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CLINICAL PHARMACOLOGY 2003 (PART 12A)

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CLINICAL PHARMACOLOGY 2003 (PART 12A)

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The nonmedical use of drugs presents social problems with important pharmacological aspects. Social aspects Rewards for the individual Decriminalisation and legalisation Dependence Drugs and sport Tobacco Dependence Nicotine pharmacology Effects of chronic smoking Starting and stopping use Passive smoking Ethyl alcohol Pharmacology Car driving and alcohol Chronic consumption Withdrawal Pregnancy Pharmacological deterrence Psychodysleptics • Experiences with psychodysleptics • Individual substances, especially cannabis Stimulants • cocaine, • amfetamines. • methylxanthines (caffeine), ginseng, khat Social aspects The enormous social importance of this subject warrants discussion here. All the naturally occurring sedatives, narcotics, euphoriants, hallucinogens and excitants were discovered thousands of years ago, before...

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  1. 10 Nonmedical use of drugs SYNOPSIS The nonmedical use of drugs presents social problems Social aspects with important pharmacological aspects. The enormous social importance of this subject Social aspects warrants discussion here. Rewards for the individual Decriminalisation and legalisation All the naturally occurring sedatives, narcotics, Dependence euphoriants, hallucinogens and excitants were Drugs and sport discovered thousands of years ago, before the Tobacco dawn of civilisation ... By the late Stone Age man Dependence was systematically poisoning himself. The Nicotine pharmacology presence of poppy heads in the kitchen middens of Effects of chronic smoking the Swiss Lake Dwellers shows how early in his Starting and stopping use history man discovered the techniques of self- Passive smoking transcendence through drugs. There were dope Ethyl alcohol addicts long before there were farmers.1 Pharmacology Car driving and alcohol The drives that induce a person more or less Chronic consumption mentally healthy to resort to drugs to obtain chemical Withdrawal vacations from intolerable selfhood will be briefly Pregnancy considered here, as well as some account of the Pharmacological deterrence pharmacological aspects of drug dependence. Psychodysleptics The dividing-line between legitimate use of drugs • Experiences with psychodysleptics for social purposes and their abuse is indistinct for it • Individual substances, especially cannabis is not only a matter of which drug, but of amount of drug and of whether the effect is directed antisocially Stimulants or not. 'Normal' people seem to be able to use alcohol • cocaine, for their occasional purposes without harm but, • amfetamines. given the appropriate personality and/or environ- • methylxanthines (caffeine), ginseng, khat mental adversity, many may turn to it for relief and 1 Huxley A1957 Annals of the New York Academy of Sciences 67: 677. 165
  2. 10 N O N M E D I C A L USE OF DRUGS become dependent on it, both psychologically and may be psychological dependence, but there is little physically. But drug abuse is not primarily a or no physical dependence except with heavy doses pharmacological problem, it is a social problem of depressants (alcohol). The group includes seda- with important pharmacological aspects. tives and tranquillisers, amphetamines, cannabis, A further issue is whether a boundary can be hallucinogens, alcohol, tobacco and caffeine. drawn between the therapeutic and nontherapeutic This classification fails to recognise individual use of a therapeutic drug and, some would argue, if variation in drug use. Alcohol can be used in heavy it can be drawn, should it be? The matter has been doses that are gravely disabling and induce severe highlighted by the use of SSRI antidepressants, e.g. physical dependence with convulsions on sudden fluoxetine (Prozac), not to treat depression but to withdrawal; i.e. for the individual the drug is 'hard'. elevate mood — make a person feel 'better than But there are many people mildly psychologically well' (see nonmedical use, below). dependent on it who retain their position in home and society. Hard-use where the drug is central in the user's SOMETERMSUSED life and soft-use where it is merely incidental, are terms of assistance in making this distinction, i.e. Abuse potential of a drug is related to its capacity what is classified is not the drug but the effect it has to produce immediate satisfaction, which may be a on, or the way it is used by, the individual. feature of the drug itself (amfetamine and heroin give rapid effect while tricyclic antidepressants do Drug dependence (see p. 168). not) and its route of administration in descending order: inhalation/i.v.; i.m./s.c.; oral. Addiction. The term 'addict' or 'addiction' has not been completely abandoned in this book because it Drug abuse2 implies excessive (in terms of social remains convenient. It refers to the most severe forms norms) nonmedical or social drug use. of dependence where compulsive craving dominates the subject's daily life. Such cases pose problems as Nonmedical drug use, i.e. all drug use that is not on grave as dependence on tea-drinking is trivial. But generally accepted medical grounds, may be a term the use of the term drug dependence is welcome, preferred to 'abuse'. Nonmedical use means the because it renders irrelevant arguments about continuous or occasional use of drugs by individuals, whether some drugs are addictive or merely habit- whether of their own 'free' choice or under feelings of forming. Nonmedical drug use has two principal compulsion, to achieve their own wellbeing, or forms: what they conceive as their own wellbeing (see • Continuous use, when there is a true dependence, motives below). e.g. opioids, alcohol, benzodiazepines. Drugs used for nonmedical purposes are often • Intermittent or occasional use to obtain a divided into two groups, hard and soft. recreational experience, e.g. 'ecstasy' (tenamfetamine), LSD, cocaine, cannabis, Hard drugs are those that are liable seriously to solvents, or to relieve stress, e.g. alcohol. disable the individual as a functioning member of society by inducing severe psychological and, in the Both uses commonly occur in the same subject, case of cerebral depressants, physical, dependence. and some drugs, e.g. alcohol, are used in both ways, The group includes heroin and cocaine. but others, e.g. 'ecstasy', LSD, cannabis, are virtually confined to the second use. Soft drugs are less dependence-producing. There Drives to nonmedical (or nonprescription) drug use are: 2 The World Health Organization adopts the definition of the • Relief of anxiety, tension and depression; escape United Nations Convention on Psychotropic Drugs (1971). Drug abuse means the use of psychotropic substances in a from personal psychological problems; way that would 'constitute a public health and social detachment from harsh reality; ease of social problem'. intercourse. 166
  3. REWARDS FOR THE INDIVIDUAL 10 • Search for self-knowledge and for meaning in depends on many factors such as the subject's life, including religion. The cult of 'experience' personality, mood, environment, conditioning. The including aestheticism and artistic creation, sex drug facilitates rather than induces the experience; and 'genuine', 'sincere' interpersonal and drugs can facilitate unpleasant as well as relationships, to obtain a sense of 'belonging'. pleasant experiences. It is not surprising that mystical • Rebellion against or despair about orthodox experience can occur with a wide range of drugs social values and the environment. Fear of that alter consciousness: missing something, and conformity with own .. .I seemed at first in a state of utter blankness ... social subgroup (the young, especially). with a keen vision of what was going on in the room • Fun, amusement, recreation, excitement, around me, but no sensation of touch. I thought that curiosity (the young, especially). I was near death; when, suddenly, my soul became aware of God, who was manifestly dealing with me, handling me, so to speak, in an intense personal, Rewards for the individual present reality ... I cannot describe the ecstasy I felt.3 This experience occurred in the 19th century It is inherently unlikely that chemicals could be with chloroform; a general anaesthetic obsolete central to a constructive culture and no convincing because of cardiac depression and hepatotoxicity. support for the assertion has yet been produced. There is no good evidence that drugs can (That chemicals might be central to a destructive produce experience that passes the test of results, culture is another matter.) Certainly, like-minded i.e. fruitfulness to the individual and to society. people practising what are often illegal activities Plainly there is a risk of the experience becoming an will gather into closely knit subgroups for mutual end in itself rather than a means of development. support, and will feel a sense of community, but that is hardly a 'culture'. Even when drug-using sub- CONCLUSIONS groups are accepted as representing a subculture, it may be doubted if drugs are sufficiently central to The value of nonmedical use of psychotropic drugs their ideology to justify using 'drug' in the title. But can be summed up thus. claims for value to the individual and to society of • For relaxation, recreation, protection from and drug experience must surely be tested by the relief of stress and anxiety; relief of depression: criterion of fruitfulness for both, and the judgement moderate use of some 'soft' drugs may be of the individual concerned alone is insufficient; it accepted as part of our society. must be agreed by others. The results of both legal • For spiritually valuable experience: justification and illegal drug use do not give encouragement to is extremely doubtful. press for a large-scale experiment in this field. • As basis for a 'culture' in the sense that drug It is claimed that drugs provide mystical experience experience (a) can be, and (b) should be central and that this has valid religious content. Mystical to an individually or socially constructive way of experience may be defined as a combination of life: a claim without validity. feelings of unity (oneness with nature and/or God), • For acute excitement: extremely dangerous. ineffability (experience beyond the subject's power to express), joy (peace, sacredness), knowledge (insight into truths of life and values, illuminations), and GENERAL PATTERN OF USE transcendence (of space and time). Divisions are not rigid and they change with fashion. When such states do occur there remains the question whether they tell us something about a reality outside the individual or merely something 3 Quoted in James W (1902) Varieties of religious experience. about the mind of the person having the experience. Longmans, Harlow, and many subsequent editions of this Mystical experience is not a normal dose-related classic. See also Leary T (1970). The politics of ecstasy. pharmacodynamic effect of any drug, its occurrence MacGibbon and Kee, London. Other editions, USA. 167
  4. 10 NONMEDICAL USE OF DRUGS • Any age: alcohol; tobacco; mild dependence on But though written laws are so often inflexible and hypnotics and tranquillisers; occasional use of combine what would best be separated, informal LSD and cannabis. judicial discretion under present law may be per- • Aged 16-35 years: hard-use drugs, chiefly mitting more experimentation than would recurrent heroin, cocaine and amphetamines (including legislative debate. It is recognised that this untidy 'ecstasy'). Surviving users tend to reduce or approach, which may be best for the time being, relinquish heavy use as they enter middle age. cannot satisfy the extravagant advocates either of • Under 16 years: volatile inhalants, e.g. solvents licence or of repression. of glues, aerosol sprays, vaporised (by heat) A suggested intermediate course for cannabis, paints, 'solvent or substance' abuse, 'glue- and perhaps even for heroin, is that penalties for sniffing'. possession of small amounts for personal con- • Miscellaneous: any drug or combination of sumption should be removed (decriminalisation as drugs reputed to alter consciousness may have a opposed to legalisation), whilst retaining criminal local vogue, however brief, e.g. drugs used in penalties for suppliers. Such an approach is parkinsonism and metered aerosols for asthma. increasingly and informally being implemented. Nobody knows what would happen if the production, supply and use of the major drugs, cannabis, heroin and cocaine, were to be legalised, as Decriminalisation and tobacco and alcohol are legalised (with weak selling legalisation restrictions). There are those who, shocked by the evils of illegal trade, consider that legalisation could only make matters better. The debate continues The decision whether any drug is acceptable in about what kinds of evils affecting the individual medical practice is made after an evaluation of its and society can be tolerated and how they can be safety in relation to its efficacy. The same principle balanced against each other. should be used for drugs for nonmedical or social use. But the usual scientific criteria for evaluating efficacy are hardly applicable. The reasons why people choose to use drugs for nonmedical purposes are listed above. None of them carries serious weight Dependence if the drug is found to have serious risks to the individuals4 or to society, with either acute or chronic Drug dependence is a state arising from repeated, use. Ordinary prudence dictates that any such risks periodic or continuous administration of a drug, that should be carefully defined before a decision on results in harm to the individual and sometimes to legalisation is made. society.The subject feels a desire, need or compulsion to There is no doubt that many individuals think, continue using the drug and feels ill if abruptly deprived of rightly or wrongly, that private use of cannabis, if it (abstinence or withdrawal syndrome). not of 'harder' drugs, is their own business and that the law should permit this freedom. The likelihood that demand can be extinguished by education or by For discussion of abrupt withdrawal of drugs in threats appears to be zero. The autocratic imple- general see page 119. Drug dependence is char- mentation of laws that are not widely accepted in the acterised by: community leads to violent crime, corruption in the • Psychological dependence: the first to appear; police, and alienation of reasonable people who there is emotional distress if the drug is would otherwise be an important stabilising influ- withdrawn. ence in society. • Physical dependence: accompanies psychological dependence in some cases; there is 4 Hazard to the individual is not a matter for the individual a physical illness if the drug is withdrawn. alone if it also has consequences for society. • Tolerance. 168
  5. DEPENDENCE 10 PSYCHOLOGICAL DEPENDENCE cerebral depressants, but is minor or absent with excitant drugs. This may occur with any drug that alters con- There is commonly cross-tolerance between sciousness however bizarre, e.g. muscarine (see drugs of similar, and sometimes even of dissimilar, p. 436) and to some that, in ordinary doses, do not, chemical groups, e.g. alcohol and benzodiazepines. e.g. non-narcotic analgesics, purgatives, diuretics; There is danger in personal experimentation; as these latter provide problems of psychopathology an American addict has succinctly put it, 'They all rather than of psychopharmacology. think they can take just one joy-pop but it's the first Psychological dependence can occur merely on a one that hooks you'.5 tablet or injection, regardless of its content, as well Unfortunately subjects cannot decide for them- as to drug substances. Mild dependence does not selves that their dependence will remain mild. require that a drug should have important psychic effects; the subject's beliefs as to what it does are as important, e.g. purgative and diuretic dependence TYPES OF DRUG DEPENDENCE in people obsessed with dread of obesity. We are all The World Health Organization recommends that physically dependent on food, and some develop a drug dependence be specified by 'type' when under strong emotional dependence and eat too much (or detailed discussion. the reverse); sexual activity, with its unique mix of arousal and relaxation, can for some become Morphine-type: compulsive or addictive. — psychological dependence severe — physical dependence severe; develops quickly — tolerance marked PHYSICAL DEPENDENCE AND — cross-tolerance with related drugs TOLERANCE — naloxone induces abstinence syndrome. Physical dependence and tolerance imply that adaptive changes have taken place in body tissues Barbiturate-type: so that when the drug is abruptly withdrawn these — psychological dependence severe adaptive changes are left unopposed, resulting — physical dependence very severe; develops generally in a rebound overactivity The discovery slowly at high doses that the CNS employs morphine-like substances — tolerance less marked than with morphine (endomorphins, dynorphins) as neurotransmitters — cross-tolerance with alcohol, chloral, offers the explanation that exogenously admin- meprobamate, glutethimide, chlordiazepoxide, istered opioid may suppress endogenous pro- diazepam, etc. duction of endorphins by a feedback mechanism. When administration of opioid is suddenly Amfetamine-type: stopped there is an immediate deficiency of end- — psychological dependence severe ogenous opioid, which thus causes the withdrawal — physical dependence slight: psychoses occur syndrome. during use Tolerance may result from a compensatory — tolerance occurs. biochemical cell response to continued exposure to opioid. In short, both physical dependence and Cannabis-type: tolerance may follow the operation of homeostatic — psychological dependence adaptation to continued high occupancy of opioid — physical dependence dubious (no characteristic receptors. Changes of similar type may occur with abstinence syndrome) GABA transmission, involving benzodiazepines. — tolerance occurs. Tolerance also results from metabolic changes (enzyme induction) and physiological/behavioural adaptation to drug effects, e.g. opioids. Physical 5 Maurer D W, Vogel V H 1962 Narcotics and narcotic dependence develops to a substantial degree with addiction. Thomas, Springfield. 169
  6. 10 NONMEDICAL USE OF DRUGS Cocaine-type: addiction is permitted under strict legal limitations. — psychological dependence severe Addicts must be notified by the physician to the — physical dependence slight Home Office and in the case of some opioids and — tolerance slight (to some actions). cocaine, the physician requires a special licence. By such procedure it is hoped to limit the expansion of Alcohol-type: the illicit market, and its accompanying crime and — psychological dependence severe dangers to health, e.g. from infected needles and — physical dependence with prolonged heavy use syringes. The object is to sustain young (usually) — cross-tolerance with other sedatives. addicts, who cannot be weaned from drug use, in reasonable health until they relinquish their Tobacco-type: dependence (often over about 10 years). — psychological dependence When injectable drugs are prescribed there is — physical dependence. currently no way of assessing the truth of an addict's statement that he/she needs x mg of heroin (or other Drug mixtures: Barbiturate-amfetamine mixtures drug), and the dose has to be assessed intuitively by induce a characteristic alteration of mood that does the doctor. This has resulted in addicts obtaining not occur with either drug alone more than they need and selling it, sometimes to — psychological dependence strong initiate new users. The use of oral methadone or — physical dependence occurs other opioid for maintenance by prescription is — tolerance occurs. devised to mitigate this problem. Heroin-cocaine mixtures: similar characteristics. TREATMENT OF DEPENDENCE ROUTE OF ADMINISTRATION AND EFFECT Withdrawal of the drug. Whilst obviously impor- tant, this is only a step on what can be a long and With the i.v. route or inhalation much higher peak often disappointing journey to psychological and plasma concentrations can be reached than with social rehabilitation, e.g. in 'therapeutic commu- oral administration. This accounts for the 'kick' or nities'. A heroin addict may be given methadone as 'flash' that abusers report and which many seek, part of a gradual withdrawal programme (see p. 337) likening it to sexual orgasm or better. As an addict for this drug has a long duration of action and said 'The ultimate high is death' and it has been blocks access of injected opioid to the opioid receptor reported that when hearing of someone dying of an so that if, in a moment of weakness, the subject takes overdose, some addicts will seek out the vendor since heroin, the 'kick' is blocked. More acutely, the it is evident he is selling 'really good stuff'.6 Addicts physical features associated with discontinuing high who rely on illegal sources are inevitably exposed to alcohol use may be alleviated by chlordiazepoxide being supplied diluted or even inert preparations at given in decreasing doses for 4-6 days. Sympathetic high prices. North American addicts who have come autonomic overactivity can be treated with a (3- to the UK believing themselves to be accustomed to adrenoceptor blocker (or clonidine) (see Abrupt high doses of heroin have suffered acute poisoning withdrawal of drugs). when given, probably for the first time, pure heroin at an official UK drug dependence clinic. Maintenance and relapse. Relapsed addicts who live a fairly normal life are sometimes best treated SUPPLY OF DRUGSTO ADDICTS by supplying drugs under supervision. There is no In the UK, supply of officially listed drugs (a range legal objection to doing this in the UK (see above) of opioids and cocaine) for the purpose of sustaining but naturally this course, which abandons hope of cure, should not be adopted until it is certain that 6 Bourne P 1976 Acute drug abuse emergencies. Academic cure is virtually impossible. A less harmful drug Press, New York. by a less harmful route may be substituted, e.g. oral 170
  7. DEPENDENCE 10 methadone for i.v. heroin. Addicts are often par- to psychosocial factors, although increased sug- ticularly reluctant to abandon the i.v. route, which gestibility induced by cannabis may contribute. provides the 'immediate high' that they find, or originally found, so desirable. De-escalation also occurs as users become disil- lusioned with drugs over about 10 years. Severe pain in an opioid addict presents a special problem. High-efficacy opioid may be ineffective 'Designer drugs' (tolerance) or overdose may result; low-efficacy opioids will not only be ineffective but may induce This unhappily chosen term means molecular mod- withdrawal symptoms, especially if they have some ifications produced in secret for profit by skilled and antagonist effect, e.g. pentazocine. This leaves as criminally minded chemists. Manipulation of drugs of choice nonsteroidal anti-inflammatory fentanyl has resulted in compounds of extraordinary drugs (NSAIDs), e.g. indometacin, and nefopam potency. (which is neither opioid nor NSAID). In 1976 a too-clever 23-year-old addict seeking to manufacture his own pethidine 'took a synthetic shortcut and injected himself with what was later Mortality with his help proved to be two closely related Young illicit users by i.v. injection (heroin, benzo- byproducts; one was MPTP (methylphenyltetra- diazepines, amphetamine) have a high mortality. hydropyridine).8,9 Three days later he developed a Either death follows overdose, or septicaemia, endo- severe parkinsonian syndrome that responded to carditis, hepatitis, AIDS, gas gangrene, tetanus and levodopa. MPTP selectively destroys melanin- pulmonary embolism ensue from the contaminated containing cells in the substantia nigra. Further such materials used without aseptic precautions (schemes cases have occurred from use of supposed synthetic to provide clean equipment mitigate this). Smugglers heroin. MPTP has since been used in experimental of illicit cocaine or heroin sometimes carry the drug research on parkinsonism. What the future holds in plastic bags concealed by swallowing or in the for individuals and for society in this area can only rectum ('body packing'). Leakage of the packages, be imagined. not surprisingly, may have a fatal result.7 Volatile substance abuse Escalation Seekers of the 'self-gratifying high' also inhale any A variable proportion of subjects who start with volatile substance that may affect the central nervous cannabis eventually take heroin. This disposition to system. These include: adhesives ('glue-sniffing'), progress from occasional to frequent soft use of lacquer-paint solvents, petrol, nail varnish, any drugs through to hard drug use, when it occurs, is pressurised aerosol and butane liquid gas (which less likely to be due to pharmacological actions, than latter especially may 'freeze' the larynx, allowing fatal inhalation of food, drink, gastric contents, or 7 A 49-year-old man became ill after an international flight. even the liquid itself to flood the lungs). Even An abdominal radiograph showed a large number of solids, e.g. paint scrapings, solid shoe polish, may spherical packages in his gastrointestinal tract, and body- be volatilised over a fire. These substances are packing was suspected. As he had not defaecated, he was particularly abused by the very young (school- given liquid paraffin. He developed ventricular fibrillation and died. Post mortem examination showed that he had children), no doubt largely because they are ingested more than 150 latex packets, each containing 5 g of accessible at home and in ordinary shops and they cocaine, making a total of almost 1 kg (lethal oral dose 1-3 g). cannot easily buy alcohol or 'street' drugs (although The liquid paraffin may have contributed to his death as the this latter may be changing as dealers target the mineral oil dissolves latex. Sorbitol or lactulose with youngest). CNS effects include confusion and activated charcoal should be used to remove ingested packages, or surgery if there are signs of intoxication. (Visser 8 L et al 1998 Do not give liquid paraffin to packers. Lancet Williams A1984 British Medical Journal 289: 1401-1402. 9 352: 1352) Davis G C et al 1979 Psychiatry Research 1: 249. 171
  8. 10 NONMEDICAL USE OF DRUGS hallucinations, ataxia, dysarthria, coma, convul- For 'strength sports' in which body weight and sions, respiratory failure. Liver, kidney, lung and brute strength are the principal determinants heart damage occur. Sudden cardiac death may be (weight lifting, rowing, wrestling): anabolic agents, due to sensitisation of the heart to endogenous e.g. clenbuterol (B-adrenoceptor agonist), andro- catecholamines. If the substance is put in a plastic stenedione, methandienone, nandrolone, stanozolol, bag from which the user takes deep inhalations, or testosterone. Taken together with a high-protein diet is sprayed in a confined space, e.g. cupboard, there and exercise, these increase lean body weight is particularly high risk. (muscle) but not necessarily strength. It is claimed they allow more intensive training regimens A 17-year-old boy was offered the use of a plastic (limiting cell injury in muscles). Rarely, there may bag and a can of hair spray at a beach party. The be episodes of violent behaviour, known amongst hair spray was released into the plastic bag and the athletes as 'roid [steroid] rage'. teenager put his mouth to the open end of the bag High doses are used, with risk of liver damage and inhaled ... he exclaimed, 'God, this stuff hits (cholestatic, tumours) especially if the drug is ya fast!' He got up, ran 100 yards; and died.10 taken long-term, which is certainly insufficient to Signs of frequent volatile substance abuse deter 'sportsmen'. They may be more inclined to include perioral eczema and inflammation of the take more seriously the fact that anabolic steroids upper respiratory tract. suppress pituitary gonadotrophin, and so testos- terone production. Growth hormone (somatrem, somatropin) and corticotrophin use may be combined with that of Drugs and sport anabolic steroids. Chorionic gonadotrophin may be taken to stimulate testosterone production (and prevent testicular atrophy). Similarly, tamoxifen The rewards of competitive sport, both financial (antioestrogen) may be used to attenuate some of and in personal and national prestige, are the the effects of anabolic steroids. cause of determination to win at (almost) any cost. For events in which output of energy is explosive Drugs are used to enhance performance though (100 m sprint): stimulants, e.g. amphetamine, bro- efficacy is largely undocumented. Detection can be mantan, carphendon, cocaine, ephedrine and caffeine difficult when the drugs or metabolites are closely (> 12 mg/1 in urine). Death has probably occured in related to or identical with endogenous sub- bicycle racing (continuous hard exercise with short stances, and when the drug can be stopped well periods of sprint) due to hyperthermia and cardiac before the event without apparent loss of efficacy, arrhythmia in metabolically stimulated and vaso- e.g. anabolic steroids (but suppression of constricted subjects exercising maximally under a endogenous trophic hormones can be measured, hot sun. and can assist). For endurance sports to enhance the oxygen carrying capacity of the blood (bicycling, mar- athon running): erythropoietin, 'blood doping' (the PERFORMANCE ENHANCEMENT athlete has blood withdrawn and stored, then There follow illustrations of the mechanisms by transfused once the deficit had been made up which drugs can enhance performance in various naturally, so raising the plasma haemoglobin sports; naturally, these are proscribed by the above normal). authorities (International Olympic Committee (IOC) For events in which steadiness of hand is essential Medical Commission, and the governing bodies of (pistol, rifle shooting): B-adrenoceptor blockers. Tremor individual sports). is reduced by the B2-adrenoceptor blocking effect, as are somatic symptoms of anxiety. For events in which body pliancy is a major factor 10 Bass M 1970 Sudden sniffing death. Journal of the (gymnastics): delaying puberty in child gymnasts by American Medical Association 212: 2075. endocrine techniques. 172
  9. TOBACCO 10 For weight reduction, e.g. boxers, jockeys: diuretics. These are also used to flush out other Tobacco drugs in the hope of escaping detection; severe volume depletion can cause venous thrombosis and Tobacco was introduced to Europe from South pulmonary embolism. America in the 16th century. Although its potential Generally, owing to recognition of natural bio- for harm was early recognised its use was taken up logical differences most competitive events are sex avidly in every society that met it. Current estimates segregated. In many events men have a natural are that there are 1.1 billion smokers worldwide. In physical biological advantage and the (inevit- 1990 there were 3 million smoking-related deaths able) consequence has been that women have per year, projected to rise to 8 million by 2020 been deliberately virilised (by administration of (representing 12% of all deaths).12 androgens) so that they may outperform their sisters. COMPOSITION It seems safe to assume that anything that can be thought up to gain advantage will be tried by The principal components are tar and nicotine, the competitors eager for immediate fame. Reliable amounts of which can vary greatly depending on data are difficult to obtain in these areas. No the country in which cigarettes are sold. Regulation doubt placebo effects are important, i.e. beliefs as and voluntary agreement by manufacturers aspires to what has been taken and what effects ought to to achieve a 'global cigarette' containing at most follow. 12 mg of tar and 1 mg of nicotine. The dividing line between what is and what is The composition of tobacco smoke is complex not acceptable practice is hard to draw. Caffeine can (about 500 compounds have been identified) and improve physical performance and illustrates the varies with the type of tobacco and the way it is difficulty of deciding what is 'permissible' or smoked. The chief pharmacologically active ingre- 'impermissible'. A cup of coffee is part of a normal dients are nicotine (acute effects) and tars (chronic diet, but some consider taking the same amount of effects). caffeine in a tablet, injection or suppository to be Smoke of cigars and pipes is alkaline (pH 8.5) and 'doping'. nicotine is relatively un-ionised and lipid-soluble so For any minor injuries sustained during athletic that it is readily absorbed in the mouth. Cigar and training NSAIDs and corticosteroids (topical, intra- pipe smokers thus obtain nicotine without inhaling articular) suppress symptoms and allow the training (they also have a lower death rate from lung cancer; to proceed maximally. Their use is allowed subject to which is caused by non-nicotine constituents). restrictions about route of administration, but strong Smoke of cigarettes is acidic (pH 5.3) and nicotine is opioids are disallowed. Similarly, the IOC Medical relatively ionised and insoluble in lipids. Desired Code defines acceptable and unacceptable treatments amounts are absorbed only if nicotine is taken into for relief of cough, hay fever, diarrhoea, vomiting, the lungs, where the enormous surface area for pain and asthma. Doctors should remember that absorption compensates for the lower lipid solubility. they may get their athlete patients into trouble with Cigarette smokers therefore inhale (and have a high sports authorities by inadvertent prescribing of rate of death from tar-induced lung cancer). The banned substances.11 amount of nicotine absorbed from tobacco smoke Some of the isssues seem to be ethical rather than varies from 90% in those who inhale to 10% in those medical as witness the reported competition who do not. success of a swimmer who, it is alleged, had been Tobacco smoke contains 1-5% carbon monoxide persuaded under hypnosis into the belief that he and habitual smokers have 3-7% (heavy smokers as was being pursued by a shark. much as 15%) of their haemoglobin as carboxy- 11 12 UK prescribers can find general advice in the British Editorial 1999 Tobacco money and medical research. National Formulary. Nature Medicine 5:125 173
  10. 10 NONMEDICAL USE OF DRUGS haemoglobin, which cannot carry oxygen. This is and tolerance to the adverse effects occurs. Thus to sufficient to reduce exercise capacity in patients with the psychosocial pressure is now added pharma- angina pectoris. Chronic carboxyhaemoglobinaemia cological pleasure. causes polycythaemia (which increases the viscosity Tolerance and some physical dependence occur. of the blood). Transient withdrawal effects include EEG and sleep Substances carcinogenic to animals (polycyclic changes, impaired performance in some psycho- hydrocarbons and nicotine-derived N-nitrosamines) motor tests, disturbance of mood, and increased have been identified in tobacco smoke condensates appetite (with weight gain), though it is difficult to from cigarettes, cigars and pipes. Polycyclic hydro- disentangle psychological from physical effects in carbons are responsible for the hepatic enzyme these last. induction that occurs in smokers. ACUTE EFFECTS OF SMOKING TOBACCO Tobacco dependence • Increased airways resistance occurs due to the nonspecific effects of submicronic particles, e.g. Psychoanalysts have made a characteristic con- carbon particles less than 1 um across. The effect tribution to the problem. 'Getting something orally', is reflex; even inert particles of this size cause one asserted..., 'is the first great libidinous bronchial narrowing sufficient to double airways experience in life'; first the breast, then the bottle, then resistance; this is insufficient to cause dyspnoea, the comforter, then food and finally the cigarette.13 though it might affect athletic performance. Pure Sigmund Freud, inventor of psychoanalysis, was nicotine inhalations of concentration comparable a lifelong tobacco addict. He suggested that some to that reached in smoking do not increase children may be victims of a 'constitutional airways resistance. intensification of the erotogenic significance of the • Ciliary activity, after transient stimulation, is labial region', which, if it persists, will provide a depressed, and particles are removed from the powerful motive for smoking.14 lungs more slowly. While psychological dependence is strong and • Carbon monoxide absorption may be clinically accounts for part of the difficulty of stopping important in the presence of coronary heart smoking, nicotine possesses all the characteristics of disease (see above) although it is physiologically a drug of dependence and there is powerful reason insignificant in healthy young adults. to regard nicotine addiction as a disease. A report on the subject concludes that most smokers do not do so from choice but because they are addicted to nicotine.15 The immediate satisfaction of smoking is Nicotine pharmacology due to nicotine and also to tars, which provide flavour. Initially the factors are psychosocial; pharma- Pharmacokinetics codynamic effects are unpleasant. But under the psychosocial pressures the subject continues, learns Nicotine is absorbed through mucous membranes to limit and adjust nicotine intake, so that the in a highly pH-dependent fashion. The t1/2 is 2 h. It is pleasant pharmacological effects of nicotine develop largely metabolised to inert substances, e.g. cotinine, though some is excreted unchanged in the 13 Scott R B 1957 British Medical Journal 1: 67 1. urine (pH dependent, it is un-ionised at acid pH). 14 Quoted in Royal Collage of Physicians 1977 Smoking or Cotinine is used as a marker for nicotine intake in health. Pitman, London. In 1929 Freud posed for a smoking surveys because of its convenient t1/2 (20 h). photograph holding a large cigar prominently. 'He was always a heavy smoker—twenty cigars a day were his usual allowance and he tolerated abstinence from it with the 15 greatest difficulty'. Jones E 1953 Sigmund Freud: life and Tobacco Advisory Group, Royal College of Physicians 2000 work. Hogarth Press, London. Nicotine addiction in Britain. London RCP. 174
  11. NICOTINE PHARMACOLOGY 10 Pharmacodynamics the muscles, tachycardia and a rise in blood pressure of about 15 mmHg systolic and 10 mmHg Large doses.16 Nicotine is an agonist to receptors at diastolic, and increased plasma noradrenaline the ends of peripheral cholinergic nerves whose cell (norepinephrine). Ventricular extrasystoles may bodies lie in the central nervous system, i.e. it acts at occur. Cardiac output, work and oxygen consump- autonomic ganglia and at the voluntary neuro- tion rise. Increased demand for blood flow that is not muscular junction (see Fig. 21.1). This is what is met because coronary vessels are narrowed by meant by the term 'nicotine-like' or 'nicotinic' atherosclerosis may be a mechanism of tobacco- effect. Higher doses paralyse at the same points. The induced angina pectoris. Nicotine increases platelet central nervous system is stimulated, including the adhesiveness, an effect that may be clinically vomiting centre, both directly and via chemore- significant in atheroma and thrombosis. ceptors in the carotid body; tremors and convulsions Metabolic rate. Nicotine increases the metabolic may occur. As with the peripheral actions, depression rate, only slightly at rest,17 but approximately doubles follows stimulation. it during light exercise (occupational tasks, house- work). This may be due to increase in autonomic Doses from/with smoking. Nicotine causes release sympathetic activity. The effect declines over 24 h of catecholamines in the CNS, also serotonin, and on stopping smoking and accounts for the char- antidiuretic hormone, corticotrophin and growth acteristic weight gain that is so disliked and which hormone. The effects of nicotine on viscera are is sometimes given as a reason for continuing or probably largely reflex, from stimulation of resuming smoking. Smokers weigh 2-4 kg less sensory receptors (chemoreceptors) in the carotid than nonsmokers (not enough to be a health and aortic bodies, pulmonary circulation and left issue). ventricle. Some of the results are mutually antagonistic. Tolerance develops to some of the effects of The following account tells what generally nicotine, taken repeatedly over a few hours; a first happens after one cigarette, from which about 1 mg experience commonly causes nausea and nicotine is absorbed, although much depends on vomiting, which quickly ceases with repetition of the amount and depth of inhalation and on the smoking. Tolerance is usually rapidly lost; the first duration of end-inspiratory breath-holding. cigarette of the day has a greater effect on On the cardiovascular system the effects are those the cardiovascular system than do subsequent of sympathetic autonomic stimulation. There is cigarettes. vasoconstriction in the skin and vasodilatation in Conclusion: the pleasurable effects of smoking are derived from a complex mixture of multiple phar- 16 macological and nonpharmacological factors. Fatal nicotine poisoning has been reported from smoking, In this account nicotine is represented as being from swallowing tobacco, from tobacco enemas, from topical application to the skin and from accidental drinking of nicotine the major (but not the sole) determinant of tobacco insecticide preparations. In 1932 a florist sat down on a chair, dependence after the smoker has adapted to the on the seat of which a 40% free nicotine insecticide solution usual initial unpleasant effects. But there remains had been spilled. Fifteen minutes later he felt ill (vomiting, some uncertainty as to its role, e.g. nicotine i.v. sweating, faintness, and respiratory difficulty, followed by fails adequately to substitute the effects of loss of consciousness and cardiac irregularity). He recovered in hospital over about 24 h. On the fourth day he was smoking. An understanding of the full function of deemed well enough to leave hospital and was given his nicotine is important if less harmful alternatives clothes which had been kept in a paper bag. He noticed the to smoking, such as nicotine chewing gum, are to trousers were still damp. Within one hour of leaving hospital be exploited. he had to be readmitted suffering again from poisoning due to nicotine absorbed transdermally from his still contaminated trousers. He recovered over three weeks, apart 17 from persistent ventricular extrasystoles [Faulkner J M 1933 The metabolic rate at rest accounts for about 70% of daily 1AM A100: 1663]. energy expenditure. 175
  12. 10 NONMEDICAL USE OF DRUGS Atherosclerotic narrowing of the smallest coronary Effects of chronic smoking arteries is enormously increased in heavy and even in moderate smokers; the increased platelet adhe- siveness caused by smoking increases the readiness SMOKING AND CANCER with which thrombi form. Stopping smoking reduces the excess risk of Bronchogenic carcinoma CHD in people under the age of 65, and after about Between 1920 and 1950 an epidemic of bronchogenic 4 years of abstinence the risk approximates to that carcinoma occurred (rate in men increased 20-fold) of nonsmokers. which can be attributed to cigarette smoking; lesser Pipe and cigar smokers run little or no excess causes include exposure to a variety of industrial risk of CHD provided they are not heavy smokers chemicals and atmospheric pollution. The risk of and do not inhale. Heavy cigarette smokers who death from lung cancer is related to the number of change over to pipe or cigar smoking often continue cigarettes smoked and the age of starting. Giving to inhale and thereby fail to reduce their risk. up smoking reduces the risk of death progressively from the time of cessation.18 SMOKING AND CHRONIC LUNG DISEASE Other cancers The adverse effects of cigarette smoke on the lungs The risk of smokers developing cancer of the may be separated into two distinct conditions. mouth, throat and oesophagus is 5-10 times greater • Chronic mucus hyper secretion, which causes than that of nonsmokers. It is as great for pipe and persistent cough with sputum and fits with the cigar smokers as it is for cigarette smokers. Cancer original definition of simple chronic bronchitis. of the pancreas, kidney and urinary tract is also This condition arises chiefly in the large airways, commoner in smokers. usually clears up when the subject stops smoking and does not on its own carry any DISEASES OF THE HEART AND BLOOD substantial risk of death. VESSELS • Chronic obstructive lung disease, which causes difficulty in breathing due to narrowing of the Coronary heart disease (CHD) is now the leading air passages in the lungs. This condition cause of death in many developed countries. In the originates chiefly in the small airways, includes a UK about 30% of these deaths can be attributed to variable element of destruction of peripheral smoking. lung units (emphysema), is progressive and largely irreversible and may ultimately lead to Under the age of 65 years smokers are about twice as likely disability and death. to die of ischaemic heart disease as are nonsmokers, and Both conditions can coexist in one person and they heavy smokers about 3.5 times as likely. predispose to recurrent acute infective illnesses. The obstructive syndrome is as specifically related to Sudden death may be the first manifestation of smoking as is lung cancer. Despite this, in discussing CHD and, especially in young men, is related to the health effects of tobacco, there has generally been cigarette smoking. Smoking is especially dangerous far more emphasis on lung cancer than on this more for people in whom other risk factors (increased disabling, but equally fatal disorder. blood cholesterol, high blood pressure) are present. INTERACTIONS WITH DRUG 18 Peto R et al 2000 Smoking, smoking cessation, and lung THERAPY cancer in the UK since 1950: combination of national statistics with two case-control studies. British Medical Induction of hepatic drug metabolising enzymes by Journal 321: 323-329. non-nicotine constituents of smoke causes increased 176
  13. STARTING AND STOPPING USE 10 metabolism of a range of drugs, including oestrogens, Though they are as aware of the risks of smoking theophylline, warfarin. as men, women find it harder to stop; they con- sistently have lower success rates. This trend crosses every age group and occupation. Women particularly WOMEN AND SMOKING dislike the weight gain. Fertility. Women who smoke are more likely to be Aids to giving up. The addictive effects of tobacco infertile or take longer to conceive than women who smoking are substantially due to nicotine, and it is do not smoke. In addition, smokers are more liable to logical to substitute nicotine for tobacco smoke as a have an earlier menopause than are nonsmokers. pharmacological aid to quitting. Nicotine is available Increased metabolism of oestrogens may not be the in a number of formulations, including chewing whole explanation. gum, transdermal patch, oral and nasal spray. When used casually without special attention to technique, Complications of pregnancy. The risks of sponta- nicotine formulations have proved no better than neous abortion, stillbirth, and neonatal death are other aids but, if used carefully and withdrawn as approximately doubled. There are various placental recommended, the accumulated results are almost abnormalities. The placenta is heavier in smoking two times better than in smokers who try to stop than nonsmoking women and its diameter larger. without this assistance.19 Restlessness during The enlarged placenta and placental abnormalities terminal illness may be due to nicotine withdrawal may represent adaptations to lack of oxygen due to and go unrecognised; a nicotine patch may benefit a smoking, secondary to raised concentrations of (deprived) heavy smoker. Nicotine transdermal circulating carboxyhaemoglobin. patches may cause nightmares and abnormal dreaming, and skin reactions (rash, pruritus and The child. The babies of women who smoke are 'burning' at the application site). approximately 200 g lighter than those of women Amfebutamone/bupropion may provide an alter- who do not smoke. They have an increased risk of native, or addition, to nicotine. When the drug was death in the perinatal period which is independent being investigated as an antidepressant, researchers of other variables such as social class, level of noticed that patients gave up smoking, and it was education, age of mother, race or extent of antenatal developed as an aid to smoking cesation. Amfe- care. The increased risk rises two-fold or more in butamone selectively inhibits neuronal uptake of heavy smokers and appears to be entirely accounted noradrenaline (norepinephrine) and dopamine and for by the placental abnormalities and the conse- may reduce nicotine craving by an action on the quences of low birthweight. Ex-smokers and women mesolimbic system. Evidence from a small number of who give up smoking in the first 20 weeks of clinical trials suggests that amfebutamone may be at pregnancy have offspring whose birthweight is least as effective as the nicotine patch with which it similar to that of the children of women who have may usefully be combined. It may cause dry mouth never smoked. and insomnia, and is contraindicated in those with a history of epilepsy. If the patient is heavily tobacco-dependent and severe anxiety, irritability, headache, insomnia and Starting and stopping use weight gain (about 3 kg) and tension are concomi- tants of attempts to stop smoking, an anxiolytic Contrary to popular belief it is not generally difficult sedative (or B-adrenoceptor blocker) may be useful to stop, only 14% finding it Very difficult'. But ex- for a short time, but it is important to avoid smoker status is unstable and the long-term success substituting one drug-dependence for another. rate of a smoking withdrawal clinic is rarely above 30%. The situation is summed up by the witticism, 19 Lancaster T et al 2000 Effectiveness of interventions to help 'Giving up smoking is easy, I've done it many people to stop smoking: findings from the Cochrane Library. times'. British Medical Journal 321: 355-358. 177
  14. 10 N O N M E D I C A L USE OF DRUGS There is ample evidence to warrant strong advice and some carcinogens (e.g. benzo-a-pyrene x 3.4). against starting to smoke but over-hasty and un- Sidestream smoke constitutes about 85% of smoke reasonable prohibitions on patients' longstanding generated in an average room during cigarette pleasures (or vices) do no good. The pliable patient smoking. is made wretched, but most are merely alienated. My doctor's issued his decree That too much wine is killing me, And furthermore his ban he hurls Ethyl alcohol (Ethanol) Against my touching naked girls. How then? Must I no longer share The services rendered by intoxicating substances in Good wine or beauties, dark and fair? the struggle for happiness and in warding off Doctor, goodbye, my sail's unfurled, misery rank so highly as a benefit that both I'm off to try the other world. individuals and races have given them an D G Rossetti, poet (1828-82) established position within their libido-economy. It is not merely the immediate gain in pleasure which one owes to them, but also a measure of that independence of the outer world which is so sorely craved ... We are aware that it is just this property Passive (involuntary) which constitutes the danger and injuriousness of smoking intoxicating substances.. .22 Alcohol is chiefly important in medicine because of Many nonsmokers are exposed to tobacco smoke, the consequences of its misuse/abuse. Alcohol and environmental tobacco smoke has been classified misuse is a social problem with pharmacological as a known human carcinogen in the USA since aspects, which latter are discussed here. The history 1992.20 Although the risks are, naturally, smaller, the of alcohol is part of the history of civilisation 'ever number of people affected is large. One study since Noah made his epoch-making discovery'.23 estimated that breathing other people's smoke increases a person's risk of ischaemic heart disease Pharmacokinetics by a quarter.21 Smoke drawn through the tobacco and taken in Absorption of alcohol taken orally is rapid, for it is by the smoker is known as mainstream smoke. highly lipid-soluble and diffusible from the stomach Smoke which arises from smouldering tobacco and and the small intestine. Solutions above 20% are passes directly into the surrounding air, whence it absorbed more slowly because high concentrations of may be inhaled by smokers and nonsmokers alike, alcohol inhibit gastric peristalsis, thus delaying the is known as sidestream smoke. Mainstream and arrival of the alcohol in the small intestine which is sidestream smoke differ in composition, partly the major site of absorption. because of the different temperatures at which they Absorption is delayed by food, especially milk, the are produced. Substances found in greater con- effect of which is probably due to the fat it contains. centrations in undiluted sidestream smoke than in Carbohydrate also delays absorption of alcohol. undiluted mainstream smoke include: nicotine (x 2.7), carbon monoxide (x 2.5), ammonia (x 73), Distribution of alcohol is rapid and throughout the body water (dist. vol. 0.7 1/kg men: 0.6 1/kg 20 Environmental Protection Agency (EPA 1992 A/600/6- women); it is not selectively stored in any tissue. 90/006F). 21 22 Law M R, Morris J K, Wald N J 1997 Environmental Freud S 1939 Civilisation, war and death, Psycho-analytic tobacco smoke exposure and ischaemic heart disease: an epitomes, No. 4. Hogarth Press, London. 23 evaluation of the evidence. British Medical Journal 315: Genesis; 9: 21; Huxley A1957 Annals of the New York 973-988. Academy of Sciences 67: 675. 178
  15. ETHYL ALCOHOL (ETHANOL) 10 doses. Once the blood concentration exceeds about 10 mg/100 ml the enzymatic processes are saturated and elimination rate no longer increases with increasing concentration but becomes steady at 10-15 ml per hour in occasional drinkers. Thus alcohol is subject to dose-dependent kinetics, i.e. saturation or zero-order kinetics, with potentially major consequences for the individual. Induction of hepatic drug metabolising enzymes occurs with repeated exposure to alcohol and this contributes to tolerance in habitual users, and to toxicity. Increased formation of metabolites causes organ damage in chronic over-consumption (acetaldehyde in the liver and probably fatty ethyl esters in other organs) and increases susceptibility to liver injury when heavy drinkers are exposed to anaesthetics, industrial solvents and to drugs. But chronic use of large amounts reduces hepatic Fig. 10.1 Approximate blood concentrations after three doses of metabolic capacity by causing cellular damage. An alcohol. acute substantial dose of alcohol (binge drinking) inhibits hepatic drug metabolism. Maximum blood concentrations after oral alcohol Inter-ethnic variation is recognised in the ability to therefore depend on numerous factors including the metabolise alcohol (see p. 184). total dose, sex, the strength of the solution, the time Blood concentration of alcohol (Fig. 10.1) has great over which it is taken, the presence or absence of medicolegal importance. Alcohol in alveolar air is in food, the time relations of taking food and alcohol equilibrium with that in pulmonary capillary blood and the kind of food eaten, as well as on the speed of and reliable, easily handled measurement devices metabolism and excretion. A single dose of alcohol, (breathalyser) are used by police at the roadside on say 60 ml (48 g) (equivalent to 145 ml of whisky, both drivers and pedestrians.24 5-6 measures, or units; see Fig. 10.1), taken over a few minutes on an empty stomach will probably Pharmacodynamics produce maximal blood concentration at 30-90 min and will not all be disposed of for 6-8 h or even Alcohol acts on the central nervous system in a more. There are very great individual variations. manner broadly similar to volatile anaesthetics, exerting on cells a generally depressant effect that is Metabolism. About 95% of absorbed alcohol is probably mediated through particular membrane ion metabolised, the remainder being excreted in the channels and receptors. Alcohol enhances (inhibitory) breath, urine and sweat; convenient methods of GABA-stimulated flux of chloride through receptor- estimation of alcohol in all these are available. gated membrane ion channels, a receptor subtype Alcohol in the systemic circulation is oxidised in the liver; principally (90%) by alcohol dehydrogenase 24 An arrested man was told, in a police station, by a doctor, to acetaldehyde and then by aldehyde dehydro- that he was drunk. The man asked, 'Doctor, could a drunk genase to products that enter the citric acid cycle or man stand up in the middle of this room, jump into the air, are utilised in various anabolic reactions. Other turn a complete somersault, and land down on his feet?' The alcohol-metabolising enzymes are microsomal cyto- doctor was injudicious enough to say, "Certainly not"—and chrome P450 2E1 (which is also induced by alcohol) was then and there proved wrong. (Worthing C L 1957 British Medical Journal 1: 643.) The introduction of the and catalase. breathalyser, which has a statutory role only in road traffic Alcohol metabolism by alcohol dehydrogenase situations, has largely eliminated such professional follows first-order kinetics after the smallest humiliations. 179
  16. 10 NONMEDICAL USE OF DRUGS effect that may be involved in the motor impairment Ho! Ho! Yes! Yes! It's very all well, caused by alcohol. Other possible modes of action You may drunk I am think, but I tell you I'm not, include inhibition of calcium entry via voltage-gated I'm as sound as a fiddle and fit as a bell, (L type) calcium channels, and inhibition of the And stable quite ill to see what's what... (excitatory) NMDA (N-methyl-D-aspartate) receptor. And I've swallowed, I grant, a beer of lot — (See page 184 for chronic effects of alcohol on the But I'm not so think as you drunk I am... brain.) I shall stralk quite weight and not yutter an ell, My feech will not spalter the least little jot: It is not a stimulant; hyperactivity, when it occurs, If you knownly had own!—well, I gave him a dot, is due to removal of inhibitory effects. Alcohol in And I said to him,'Sergeant, I'll come like a lamb — ordinary doses may act chiefly on the arousal The floor it seems like a storm in a yacht, mechanisms of the brainstem reticular formation, But I'm not so think as you drunk I am. inhibiting polysynaptic function and enhancing I'm sorry, I just chair over a fell — presynaptic inhibition. Direct cortical depression A trifle—this chap, on a very day hot — probably only occurs with high doses. With If I hadn't consumed that last whisky of tot! As I said now, this fellow, called Abraham — increasing doses the subject passes through all the Ah? One more? Since it's you! just a do me will spot — stages of general anaesthesia and may die of But I'm not so think as you drunk I am. respiratory depression.25 Psychic effects are the most important socially (Fig. 10.2), and it is to obtain these that the drug is Innumerable tests of physical and mental per- habitually used in so many societies, to make social formance have been used to demonstrate the effects intercourse not merely easy but even pleasant. They of alcohol. Results show that alcohol reduces visual have been admirably described by Sollmann: acuity and delays recovery from visual dazzle; it impairs taste, smell and hearing, muscular co- The first functions to be lost are the finer grades of ordination and steadiness and prolongs reaction judgement, reflection, observation and attention— time. It also causes nystagmus and vertigo. At the the faculties largely acquired through education, same time the subjects commonly have an which constitute the elements of the restraint and increased confidence in their ability to perform well prudence that man usually imposes on his actions. when tested and underestimate their errors, even The orator allows himself to be carried by the after quite low doses. Attentiveness and ability to impulse of the moment, without reflecting on assimilate, sort and quickly take decisions on con- ultimate consequences, and as his expressions become freer, they acquire an appearance of warmth, of feeling, of inspiration. Not a little of this inspiration is contributed by the audience if they are in a similar condition of increased appreciation ... Another characteristic feature, evidently resulting from paralysis of the higher functions, is the loss of power to control moods.26 Environment, personality, mood and dose of alcohol are all relevant to the final effect on the individual. These and other effects that are characteristic of alcohol, have been celebrated in the following couplets:27 Fig. 10.2 Four standard units of drink (in which social 25 consumption is measured). A unit contains approx. 10 ml (8 g) of Loss of consciousness occurs at blood concentrations alcohol. Knowledge of blood alcohol concentration does not allow around 300 mg/100 ml; death at about 400 mg/100 ml. But a reliable estimate of how much has been consumed. the usual cause of death in acute alcohol poisoning is inhalation of vomit. 26 27 Sollmann T 1957 Manual of pharmacology, 8th edn. By Sir J C Squire (1884-1958). Quoted, by permission, R H Saunders, Philadelphia. A Squire. 180
  17. CAR DRIVING AND ALCOHOL 10 tinuously changing information input, decline. This urine sample; the subject refused on the ground results particularly in inattentiveness to the peripherythat he had offered blood and that his offer had of the visual field, which is important in motoring. been refused. He was acquitted, but a Court has All these are evidently highly undesirable effects since decided that the choice of site for blood-taking when a person is in a position where failure to is for the physician, not for the subject, and that perform well may be dangerous. such transparent attempts to evade justice should be treated as unreasonable refusal to supply a specimen under the law. The subject is then treated as though he had provided a specimen that was Car driving and alcohol above the statutory limit. Yet another trick is to take a dose of spirits after the accident and before the The effects of alcohol and psychotropic drugs on police arrive. The police are told it was taken as a motor driving (Fig. 10.3) have been the subject of remedy for nervous shock. This is known is the well-deserved attention, and many countries have 'hip-flask' defence. made laws designed to prevent motor accidents Where blood or breath analysis is not immediately caused by alcohol. The problem has nowhere been available after an accident it may be measured hours solved. In general it can be said that the weight of later and 'back calculated' to what it would have been evidence points to a steady deterioration of driving at the time of the accident. It is usual to assume that skill and an increased liability to accidents beginning the blood concentration falls at about 15 mg/100 with the entry of alcohol into the blood and steadily ml/h. Naturally, the validity of such calculations increasing with blood concentration. leads to acrimonious disputes in the courts of law. Alcohol plays a huge part in causing motor accidents, being a factor in as many as 50%. For this Prescribed medicines and driving reason, the compulsory use of a roadside breath test is acknowledged to be in the public interest. In the Ability to drive can be impaired by many prescribed UK a blood concentration exceeding 80 mg alcohol/ drugs. In road traffic accident fatalities 7.4% of 100 ml blood (17.4 mmol/1)28 whilst in charge of a car persons had taken a drug 'likely' to affect the CNS is a statutory offence. At this concentration, the (chiefly older subjects). In addition, cannabis was liability to accident is about twice normal. Other found in 2.6%. Unfortunately, accurate control figures countries set lower limits, e.g. Nordic countries,29 are not available except in the case of epilepsy: 1.3% some states of USA, Australia, Greece. of fatalities had taken an antiepileptic drug and So clearly is it in the public interest that drunken the incidence of the disease in the general driving be reduced that the privileges normally population is 0.4%.30 Driving may also be influenced attaching to freedom of conscience as well as to by antihistamines (drowsiness, but less commonly personal eccentricity must take second place. In one with newer nonsedative agents), mydriatics and instance, an ingenious driver, having provided a antimicrobials for topical ocular use (blurred vision), positive breath test, offered a blood sample on the antihypertensives (hypotension) and insulins and condition it should be taken from his penis; the oral antidiabetic agents (hypoglycaemia). physician refused to take it; the police demanded a FURTHER EFFECTS OF ALCOHOL 28 Approximately equivalent to 35 micrograms alcohol in CONSUMPTION 100 ml expired air (or 107 mg in 100 ml urine). In practice, prosecutions are undertaken only when the concentration is significantly higher to avoid arguments about biological Peripheral vasodilatation. Alcohol depresses the variability and instrumental error. Urine concentrations are vasomotor centre and this accounts for the feeling little used since the urine is accumulated over time and does not provide the immediacy of blood and breath. 29 30 In 1990 Sweden lowered the limit to 20 mg/100 ml, which Advice to patients on prescribed medicines is contained in has been approached by ingestion of glucose which becomes Medical Commission on Accident Prevention 1995 Medical fermented by gut flora—the 'autobrewery' syndrome. Aspects of Fitness to Drive; HMSO, London. 181
  18. 10 N O N M E D I C A L USE OF DRUGS Fig. 10.3 Alcohol and driving. of warmth that follows taking the drug. Body heat Blood pressure. An acute dose of 4-5 units raises loss is increased so that it is undesirable to take the blood pressure which parallels the blood alcohol before going out into severe cold for any concentration. The mechanism appears to involve length of time, but it may be harmlessly employed centrally mediated sympathetic stimulation. on coming into a warm environment from the cold to provide quickly a pleasant feeling of Diuretic effect. Alcohol acts by inhibiting secretion warmth. of antidiuretic hormone by the posterior pituitary 182
  19. CAR DRIVING AND ALCOHOL 10 gland. The reason it is useless as a diuretic in heart feminisation may be seen and men have been failure is that the diuresis is of water, not of salt. threatened with genital shrinkage. Gastric mucosa. Injury occurs because alcohol Source of energy. Alcohol may be useful as an allows back diffusion of acid from the gastric lumen energy source (rather than a food) in debilitated into the mucosa. After an acute binge the mucosa patients. It is rapidly absorbed from the alimentary shows erosions and also petechial haemorrhages tract without requiring digestion and it supplies 7 (recovery may take 3 weeks) and up to 60% of calories31 per gram as compared with 9 from fat and chronic alcoholics show chronic gastritis. 4 from carbohydrate and protein. Heavy doses cause hyperlipidaemia in some people. Vomiting. This common accompaniment of acute Tolerance to alcohol can be acquired and the point alcoholism seems to be partly a central effect, for the has been made that it costs the regular heavy incidence of vomiting at equivalent blood alcohol drinker 2.5 times as much to get visibly drunk as it concentrations is similar following oral or i.v. admin- would cost the average abstainer. This is probably istration. This is not to deny that very strong solutions due both to enzyme induction and to adaptation of and dietary indiscretions accompanying acute and the central nervous system. chronic alcoholism can cause vomiting by local gastric effects. That said, when death occurs, it is Intolerance. Inter-ethnic variation in tolerance to commonly due to suffocation from inhaled vomit. alcohol is well recognised, for Asian persons, particularly Japanese, develop flushing, headache Glucose tolerance. Alcohol initially increases the and nausea after what are, by Caucasian standards, blood glucose, due to reduced uptake by the small amounts of the substance. Genetic deficiency tissues. This leads to increased glucose metabolism. of aldehyde dehydrogenase with slow metab- But alcohol also inhibits gluconeogenesis and a olism of (toxic) acetaldehyde may explain these person whose hepatic glycogen is already low, e.g. a features. person who is getting most of his calories from alcohol or who has not eaten adequately for 3 days, Acute alcohol poisoning is a sufficiently familiar can experience hypoglycaemia that can be severe condition not to require detailed description. It is enough to cause irreversible brain damage. Hypo- notorious that the characteristic behaviour changes, glycaemia can be difficult to recognise clinically excitement, mental confusion (including 'blackouts'), in a person who has been drunk, and this adds to incoordination and even coma, can be due to the risk. numerous other conditions and diagnosis can be extremely difficult if a sick or injured patient happens Hyperuricaemia occurs (with precipitation of to have taken alcohol as well. Alcohol can cause gout) due to accelerated degradation of adenine severe hypoglycaemia (see above). Measurement of nucleotides resulting in increased production of blood alcohol may clarify the situation. uric acid and its precursors. Only at high alcohol If sedation is essential, diazepam in low dose is concentrations does alcohol-induced high blood least hazardous. Alcohol dialyses well, but dialysis lactate compete for renal tubular elimination and so will only be used in extreme cases. diminish excretion of urate. Acute hepatitis, which may be extremely severe, can occur with extraordinarily heavy acute drinking Effects on sexual function. Nothing really new has bouts. The serum transaminase rises after alcohol in been said since William Shakespeare wrote that alcoholics but not in others. The single case-report alcohol 'provokes the desire, but it takes away the that after a binge the cerebrospinal fluid tasted of performance'. Performance in other forms of athletics gin remains unconfirmed. is also impaired. Prolonged substantial consumption lowers plasma testosterone concentration at least 31 partly as a result of hepatic enzyme induction; 1 calorie = 4.2 joules. 183
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