PL EN A R Y S E S S I O N 4:PHARMACOLOGICAL AND PHYSIOLOGICAL ASPECTS OF

A L C O H O L I C I N T O X I C A T I O N

Chairman: A. PONSOLD (Germany)Secretary: G. E. McCLEARN (U.S.A.)

ALCOHOL AND DRIVING— THE PHARMACOLOGICAL BACKGROUND

by E. J. WAYNE*

a k n o w l e d g e of the main pharmacological properties of ethyl-alcohol is essential for a proper understanding of the place which this substance plays in increasing the hazards of road travel. Thus, the effects on the nervous system are of great importance in explaining why impairment of driving performance results from the consumption of alcohol. Moreover, the results obtained in the various tests used in medico-legal practice can only be interpreted by those who are aware of the way in which alcohol is absorbed, distributed and eliminated. The field is wide and I shall deal only with those pharmacological aspects which can be related directly or indirectly to driving capacity.

The immediate action of any drug is determined largely by the concentration in which it arrives at its site of action, and this depends on its rate of absorption, its distribution in the body and its rate of elimination.

AbsorptionAlcohol is absorbed through all the

mucous membranes of the body. Its low molecular weight confers upon it high solubility and rapid diffusibility, and in comparison with other ingested substances it is rapidly absorbed from the alimentary canal. Thus, when taken on an empty stomach, about 90% is absorbed in the first hour mainly from the duodenum. Neat spirits (which contain about 40% alcohol) tend to cause pylorospasm and absorption may be delayed. Partial dilution may assist

absorption. Full dilution, however, such as occurs in beer, retards the rate of absorp­tion but only after about a pint has been drunk (Ponsold 1962). The presence of food in the stomach tends to retard absorption, largely by delaying the passage of alcohol from stomach to intestine. The effect is less with beer than with spirits. There is little evidence to support the view that any particular food such as milk is especially effective in this way. The maximum blood levels achieved are greatly affected by these factors. Thus, the same amount of alcohol as whisky on an empty stomach, beer on an empty stomach and whisky with food can give average maxi­mum blood concentrations of 80 mg./ 100 ml., 45 mg./100 ml. and 26 mg./lOO ml. respectively (Goodman and Gilman 1955). Other factors such as habituation and the presence of carbonic acid in drinks such as champagne may also affect absorption, but are relatively less important.

DistributionThe absorption of alcohol is rapid and

it soon diffuses into the tissue fluids. Absorption is much faster than elimina­tion so that the concentration of alcohol in the bloodstream rises rapidly to reach a peak about one-half to two hours after ingestion, the exact time depending mainly on the dose. At the peak concentration the rate of absorption and elimination are equal, and the concentration of alcohol then falls*M.D., Ph.D., F.R.C.P., Reguis Professor o f Practice of Medicine, University o f Glasgow.

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unless further drinks are taken. Behaviour after the consumption of alcohol depends on the concentration of alcohol in the brain and nervous system, and this closely follows the concentration in the blood. Hence graphs representing blood alcohol concentrations at various times after ingestion give much valuable information.

Figure 1 shows the average levels in the blood after six different doses of alcohol on an empty stomach. There is a rapid

women have a greater proportion of the body weight present as adipose tissue. Widmark’s ratio:

per cent of alcohol in body as a whole per cent of alcohol in blood

is 0-68 in the average man and 0-55 in the average woman. In the obese it may be as low as 0-60 and 0-50 respectively. From it can be calculated the expected maximum blood alcohol after a given dose assuming

HOURS AFTER DRINKING F ig . 1. Relation between the level o f alcohol in the blood and the time after ingestion for six different doses o f alcohol taken as distilled spirits. The lowest dose o f 0-2 g./kg. is equivalent to rather less than a pint o f beer taken by a 154-pound (70 kg.) man. The dose o f 0-65 g./kg. is equivalent to three pints (1-7 litres) of beer or approximately five whiskies taken by a 154-pound (70 kg.) man. The graph for the dose 1 g./kg. shows a typical “ over-shoot” peak from high concentra­

tion taken as distilled spirits. (British Medical Association, 1960.)

rise to a maximum concentration at one- half to two hours. The “overshoot” peak and slow rate of elimination with high doses of spirits is well illustrated.

The extent to which alcohol enters tissues is determined by their water content, and since adipose tissue and bone are relatively water-free they retain only a small proportion of the alcohol which passes to them in the blood stream. The proper reference standard when trying to estimate the blood and tissue alcohol which results from a given dose of ab­sorbed alcohol is, therefore, the lean body mass rather than the body weight. This can be estimated by using water in which the hydrogen is replaced by its isotopes, deuterium or tritium, but so far no direct correlations using this reference standard have been made. It is, however, known that the same amount of alcohol gives significantly lower blood concentrations in women than in men. and it is known that

rapid and complete absorption or, con­versely, the amount of alcohol which must have been taken to give a known blood concentration. By taking the lowest figure of r for men and for women it has been used (British Medical Association 1958) to produce tables showing the minimum intake of beer or spirits which must have been taken to give known blood or urine alcohol levels. These figures are accept­able in courts in Great Britain as a check on the trustworthiness of a defendant. If an accused person declares at the time of his arrest he has taken “two small beers” , and the alcohol estimation reveals that he must have taken at least three or four times that amount, the court may conclude that either his memory or his veracity is at fault.

One point of practical importance is the tendency of muscle to take up alcohol relatively slowly as compared with other tissues. Thus, shortly after alcohol has

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been taken the arterial blood, and hence breath and urine, may contain more alcohol than venous blood taken from superficial veins. It may also explain why sobering-up may occur shortly after the initial effects of a stiff drink on an empty stomach.

EliminationAlcohol is removed from the body mainly

by oxidation, although a small proportion is eliminated in the urine and breath. The rate of oxidation differs from person to person, but is relatively constant in one individual. The average rate is 100 mg. per kg. per hour, so that a 70 kg. man rids himself of 7 gm. (9 ml.) of alcohol an hour, or roughly the amount present in a small whisky. The blood alcohol falls by about 15 mg./lOO ml. per hour with average doses, and rather more rapidly with large doses. Thus, the alcohol from a pint of beer takes two to three hours to disappear. The alcohol is oxidized to acetaldehyde by an enzyme, alcohol dehydrogenase with the coenzyme diphosphopyridine nucleo­tide (DPN) acting as a hydrogen acceptor. This stage occurs in the liver. The acetalde­hyde is converted in the liver and other tissues to acetylcoenzyme A. This key substance to which many other substances are metabolised can be used either for synthesis of fats, non-essential amino-acids or carbohydrates. It can enter the Krebs cycle and be oxidized to carbon-dioxide and water, yielding energy in the process.

The enzyme alcohol dehydrogenase is highly specific for alcohols, and can be used to estimate alcohol in body fluids. Bjerver et al. (1951) showed that the results on blood confirmed those obtained by the Widmark method. It was, however, more accurate when post-mortem samples of blood and urine were tested.

Alcohol yields on full oxidation seven calories per gm., and theoretically the individual can obtain 2,000 calories in24 hours from the continuous oxidation of alcohol at maximum rates. Alcoholics who satisfy a large proportion of their energy requirements with alcohol are apt to suffer from vitamin and mineral deficien­cies which lead to neurological complica­tions. These must, of course, increase still further, their inability to drive safely.

Between 2% and 10% of alcohol, depend­ing on the blood level attained, is removed from the body through excretion in the urine and in the breath. Sweat and saliva both contain alcohol, and estimation of

alcohol in saliva has been used as an indirect measure of blood alcohol.

The UrineSince the analysis of urine has many

advantages for forensic purposes, con­siderable attention has been paid to the relationship between its alcohol content and that of blood. The kidneys do not concentrate alcohol, but since urine con­tains a higher proportion of water than does the blood, the concentration of alcohol in it is higher. The ratio varies from 1-2 to 1-4, depending in part on the specific gravity of the urine (letter 1941-42). At a specific gravity of 1-015 letter found it to be 1-33, and this is the average figure reported in a number of studies in which direct comparison has been made. It varies with the time after drinking. Drew et al. (1958) found the factor 1-30 at 60 minutes and 1-36 at 90 minutes after drinking. These observers report that the peak alcohol concentration is reached in the urine 20 to 25 minutes later than in blood.

There has been much controversy over the diuretic activity of alcohol. Dilute alcoholic beverages produce an increased flow of urine from their water content, and some spirits such as gin contain volatile oils which are diuretic. The balance of evidence favours the view that alcohol is a diuretic in its own right (see Goodman and Gilman 1955), and acts probably by inhibiting the secretion of anti­diuretic hormone (see Kalant 1962). Its potency in this respect appears to differ considerably from individual to individual. This diuretic action does not, however, affect the ratio of blood to urine alcohol content to any important extent.

Some early work suggested that the alcohol in urine in the bladder was always in equilibrium with that in blood. Haggard et al. (1940), however, showed that this was not so. This fact could lead to errors in medico-legal practice since urine ob­tained early after heavy drinking in a person who has not emptied his bladder for some time would be diluted, and would give lower blood values than blood simul­taneously taken. It is doubtful if this factor is important in actual practice, but it can be avoided if the subject is asked to empty his bladder, and if a further sample for analysis is taken 30 minutes later. This procedure also has the advantage that if both samples are analysed it is possible to say whether the blood alcohol is rising or falling.

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BreathBreath has many advantages over urine

as an index of the level of alcohol in the blood. The ratio of concentrations is only 1 : 2-100, but a large volume of alveolar air is easily obtained. Comparisons of blood and breath analyses carried out in Great Britain have shown considerable agreement between them (Drew et al. 1959, Begg et al. 1962). A recent development of the Borkenstein Breathalyzer is that in which Etzlinger plastic bags are used to store alveolar air. This has made this method much more attractive from a medico-legal point of view, since breath samples can be taken by relatively inexpert persons and analysed up to 24 hours later in properly staffed laboratories.

The Action of Alcohol on the Nervous System

It has been recognized from the earliest times that alcohol has a profound effect on human behaviour. It produces loss of emotional restraint and diminishes the inhibitions which civilization imposes on human conduct. Because in a social environment many people become more active, both in speech and manner, it is widely regarded as a stimulant. Its effects are, however, much more readily explained by the view, first proposed by Schmiedberg 80 years ago, that it depresses the nervous system. It is usually stated in text-books that alcohol produces a progressive depres­sion of the nervous system affecting first the more highly developed part of the brain, the cerebral cortex. Recently the objec­tions to this concept have been summarized in two excellent reviews by Kalant (1962). He makes a case for a different primary site of action. The great central regulatory and integrating system of the brain is now thought to reside in a core of grey matter running from the medulla to the third ventricle and called the reticular formation or structure. It can be regarded as a sort of central switchboard regulating and correlating the activity of various parts of the brain. Sensory impulses stimulate appropriate sectors, and in its turn it selectively activates or inhibits the appro­priate areas of the cerebral cortex as well as lower centres in the thalamus and hypothalamus. Alcohol depresses parts of the reticular formation and produces an increasing tendency for the cortex to lapse into behaviour patterns which do not necessarily subserve any particular func­tion. One merit of this view which is

supported by experimental evidence (Caspers 1958) is that it explains the action of alcohol in increasing some spinal reflexes, in producing positional alcohol nystagmus and in giving rise to automatic and endocrine effects. Interesting though this new information about the mode of action of alcohol on the nervous system is, it does not fundamentally alter the classical view that alcohol gives an apparent stimu­lant effect mainly by releasing lower centres from the influence of the inhibitory action of higher centres and that, in general, the individual tends to overestimate his capacity to carry out physical and mental tasks while underestimating the mistakes he makes during their performance. The skills involved in driving a motor vehicle are, of course, specially vulnerable when this occurs.

Synergism and Potentiation of Alcohol by Drugs

Pharmacologists distinguish between simple additive effects of drugs and syner­gism or potentiation. Veldestra (1956) uses the latter terms to mean “a co-operative action of discrete agencies such that the total effect is greater than the sum of the two effects taken independently” . The evidence for synergism in this sense between alcohol and barbiturates is conflicting. Several authors (e.g. Smith and Loomis, 1951) have found that the sleeping time of animals is longer when alcohol and barbi­turates are given together than when given alone in equivalent doses. Gruber (1955) has analysed results of this type and shown that when allowance is made for the dif­ferent times of action of the depressant drugs and the different methods of adminis­tration, the balance of evidence is in favour of a simple additive effect. In man there is evidence that death has occurred after alcohol and barbiturates in combination in doses which, given separately, would have been safe (see Wayne, 1954). Joyce et al. (1959) have recently investigated the combined effects of alcohol and pheno- barbitone on the “complex reaction time” and on typing performance of young healthy males. Phenobarbitone alone reduced the rate at which test passages were typed and reduced the errors made. Alcohol had the opposite effect, but when phenobarbitone was added both the rate of typing and the number of errors increased further. Their results suggest potentiation of alcohol effects by barbitu­rates rather than simple additive effects.

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There is evidence that similar additive effects, or even potentiation, may occur between alcohol and other depressant drugs such as the non-barbiturate hyp­notics, the tranquillizers and the anti­histamines. Thus, Zirkle et al. (1960), in a placebo-controlled trial, have shown that a combination of meprobamate and alcohol produce a worse performance in psycho­logical tests than either substance alone, and 18 out of 22 subjects judged them­selves less safe drivers under the combined drug regime. Goldberg (1961), in a com­prehensive study, concludes that “tranquil­lizing agents and central nervous system depressant drugs potentiate the effect of alcohol” . The drugs studied included antihistamines and both major tranquil­lizers such as chlorpromazine and minor tranquillizers such as meprobamate. Loomis (1962) concludes that in man barbiturates and tranquillizers have an additive rather than a potentiating action, and that in ordinary therapeutic doses they may have no consistently measurable effect.

Tolerance to AlcoholAs with other drugs, tolerance to

alcohol may be either natural or acquired. Even in a population of inbred animals of uniform weight, age and sex, there is con­siderable variation in the dose of a drug required to give the same effect. Thus, different individuals respond differently to the same dose of a drug even if they have never been exposed to it before. Alcohol is no exception, and even at the same blood alcohol levels, when performance has been measured in individuals with a limited range of drinking habits, a difference in response has been found (Drew et al. 1958). These observers discovered a correlation with personality structure, so that extra- verts did not alter their driving speed much but showed large increases in error while introverts showed considerable changes in speed and on the average a less increase in error. In social drinking, of course, there will be other factors to take into account such as variations in body weight and speed of drinking, and these will still further modify the apparent effect of the same dose of the same drink in different individuals.

The repeated use of alcohol leads to the development of acquired tolerance, so that larger doses than previously must be taken to produce the same effects. This tolerance is not due to a diminished rate

of absorption in the heavy drinker. There is, however, some evidence that it is in part due to a greater rate of removal by oxida­tion (Goldberg 1951). But tolerance to alcohol is mainly a tissue tolerance, so that the tissues of the reticular formation require larger doses than previously to modify their function. In rather cruder terms, if the cells of the nervous system are bathed day after day in a dilute solution of alcohol this will, after a time, become their “normal” environment and relatively large increases in alcohol concentration will be required before its characteristic effects will be observed.

It is thus clear that at a given blood alcohol level the habitual heavy drinker will give less objective evidence of impair­ment of function than the occasional light drinker. But matters are not quite so simple. In practice, as Goldberg (1951) has pointed out, not only is the heavy drinker capable of taking much more drink without vomiting, but he increases his intake to the point at which he obtains the full effect of alcohol. This is what he has been seeking. After all, people do not drink to obtain a given blood level but to achieve euphoria. Much confusion in medico-legal practice would be avoided if this simple fact were more often kept in mind.R eferences

Begg, T. B., Hill, I. D ., Nickolls, L. C. (1962). Proceedings o f Third International Conference on Alcohol and Road Traffic.Bjerver, K ., Bonnichsen, R. K ., Goldberg, L., Theorell, H. (1951). Proceedings o f First International Conference on Alcohol and Traffic. Stockholm.British Medical Association (1958). Recogni­tion o f Intoxication. Revised Edition, London.------ (1960). Relation o f Alcohol to RoadAccidents, London.Caspers, H. (1958). Z . ges. exp. Med., 129, 582. Drew, G. C., Colquhoun, W. P., Long, Hazel, A. (1958). Brit. med. J. 2, 993.Goldberg, L. (1951). Proceedings o f First International Conference on Alcohol and Traffic. Stockholm, p. 85.Goldberg, L. (1961). Quart. J. Stud. Alcohol. Suppl. No. 1, p. 37.Goodm an, L. S., and Gilman, A. (1955). The Pharmacological Basis o f Therapeutics, 2nd Ed. MacMillan. New York, p. 103.Gruber, C. M. (1955). Arch. int. Pharmacodyn., 102, 17.Haggard, H. W., Greenberg, L. A., Carroll, R. P., Miller, D. P. J. Amer. med. Ass. 1940, 115, 1680.Jetter, W. W. (1941-42). Quart. J. Stud. Alcohol, 2, 512.Joyce, C. R. B., Edgecombe, P. C. E., K ennard, D. A., W eatherall, M., W oods, D. P. (1959). J. ment. Sci., 105, 51.Kalant, H. (1961). Quart. J. Stud. Alcohol. Suppl. No. 1.K alant, H. (1962). Quart. J. Stud. Alcohol, 23,52. Loomis, T. A. (1962). Proceedings o f Third International Conference on Alcohol and Road Traffic.

R eferences (conf.)Ponsold, A. (1962). Proceedings o f Third International Conference on Alcohol and Road Traffic.Smith, J. W., Loomis, T. A. (1951). Proc. Soc. exp. Biol. (TV. Y.), 78, 827.

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Veldestra, H. (1956). Pharmacol. Rev., 8, 339 Wayne, E. J. (1954). J. forens. Med. 19541, 172.Zirkle, G. A., McAtee, O. B., King, P D Van Dyke, R. (1960). J. Amer. med. Ass ’ 173, 1823. ’

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DISCUSSIONMr. Rees (U.K.): Do you think it possible that a person who had consumed alcohol could retain his urine for such a long period that eventually the urine would contain all the residual alcohol from metabolism and the body tissues none at all? Furthermore, is it possible that abnormal distention of the stomach by carbon-dioxide can accentuate the effects of alcohol?Professor Wayne: Some interesting observa­tions made by Dr. Haggard show that it is possible, under unusual conditions, for a person to retain urine sufficiently long for there to be a high concentration of alcohol in the urine, with a very low concentration in the blood. However, these conditions are so artificial that they have, I think, no medico­legal significance.

I think that distention of the stomach by carbon-dioxide does not affect the absorption of alcohol. The important factor is the vasodilatation which carbon-dioxide produces on blood vessels.Dr. Van Loon (Netherlands): Would not nausea or an acute lack of appetite retard the absorption of alcohol from the stomach ?Professor Wayne: Nausea is often due to pylorospasm, and usually precedes vomiting. I’m sure that this would diminish the rate of absorption of alcohol.Professor Froentjes (Netherlands): You stated that the ratio between urine alcohol concentra­tion arid blood alcohol concentration was between 1-2 and 1-3. From how many cases were these figures obtained ?Professor Wayne: The figure is taken from a very large number of estimations. Jetter originally found a mean of about 1-3, with some variation related to differences in specific gravity. Drew made a large number of observations at rising and falling blood levels, and found the equilibrium to be about 1-3. Begg has also found a mean value of about 1 -3. I used 1 -33 in my calculations. A lower value would, of course, give a higher blood alcohol estimate and not a lower one.Dr. Scroggie (Australia): The Widmark factor referred to is a physiological ratio, relating the concentration of alcohol in the body as a whole to the concentration in the blood. Could you therefore explain the statement

in the BMA booklet, Recognition of Intoxica­tion, that for beer this factor becomes unity?Professor Wayne: I took this from Widmark’s own publications, but of course they were made a very long time ago and may be in error. I wonder if Professor Goldberg could comment on this ?Professor Goldberg: Experiments show that this ratio is only reached under very specific conditions: namely, if distilled spirits of about 40% by volume is given to fasting subjects. Then you might reach the ideal condition and the factor will be 0-7. Under other conditions, with different types of beverages, and if alcohol is taken with food, the factor may rise to 0-8, 0-9, 10, or even up to 2 or more. This poses an interesting scientific problem, because if the ratio is higher than 1, it means that part of the alcohol which is ingested is lost and has never come out into the circulation. We are starting experiments with C14 labelled alcohol to see if we can trace that part of the alcohol, and determine if it is really not absorbed.Dr. Marshall (Northern Ireland): Would you comment on the proposition that it is unscien­tific to analyse a random sample of urine to obtain an estimate of a driver’s blood alcohol level at the time of a medical examination; that the bladder should first be emptied, this sample temporarily retained, and that the urine subsequently excreted during the clinical examination analysed ?Professor Wayne: Professor Drew has shown that under ordinary circumstances the alcohol level in the urine represents, in general, that in the blood about a quarter to a half-an-hour previously. Sometimes, in efforts to cast doubt upon the accuracy of urine analysis, extraordinary situations are postulated, such as that of the heroic man who sits in the public- house with a bursting bladder and doesn’t empty it for 12 hours or more, or of the individuals who drink pints of water or milk before they have a pint of beer. All of these are quite unrealistic situations and I think that, in general, a sample of urine taken in a police station represents pretty accurately the alcohol which that person had in his blood about half-an-hour previously. But the most satisfactory procedure is, as I have already said, that suggested by Dr. Marshall.