional concerns. Information regarding the therapeutic use of paracetamol in alcoholics is limited and conflicting. Considering the evidence available, current practice is not to reduce the dose of paracetamol in alcoholics. However, if the patient were malnourished a dose reduction might be considered. 

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