pharmacology alcohal

1 Name / Pharmacology-Alcohol

Pharmacology- Alcohol

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Abstract

Drugs of abuse interact with the neurochemical mechanisms of the brain. Some of these interactions are directly related to the reinforcing properties of a drug, while others are related to other effects associated with the drug. As in other areas of neuroscience, the level of understanding about these interactions and the mechanisms involved has increased tremendously over the last decade. The fundamentals of information processing in the brain and how psychoactive drugs can alter these processes are being elucidated. For drugs of abuse, certain commonalities have begun to emerge. While drugs of abuse have a wide range of specific individual actions in the brain, there is growing evidence that their reinforcing properties may result from a shared ability to interact with the brain’s reward system. For each drug of abuse, this action, coupled with its actions in other areas of the brain, contributes to the overall behavioral effect the drug produces. In some cases, the relationship of a drug’s neurochemical action and the behavioral effects it produces have been clearly elucidated, while in others much remains to be learned.

Keywords:

Alcohol dependence syndrome, Alcoholism, Acamprosate, Campral and Naltrexone

Introduction

Alcohol is a licit drug. Its consumption is sanctioned by cultural norms and social practices, and its production contributes significantly to Australia’s gross national product (GNP). Alcohol is a central nervous system (CNS) depressant. Its psychoactive properties contribute to changes in mood, cognition and behavior. The main psychoactive ingredient in beverage alcohol is ethyl alcohol (ethanol, or C H OH). The estimated annual cost of substance use disorders in the United States is $510 billion (3).


Blood Alcohol Concentration (BAC) is a reasonable guide to level of intoxication (see Table 3–1). BAC indicates the amount of alcohol in the bloodstream in grams of alcohol per 100 ml blood. A BAC of 0.05 means a person has 0.05 g of alcohol per 100 ml of blood (or a BAC of 0.05% = 11 mmol / L) (Victoria Police, 2001). A person of average build will metabolize alcohol at a constant rate of around one standard drink per hour. One standard drink (see Table 3–2) per hour will cause a rise in BAC of 0.01% to 0.02% in an hour; however:

• Small females will have higher blood peak levels than large males for the same volume consumed

• High tolerance to alcohol may result in faster metabolism (hence more rapid reduction in BAC)

Pharmacology, Pharmakinetics and Pharmadynamics of alcohol

Absorption, Distribution, Excretion

Alcohol is unique as a drug because of its molecular weight (46) and its infinite water solubility. It is a clear, colorless flammable liquid which absorbs water rapidly from the air. Its boiling point is 78.5° C, its freezing point -130° C. Alcohol is generally prepared by the fermentation of sugar by yeast. Since yeast does not survive in greater than 15 percent alcohol, stronger solutions of alcohol are prepared by distillation. Wine and beer generally contain 2 to 20 percent alcohol, while the distilled preparations contain 30 to 60 percent. Alcohol usp contains 49 percent ethyl alcohol by volume (42 percent by weight). In the United States 100 proof alcohol contains 50 percent ethyl alcohol by volume. During the process of fermentation a mixture of higher alcohols is formed; these are converted to their esters during the process of aging and impart to the final product some of the distinctive flavor and bouquet (5)

Alcohol, a small molecule which is neutral in water solution, is one of the few substances which may be absorbed directly by simple diffusion from the stomach and upper gastrointestinal tract. Unlike carbohydrates, proteins and fats it does not have to be digested before it can be absorbed and no active processes are involved in its absorption. About 30 percent of the alcohol taken orally is absorbed from the stomach and the majority of the remainder from the proximal small intestine. Alcohol does not appear in the stool; it is completely absorbed and eliminated by other routes. During early absorption from the gastrointestinal tract the concentration of alcohol in the arterial blood may significantly exceed that in the venous blood for at least one hour. If active absorption of alcohol is still occurring, then breath analysis will tend to correlate better than venous blood analysis with the effects of alcohol depression of the central nervous system (2). Vaporized alcohol can be absorbed by the lungs, but absorption through the intact skin is minimal.


Alcohol concentration, speed of ingestion, diluents mixed with the alcohol, food in the stomach, and the intrinsic emptying time of the stomach all influence the rate of absorption. Alcohol absorption is particularly delayed when it is taken with fatty foods. After gastrectomy, patients are often exquisitely sensitive to alcohol, since absorption is most efficient in the intestine. Carbonation enhances alcohol absorption by increasing gastric emptying. Because of this effect champagnes are notorious for their rapid effect. Beers and wines contain some foodstuffs which delay absorption. Since absorption is so much more efficient than metabolism, pharmacologically significant blood levels are reached quickly, usually attaining a peak 30 to 60 minutes after ingestion and falling to normal in eight to ten hours.

Alcohol distributes in body tissues and body fluids proportionally with their water content. The approximate water content of the whole body is 65 percent and that of blood approximately 83 percent; therefore at equilibrium the alcohol content of blood will be 1.27 times that of the whole body. Shortly after ingestion, alcohol is present in the cerebrospinal fluid at a concentration lower than that in blood. However, later, when the blood concentration of alcohol is falling, the concentration in the cerebrospinal fluid may remain high.

Alcohol crosses the placenta readily and enters fetal circulation. It may be present in the milk of the lactating mother (8).Alcohol is 90 to 98 percent oxidized by the liver; the remainder is excreted unchanged in the urine, breath, perspiration, tears, milk, saliva or bile.

Thus, induced diuresis or hyperventilation will not significantly hasten detoxification. Even without exogenous intake, normal human blood contains trace amounts of alcohol in concentrations up to 1.5 mg per liter (9). The combined rates of alcohol absorption, distribution, metabolism and excretion are reflected in the blood alcohol concentration. It is clear that the blood alcohol levels are greatly affected by the character of the drink and the presence of food in the digestive tract. Leake and Silverman5 have shown that the blood alcohol curves produced when the same total amounts of alcohol (0.6 gm per kg of body weight) are administered in a fasting state to normal subjects are dependent on the variety of the alcoholic beverage.

The sharpest rises and the highest peaks are produced by the "clinically most potent" spirits such as gin and vodka (5).The disappearance of alcohol from the blood is unique and deserves special emphasis. The rate of disappearance of most drugs from the blood represents a hypobolic curve, meaning that for a given time a variable amount may disappear (first order). Alcohol disappears as a straight line, meaning a fixed amount will disappear over a given time (zero order). There are individual differences between patients, but the rate is remarkably constant for each individual. For most subjects this rate of disappearance is 10 to 20 mg per 100 ml per hour per 150 pounds or approximately 10 to 20 ml of alcohol per hour. Thus, one can calculate that if a


person consumes approximately two-thirds ounce of whiskey per 150 pounds per hour he would never become intoxicated.

The effects of alcohol vary greatly among individuals and can be different in the same person on different occasions. The correlation of blood level with behavior has assumed immense importance because of the role of alcohol in auto accidents. The blood level obtained from a given amount of alcohol is approximately 0.001 percent for each milliliter consumed, so that ingestion of as little as one ounce of whiskey or a half pint of beer will yield a blood level of 0.01 percent alcohol.

Metabolism

Alcohol has many properties which make it an' excellent "energy food." Approximately 7 calories are liberated in the complete oxidation of 1 gram of alcohol. Only fat, liberating 9 calories per gram exceeds the nutritional value of alcohol. If 10 to 20 ml is metabolized per hour per 150 pounds, it is apparent that during a 24-hour period a heavy drinker can derive all his daily caloric requirements from alcohol. As an energy fuel, alcohol acts quickly and requires no digestive energy. The disadvantage of alcohol is that its energy cannot be stored, and it contains very few vitamins, minerals or essential amino acids. Since many of these essential nutrients are required for the metabolism of alcohol, nutritional disorders are the rule in chronic alcoholics.

Like most drugs, alcohol is primarily metabolized enzymatically by the liver. The ultimate products of the metabolism of alcohol are carbon dioxide and water. The primary step in the oxidation of alcohol to acetaldehyde is by the zinc-containing soluble enzyme alcohol dehydrogenase (ADH) which utilizes nicotinamide-adenine-dinucleotide (NAD) as the hydrogen acceptor. Many tissues possess a limited capacity to oxidize alcohol, but their quantitative contributions to total alcohol metabolism are quite small. Apparently the vast majority of ethanol oxidation occurs in the liver, although Mistilisli recently showed that the stomach and intestine of rats contain alcohol dehydrogenase, and that this extrahepatic ADH increases with repeated doses of alcohol. It is possible that extrahepatic ADH may account for more alcohol oxidation than was previously suspected.

The metabolism of acetaldehyde, proceeding at a much more rapid rate than that of alcohol, indicates that the initial oxidative step is ratelimiting. Since alcohol dehydrogenase is apparently saturated at such a low substrate concentration (10 ml per hour), the rate of oxidation appears as a straight line (zero order kinesis). For many years this linear rate of oxidation was attributed only to saturation of the enzyme. More recently, with better estimates of the km for the enzyme, it became clear that even with near lethal alcohol levels the enzyme could not be fully saturated. The linear kinesis of alcohol apparently arises from an insufficient supply of NAD. In fact, if


substrates such as fructose are given which stimulate the conversion of nicotinamide alcohol dehydrogenase (NADH) to NAD, the rate of alcohol metabolism may be partially accelerated.

Pharmacological Effects

Depression of the central nervous system is the principal pharmacological action of alcohol and is the basis for its social use. The first mental processes to be affected are usually those dealing with self-restraint. In general, the central nervous system effects are proportional to the blood alcohol level but, as previously mentioned, the most pronounced effects for any given level occur as the blood level is rising. In a sense alcohol is a general anesthetic, but it differs greatly from the volatile anesthetics, which undergo little oxidation and are rapidly excreted unchanged by the body.

Since alcohol is almost completely oxidized, its anesthetic properties last several hours, and there is little safety margin between the anesthetic dose and severe respiratory depression. The exact biochemical explanation of the neurochemical aberrations involved in the central nervous system effects of alcohol is currently being studied. A striking observation that normally innocuous amounts of serotonin and other biogenic amines such as dopamine greatly potentiate the central nervous system effects of alcohol, has led some investigators to suggest that the central nervous system effects of alcohol are mediated through these biogenic amines. Alcohol also is thought to enhance GABA activity in specific parts of the brain.

GABA-enhancement has been linked to the reinforcing effects of alcohol by the observation that drugs that block GABA activity also decrease alcohol intake in alcohol-preferring rats, while drugs that increase GABA activity act as a surrogate for alcohol, maintaining alcohol preference during alcohol withdrawal (10).

Alcohol in moderate doses causes only a slight rise in blood pressure, pulse and cardiac output. Very large amounts of alcohol directly depress the heart. The major cardiovascular effect is vasodilatation, especially of cutaneous vessels. The evidence that alcohol is useful as a coronary artery vasodilator agent in treating angina pectorisor in treating cerebrovascular disease is unconvincing. Alcohol increases gastric secretion and in high concentration is irritating to the gastrointestinal mucosa. In normal well-nourished people given small amounts of alcohol, fat accumulation and ultrastructural changes occur in the liver.22 if alcohol is indeed a direct hepatoxin for man, chronic alcoholism should be associated with a very high incidence of cirrhosis. Although cirrhosis of the liver is approximately eight times more common in alcoholics than in the remainder of the adult population, only one in ten alcoholic patients have


cirrhosis. This sporadic occurrence of cirrhosis in chronic alcoholism and the failure of alcohol to produce cirrhosis in laboratory animals suggest that some genetic predisposition may be involved in the pathogenesis of cirrhosis.

Management

A central descriptive characteristic of the dependence syndrome is the desire (often strong, sometimes overpowering) to take psychoactive drugs (which may or may not have been medically prescribed), alcohol or tobacco (World Health Organization, 2005). Physical and psychological dependence should be addressed if treatment of substance use is to be successful. In this case the patient a 40 year old female started drinking alcohol at the age of 16 and at forty; she starts her day with alcohol and ends with it. Hence two medications can effectively be administered, which are Naltrexone and or Acamprosate.

Pharmakinetics and pharmacodynamics of Naltrexone and or Acamprosate

Naltrexone

It can effectively interrupt the above described neurochemical mechanisms, and inhibit positive reinforcement associated with alcohol drinking. It is important to note that opioid receptor antagonists act relatively selectively in CNS and do not block all the systems involved in rewarding action of natural and chemical stimuli. From a practical point of view, it is an interesting and important issue that naltrexone does not alter the taste of ethanol, nor does it toxically react with alcohol as disulfiram does, and has no addictive potential like the opioid receptors agonists. It appears that its effectiveness depends on blocking the activity of the CNS (not peripheral) opioid receptors located in specific limbic structures (e.g. nucleus accumbens septi). There are therefore a number of theoretical and practical reasons to assume that naltrexone therapy can bring about the best results in patients who feel strongly rewarded by consuming alcohol - through the activation of the opioid system. Unfortunately, appropriate markers have not been designed to allow prediction of favorable or unfavorable response to naltrexone treatment. Naltrexone does not modulate, strongly or directly, the GABAergic, glutamatergic or noradrenergic transmission. Hence, naltrexone does not cause generalized anhedonia,

Numerous studies have shown the effectiveness of this medication in reducing drinking and preventing relapse (7). FDA in 1994 approved to treat alcohol dependence after the medication was shown to reduce the frequency of drinking and likelihood of relapse to heavy drinking (6).


Acamprosate

Acamprosate (calcium bis-acetyl-homotaurine) is a new drug that is absorbed via the particular route in gastrointestinal tract. Several placebo controlled studies have reported increased abstinence rates from alcohol among persons taking acamprosate over period ranging from six to twelve months. At steady state, it has a moderate distribution volume of about 20L. Acamprosate is not protein bound or metabolized. Half of the elimination of acamprosate occurs as unchanged aceyl homotaurine in urine, the other half might be eliminated by bilary excretion. Acamprosate disposition does not differ between males and females.

The pharmacokinetics of acamprosate

These are not modified in patients with hepatic insufficiency of chronic alcoholism. In contrast renal insufficiency influences the elimination of acamprosate and it is, therefore, contraindicated under such circumstances. It was demonstrated to be safe and effective by multiple placebo-controlled clinical studies involving alcohol-dependent patients who had already been withdrawn from alcohol, (i.e., detoxified). Campral proved superior to placebo in maintaining abstinence (keeping patients off alcohol consumption), as indicated by a greater percentage of acamprosate-treated subjects being assessed as continuously abstinent throughout treatment (10). Campral is not addicting and was generally well-tolerated this has agonist effects at gamma-aminobutyric acid receptors and inhibitory effects at N-methyl-D-aspartate receptors (8). It can be used separately or in combination with naltrexone. Study, examined the efficacy of acamprosate, naltrexone, and combined behavioral interventions (CBI) (1). But some healthcare providers, like someclients, question the value of using any drug to treat drug or alcohol addiction (4).

References:

1. Anton, R.F., O’Malley, S.S., Ciraulo, D.A., Cisler, R.A., Couper, D., Donovan, D.M., et al. (2006). Combined pharmacotherapies and behavioral interventions for alcohol dependence: The COMBINE study: A randomized controlled trial. The Journal of the American Medical Association, 295(17), 2003-2017.

2. Bruchas MR, Land BB, Chavkin C. The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors. Brain Res. 2010; 1314: 44–55.2. Balster, R.L., “Drug Abuse,” L,B. Wingard, Jr.,T.M. Brody, J. Lamer, et al. (eds.), Human Pharmacology (St Louis, MO: Mosby Year Book 1991).

3. Doweiko, H.E. (2002). Concepts of chemical dependency, 5th ed., Pacific Grove, CA: Brooks-Cole.


4. Freed, P.E. & York, L.N. (1997). Naltrexone: A controversial therapy for alcohol dependence. Journal of Psychosocial Nursing and Mental Health Services, 35(7), 24-28.

5. Garbutt, J.C., Kranzler, H.R., O’Malley, S.S., Gastfriend, D.R., Pettinati, H.M., Silverman, B.L., et al. (2005). Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: A randomized controlled trial. The Journal of the American Medical Association, 293(13), 1617-1625.

6. Kranzler, H.R., Van Kirk, J. (2001). Efficacy of naltrexone and acamprosate for alcoholism treatment: A meta-analysis. Alcoholism, Clinical and Experimental Research, 25(9), 1335-1341.

7. Keltner, N.L., and Folks, D.G. (2005). Psychotropic drugs, 4th ed. St. Louis, MO: Elsevier.

8. Tsai G, Coyle JT, The role of glutamatergic neurotransmission in the pathophysiology of alcoholism. Annual Review of Medicine, 49: 173-184, (1998).

9. Harris, R. A., Brodie, M. S., and Dunwiddie, TV.,“Possible Substrates of Ethanol Reinforcement:GABA and Doparnine,” P.W. Kalivas and H.H.Samson (eds.), The Neurobiology of Drug andAlcohol Addiction, Annals of the American Academy of Sciences 654:61-69, 1992

10. White, F. J., and Wolf, M. E., “PsychomotorStirnulants,” J. Pratt (cd.), The Biological Basis ofDrug Tolerance and Dependence (hmdon: AcademicPress, 1991).

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