MEDICAL STAFF CONFERENCE The Clinical Pharmacology of

These discussions are selected from the weekly staff conferences in the Department of Medicine, University of California, San Francisco. Taken from transcriptions, they are prepared by Drs. Sydney E. Salmon and Robert W. Schrier, Assistant Professors of Medicine, under the direction of Dr. Lloyd H. Smith, Jr., Professor of Medicine and Chairman of the Department of Medicine.

DR. SMITH: * Dr. Becker, Chief Resident in Med- are bad for children but salutary for icine, who soon will be instrumental in organiz- the elderly." ing a new service at the San Francisco General Shakespeare knew of the physiology of Hospital for the treatment of drug poisonings, alcohol. In MacBeth, MacDuff asks, "What will an center there. three things does drink provoke?" begin The porter answers, "Nose painting, sleep Today Dr. Becker will discuss the clinical phar- and urine." macology of alcohol. Pasteur believed "wine to be the most DR. BECKER:t As physicians we are accustomed healthful and most hygienic of beverages."- to giving our patients prescriptions for drugs or Osler had a somewhat different view on writing orders for drugs in the hospital chart. the therapeutic effects of alcohol. He sug- We then observe the effect of the drug on the gested to the English in 1906 that they illness and vary the dose to obtain a maximal throw all their and spirits into the Irish therapeutic effect with minimal toxicity. The Channiel, the English Channel and the North drugs appear in bottles, vials, or packets. The Sea for one year, and then the people in most common drug used by patients, however, England would be infinitely better. He be- comes in unusual containers for drugs-cans, bot- lieved such an action would "solve all the tles or decanters. The drug is alcohol. Patients problems with which the philanthropist, the of this drug to get the de- physicians and the politicians have to deal." vary their own doses The modern physician depicted in Figure sired effect and may have little regard for tox- 1 might define an alcoholic as "a man who icity. drinks more than his own doctor."1 fer- The effects of drinking spontaneously As physicians' enthusiasm on the therapeutic mented fruit juices have been known for a long value of alcohol has waned during the past 50 time. Figulre 1 illustrates a cocktail party where for and of alco- years, the struggles within our society several famous specialists on the effects against the use of alcohol for social value have hol were in attendance. begun. It is only recently that physicians have Hippocrates noted that "drinking strong directed their attention to the clinical pharma- wine cures hunger." cology of this important drug. Society has be- Maimonodes preached that "honey and gun to recognize that alcohol is a potent drug *Lloyd H. Smith, Jr., M.D., Professor and Chairman, Department and that is a disease rather than a of Medicine. tCharles E. Becker, M.D., Chief Resident in Medicine. social misadventure.2'3 CALIFORNIA MEDICINE 37 The Western Journal of Medicine which includes research, training and patient care. Senator Cranston's office and the Congres- sional Record report that the United States in- volvement in Southeast Asia costs 70 million dollars per day. Therefore, the total annual budget for "alcoholism" is less than the amount spent in Vietnam in three hours.4 As physicians we have a responsibility to help deal with this staggering social and medical problem. The initial approach to the problem must be to achieve a better understanding of the clinical ., ~~~._"" pharmacology of alcohol by reviewing the source Figure 1.-"The Cocktail Party" (as drawn by and chemistry of ; absorption, distribu- Dr. M. Balis). What these famous specialists said on the use of alcohol is noted in the text. tion and excretion; metabolism; pharmacological effects; drug interaction; and clinical importance of this drug. I hope this discussion will be some- vhat like the art of drinking and will whet your appetite for the subject, but not intoxicate you. Source and Chemistry Alcohol is unique as a drug because of its molecular weight (46) and its infinite water sol- ubility. It is a clear, colorless flammable liquid which absorbs water rapidly from the air. Its Figure 2.-Alcohol can affect man internally, ex- boiling point is 78.5° C, its freezing point -130° ternally and eternally (as drawn by Dr. M. Balis). C. Alcohol is generally prepared by the fermen- The magnitude of alcoholism has only recently tation of sugar by yeast. Since yeast does not been recognized. Alcoholism is now fourth survive in greater than 15 percent alcohol, among the nation's health problems, outranked stronger solutions of alcohol are prepared by dis- 2 to only by mental illness, heart disease and cancer. tillation. Wine and beer generally contain Dr. Roger Egeberg4 estimates that otit of the 70 20 percent alcohol, while the distilled prepara- usp con- million Americans who drink there are six to tions contain 30 to 60 percent. Alcohol seven million "out-and-out" alcoholics, vastly tains 49 percent ethyl alcohol by volume (42 outnumbering persons addicted to other drugs. percent by weight). In the United States 100 It is further estimated that 25 million non-drink- proof alcohol contains 50 percent ethyl alcohol of fermentation ers in alcoholics' families or social structure are by volume. During the process adversely affected by the problem. The Califor- a mixtu're of higher is formed; these are nia State Department of Public Health estimates converted to their esters during the process of that San Francisco houses the second greatest aging and impart to the final product some of number of alcoholics in the United States. In the distinctive flavor and bouquet.5 this city with a population of 750,000 there are approximately 48,000 alcoholics and an addi- Absorption, Distribution, Excretion tional 100,000 persons with serious drinking Alcohol, a small molecule which is neutral in problems. The rate of untreated alco- water solution, is one of the few substances holics is 58 times that of non-alcoholics. Alco- which may be absorbed directly by simple dif- holics are seven times more likely to die in a fusion from the stomach and upper gastrointes- fatal accident of any type; 10,000 deaths per tinal tract. Unlike carbohydrates, proteins and year are directly caused by alcoholism. Sixty-six fats it does not have to be digested before it can percent of the nation's 5,800 generial hospitals do be absorbed and no active processes are involved not admit patients with a diagnosis of alcohol- in its absorption. About 30 percent of the alco- ism. The Nixon Administration's 1970-71 budget hol taken orally is absorbed from the stomach has requested six million dollars for "alcoholism" and the majority of the remainder from the prox-

38 SEPTEMBER 1970 * 1 13 * 3 imal small intestine. Alcohol does not appear in the stool; it is completely absorbed and elim- inated by other routes.6 During early absorption from the gastrointestinal tract the concentration 10-20 mg/lOOml/I'our/150 lbs. 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 oc- AMOUNT FIRST ORDER curring, then breath analysis will tend to corre- METABOLIZED late better than venous blood analysis with the effects of alcohol depression of the central nerv- ous system.7 Vaporized alcohol can be absorbed by the lungs, but absorption through the intact ZERO ORDER skin is minimal. Alcohol concentration, speed of ingestion, dil- uents mixed with the alcohol, food in the stom- TIME ach, and the intrinsic emptying time of the Chart 1.-Disappearance of drugs from blood. stomach all influence the rate of absorption. Al- contains trace amounts of alcohol in concentra- cohol absorption is particularly delayed when it tions up to 1.5 mg per liter.9 is taken with fatty foods. After gastrectomy, pa- tients are often exquisitely sensitive to alcohol, The combined rates of alcohol absorption, dis- since absorption is most efficient in the intestine. tribution, metabolism and excretion are reflected Carbonation enhances alcohol absorption by in- in the blood alcohol concentration. It is clear creasing gastric emptying. Because of this effect that the blood alcohol levels are greatly affected champagnes are notorious for their rapid effect. by the character of the drink and the presence and contain some foodstuffs which of food in the digestive tract. Leake and Silver- delay absorption. Since absorption is so much man5 have shown that the blood alcohol curves more efficient than metabolism, pharmacological- produced when the same total amounts of alco- ly significant blood levels are reached quickly, hol (0.6 gm per kg of body weight) are admin- usually attaining a peak 30 to 60 minutes after istered in a fasting state to normal subjects are ingestion and falling to normal in eight to ten dependent on the variety of the alcoholic bever- hours. age. The sharpest rises and the highest peaks Alcohol distributes in body tissues and body are produced by the "clinically most potent" fluids proportionally vith their water content. spirits such as gin and vodka.5 The approximate water content of the whole The disappearance of alcohol from the blood body is 65 percent and that of blood approxi- is unique and deserves special emphasis (Chart mately 83 percent; therefore at equilibrium the 1). The rate of disappearance of most drugs alcohol content of blood will be 1.27 times that from the blood represents a hypobolic curve, of the whole body. Shortly after ingestion, alco- meaning that for a given time a variable amount hol is present in the cerebrospinal fluid at a may disappear (first order). Alcohol disappears concentration lower than that in blood. How- as a straight line, meaning a fixed amount will ever, later, when the blood concentration of al- disappear over a given time (zero order). There cohol is falling, the concentration in the cerebro- are individual differences between patients, but spinal fluid may remain high. Alcohol crosses the rate is remarkably constant for each individ- the placenta readily and enters fetal circulation. ual. For most subjects this rate of disappearance It may be present in the milk of the lactating is 10 to 20 mg per 100 ml per hour per 150 mother.8 pounds or approximately 10 to 20 ml of alcohol Alcohol is 90 to 98 percent oxidized by the per hour. Thus, one can calculate that if a person ; the remainder is excreted unchanged in the consumes approximately two-thirds ounce of urine, breath, perspiration, tears, milk, saliva or whiskey per 150 pounds per hour he would never bile. Thus, induced diuresis or hyperventilation become intoxicated. will not significantly hasten detoxification. Even The effects of alcohol vary greatly among in- without exogenous intake, normal human blood dividuals and can be different in the same per-

CALIFORNIA MEDICINE 39 The Western Journal of Medicine NAD NADH NORMAL

CH3CH2OH -> CH3- CHO ALCOHOL ETHANOL DEHYDROGENASE (ADH) ETHANOL CONCENTRATION

g/1000 ml serum NAD DEHYDROG ENASE NADH)

CO2 E-_ CETYL <-ACETATE 2 3 4 5 6 7 8 2 COENZYME A TIME IN HOURS (7 cal/gm) Chart 2.-Schema for the metabolism of alcohol. Chart 3.-Genetic polymorphism of alcoholic de- hydrogenase (ADH) (Adapted from Von Wart- burg'). son on different occasions. The correlation of blood level with behavior has assumed immense (ADH) which importance because of the role of alcohol in auto utilizes nicotinamide-adenine-dinucleotide (NAD) a accidents. The blood level obtained from given as the hydrogen acceptor. Many tissues possess amount of alcohol is approximately 0.001 percent a limited capacity to oxidize alcohol, but their for so each milliliter consumed, that ingestion of quantitative contributions to total alcohol me- as as one little ounce of whiskey or a half pint tabolism are quite small. Apparently the vast a of beer will yield blood level of 0.01 percent majority of ethanol oxidation occurs in the liver, alcohol. A diagnosis for legal purposes of "under although Mistilisli recently showed that the stom- the influence of alcohol" varies from 0.05 percent ach and intestine of rats contain alcohol dehy- to (Norway) 0.01 percent (United States). drogenase, and that this extrahepatic ADH in- creases with repeated doses of alcohol. It is pos- Metabolism sible that extrahepatic ADH may account for more Alcohol has many properties which make it an' alcohol oxidation than was previously suspected. excellent "energy food." Approximately 7 calo- Genetic polymorphism of ADH (Chart 3) may ries are liberated in the complete oxidation of 1 also play an important part in determining the gram of alcohol. Only fat, liberating 9 calories rapidity of alcohol oxidation. Von Wartburg12 per gram, exceeds the nutritional value of alco- studied an ADH genetic variant (present in 20 hol. If 10 to 20 ml are metabolized per hour per percent of the Swiss) which oxidizes alcohol at 150 pounds, it is apparent that during a 24-hour greatly increased rates. period a heavy drinker can derive all his daily The metabolism of acetaldehyde, proceeding caloric requirements from alcohol. As an energy at a much more rapid rate than that of alcohol, fuel, alcohol acts quickly and requires no diges- indicates that the initial oxidative step is rate- tive energy. The disadvantage of alcohol is that limiting. Since alcohol dehydrogenase is appar- its energy cannot be stored, and it contains very ently saturated at such a low substrate concen- few vitamins, minerals or essential amino acids. tration (10 ml per hour), the rate of oxidation Since many of these essential nutrients are re- (Chart 1) appears as a straight line (zero order quired for the metabolism of alcohol, nutritional kinesis). For many years this linear rate of oxi- disorders are the rule in chronic alcoholics. dation was attributed only to saturation of the Like most drugs, alcohol is primarily metabo- enzyme. More recently, with better estimates of lized enzymatically by the liver. The ultimate the km for the enzyme, it became clear that even products of the metabolism of alcohol are carbon with near lethal alcohol levels the enzyme could dioxide and water. Chart 2 depicts the most gen- not be fully saturated. The linear kinesis of al- erally accepted schema for metabolism of alco- cohol apparently arises from an insufficient sup- hol. The primary step in the oxidation of alcohol ply of NAD. In fact, if substrates such as fructose to acetaldehyde is by the zinc-containing soluble are given which stimulate the conversion of nic-

40 SEPTEMBER 1970 * 1 13 * 3 Tolerance, the ability to ingest increasing amounts of a drug without increasing effects, is not complete for alcohol. One of the unusual BLOOD SOBER aspects of alcohol tolerance is shown in Chart 4, ALCOHOL DrUNK which illustrates the difficulty in interpreting the behavioral effects of alcohol with a single blood alcohol level. As the blood alcohol level is ris- ing, behavioral symptoms are easily noted. How- ever, if a constant plasma level is maintained for INFUSION 8-10 HOURS 8-10 HOURS intoxicated patient may become INFUSION 8 to 10 hours, an Chart 4.-Unusual aspect of alcohol tolerance. sober. Similarly, any blood alcohol concentra- tion that is rising tends to produce behavioral otinamide alcohol dehydrogenase (NADH) to NAD, symptoms while a comparable falling level may the rate of alcohol metabolism may be partially produce no symptoms. accelerated.'3 Many investigators have invoked an increased The increasing NADH resulting from alcohol rate of metabolism of alcohol to explain the incom- metabolism may explain many influences of this plete tolerance which develops with chronic ad- drug on steroid metabolism and has been shown ministration ofIalcohol. Mendelson18 has shown to favor the chemical reduction of the 17-keto- that the blood alcohol declines more rapidly after steroid sulfates to 17-,8 hydroxysteroid sulfates."t pretreatment with alcohol; also there is more It seems likely that other important steroid pairs rapid formation of carbon dioxide after a drink- may also be influenced by alcohol oxidation. ing period of seven days. The exact mechanism Many drugs are metabolized by a microsomal involved in producing these effects is not clear, enzyme system in the liver. This system is in- although increases in alcoholic dehydrogenase ducible. That is, repeated administration of a seem most likely. Some investigators suggest drug (for example phenobarbital) increases the that alcohol tolerance is more related to a process hepatic activities of that metabolize the of adaptation of the central nervous system than drug. This induction can be non-specific and to alterations in the rate-of metabolism of eth- may result in lower blood levels of several dif- anol.19 ferent drugs and in decreased therapeutic bene- Considerable effort has been devoted to a fit. The clinical importance of this phenomenon search for some clinical method which can effec- is well recognized in the case of phenobarbital, tively speed the rate of alcohol metabolism and which accelerates the metabolism of oral anti- treat the intoxication. The administration of coagulants. Lieber'5 has shown that alcohol insulin, thyroid hormone, and cold show- leads to hypertrophy of the smooth endoplasmic ers have all been utilized to treat alcoholic in- reticulum of liver cells, a process which may be toxication, without significant success. Fructose, the morphological expression of the increased which will restore the NAD-NADH equilibrium, is microsomal drug-metabolizing enzymes. The re- currently under intense investigation. sults of his studies may explain the resistance of chronic alcoholics to the action of and other drugs. Since alcohol dehydrogenase has a Pharmacological Effects pH optimum of 11 and is not a microsomal en- Depression of the central nervous system is zyme, Lieber"6 has proposed that the major oxi- the principal pharmacological action of alcohol dation of alcohol may occur in a microsomal and is the basis for its social use. The first ethanol oxidative system (MEOS) whiclh adapts mental processes to be affected are usually those to alcohol feeding and is most active at pH 7.4. dealing with self-restraint. In general, the cen- The role of microsomal oxidation of alcohol by tral nervous system effects are proportional to MEOS has been questioned by several investiga- the blood alcohol level but, as previously men- tors; its full importance has yet to be determ- tioned, the most pronounced effects for any ined.17 It seems unlikely that these microsomal given level occur as the blood level is rising. In systems account for more than 5 percent of al- a sense alcohol is a general anesthetic, but it cohol oxidation. differs greatly from the volatile anesthetics,

CALIFORNIA MEDICINE 41 The Western Journal of Medicine ETHANOL > ACETALDEHYDE tinal mucosa. In normal well-nourished people ALCOHOL given small amounts of alcohol, fat accumulation DEHYDROGENASE + (ADH) and ultrastructural changes occur in the liver.22 DOPAMINE If alcohol is indeed a direct hepatoxin for man, chronic alcoholism should be associated with a very high incidence of . Although cir- ABERRANT rhosis of the liver is approximately eight times METABOLITES more common in alcoholics than in the remain- (ALKALOIDS) der of the adult population, only one in ten alcoholic patients has cirrhosis. This sporadic ? BASIS FOR PARTIAL occurrence of cirrhosis in chronic alcoholism and ADDICTION the failure of alcohol to produce cirrhosis in Chart 5.-Postulated mechanism for the partial laboratory animals suggest that some genetic addiction to alcohol. predisposition may be involved in the pathogene- which undergo little oxidation and are rapidly sis of cirrhosis. excreted unchanged by the body. Since alcohol is almost completely oxidized, its anesthetic Alcohol-Drug Interactions properties last several hours, and there is little safety margin between the anesthetic dose and Since most patients consume alcohol to some severe respiratory depression. degree, the fact that alcohol modifies the de- The exact biochemical explanation of the sired pharmacological effects of other simultane- neurochemical aberrations involved in the cen- ously administered drugs becomes a primary tral nervous system effects of alcohol is cur- concern. A few years ago it was estimated that rently being studied. A striking observation, that more than 20 percent of the new prescriptions normally innocuous amounts of serotonin and written in the United States were for drugs other biogenic amines such as dopamine greatly acting primarily on the central nervous system. potentiate the central nervous system effects of Since the prime effect of alcohol on the central alcohol, has led some investigators to suggest nervous system is as a depressant, potentiation that the central nervous system effects of alcohol of , and tranquilizer drugs by are mediated through these biogenic amines. alcohol is to be anticipated. Much controversy Recently Davis and Walsh''2 noted that the exists as to whether the observed enhancement brain has a limited capacity to oxidize acetalde- of central nervous system depression is simply hyde (Chart 5). They postulated that acetal- additive or synergistiC.7'23 In either case, it is dehyde alters dopamine metabolism so that important to recognize clinically that the ad- aberrant metabolites (alkaloids) are formed. ministration of drugs with central nervous sys- These metabolites could be the biochemical ex- tem depressive effects may be dangerous in the planation for the partial addiction to alcohol. presence of . Although this hypothesis has not been proved, Since alcohol and many central nervous sys- it illustrates a possible link between alcohol tem depressant drugs cause partial tolerance, metabolites and central nervous system bi'ogenic it may be inferred that this tolerance may par- amines. tially protect the patient. Unfortunately, the Alcohol in moderate doses causes only a slight therapeutic index for alcohol is very low, and rise in blood pressure, pulse and cardiac output. partial tolerance for sedative drugs and alcohol Very large amounts of alcohol directly depress does not greatly alter the lethal dose of either the heart. The major cardiovascular effect is class of drug. vasodilatation, especially of cutaneous vessels. Although the most common mechanism for The evidence that alcohol is useful as a coronary alcohol-drug interaction is probably addition of artery vasodilator agent in treating angina pec- effects, other mechanisms of the effects of alco- toris or in treating cerebrovascular disease is un- hol on other drugs are of great clinical impor- convincing. tance. Alcohol inhibits the metabolism of meth- Alcohol increases gastric secretion and in high anol and ethylene glycols, which are often concentration is irritating to the gastrointes- ingested as alcohol substitutes. is also

42 SEPTEMBER 1970 * 1 13 * 3 metabolized by alcohol dehydrogenase, but at high dose consumption of alcohol may result in a much slower rate. Methanol is metabolized myocardial depression despite adequate intake to formaldehyde and formic acid and can cause of nutrients and can also alter antiarrhythmic severe eye damage and acidosis. If alcohol is drug therapy.25 Alcohol increases the serum uric administered, the slower oxidation of methanol acid level and can precipitate acute gout. There- is delayed and a greater amount of unmetab- fore, physicians must try to avoid multiple drug olized methanol can be excreted without pro- therapy and particularly monitor drug effects ducing its toxic products. Thus, a recognized in patients who have ingested alcohol. drug interaction is of great therapeutic benefit; this is the major therapeutic indication of al- Therapeutic Use of Alcohol cohol. Alcohol has been advocated by many for use Some drugs may interfere with the metabolism as an appetite , as an antifoaming of alcohol. (Antabuse®) and calcium agent to treat pulmonary edema, as a regular carbamide (Temposil®), wbich have little phar- soporific medication, and as a ready source of macological activity when administered alone, intravenous calories. None of these uses has had produce severe reactions when combined with much proven efficacy. A "hot toddy" has little alcohol. These drugs when combined with al- effect on upper respiratory infections, although cohol block the aldehyde dehydrogenase needed popular belief has claimed that at the first sign for alcohol metabolism and lead to large in- of a cold one should hang his hat on the bed- creases in acetaldehyde, which produces severe post, swig from a bottle of good whiskey until flushing, sweating, vomiting and hypotension. two hats appear, then get intQ bed and stay Recently oral hypoglycemics (sulfonylurea) and there. a trichomonacide, metronidazole (Flagyl®), have been noted to produce a similar reaction Alcohol does have some clinical importance associated with a rise in acetaldehyde after ad- as a germicidal agent, as an astringent to help ministration of alcohol. prevent bedsores, as a diagnostic aid in gastric secretion and diabetes insipidus, as a cooling As previously discussed, alcohol induces the agent, as a vehicle for other drugs, as a neuro- microsomal drug metabolizing systems in the toxin for trigeminal neuralgia, and probably liver and may clinically alter the kinesis of many most importantly as therapy in methanol poi- commonly used drugs. Current information sug- soning. gests that the half-lives of diphenylhydantoin (Dilantin ), warfarin sodium (CoumadinR), and tolbutamide (Orinase®) may be shortened Clinical Syndromes Associated 50 to 75 percent by concurrent alcohol adminis- with Alcohol Administration tration.2 Thus, the expected pharmacological The chronic administration of alcohol leads to activity of alcohol may subtly complicate the use several well-recognized clinical syndromes which of many classes of drugs. The vasodilating ef- may shed more light on its many pharmacologic fects of alcohol may exaggerate the postural facets. I would like to comment on the effects hypotension of the antihypertensive drugs. Al- of alcohol on carbohydrate metabolism and cohol in excessive amounts may alter a vital magnesium metabolism. Alcohol affects many organ system such as the liver and further com- processes in intermediary metabolism, but its plicate the kinetics of the oral anticoagulants clinical effects on carbohydrate metabolism are or other drugs. Alcohol may exaggerate the common and often overlooked. Hepatic glyco- hypoglycemic response to oral hypoglycemics genolysis is augmented after the ingestion of or insulin and may predispose to lactic acidosis alcohol. The magnitude of the increase in he- if administered with phenformin HC1 (DBI®). patic glucose output depends upon the quantity The effect of diuretics may be potentiated by of hepatic glycogen stores and the enzymatic the administration of alcohol, and conversely the processes necessary for glycogenolysis. During resultant diuresis may increase the concentration periods of starvation, however, gluconeogenesis of blood alcohol. Alcohol, by producing gas- is the major mechanism responsible for hepatic tritis, may predispose to gastrointestinal bleed- glucose output; alcohol retards gluconeogene- ing secondary to the ingestion of aspirin. Chronic sis."2 The end result of this effect of alcohol on

CALIFORNIA MEDICINE 43 The Western Journal of Medicine abnormalities, and the convulsive seizures (rum fits) that are so common in the alcoholic. These withdrawal seizures occur with a peak incidence 13 to 24 hours after alcohol withdrawal. In SERUM Mg L about 30 percent of the patients who have with- (mEq/L) drawal seizures develops, with the seizure usually preceding the delirium. Re- cently Wolfe and Victor29 (Chart 6) using a model of photic-induced myoclonus and seizures showed that, shortly after withdrawal begins, the serum magnesium falls rapidly and there is a rapid rise in pH (respiratory alkalosis). The HOURS AFTER WITHDRAWAL tremor and hyper-reflexia which were prominent Chart 6.-Possible mechanism for alcohol with- drawal (Adapted from Wolfe29). findings during the hypomagnesemia and alka- losis abated as the serum magnesium and pH carbohydrate metabolism is an increased inci- returned to normal. This finding raises the pos- dence of hypoglycemia that develops after alcohol sibility of treating some kinds of reaction to ingestion. In a well-nourished human the blood alcohol withdrawal with carbon dioxide en- concentration of glucose increases approximately riched air, acidifying agents and magnesium. 10 percent after the ingestion of alcohol. Pa- There are many other interesting alcohol syn- tients with alcoholic hypoglycemia have striking dromes such as Zieve syndrome (hyperlipemia, decreases in blood sugar which may occur as icterus, and hemolytic anemia), hematological long as 30 hours after alcohol intake. As with abnormalities, acute and chronic psycho-neuro- other types of hypoglycemia, these patients are logical syndromes, acute skeletal muscle syn- frequently hypothermic, but they rarely have dromes, Quebec beer-drinker's cardiomyopathy, signs of excess catechol release. Glucagon and alcohol cardiomyopathy, saturnine gout after epinephrine are not effective therapeutic meas- drinking lead-contaminated whiskey, ures.27 Liver disease, , and malnu- lactic acidosis with or without phenformin HC1 trition may predispose the classic chronic alco- (DBI))therapy, precipitation of acute porphyria, holic to hypoglycemia. If physicians recognize precipitation of mast cell crises in mastocytosis, that the stuporous alcoholic may have low blood and the tenderness of lymph nodes in Hodgkin's sugar with a few recognizable symptoms, imme- disease. diate therapy with glucose can be lifesaving. Relative magnesium deficiency states may Definition ofAlcoholism occur with chronic alcoholism secondary to a After discussing the clinical pharmacology of poor dietary intake and enhanced urinary ex- total defi- alcohol, one would then expect it to be easy to cretion of magnesium. This body define the disease "alcoholism." In fact, how- ciency of magnesium may not be reflected in it is controversial. low serum magnesium, although clinically 30 ever, exceedingly difficult and are asso- Alcoholism has been present for centuries, yet percent of alcoholic withdrawal states medical or social definition is still ciated with a decreasing serum magnesium, and an accepted with lacking. Hayman3 reviewed several definitions approximately 80 percent of the patients have delirium tremens have low serum magnesium. that been proposed: Following the cessation of drinking there may "Alcoholism is any use of alcoholic bev- be an abrupt decrease in serum magnesium erages that causes any damage to the indi- which is associated with a transient decrease in vidual or society or both." the The fall in magnesium "Any form of drinking which goes beyond serum potassium. the traditional and customary dietary use or tends to correlate with the neuromuscular hy- ordinary compliance with social drinking perexcitability which characterizes the with- customs of the whole community, irrespec- drawal state.28 tive of the etiologic factors leading to such A close association may exist between mag- behavior, and irrespective also of the extent nesium metabolism, , acid-base to which etiologic factors are dependent

44 SEPTEMBER 1970 * 1 13 * 3 upon heredity, constitution or acquired TRADE AND GENERIC NAMES OF DRUGS physiopathologic and metabolic influence." Antabuse® ...... disulfiram "The chronic alcoholic is any person who Temposil ...... calcium carbamide chronically and habitually uses alcoholic Flagyl ...... metronidazole Dilantin ...... diphenylhydantoin beverages to the extent that he has lost the Coumadin ...... warfarin sodium power of self control with respect to the use Orinase ...... tolbutanmide of such beverages or while under the influ- DBI...... phenformin ence of alcohol endangers the public morals, health, safety, and welfare." "Loss of the power of choice." We have reviewed certain clinical pharma- REFERENCES 1. Strauss MB: Familiar Medical Quotations. Boston, Little, Brown cologic aspects of a commonly used drug, alco- & Company, 1968, pp 5-12 2. Alcohol and Alcoholism. Public Information Branch, National hol. It is clear this drug can adversely affect Institute of Mental Health, U.S. Government Printing Office, 1967- the pharmacologic action of other drugs and 0264-074, pp 1-23 3. Hayman M: Alcoholism: Mechanism and Management, Charles different organ systems. Figure 2 illustrates how C Thomas, Publisher, 1969, pp 3-7 4. Livingston W: Personal communication, National Council in the ingestion of alcohol may affect man inter- Alcoholism. San Francisco 5. Leake CD, Silverman M: Alcoholic Beverages in Clinical Medi- nally, externally and eternally. cine. Chicago, Yearbook Medical Publishers, Inc., 1966, pp 54-55 Dr. Smith: Dr. Becker, what is known about 6. Sardesai VM: Biochemical and Clinical Aspects of Alcohol Metabolism. Springfield, Illinois, Charles C Thomas, 1969, pp 3-7 the problem of the adverse effects of acetate? 7. Forney RB, Hughes 'FW: Combined Effects of Alcohol and Other Drugs. 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Von Wartburg JP, Schurch PM: Atypical human liver alcohol syndromes when given to animals. It is possible dehydrogenase. Ann NY Acad Sci 151: 936-946, 1968 13 Goldstein A, Aronow' L, Kalman SM: Principles of Drug that acetate or acetoin-like products could be Action. New York City, Harper '& Row, Publishers, Inc, 1968, pp 284-285, 558-561 responsible for the chronic as well as the acute 14. Admirand WH, Cronholm T, Sjovall J: Ethanol and steroid complications of alcohol excess. However, al- metabolism. Clin Res 18: 376, 1970 15. Rubin E, Lieber CS: Alcohol, other drugs and the liver cohol dehydrogenase does appear to be the rate- (Editorial). Ann Intern Med 69: 1063-1064, 1968 16. Rubin E, Lieber CS: Hepatic microsomal enzymes in man and limiting enzyme for alcohol metabolism. rat. Science 162: 690-692, 1968 17. Tephly TR, Tinelli F, Watkins WD: Alcohol metabolism: Dr. Schmid:* Dr. Becker, would you care to Role of microsomal oxidation in vivo. 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CALIFORNIA MEDICINE 45 The Western Journal of Medicine