Alcohol chronic administration

Chronic administration of opiates and alcohol leads to physical dependence a phenomenon, which is only weakly expressed following chronic administration of psychostimulants or other drugs of abuse. Physical dependence results from neuroadaptive intracellular changes to an altered pharmacological state. Abstinence from chronic opiate or alcohol use leads to a variety of physiological and psychological withdrawal symptoms based on these adaptations of the neuronal system. 

There are similarities between the biological actions of inhalants and those of alcohol and barbiturates (Bowen et al. 1996b). For example, acute administration of inhalants affects motor coordination (Moser and Balster 1981) and induces anxiolysis, whereas chronic administration is associated with physical dependence and withdrawal (Bowen et al. 1996a Evans and Balster 1991, 1993). In addition, some inhalant drugs have anticonvulsant properties (Wood et al. 1984). Like other CNS-depressant agents, inhalants have biphasic effects on spontaneous locomotor activity in rodents, with increased activity seen at lower doses and diminished locomotion seen at higher doses (Cause et al. 1985 Kjellstrand et al. 1985). 

McMillan DE, Snodgrass SH. (1991). Effects of acute and chronic administration of delta 9-tetrahydrocannabinol or cocaine on ethanol intake in a rat model. Drug Alcohol Dependence. 27(3) 263-74. 

Hall P dela M, Plummer JL, lisley AH, et al. 1990. Hepatic fibrosis and cirrhosis after chronic administration of alcohol and "low-dose" carbon tetrachloride vapor in the rat. Hepatology 13 815-819. 

The pathology of liver injruy induced by the chronic administration of alcohol and... 

Tolerance—decreased responsiveness to a drug following repeated exposure—is a common feature of sedative-hypnotic use. It may result in an increase in the dose needed to maintain symptomatic improvement or to promote sleep. It is important to recognize that partial cross-tolerance occurs between the sedative-hypnotics described here and also with ethanol (Chapter 23 The Alcohols)—a feature of some clinical importance, as explained below. The mechanisms responsible for tolerance to sedative-hypnotics are not well understood. An increase in the rate of drug metabolism (metabolic tolerance) may be partly responsible in the case of chronic administration of barbiturates, but changes in responsiveness of the central nervous system (pharmacodynamic tolerance) are of greater importance for most sedative-hypnotics. In the case of benzodiazepines, the development of tolerance in animals is associated with down-regulation of brain benzodiazepine receptors. 

Therapeutic Concentration. Chloral hydrate is difficult to detect in body fluids after normal doses. The plasma concentration of trichloroethanol is usually in the range 1.5 to 15 pg/ml. Trichloroacetic acid and urochloralic acid are present in plasma at concentrations similar to, or greater than, those of trichloroethanol. When alcohol has been taken, peak plasma concentrations of trichloroethanol are increased and remain elevated for about 6 hours after ingestion, and those of trichloroacetic acid are decreased. Trichloroacetic acid accumulates in the plasma during chronic administration of chloral hydrate. 

Moser J, Bagchi D, Akubue PI, et al. 1993. Excretion of malondialdehyde, formaldehyde, acetaldehyde and acetone in the urine of rats following acute and chronic administration of ethanol. Alcohol Alcohol 28 287-295. 

Acute and chronic administration of alcohol can inhibit the biotransformation or detoxification of many drugs, such as barbiturates, meprobamate, and amphetamines by liver enzymes. The effect can occur in two opposite ways. Alcohol and cannabinoids effects are additive. Both are CNS depressants. Animal studies indicate that simultaneous administration of alcohol and tetrahydrocannabinol (THC), the psychoactive component of marijuana, increased the tolerance and physical dependence to alcohol. Human studies show that alcohol and THC combination enhanced the impairment of physical and mental performance only, and there is no evidence of any interaction between both drugs. With barbiturates. 

Theoretically, when blood and liver levels of vitamin A are reduced as in alcoholic hepatitis and alcoholic cirrhosis, subjects should receive supplemental vitamin A. Such supplementation, as high as 3000-10,(X)0 xg daily, has been shown to correct abnormal dark adaptation in some alcoholic cirrhotics uncomplicated by zinc deficiency (Morrison et aL, 1978 Russell et aL, 1978 Mobarhan et aL, 1981). Some studies in rats, however, indicate that acute and chronic administration of ethanol impairs hepatic and/or peripheral tissue uptake of newly ingested retinyl ester and/or causes the release of retinyl esters from hepatic tissue... 

On the other hand, the ethiology of fatty livers caused by alcohol is still debated and manifold effects of alcohol have been reported. In man a fatty liver can result from acute or chronic ethanol ingestion. In the rat a single dose of ethanol or the chronic administration causes an increase in liver lipids (Dilxjzio 1958 Mallov 1955). Mallov (1961) demonstrated an increased mobilization of free fatty acids from the depots, caused by alcohol administration. On the other hand, ScHAPiRO et al. (1964) showed in the perfused liver, that addition of ethanol to the perfusate decreased the secretion of neutral glycerides by the liver. However, with ethanol no decrease in protein synthesis could be shown (Seakins and Robinson 1964), and normal or elevated plasma lipids were found. 

Wernicke s syndrome is a serious consequence of alcoholism and thiamine (vitamin Bx) deficiency. Certain characteristic signs of this disease, notably ophtalmoplegia, nystagmus, and ataxia, respond rapidly to the administration of thiamine but to no other-vitamin. Wernicke s syndrome may be accompanied by an acute global confusional state that may also respond to thiamine. Left untreated, Wernicke s syndrome frequently leads to a chronic disorder in which learning and memory are strongly impaired. This so-called Korsakoff s psychosis is characterized by confabulation, and is less likely to be reversible once established. 

Theophylline is a narrow therapeutic index drug with significant difference in bioavailability following oral administration. The half-life of the drug is increased by heart failure, cirrhosis and viral infections, in elderly patients, and by certain drugs, such as cimetidine, ciprofloxacin, oral contraceptives and fluvoxamine. The half-life is decreased in smokers, chronic alcoholism, and by certain drugs, such as phenytoin, rifampicin and carbamazepine. 

Joly JG, Villeneuve JP, Marier P. 1977. Chronic ethanol administration induced a form of cytochrome P-450 with specific spectral and catalytic properties. Alcoholism 1 17-25. 

The use of corticosteroids is often suggested for elderly patients with chronic tophaceous gout, since gout in the older individual often displays symptoms similar to those of rheumatoid arthritis. Patients can be given short-term administration of corticosteroids, especially for acute flare-ups. The concomitant use of alcohol, nonsteroidal antiinflammatory drugs, and most diuretics should be avoided. 

The standard pharmacokinetic parameters of the compound such as a half-life or bioavailability cannot be reliably calculated, because the concentrations in plasma are below lOpg/mL. As analogously expected from the results on the shift in keto-alcohol equilibrium of 16,16-difluoro-PGE2, it is rapidly metabolized by C-15 reduction mediated by the ubiquitously expressed carbonyl reductase. The metabolism followed by jS-oxidation and co-oxidation forms a mixture of a and fi epimers at the 15-hydroxy moiety as a sole measurable metabolite [46], In 2006, the US Food and Drug Administration approved the drug application for an oral treatment of chronic idiopathic constipation in adults, estimating that 4-5 million Americans are affected. Lubiprostone has also completed a phase II trial in constipation-predominant irritable bowel syndrome, and has been further evaluated for other bowel dysfunctions. 

The spectrum of cognitive deficits associated with chronic alcohol use extends to the extreme of Wernicke s encephalopathy and Korsakoff s psychosis. Wernicke s encephalopathy is an acute neurologic syndrome caused by thiamine deficiency. Symptoms include mental confusion, ophthalmoplegia, and ataxia. Many of these symptoms reverse with administration of thiamine however about 50% of patients are left with some degree of ataxia. Left untreated, Wernicke s encephalopathy can progress to stupor, coma, and death. Approximately 80% to 90% of alcoholics treated for Wernicke s encephalopathy are left with Korsakoff s psychosis, a syndrome of impaired learning and recent memory produced by lesions of the medial dorsal nuclei of the thalamus. 

Johnson, K.M., and Balster, R.L. Acute and chronic phencyclidine administration Relationships between biodispositional-factors and behavioral effects. Subst. Alcohol Actions/Misuse 2 131-142, 1981. 

The increasingly accepted hypothesis that acetaldehyde may be the causative agent in initiating the multitude of acute pharmacological and chronic pathophysiological effects of alcohol prompted Nagasawa et al. to seek methods to reduce its blood levels. One possibility would be the administration of (S)-penicillamine (4), a compound related to cysteine. The condensation of this amino acid with acetaldehyde produced 2,5,5-trimethylthiazolidine-4-carboxylic acid 242). The chirality of this compound was deducted by NMR analysis to be 72% 2S, 4S and 28% 2R, 4S. Thus, this result is consistent with the configuration found previously for the thiazolidines formed from (R)-cysteine and aldehydes 241 ... 

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