Alcohol

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LogoKeyPointsBox.pngAlcohol has been estimated to be globally responsible for 3.8% of death and 4.6% of disability adjusted life years (DALYs) lost [1].

Strictly speaking, an alcohol is any organic compound with the R-OH formula. However, in common usage, alcohol refers to ethanol (C2H5OH) and ethanol-containing fermented beverages. This is a natural part of the normal human diet, and indeed rather difficult to eliminate totally if you eat plants. As a beverage it is possible to define optimal adult intake to reduce all cause mortality as being about 100g/week or below. For some causes of death such as cardiovascular disease a J shaped curve exists with nadir at 100g/week. Some other diseases such as stroke actually appear to have risk increased proportionate to any alcohol consumption. The condition alcohol seems to protect against most effectively is myocardial infarction. Other small chain alcohols include methanol (CH3OH) and propanol (C2H5OH).

Contents

Metabolism

Comparison of kinetics after single oral dose ethanol iv verus oral verus oral with anticholinergic to delay gastric emptying
Ethanol metabolism.gif

It is well known that there is variability in the rate and extent of absorption, distribution and elimination of alcohol. Up to 98% of ingested alcohol is metabolised and the remainder is excreted in breath, urine and sweat.

Elimination

The bulk of ethanol is broken down in the liver. However gastric mucosal metabolism is not negligible[2]. Alcohol dehydrogenase of which there are multiple isoenzymes is the main enzyme, but microsomal enzymes play a smaller role. Alcohol dehydrogenase converts ethanol to acetyldehyde, which in turns is rapidly degraded into acetic acid by acetyldehyde dehydrogenase. Alcohol is unusual in pharmacokinetic terms as its breakdown is usually governed by zero-order kinetics, i.e. the amount of alcohol metabolised is fixed. The explanation for this is that at the amounts of alcohol that most people drink, the liver's capacity to metabolise alcohol, principally with cytosolic alcohol dehydrogenase (ADH), is overwhelmed and the amount of alcohol metabolised per unit time is therefore constant. This amount in individual normal adults varies two fold due to ADH polymorphism, but the differential metabolism has been well characterised and is open to fairly accurate estimation for forensic purposes[3]. This rate-limiting step in oxidation has a Michaelis-Menten constant (Km) of 0.05-0.1 g/L[4]. Another ethanol-metabolising cytochrome P450 enzyme CYP2E1, has a higher Km (0.5-0.8 g/L) and is inducible, so that the clearance of ethanol is increased in heavy drinkers.

Absorption

Absorption of ethanol from the gut depends on:

  • Time of day
  • Drinking pattern
  • Dose form[5]
  • Concentration of ethanol in the beverage
  • Recent and current food (it tends to be much higher in fasting)
  • Gastric emptying time (drugs or pathology that alter gastric emptying change alcohol metabolism and indeed can prevent a proportion ever getting into the blood).

Subject to the caveats above, consumption of 1ml/kg (=0.8g/kg) of alcohol can be expected to raise the blood levels by 100-150mg/dL. In a 60kg person, this equates to approximately 6 alcohol units. The UK legal limit of driving is 80mg/dL, but is 50mg/dL in many other countries.[6]

Distribution

The rate of equilibration is governed by the ratio of blood flow to tissue mass and body composition. Ethanol has low solubility in lipids and does not bind to plasma proteins, so volume of distribution is closely related to the amount of water in the body, contributing to sex- and age-related differences. Recent work confirms that a multicompartment model to describe the disposition of ethanol is more accurate than the traditional one-compartment model with zero-order elimination[7].

Effects of Alcohol

It is classified as a sedative, but is often taken for the pleasure of the drink as well as its for its disinhibiting effect. Acute ingestion of a toxic fatal quantity is possible without the person ingesting it being aware of this risk, although most attributable fatalities are associated with secondary consequences such as accidents, inhalation of vomit or seizures.

The increase in reaction time has proved particularly problematical with driving and other skilled tasks. An advanced state of alcoholic intoxication is termed being "drunk" and is very familiar in most Western Societies. Children, the elderly, those with small amounts of body fat and those taking most medications will be at higher risk of alcohol toxicity.

There is quite a large literature on the association between a moderate alcohol consumption and lower risk of a number of conditions. This leads to the J shaped curve where both low and high alcohol consumption is associated with health loss.[8] There is often the potential for confounding in such studies. The pattern of drinking, type of drink[9][10] and selection by the disease against or for alcohol consumption might be such confounders[11]. Such fragile associations have been demonstrated for cognition[12], ischaemic heart disease[13], ischaemic stroke[14], insulin resistence[15], hip fracture[16], mental health[17], elderly well being [18], healthcare costs[19] and all cause mortality[20]. This area gets even more interesting given malignacy risk is increased[21].

Chronic Effects

The metabolism of alcohol can provide energy at the risk of disturbance of normal energy metabolism and toxicity. Acute alcoholic hepatitis is different from alcoholic cirrhosis, although the two may coexist. There is a higher incidence of trauma presentations, cardiomyopathy, neuropathy, cerebellar degeneration, pancreatitis and many other diseases in those with a high prolonged intake of alcohol. Many common medical presentations, such as gastro-intestinal bleeds, atrial fibrillation, hyponatraemia and confusion are associated with alcohol use. An intake of more than 350 g/week loses about 5 years of life for those aged up to 55.

Cancer

A causal link between alcohol and cancer with evidence of a dose-response relationship is established for[22]:

Cardiovascular disease

While the J shaped mortality curve with ischaemic heart disease incidence is well known, and used often to justify light to moderate alcohol intake, the incidence of hypertensive disease, haemorrhagic stroke or atrial fibrillation increases in proportion to consumption[22].

Chronic liver disease

Alcoholic liver cirrhosis incidence is directly proportional to population exposure to alcohol. The effects of changes in regulation of alcohol consumption is relatively easy to quantify as morbidity and mortality change within 1 year and the lag effect is now well characterised. Indeed the epidemiology is now well understood[23]:

  • Daily drinking is associated with the highest risk
  • From a lifetime perspective, recent drinking in the last decade, is more important compared to earlier drinking
  • Wine may have lower risk for the same amount of alcohol compared to beer or spirits in light to moderate drinkers

Foetal alcohol syndrome

Fetal alcohol syndrome is rather important to be aware of as a risk with alcohol consumption in pregnancy and for the mother to be advised accordingly.

Alcohol Dependence

(follow heading link for main article)

(AKA alcoholism, alcoholic state.) See description of dependence syndromes.

Diagnosis

History

Special Questionnaires
  • FAST test[24][25][26]
  • CAGE and other tests[27]
  • Alcohol Use Disorders Identification Test (AUDIT) test[28]

Clinical examination

Laboratory tests

[e.g. Gamma GT]

Predisposing Factors

  • Genetics
    • Higher concordance in MZ twins than DZ
    • Adoption studies show higher­ rates in adopted children from alcoholic parents
  • Personality
  • Advertising
  • Peer group pressures
  • Psychiatric illness
  • Social factors
    • Religion
    • Tradition / cultural factors
    • Economic factors (cheap price leads to greater­ consumption)
    • Occupation
      • Availability of alcohol (Landlords, bartenders etc)
      • Stress of job (Doctors!)

Complications of Alcohol Dependence

Alcohol Withdrawal

(follow heading link for main article)

LogoWarningBox4.pngWHEN TO USE PARENTAL VITAMIN B

A common cause of confusion, both in patients and the doctor who fails to recognise the reason for a patient's new confusion. The diagnosis may not be straight forward due to the stigmata associated with admitting to excess alcohol use. While much alcohol withdrawal can be managed in the community there are catches. The most important are:

  1. the prevention of Wernicke's encephalopathy. In those at risk this requires 3 days of parental thiamine, not just oral thiamine
  2. in advanced hepatitic disease or alcoholic hepatitis chlordiazepoxide is safer than diazepam or lorazepam.
  3. use of iv benzodiazepines is not without risk
  4. Clomethiazole (chlormethiazole), particularily the iv preparation, is associated with a higher life-threatening complication rate than benzodiazipines

Chronic alcohol use leads to gradual upregulation of N-methyl-d-aspartate receptors; withdrawal of alcohol leads to overwhelming excitatory action mediated by the glutamatergic system.

Symptoms & Signs

Acute withdrawal usually occurs between 6 and 12 hours after last alcohol consumption. Symptoms may last 4-5 days.

  • Autonomic hyperactivity
  • Perceptual disturbances
    • Transient visual, tactile or auditory hallucinations or illusions
    • Reality testing is generally intact i.e. person recognises these as hallucinations
  • Withdrawal seizures
    • These are not associated with "latent epilepsy" as EEG is normal before and after seizures

Delirium Tremens

An acute confusional state caused by withdrawal from alcohol. Usually begins 3-4 days after withdrawal, though may occur while individual is still drinking (possibly due to a reduced alcohol level). It is either of sudden onset or there is a prodromal phase of restlessness, anxiety and insomnia, with above symptoms of alcohol withdrawal. Additionally there is reduced level of consciousness, disorientation in time and place, impairment of sensory stimuli with hallucinations. Visual hallucinations may be Lilliputian, complex, frightening or vivid. The symptoms are worse at night and last for 2-3 days. If untreated, they may end with a deep prolonged sleep, waking symptom-free & with no memory of delirium.

Management of Alcohol Withdrawal

  • Rehydration
  • Correct any electrolyte imbalance
  • Correct hypoglycaemia with caution
    • Risk of precipitating Wernicke’s encephalopathy
  • Oral/parenteral thiamine
  • Reducing regimen of benzodiazepines or Chlordiazepoxide
  • Treat seizures with rectal or IV diazepam
    • Consider anticonvulsant for elective withdrawal if there is a history of withdrawal seizures

Medicinal Uses of Alcohol

Traditionally ethanol has been used in the treatment of methanol poisoning. Methanol is broken down by alcohol dehydrogenase to formaldehyde, a toxic metabolite which can cause serious morbidity including blindness. Ethanol is given as this will overwhelm the alcohol dehydrogenase, thus reducing the levels of formaldehyde produced by methanol metabolism.

Laboratory Uses of Alcohol

Ethanol is used as a fixative and solvent within the microbiology laboratory.

A 70% ethanol or propanol solution has disinfectant properties, possibly through denaturation of bacterial proteins. Either compound may be found in hand disinfectant gels. Ethanol is also commonly used in conjunction with other antiseptics such as chlorhexidine or povidone-iodine. When used, it should be allowed to dry before a procedure is undertaken. This is because some of the action may depend on evapouration, but also because it is flammable and there is a risk of ignition if diathermy is to be used.

References

  1. World Health Organization. Mortality and burden of disease attributable to selected major risks. Geneva, Switzerland: World Health Organization; 2009. Global Health Risks.
  2. Frezza M, di Padova C, Pozzato G, Terpin M, Baraona E, Lieber CS. High blood alcohol levels in women. The role of decreased gastric alcohol dehydrogenase activity and first-pass metabolism. N Engl J Med. 1990;322(2):95-9. Erratum in: N Engl J Med 1990 ;323(8):553. N Engl J Med 1990;322(21):1540. (Direct link)
  3. Brick J. Standardization of alcohol calculations in research. Alcoholism, clinical and experimental research 2006;30(8):1276-87. (Direct link – subscription may be required.)
  4. Norberg A, Jones AW, Hahn RG, Gabrielsson JL. Role of variability in explaining ethanol pharmacokinetics: research and forensic applications. Clinical pharmacokinetics 2003;42(1):1-31.
  5. Roberts C, Robinson SP. Alcohol concentration and carbonation of drinks: The effect on blood alcohol levels. Journal of forensic and legal medicine. 2007 Oct; 14(7):398-405.(Link to article – subscription may be required.)
  6. International Centre for Alcohol Policies
  7. Norberg A, Jones AW, Hahn RG, Gabrielsson JL. Role of variability in explaining ethanol pharmacokinetics: research and forensic applications. Clinical pharmacokinetics 2003;42(1):1-31.
  8. Klatsky AL, Udaltsova N. Alcohol drinking and total mortality risk. Annals of epidemiology 2007;17(5 Suppl):S63-7. (Direct link – subscription may be required.)
  9. Grønbaek M, Deis A, Sørensen TI, Becker U, Schnohr P, Jensen G. Mortality associated with moderate intakes of wine, beer, or spirits. BMJ (Clinical research ed.) 1995;310(6988):1165-9.
  10. Strandberg TE, Strandberg AY, Salomaa VV, Pitkälä K, Tilvis RS, Miettinen TA. Alcoholic beverage preference, 29-year mortality, and quality of life in men in old age. The journals of gerontology. Series A, Biological sciences and medical sciences 2007;62(2):213-8.
  11. Grønbæk M. Confounders of the Relation between Type of Alcohol and Cardiovascular Disease. Ann Epidemiol 2007;17(5S):S13-S15. (Direct link – subscription may be required.)
  12. Letenneur L. Moderate alcohol consumption and risk of developing dementia in the elderly: the contribution of prospective studies. Annals of epidemiology 2007;17(5 Suppl):S43-5. (Direct link – subscription may be required.)
  13. Fillmore KM, Stockwell T, Chikritzhs T, Bostrom A, Kerr W. Moderate Alcohol Use and Reduced Mortality Risk: Systematic Error in Prospective Studies and New Hypotheses. Ann Epidemiol 2007;17(5S):S16-S23. (Direct link – subscription may be required.)
  14. Mukamal KJ, Chung H, Jenny NS, Kuller LH, Longstreth WT, Mittleman MA, et al. Alcohol use and risk of ischemic stroke among older adults: the cardiovascular health study. Stroke; a journal of cerebral circulation 2005;36(9):1830-4. (Direct link – subscription may be required.)
  15. Fueki Y, Miida T, Wardaningsih E, Ito M, Nakamura A, Takahashi A, et al. Regular alcohol consumption improves insulin resistance in healthy Japanese men independent of obesity. Clin Chim Acta 2007.(Epub ahead of print) (Direct link – subscription may be required.)
  16. Mukamal KJ, Robbins JA, Cauley JA, Kern LM, Siscovick DS. Alcohol consumption, bone density, and hip fracture among older adults: the cardiovascular health study. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 2007;18(5):593-602. (Direct link – subscription may be required.)
  17. El-Guebaly N. Investigating the association between moderate drinking and mental health. Annals of epidemiology 2007;17(5 Suppl):S55-62. (Direct link – subscription may be required.)
  18. Lang I, Wallace RB, Huppert FA, Melzer D. Moderate alcohol consumption in older adults is associated with better cognition and well-being than abstinence. Age and ageing 2007;36(3):256-61. (Direct link – subscription may be required.)
  19. Mukamal KJ, Lumley T, Luepker RV, Lapin P, Mittleman MA, McBean AM, et al. Alcohol consumption in older adults and Medicare costs. Health care financing review 2006;27(3):49-61.
  20. Fillmore KM, Stockwell T, Chikritzhs T, Bostrom A, Kerr W. Moderate Alcohol Use and Reduced Mortality Risk: Systematic Error in Prospective Studies and New Hypotheses. Ann Epidemiol 2007;17(5S):S16-S23. (Direct link – subscription may be required.)
  21. McPherson K. Moderate alcohol consumption and cancer. Annals of epidemiology 2007;17(5 Suppl):S46-8. (Direct link – subscription may be required.)
  22. a b Parry CD, Patra J, Rehm J. Alcohol consumption and non-communicable diseases: epidemiology and policy implications. Addiction (Abingdon, England). 2011 Oct; 106(10):1718-24.(Link to article – subscription may be required.)
  23. Rehm J, Roerecke M. Patterns of drinking and liver cirrhosis - what do we know and where do we go? Journal of hepatology. 2015 May; 62(5):1000-1.(Link to article – subscription may be required.)
  24. Fast test page at About.Com. updated: July 19, 2007, last viewed 4/3/09
  25. Fast test page at NHS Lothian web site. Last viewed 4/3/09
  26. Ray Hodgson, Tina Alwyn, Bev John, Alyson Smith, Robert Newcombe, Cheryl Morgan, Betsy Thom, Rachel Hodgson, Seta Waller. Fast Test Manual. Undated. Last viewed 4/3/09
  27. Short Alcohol Tests Ideal for Healthcare Screening page at About.Com. updated: July 19, 2007, last viewed 4/3/09
  28. Alcohol Use Disorders Identification Test page at About.Com. updated: July 19, 2007, last viewed 4/3/09
  29. Appendix toWorking Party of the Royal College of Physicians ALCOHOL – can the NHS afford it? Recommendations for a coherent alcohol strategy for hospitals Royal College of Physicians of London 2001