Stephen Haydock
Synopsis
Drugs used for non-medical purposes (abused, misused, used for recreational purposes) present a range of social problems, all of which have important pharmacological dimensions. General topics include:
• Introduction.
• Definitions.
• General patterns of use.
• Sites and mechanisms of action.
• Routes of administration and effect.
• Prescribing for drug dependence.
• Treatment of dependence.
• Mortality.
• Escalation.
• Designer drugs.
• Drugs and sport.
Individual substances are discussed:
• Opioids (see pp. 282–288).
• Ethyl alcohol and other cerebral depressants (benzodiazepines, GHB).
• Tobacco.
• Psychodysleptics (LSD, mescaline, tenamfetamine, phencyclidine, cannabis).
• Psychostimulants (cocaine, amfetamines, methylxanthines, khat).
• Volatile substances.
Introduction
The dividing line between legitimate use of drugs for social purposes and their abuse is indistinct, for it is not only a matter of which drug, but of the amount of drug and of whether the effect is antisocial or not. In the UK and elsewhere, the classification of drugs of abuse continues to be subject to controversy.1
‘Normal’ people seem to be able to use alcohol for their occasional purposes without harm but, given the appropriate personality and/or environmental adversity, many may turn to it for relief and become dependent on it, both psychologically and physically. But drug abuse is not primarily a pharmacological problem; it is a social problem with important pharmacological aspects.
Abuse of drugs to improve performance in sport stems from a distinct and different motivation, namely, the obtaining of advantage in competition, but the practice yet has major implications for the health of the individual and for the participating and spectating sporting community.
Definitions
Substance dependence
is defined as:
when an individual persists in use of alcohol or other drugs despite problems related to use of the substance, substance dependence may be diagnosed. Compulsive and repetitive use may result in tolerance to the effect of the drug and withdrawal symptoms when use is reduced or stopped.2
Substance abuse
is a term that is less clearly defined and becoming less used, in favour of the term substance dependence. Nevertheless, the terms ‘addict’ or ‘addiction’ have not been completely abandoned in this book because they remain convenient. The WHO Expert Committee on Addiction Producing Drugs 1957 defined substance abuse in the context of two components:
Substance addiction
is a state of periodic or chronic intoxication produced by the repeated consumption of a drug (natural or synthetic). Its characteristics include: (i) an overpowering desire or need (compulsion) to continue taking the drug and to obtain it by any means; (ii) a tendency to increase the dose; (iii) a psychic (psychological) and generally a physical dependence on the effects of the drug; and (iv) detrimental effects on the individual and on society.
Substance habituation
is a condition resulting from the repeated consumption of a drug. Its characteristics include (i) a desire (but not a compulsion) to continue taking the drug for the sense of improved well-being which it engenders; (ii) little or no tendency to increase the dose; (iii) some degree of psychic dependence on the effect of the drug, but absence of physical dependence and hence of an abstinence syndrome [withdrawal], and (iv) detrimental effects, if any, primarily on the individual.
Psychological dependence
is characterised by emotional distress if the drug of dependence is withdrawn. The subject may develop craving for the drug with anxiety, insomnia and dysphoria. It develops before physical dependence.
Physical (physiological) dependence
implies that continued exposure to a drug induces adaptive changes in body tissues so that tolerance occurs, and that abrupt withdrawal of the drug leaves these changes unopposed, resulting generally in a discontinuation (withdrawal) syndrome, usually of rebound overactivity.
Tolerance follows the operation of homeostatic adaptation, e.g. to continued high occupancy of opioid receptors. Changes of similar type may occur with γ-aminobutyric acid (GABA) transmission, involving benzodiazepines. It also results from metabolic changes (enzyme induction) and physiological or behavioural adaptation to drug effects, e.g. opioids. Physiological adaptation develops to a substantial degree with cerebral depressants, but is minor or absent with excitant drugs. There is commonly cross-tolerance between drugs of similar, and sometimes even of dissimilar, chemical groups, e.g. alcohol and benzodiazepines. A general account of tolerance appears on page 78.
A discontinuation (withdrawal) syndrome occurs, for example, when administration of an opioid is suddenly stopped. Morphine-like substances (endomorphins, dynorphins) act as CNS neurotransmitters, and exogenously administered opioid suppresses their endogenous production by a feedback mechanism. Abrupt discontinuation results in an immediate deficiency of endogenous opioid, which thus causes the withdrawal syndrome. A general discussion of abrupt withdrawal of drug therapy appears on page 99.
Drugs of dependence are often divided into two groups, hard and soft. There are again no absolute definitions of these categories.
Hard drugs
are those that are liable seriously to disable the individual as a functioning member of society by inducing severe psychological and, in the case of cerebral depressants, physical dependence. The group includes heroin and cocaine.
Soft drugs
are less dependence producing. There may be psychological dependence, but there is little or no physical dependence except with heavy doses of depressants (alcohol). The group includes sedatives and tranquillisers, amfetamines, cannabis, hallucinogens, alcohol, tobacco and caffeine.
This classification fails to recognise individual variation in drug use. Alcohol can be used in heavy doses that are gravely disabling and induce severe physical dependence with convulsions on sudden withdrawal; i.e. for the individual the drug is ‘hard’. But there are many people mildly psychologically dependent on it who retain their position in the home and society.
Hard use, where the drug is central in the user's life, and soft use, where it is merely incidental, are terms of assistance in making this distinction, i.e. what is classified is not the drug but the effect it has on, or the way it is used by, the individual. The term ‘recreational’ is often applied to such use, conferring an apparent sanction that relates more to the latter category.
Dependence/abuse liability
of a drug is related to its capacity to produce immediate gratification, which may be a feature of the drug itself (amfetamine and heroin give rapid effect whereas tricyclic antidepressants do not), and its route of administration, in descending order: inhalation/intravenous, intramuscular/subcutaneous. Those drugs with high dependence/abuse liability are subject to regulation and non-medicinal use may be a criminal offence. The current UK list of controlled substances as proscribed by the Misuse of Drugs Act 1971 is shown in Table 11.1. Readers will be aware that the list is subject to change according to social factors and political expediency.
Table 11.1 Current list of UK proscribed drugs
Drug abuse use has two principal forms:
continuous use describes a true dependence, e.g. opioids, alcohol, benzodiazepines; intermittent or occasional use describes either a recreational experience, e.g. ‘ecstasy’ (tenamfetamine), LSD, cocaine, cannabis, solvents, or use to relieve stress, e.g. alcohol. Some drugs, e.g. alcohol, are used in both ways, but others, e.g. ecstasy, LSD, cannabis, are virtually confined to intermittent use.
Drives to drug abuse can be grouped as follows:
1. Relief of anxiety, tension and depression; escape from personal psychological problems; detachment from harsh reality; ease of social intercourse.
2. Rebellion against or despair about orthodox social values and the environment. Fear of missing something, and conformity with own social subgroup (the young, especially).
3. Fun, amusement, recreation, excitement, curiosity (the young, especially).
4. Improvement of performance in competitive sport (a distinct motivation, see below).
General patterns of use
Patterns of drug dependence differ with age. Men are more commonly involved than women. Patterns change as drugs come in and out of vogue. The general picture in the UK is shown in Table 11.2. Data on illicit drug use in the UK are provided from a number of sources but up-to-date information on prevalence and patterns of usage can be obtained from the annual British Crime Survey. Data from the 2008/2009 survey indicate that one in three people between the ages of 16 and 59 had ever used illicit drugs while 1 in 10 had used an illicit substance in the previous year. The survey also allows observations on the trends in illicit drug use over time, as shown in Table 11.3.
Table 11.2 Use of drugs of dependence by age in UK
|
Age group |
|
|
Under 14 years |
Volatile inhalants, e.g. solvents of glues, aerosol sprays, vaporised (by heat) paints, ‘solvent or substance’ abuse, ‘glue sniffing’ |
|
Age 14–16 years |
Cannabis, ecstasy, cocaine |
|
Age 16–35 years |
Hard-use drugs, chiefly heroin, cocaine and amfetamines (including ‘ecstasy’). Surviving users tend to reduce or relinquish heavy use as they enter middle age |
|
Any age |
Alcohol, tobacco, mild dependence on hypnotics and tranquillisers, occasional use of LSD and cannabis |
Table 11.3 Trends in drug use in UK (Information derived from 2008/2009 British Crime Survey)
|
Increased use |
Decreased use |
Stable use |
|
Between 1996 and 2008/2009 |
||
|
• Any Class A drug • Cocaine powder • Tranquillisers |
• Hallucinogens • LSD • Amphetamines • Anabolic steroids |
• Any stimulant drug • Opiates • Crack cocaine • Ecstasy • Magic mushrooms • Heroin • Amyl nitrate • Glues |
|
Between 2007/8 and 2008/9 |
||
|
• Any Class A drug • Any stimulant drug • Cocaine powder • Ecstasy • Tranquillisers • Anabolic steroids • Ketamine |
None |
• Hallucinogens • Opiates • Crack cocaine • LSD • Magic mushrooms • Heroin • Methadone • Amfetamines • Cannabis • Amyl nitrate • Glues |
Sites and mechanisms of action
Drugs of abuse are extremely diverse in their chemical structures, mechanisms of action and anatomical and cellular targets. Nevertheless, there is an emerging consensus that addictive drugs possess a parallel ability to modulate the brain reward system that is key to activities that are vital for survival (e.g. eating and sexual behaviour). Of particular relevance is the medial forebrain bundle (MFB) that connects the ventral tegmental area and the nucleus accumbens. Natural and artificial rewards (including drugs of abuse) have been shown to activate the dopaminergic neurones within the MFB. It seems that drugs of abuse can converge on common neural mechanisms in these areas to produce acute reward and chronic alterations in reward systems that lead to addiction. This is summarised in Figure 11.1.
Fig. 11.1 Common pathway of drugs of addiction on the dopaminergic neurones.
Increasing evidence suggests that drugs of addiction all act by modulating dopaminergic transmission in the medial forebrain bundle.
Route of administration and effect
With the intravenous route or inhalation, much higher peak plasma concentrations can be reached than with oral administration. This accounts for the ‘kick’ or ‘flash’ that abusers report and which many seek, likening it to sexual orgasm or better. As an addict said, ‘The ultimate high is death’, and it has been reported that, when hearing of someone dying from an overdose, some addicts will seek out the vendor as it is evident he is selling ‘really good stuff’.3
Prescribing for drug dependence
In the UK, supply of certain drugs for the purpose of sustaining addiction or managing withdrawal is permitted under strict legal limitations, usually by designated doctors. Guidance about the responsibilities and management of addiction is available.4 By such procedures it is hoped to limit the expansion of the illicit market, and its accompanying crime and dangers to health, e.g. from infected needles and syringes. The object is to sustain young (usually) addicts, who cannot be weaned from drug use, in reasonable health until they relinquish their dependence (often over about 10 years).
When injectable drugs are prescribed there is currently no way of assessing the truth of an addict's statement that he or she needs x mg of heroin (or other drug), and the dose has to be assessed intuitively by the doctor. This has resulted in addicts obtaining more than they need and selling it, sometimes to initiate new users. The use of oral methadone or other opioid for maintenance by prescription is devised to mitigate this problem.
Treatment of dependence
About £1.4 billion is spent per year in England alone on the management of drug dependence. This is directed at an estimated one-third of a million subjects. The majority are dependent on heroin. These are managed by either abstinence or, more commonly, maintenance on prescribed alternatives such as methadone.
Withdrawal of the drug
While obviously important, this is only a step on what can be a long and often disappointing journey to psychological and social rehabilitation, e.g. in ‘therapeutic communities’. A heroin addict may be given methadone as part of a gradual withdrawal programme (see p. 286), for this drug has a long duration of action and blocks access of injected opioid to the opioid receptor so that if, in a moment of weakness, the subject takes heroin, the ‘kick’ is reduced. More acutely, the physical features associated with discontinuing high alcohol use may be alleviated by chlordiazepoxide given in decreasing doses for 7–14 days. Sympathetic autonomic overactivity can be treated with a β-adrenoceptor blocker.
Maintenance and relapse
Relapsed addicts who live a fairly normal life are sometimes best treated by supplying drugs under supervision. There is no legal objection to doing this in the UK. A less harmful drug by a less harmful route may be substituted, e.g. oral methadone for intravenous heroin. Addicts are often particularly reluctant to abandon the intravenous route, which provides the ‘immediate high’ that they find, or originally found, so desirable.
Severe pain in an opioid addict
presents a special problem. High-efficacy opioid may be ineffective (tolerance) or overdose may result; low-efficacy opioids will not only be ineffective but may induce withdrawal symptoms, especially if they have some antagonist effect, e.g. pentazocine. This leaves as drugs of choice non-steroidal anti-inflammatory drugs (NSAIDs), e.g. indometacin, and nefopam (which is neither opioid nor NSAID).
Mortality
Young illicit users by intravenous injection (heroin, benzodiazepines, amfetamine) have a high mortality rate. Death follows either overdose or the occurrence of septicaemia, endocarditis, hepatitis, AIDS, gas gangrene, tetanus or pulmonary embolism from the contaminated materials used without aseptic precautions (schemes to provide clean equipment mitigate this). Smugglers of illicit cocaine or heroin sometimes carry the drug in plastic bags concealed by swallowing or in the rectum (‘body packing’). Leakage of the packages, not surprisingly, may have a fatal result.5
Escalation
A variable proportion of subjects who start with cannabis eventually take heroin. This disposition to progress from occasional to frequent soft use of drugs through to hard drug use, when it occurs, is less likely to be due to pharmacological actions than to psychosocial factors, although increased suggestibility induced by cannabis may contribute.
De-escalation
also occurs as users become disillusioned with drugs over about 10 years.
‘Designer drugs’
This unhappily chosen term has been generally taken to refer to molecular modifications produced in secret for profit by skilled and criminally minded chemists to produce drugs which are structurally and pharmacologically very similar to a controlled substance but are not themselves controlled substances. Increasingly the production of such agents is becoming more sophisticated. The World Wide Web enables customers to order such ‘research chemicals’ online from large laboratories based in countries where the production of such compounds is not legally restricted. It is then hard to detect such compounds entering the country through the postal system. Popularity trends of such agents develop. As ecstasy use in the UK has fallen, designer drugs of the phenylethylamine class such as 2 C-B and 2 C-I have arrived on the club scene. These drugs are structurally similar to mescaline and MDMA. They have similar effects to ecstasy but in addition, mild LSD-like perceptional distortions.
Globalisation and the use of the internet have spawned a large market for the development and sale of new designer drugs based upon older drugs of abuse.
Drugs and sport
Drugs are frequently used to enhance performance in sport, although efficacy is largely undocumented. Detection can be difficult when the drugs or metabolites are closely related to or identical with endogenous substances, and when the drug can be stopped well before the event without apparent loss of efficacy. In order to get round this problem, regulatory bodies set ‘benchmarks’. Detection of levels of the naturally occurring compound above this level indicates potential doping. There remain unresolved issues at where exactly these benchmarks should be set. Research continues for improved methods of detecting drugs used in sport. The use of mass spectrometry6 to detect the isotope content of compounds might enable natural and synthetic steroids to be differentiated. Other indirect methods are employed. Testosterone and its related compound, epitestosterone, are both eliminated in urine. The ratio of testosterone to epitestosterone increases with use of anabolic steroids and can be used to detect anabolic steroid use.
Performance enhancement
Table 11.4 summarises the mechanisms by which drugs can enhance performance in various sports; naturally, these are proscribed by the authorities (International Olympic Committee (IOC) Medical Commission, and the governing bodies of individual sports).
Table 11.4 Use of illicit drugs in sport
In addition, owing to the recognition of natural biological differences, most competitive events are sex segregated. In many events men have a natural physical biological advantage and the (inevitable) consequence has been that women have been deliberately virilised (by administration of androgens) so that they may outperform their sisters.
It seems safe to assume that anything that can be thought up to gain advantage will be tried by competitors eager for immediate fame. Reliable data are difficult to obtain in these areas. No doubt placebo effects are important, i.e. beliefs as to what has been taken and what effects ought to follow.
For any minor injuries sustained during athletic training, NSAIDs and corticosteroids (topical, intra-articular) suppress symptoms and allow the training to proceed maximally. Their use is allowed subject to restrictions about route of administration, but strong opioids are disallowed. Similarly, the IOC Medical Code defines acceptable and unacceptable treatments for relief of cough, hay fever, diarrhoea, vomiting, pain and asthma. Doctors should remember that they may get their athlete patients into trouble with sports authorities by inadvertent prescribing of banned substances. The British National Formulary provides general advice for UK prescribers (further information and advice, including the status of specific drugs in sport, can be obtained at http://www.uksport.gov.uk).
Types of drug dependence
The World Health Organization recommends that drug dependence be specified by type for purposes of detailed discussion. The subject can be treated according to the following principal types:
• opioids (see pp. 288–289);
• alcohol and other cerebral depressants (benzodiazepines, γ-hydroxybutyrate);
• tobacco;
• psychodysleptics (LSD, mescaline, tenamfetamine, phencyclidine, cannabis);
• psychostimulants (cocaine, amfetamines, methylxanthines, khat);
• volatile substances.
Ethyl alcohol (ethanol)
Alcohol is important in medicine chiefly because of the consequences of its misuse/abuse. Alcohol-related mortality has increased steadily since the 1990s, with over 9000 deaths attributed to alcohol in 2008. Alcohol-related deaths are over twice as common in men as in women.
Pharmacokinetics
Absorption
The gastrointestinal absorption of alcohol taken orally is rapid as it is highly lipid soluble and diffusible. The major site of absorption is the small intestine; solutions above 20% are absorbed more slowly because high concentrations of alcohol inhibit gastric peristalsis, thus delaying the arrival of the alcohol in the small intestine. Absorption is delayed by food, especially milk, the effect of which is probably due to the fat it contains. Carbohydrate also delays absorption of alcohol.
Distribution
It is distributed rapidly and throughout the body water (dist. vol. 0.7 L/kg men; 0.6 L/kg women) with no selective tissue storage. Maximum blood concentrations after oral alcohol therefore depend on numerous factors including: the total dose; sex; the strength of the solution; the time over which it is taken; the presence or absence of food in the stomach; the time relations of taking food and alcohol, and the kind of food eaten; the speed of metabolism and excretion.
Alcoholic drinks taken on an empty stomach will probably produce maximal blood concentration at 30–90 min and will not all be disposed of for 6–8 h or even more. There are very great individual variations.
Metabolism
About 95% of absorbed alcohol is metabolised by the liver, the remainder being excreted in the breath, urine and sweat; convenient methods of estimation of alcohol in all these media are available (Fig. 11.2).
Fig. 11.2 Metabolism of ethanol by the liver.
Alcohol metabolism by alcohol dehydrogenase follows first-order kinetics after the smallest 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/h 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. 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 drugs. But chronic use of large amounts reduces hepatic metabolic capacity by causing cellular damage. An acute substantial dose of alcohol (binge drinking) inhibits hepatic drug metabolism.
Inter-ethnic variation is recognised in the ability to metabolise alcohol (see p. 145).
The blood concentration of alcohol (see Fig. 11.3) has great medicolegal importance. Alcohol in alveolar air is in equilibrium with that in pulmonary capillary blood, and reliable, easily handled measurement devices (breathalysers) are used by police at the roadside on both drivers and pedestrians.7
Fig. 11.3 Stimulatory and depressant effects of acute alcohol ingestion.
Pharmacodynamics
Alcohol exerts on cells in the CNS a generally depressant effect that is probably mediated through particular membrane ion channels and receptors. It seems likely that acetaldehyde acts synergistically with alcohol to determine the range of neurochemical and behavioural effects of alcohol consumption. There is considerable evidence that ethanol affects neurotransmitter release and activity. Alcohol enhances dopamine release, inhibits the reuptake of brain amines and enhances (inhibitory) GABAA-stimulated flux of chloride through receptor-gated membrane ion channels, a receptor subtype effect that may be involved in the motor impairment caused by alcohol (see p. 145). Other possible modes of action include inhibition of the (excitatory) N-methyl-D-aspartate (NMDA) receptor and inhibition of calcium entry via voltage-gated (L type) calcium channels.
Alcohol is not a stimulant; hyperactivity, when it occurs, is due to removal of inhibitory effects. Psychic effects are the most important socially, and it is to obtain these that the drug is habitually used in so many societies, to make social intercourse not merely easy but even pleasant. Environment, personality, mood and dose of alcohol are all relevant to the final effect on the individual.
Alcohol in ordinary doses may act chiefly on the arousal mechanisms of the brainstem reticular formation, inhibiting polysynaptic function and enhancing presynaptic inhibition. Direct cortical depression probably occurs only with large amounts. With increasing doses the subject passes through all the stages of general anaesthesia and may die from respiratory depression. Loss of consciousness occurs at blood concentrations around 300 mg/100 mL, death at about 400 mg/100 mL. The usual cause of death in acute alcohol poisoning is inhalation of vomit.
Innumerable tests of physical and mental performance have been used to demonstrate the effects of alcohol. Results show that alcohol reduces visual acuity and delays recovery from visual dazzle, impairs taste, smell and hearing, muscular coordination and steadiness, and prolongs reaction time. It also causes nystagmus and vertigo. It commonly increases subjects' confidence in their ability to perform well when tested and tendency to underestimate their errors, even after quite low doses. There is a decline in attentiveness and ability to assimilate, sort and take quick decisions on continuously changing information input; an example is inattentiveness to the periphery of the visual field, which is important in motoring.
All of these are clearly highly undesirable effects when a person is in a position where failure to perform well may be dangerous. Some other important physiological and metabolic effects of acute alcohol ingestion are described in Table 11.5.
Table 11.5 Other physiological, pathological and metabolic effects of acute alcohol ingestion
|
Effect |
Comments |
|
Vomiting |
• Partly a central effect (similar effects for oral and i.v. dose) • Also a local gastric effect • May cause death from inhalation of vomit |
|
Diuresis |
• Inhibition of pituitary ADH secretion |
|
Gastric irritation |
• Ethanol permits back diffusion of acid into the gastric mucosa • Acute binge produces erosions and petechial haemorrhages that can take 3 weeks to recover • 60% chronic alcoholics have chronic gastritis |
|
Impaired glucose tolerance |
• Initially increases blood glucose by blocking glucose uptake • Inhibits gluconeogenesis • In presence of low glycogen stores can precipitate severe hypoglycaemia causing permanent neurological damage • Hypoglycaemia may be difficult to recognise in an intoxicated patient |
|
Hyperuricaemia |
• Gout may be precipitated due to increased uric acid levels due to degradation of adenine nucleotides • At high alcohol levels, generated lactate also competes for renal tubular elimination of urate |
|
Abnormal lipid profile |
• Large dose may precipitate hyperlipidaemia in some individuals |
|
Sexual function |
• Acute intoxication may result in impotence • Chronic consumption in addition lowers plasma testosterone |
|
Calorific affect |
• May be a useful source of energy in debilitated patients • Rapid absorption from GI tract without need for digestion • Supplies 7 calories per gram (fat supplies 9 calories per gram and carbohydrate/protein 4 calories per gram) |
|
Acute hepatitis |
• May occur with large alcohol binge and be extremely severe |
|
Acute pancreatititis |
• Usually a feature of long term chronic alcohol usage • Less commonly can occur in ‘weekend binge drinkers’ • Has been described for a sole large alcohol load precipitating a first attack |
|
Inter-ethnic intolerance |
Inter-ethnic variation in acute alcohol tolerance is well described |
Acute alcohol poisoning is characterised by behaviour changes, excitement, mental confusion (including ‘blackouts’), incoordination and even coma. Numerous other conditions can mimic this presentation and diagnosis can be difficult if a sick or injured patient happens to have taken alcohol as well. Alcohol can cause severe hypoglycaemia; measurement of blood alcohol may clarify the situation. If sedation is essential, diazepam in low dose is least hazardous. Alcohol dialyses well, but dialysis is used only in extreme cases.
Chronic consumption
Tolerance
to alcohol can be acquired and the point has been made that it costs the regular heavy drinker 2.5 times as much to get visibly drunk as it would cost the average abstainer. This is probably due both to enzyme induction and to adaptation of the CNS.
The effects of chronic alcohol usage are summarised in Table 11.6. Reversal of all or most of the above effects is usual in early cases if alcohol is abandoned. In more advanced cases the disease may be halted (except cancer), but in severe cases it may continue to progress. When wine rationing was introduced in Paris during the Second World War, deaths from hepatic cirrhosis dropped to about one-sixth of the previous level; 5 years after the war they had regained their former level.
Table 11.6 Physiological, pathological and metabolic effects of chronic alcohol ingestion
|
Effect |
Comments |
|
Organ damage |
• Hepatic cirrhosis • CNS dysfunction – seizures – Korsakoff's syndrome – dementia – Wernicke's encephalopathy – episodic memory loss • Peripheral neuropathy • Myopathy including cardiomyopathy • Cancer especially of the upper alimentary tract and lungs • Chronic pancreatitis |
|
Malnutrition |
• In heavy drinkers all calorie requirement comes from ethanol • They cease to eat adequately and develop nutritional deficiencies esp. of B-group vitamins and folate • Megalobastosis occurs |
|
Hypertension |
• Heavy chronic alcohol consumption is a common cause of hypertension • Hypertension is difficult to control in this circumstance |
|
Abnormal lipid profile |
• Moderate alcohol intake improves the HDL/LDL ratio • This may explain the protective effect on heart disease • Severe hypertriglyceridaemia may occur |
|
Hyponatraemia |
• Chronic alcoholism is frequently associated with significant hyponatraemia • Several mechanisms are important – hypovolaemia – severe hypotriglyceridaemia (pseudohyponatraemia) – cerebral salt wasting – reset osmostat syndrome – beer potomania (large volume of beer and very little dietary sodium |
|
Psychosocial |
• The effects of chronic alcohol use on family and personal life are profound though outside the scope of this book |
|
Reduced fertility |
• Male fertility is reduced (lower testosterone, reduced sperm count and function) • Pregnancy is unlikely in alcoholic women with amenorrheoa due to liver injury • The spontaneous miscarriage rate doubles in second trimester by consumption of 1–2 units per day • The profound effects on developing fetus and baby are discussed in the text |
Car driving and alcohol
The effects of alcohol and psychotropic drugs on motor car driving have been the subject of well-deserved attention, and many countries have passed laws designed to prevent motor accidents caused by alcohol.
Alcohol is a factor in as many as 50% of motor accidents. For this reason, the compulsory use of a roadside breath test is acknowledged to be in the public interest. In the UK, having a blood concentration exceeding 80 mg alcohol per 100 mL blood (17.4 mmol/L)8 while in charge of a car is a statutory offence. At this concentration, the liability to accident is about twice normal. Other countries set lower limits, e.g. Nordic countries,9 some states of the USA, Australia, Greece.
Where blood or breath analysis is not immediately available after an accident, it may be measured hours later and ‘back calculated’ to what it would have been at the time of the accident. It is usual to assume that the blood concentration falls at about 15 mg/100 mL/h. Naturally, the validity of such calculations leads to acrimonious disputes in the courts of law. (See also: Drugs and skilled tasks, p. 113.)
Alcohol-dependence syndrome
Alcohol dependence is a complex disorder with environmental, drug-induced and genetic components with multiple genes probably contributing to vulnerability to the condition. The major factors determining physical dependence are dose, frequency of dosing, and duration of abuse . Development involves alterations in CNS neurotransmission:
• Acute effect of alcohol appears to be blockade of NMDA receptors for which the normal agonist is glutamate, the main excitatory transmitter in the brain.
• Chronic exposure increases the number of (excitatory) NMDA receptors and also ‘L type’ calcium channels, while the action of the (inhibitory) GABAA neurotransmitter is reduced.
• The resulting excitatory effects may explain the anxiety, insomnia and craving that accompanies sudden withdrawal of alcohol (and may explain why resumption of drinking brings about relief, perpetuating dependence).
Withdrawal of alcohol
Abrupt withdrawal of alcohol from a person who has developed physical dependence, such as may occur when an ill or injured alcoholic is admitted to hospital, can precipitate withdrawal syndrome (agitation, anxiety and excess sympathetic autonomic activity) in 6–12 h. This may be followed by: alcohol withdrawal seizures (rum fits) in 6–48 h; alcoholic hallucinosis (commonly visual) in 10–72 h; delirium tremens in 3–7 days. Mortality from the last is high.
Generally, withdrawal should be supervised in hospital. Fixed dose regimens have been traditionally used where patients received chlordiazepoxide by mouth, 10–50 mg four times daily, gradually reducing over 7–14 days. Due to the risk of over- or under-prescribing, increasingly symptom-triggered prescribing is used to facilitate the inpatient detoxification. Longer exposure to chlordiazepoxide should be avoided as it has the potential to induce dependence. A β-adrenoceptor blocker may be given to attenuate symptoms of sympathetic overactivity. General aspects of care, e.g. attention to fluid and electrolyte balance, are important.
It is usual to administer vitamins, especially thiamine, in which alcoholics are commonly deficient, and intravenous glucose unaccompanied by thiamine may precipitate Wernicke's encephalopathy.
Clomethiazole is an alternative, also for inpatient use, but it carries significant risk of dependence and should not be given if the patient is likely to persist in drinking alcohol. It is now rarely used in the UK. Anticonvulsants, e.g. carbamazepine, topiramate, have also been used to alleviate symptoms of alcohol withdrawal.
Acute alcohol withdrawal with tremors, sweating and restlessness is common after abstinence in heavy habitual drinkers. Delirium tremens is less common and needs to be recognised early due to very high mortality if not correctly managed.
Treatment of alcohol dependence
Psychosocial support is more important than drugs, which nevertheless may help.
Acamprosate
chemically similar to both glutamate and GABAA, appears to reduce the effect of excitatory amino acids such as glutamate, and modifies GABAA neurotransmission during withdrawal. If taken for 1 year (accompanied by counselling and psychosocial support), acamprosate increases the number of alcohol-free days and also the chance of subsequent complete abstinence. The benefit may last for 1 year after stopping treatment.
Acamprosate may cause diarrhoea, and cutaneous eruptions.
Disulfiram
(Antabuse) discourages drinking by inducing immediate unpleasantness. It is an aldehyde dehydrogenase inhibitor, so that acetaldehyde (a toxic metabolite of alcohol) accumulates. It should be administered only under specialist supervision. A typical reaction of medium severity comes on about 5 min after taking alcohol and consists of generalised vasodilatation and fall in blood pressure, sweating, dyspnoea, headache, chest pain, nausea and vomiting. These features may result from even small amounts of alcohol (such as may be present in some oral medicines or mouthwashes).
Severe reactions include convulsions and circulatory collapse, and may last several hours. Some advocate the use of a test dose of alcohol under supervision (after the 5th day of taking), so that patients can be taught what to expect, and also to induce an aversion from alcohol.
There is clinical trial evidence for other drugs to assist with alcohol withdrawal. In particular naltrexone (an opioid antagonist) is registered by the Food and Drug Administration (FDA) in the USA for this indication but not in the UK. This remains an extremely active area of research.
Safe limits for chronic consumption
These cannot be defined accurately. But both patients and non-patients justifiably expect some guidance, and doctors and government departments will wish to be helpful. They may reasonably advise, as a ‘safe’ or prudent maximum (there being no particular individual contraindication):
For men not more than 21 units per week (and not more than 4 units in any 1 day); for women not more than 14 units per week (and not more than 3 units in any 1 day).10
Consistent drinking of more than these amounts carries a progressive risk to health. In other societies recommended maxima are higher or lower. Alcoholics with established cirrhosis have usually consumed about 23 units (230 mL; 184 g) daily for 10 years. Heavy drinkers may develop hepatic cirrhosis at a rate of about 2% per annum. The type of drink (beer, wine, spirits) is not particularly relevant to the adverse health consequences; a standard bottle of spirits (750 mL) contains 300 mL (240 g) of alcohol (i.e. 40% by volume). Most people cannot metabolise more than about 170 g/day. On the other hand, regular low alcohol consumption may confer benefit: up to one drink per day appears not to impair cognitive function in women and may actually decrease the risk of cognitive decline,11 and light-to-moderate alcohol consumption may reduce risk of dementia in people aged 55 years or more.12
The curve that relates mortality (vertical axis) to alcoholic drink consumption (horizontal axis) is J-shaped. As consumption rises above zero the all-cause mortality declines, then levels off, and then progressively rises. The benefit is largely a reduction of deaths due to cardiovascular and cerebrovascular disease for regular drinkers of 1–2 units per day for men aged over 40 years and postmenopausal women. Consuming more than 2 units a day does not provide any major additional health benefit. The mechanism may be an improvement in lipoprotein (HDL/LDL) profiles and changes in haemostatic factors.13 The effect appears to be due mainly to ethanol itself, but non-ethanol ingredients (antioxidants, phenols, flavinoids) may contribute. The rising (adverse) arm of the curve is associated with known harmful effects of alcohol (already described), but also, for example, with pneumonia (which may be secondary to direct alcohol effects, or with the increased smoking of alcohol users).
Alcohol in pregnancy and breast feeding
There is no level of maternal consumption that can be guaranteed safe for the fetus and fetal injury can occur early in pregnancy (4–10 weeks), often before the pregnancy has been diagnosed (usually 3–8 weeks). The current advice in the UK is therefore that women should abstain from alcohol if they are pregnant or intending to become pregnant. The mechanisms by which alcohol exerts its toxicity on the fetus are complex and involve both ethanol and its metabolite acetaldehyde.
In addition to the fetal alcohol syndrome there is general fetal/embryonic growth retardation (1% for every 10 g alcohol per day) and this is not ‘caught up’ later.
Fetal alcohol syndrome
is a term that covers a spectrum of disorders;14 it includes the following characteristics: microcephaly, mental retardation, low body-weight, poor coordination, hypotonia, small eyeballs and short palpebral fissures, lack of nasal bridge.15
Children of about 10% of alcohol abusers may show the syndrome. In women consuming 12 units of alcohol per day the incidence may be as high as 30%.
Lactation
Even small amounts of alcohol taken by the mother delay motor development in the child; an effect on mental development is uncertain.
There is no ‘safe’ level of alcohol consumption in pregnancy.
Alcohol and other drugs
The important interactions of alcohol with other drugs are shown in Table 11.7.
Table 11.7 Important interactions of alcohol with other drugs
|
Drug class |
Example |
Comments |
|
Antibiotics |
Metronidazole, trimethoprim, cephalosporins |
Disulfuram like action resulting in facial flushing, headaches, tachycardia and feinting |
|
Vasodilators |
GTN |
Increased adverse effects with risk of hypotension and falls |
|
Opioid analgesics |
morphine |
Exacerbation of adverse effects with increased sedation |
|
Non-steroidal anti-inflammatory agents |
Ibuprofen, naproxen |
Increased risk of GI ulceration and bleeding |
|
Hypoglycaemic agents |
Insulin, sulphonylureas |
Increased hypoglycaemic risk |
|
Anticoagulants |
warfarin |
Acute alcohol ingestion inhibits metabolism and increases bleeding risk |
|
Anticonvulsants |
phenytoin |
Acute alcohol ingestion increases availability and side effect profile |
|
Anaesthetics |
propofol |
Chronic alcohol ingestion results in resistance to effects of anaesthetic agents such that increased doses are required. |
|
Tricyclic antidepressants |
amitriptyline |
Acute and chronic ingestion can increase availability and worse sedation and side effects |
Miscellaneous uses of alcohol
• Used as a skin antiseptic, 70% by weight (76% by volume) is most effective. Stronger solutions are less effective.
• Alcohol injections are sometimes used to destroy nervous tissue in cases of intractable pain (trigeminal neuralgia, carcinoma involving nerves).
• As a treatment in ethylene glycol (antifreeze) poisoning.
Other cerebral depressants
Alcohol, benzodiazepines, clomethiazole and barbiturates broadly possess the common action of influencing GABA neurotransmission through the GABAA–benzodiazepine receptor complex (see p. 339 and Fig. 20.5) and all readily induce tolerance and dependence.
γ-Hydroxybutyrate
(GHB) is a metabolite of GABA, the major inhibitory transmitter in the CNS. It acts by binding to GABA receptors but additionally affects dopamine, serotonin and endogenous systems. It has euphoric and sedative effects and is popular at dance parties where it has achieved notoriety as a ‘date-rape drug’. It is highly addictive and frequent ingestion may induce dependency and a severe withdrawal state.
Benzodiazepine
dependence is discussed on page 339.
Clomethiazole and barbiturate
are now rarely used, and accordingly opportunity for abuse is limited.
Tobacco
In 1492, the explorer Christopher Columbus observed Native Americans using the dried leaves of the tobacco plant (later named Nicotiana16) for pleasure and also to treat ailments.
Following its introduction to Europe in the 16th century, tobacco enjoyed popularity to the extent of being considered a panacea, being called ‘holy herb’ and ‘God's remedy’.17 Only relatively recently have the harmful effects of tobacco come to light, notably from mortality studies among British doctors.18 Current estimates hold that there are more than a billion smokers worldwide. In 1990 there were 3 million smoking-related deaths per year, projected to reach 10 million by 2030.19
Composition
Tobacco smoke is complex (over 4000 compounds have been identified) and varies with the type of tobacco and the way it is smoked. The chief pharmacologically active ingredients are nicotine, responsible for acute effects (1–2 mg per cigarette); tars, responsible for chronic effects (10–15 mg per cigarette). Amounts of both can vary greatly (even for the same brand) depending on the country in which cigarettes are sold.
Smoke of cigars and pipes is alkaline (pH 8.5). Nicotine is relatively un-ionised at this pH, and is readily absorbed in the mouth. Cigar and pipe smokers thus obtain nicotine without inhaling, and thus have a lower death rate from lung cancer, which is caused by non-nicotine constituents.
Smoke of cigarettes is acidic (pH 5.3). Nicotine is relatively ionised and insoluble in lipids. Desired amounts are absorbed only if nicotine is taken into the lungs, where the enormous surface area for absorption compensates for the lower lipid solubility. Cigarette smokers therefore inhale (and have a high rate of death from tar-induced lung cancer). The amount of nicotine absorbed from tobacco smoke varies from 90% in those who inhale to 10% in those who do not. Smoke drawn through the tobacco and taken in by the smoker is known as main-stream smoke; smoke that arises from smouldering tobacco and passes directly into the surrounding air is known as side-stream smoke. These differ in composition, partly because of the different temperatures at which they are produced. Side-stream smoke constitutes about 85% of smoke generated in an average room during cigarette smoking.
Environmental tobacco smoke has been classified as a known human carcinogen in the USA since 1992.20 Although the risks of passive smoking are naturally smaller, the number of people affected is large. One study estimated that breathing other people's smoke increases a person's risk of ischaemic heart disease by a quarter.21 Tobacco smoke contains 1–5% carbon monoxide and habitual smokers have 3–7% (heavy smokers as much as 15%) of their haemoglobin as carboxyhaemoglobin, which cannot carry oxygen. This is sufficient to reduce exercise capacity in patients with angina pectoris. Chronic carboxyhaemoglobinaemia causes polycythaemia (which increases the viscosity of the blood). Substances carcinogenic to animals (polycyclic hydrocarbons and nicotine-derived N-nitrosamines) have been identified in tobacco smoke condensates from cigarettes, cigars and pipes. Polycyclic hydrocarbons are responsible for the hepatic enzyme induction that occurs in smokers.
Tobacco dependence
The immediate satisfaction of smoking is due to nicotine and also to tars, which provide flavour. Initially the factors are psychosocial; pharmacodynamic effects are unpleasant. But under the psychosocial pressures the subject continues, learns to limit and adjust nicotine intake, so that the pleasant pharmacological effects of nicotine develop and tolerance to the adverse effects occurs. Thus to the psychosocial pressure is now added pharmacological pleasure.
Nicotine possesses all the characteristics of a drug of dependence:
• It modulates dopamine activity in the midbrain, particularly in the mesolimbic system, which promotes the development and maintenance of reward behaviour.
• Nicotine inhaled in cigarette smoke reaches the brain in 10–19 s.
• Short elimination t½ requires regular smoking to maintain the effect.
• Inhaling cigarette smoke is thus an ideal drug delivery system to institute behavioural reinforcement and then dependence.
A report on the subject concludes that most smokers do not do so from choice but because they are addicted to nicotine.22
Tolerance and some physical dependence occur. Transient withdrawal effects include EEG and sleep changes, impaired performance in some psychomotor tests, disturbance of mood and increased appetite (with weight gain). It is, however, difficult to disentangle psychological from physical effects in these last effects.
Nicotine shows all the characteristics of a drug of dependence with both tolerance and some physical dependence.
Acute effects of smoking tobacco
• Increased airways resistance occurs due to the non-specific effects of submicronic particles, e.g. carbon particles less than 1 micrometre across. The effect is reflex: even inert particles of this size cause bronchial narrowing sufficient to double airways resistance; this is insufficient to cause dyspnoea, though it might affect athletic performance. Pure nicotine inhalations of concentration comparable to that reached in smoking do not increase airways resistance.
• Ciliary activity, after transient stimulation, is depressed, and particles are removed from the lungs more slowly.
• Carbon monoxide absorption may be clinically important in the presence of coronary heart disease (see above), although it is physiologically insignificant in healthy young adults.
Nicotine pharmacology
Pharmacokinetics
Nicotine is absorbed through mucous membranes in a highly pH-dependent fashion. The t½ is 2 h. It is metabolised largely by P450 (CYP) 2A6 to inert substances, e.g. cotinine, although some is excreted unchanged in the urine (pH dependent, it is un-ionised at acid pH). Cotinine is used as a marker for nicotine intake in smoking surveys because of its conveniently long t½ (20 h).
Pharmacodynamics
Large doses23
Nicotine is an agonist to receptors at the ends of peripheral cholinergic nerves whose cell bodies lie in the CNS: i.e. it acts at autonomic ganglia and at the voluntary neuromuscular junction (see Fig. 22.1). This is what is meant by the term ‘nicotine-like’ or ‘nicotinic’ effect. Higher doses paralyse at the same points. The CNS is stimulated, including the vomiting centre, both directly and via chemoreceptors in the carotid body. Tremors and convulsions may occur. As with the peripheral actions, depression follows stimulation.
Doses from/with smoking
Nicotine causes release of CNS catecholamines, serotonin, antidiuretic hormone, corticotropin and growth hormone. The effects of nicotine on viscera are probably largely reflex, from stimulation of sensory receptors (chemoreceptors) in the carotid and aortic bodies, pulmonary circulation and left ventricle. Some of the results are mutually antagonistic.
The following account tells what generally happens after one cigarette, from which about 1 mg of nicotine is absorbed, although much depends on the amount and depth of inhalation and on the duration of end-inspiratory breath-holding.
On the cardiovascular system the effects are those of sympathetic autonomic stimulation. There is vasoconstriction in the skin and vasodilatation in the muscles, tachycardia and a rise in blood pressure of about 15 mmHg systolic and 10 mmHg diastolic, and increased plasma noradrenaline/norepinephrine. Ventricular extrasystoles may occur. Cardiac output, work and oxygen consumption rise. Nicotine increases platelet adhesiveness, an effect that may be clinically significant in the development of atheroma and thrombosis.
Metabolic rate. Nicotine increases the metabolic rate only slightly at rest,24 but approximately doubles it during light exercise (occupational tasks, housework). This may be due to increase in autonomic sympathetic activity. The effect declines over 24 h on stopping smoking and accounts for the characteristic weight gain that is so disliked and which is sometimes given as a reason for continuing or resuming smoking. Smokers weigh 2–4 kg less than non-smokers (not enough to be a health issue).
Tolerance
develops to some of the effects of nicotine, taken repeatedly over a few hours; a first experience commonly causes nausea and vomiting, which quickly ceases with repetition of smoking. Tolerance is usually rapidly lost; the first cigarette of the day has a greater effect on the cardiovascular system than do subsequent cigarettes.
Conclusion
The pleasurable effects of smoking are derived from a complex mixture of multiple pharmacological and non-pharmacological factors.
In this account nicotine is represented as being the major (but not the sole) determinant of tobacco dependence after the smoker has adapted to the usual initial unpleasant effects. But there remains some uncertainty as to its role, e.g. intravenous nicotine fails adequately to substitute the effects of smoking. An understanding of the full function of nicotine is important if less harmful alternatives to smoking, such as nicotine chewing gum, are to be exploited.
Effects of chronic smoking
Bronchogenic carcinoma
• The risk of death from lung cancer is related to the number of cigarettes smoked and the age of starting.
• It is similar between smokers of medium (15–21 mg), low (8–14 mg) and very low (<0.5 mg) tar cigarettes.
• Giving up smoking reduces the risk of death progressively from the time of cessation.25
Other cancers
The risk of smokers developing cancer of the mouth, throat and oesophagus is 5–10 times greater than that of non-smokers. It is as great for pipe and cigar smokers as it is for cigarette smokers. Cancer of the pancreas, kidney and urinary tract is also commoner in smokers.
Coronary heart disease (CHD)
In the UK about 30% of CHD deaths can be attributed to smoking. Sudden death may be the first manifestation of CHD and, especially in young men, is related to cigarette smoking. Smoking is especially dangerous for people in whom other risk factors (raised blood cholesterol, high blood pressure) are present. Atherosclerotic narrowing of the smallest coronary arteries is enormously increased in heavy and even in moderate smokers; the increased platelet adhesiveness caused by smoking increases the readiness with which thrombi form. Stopping smoking reduces the excess risk of CHD in people under the age of 65 years, and after about 4 years of abstinence the risk approximates to that of non-smokers.
Chronic lung disease
The adverse effects of cigarette smoke on the lungs may be separated into two distinct conditions:
• Chronic mucus hypersecretion, which causes persistent cough with sputum and fits with the original definition of simple chronic bronchitis. This condition arises chiefly in the large airways, usually clears up when the subject stops smoking and does not on its own carry any substantial risk of death.
• Chronic obstructive lung disease, which causes difficulty in breathing chiefly due to narrowing of the small airways, includes a variable element of destruction of peripheral lung units (emphysema), is progressive and largely irreversible and may ultimately lead to disability and death.
Both conditions can coexist in one person and they predispose to recurrent acute infective illnesses.
Other effects
About 120 000 men in the UK aged 30–50 years are impotent because of smoking.26
Interactions with drug therapy
Induction of hepatic drug metabolising enzymes by non-nicotine constituents of smoke causes increased metabolism of a range of drugs, including oestrogens, theophylline and warfarin.
Women and smoking
Fertility
Women who smoke are more likely to be infertile or take longer to conceive than women who do not smoke:
• Smokers are more liable to have an earlier menopause than are non-smokers.
• Increased metabolism of oestrogens may not be the whole explanation.
Complications of pregnancy
• The risks of spontaneous abortion, stillbirth and neonatal death are approximately doubled.
• The placenta is heavier in smoking than non-smoking women and its diameter larger, possibly from adaptations to lack of oxygen due to smoking, secondary to raised concentrations of circulating carboxyhaemoglobin.
The child
• The babies of women who smoke are approximately 200 g lighter than those of women who do not smoke.
• They have an increased risk of death in the perinatal period which is independent of other variables such as social class, level of education, age of mother, race or extent of antenatal care.
• The increased risk rises two-fold or more in heavy smokers and appears to be accounted for entirely by the placental abnormalities and the consequences of low birth-weight.
• Ex-smokers and women who give up smoking in the first 20 weeks of pregnancy have offspring whose birth-weight is similar to that of the children of women who have never smoked.
Starting and stopping use
Contrary to popular belief it is not generally difficult to stop, only 14% finding it ‘very difficult’. But ex-smoker status is unstable and the long-term success rate of a smoking withdrawal clinic is rarely above 30%. The situation is summed up by the witticism, ‘Giving up smoking is easy, I've done it many times’.
Though they are as aware of the risks of smoking as men, women find it harder to stop; they have consistently lower success rates. This trend crosses every age group and occupation. Women particularly dislike the weight gain.
Aids to giving up
For those smoking more than 10 cigarettes per day, nicotine replacement and bupropion can provide effective therapy, particularly if supported by access to a smoking cessation clinic for behavioural support. Ideally, smoking should stop completely before embarking on a cessation regimen.
Nicotine
is principally responsible for the addictive effects of tobacco smoking, and is therefore a logical pharmacological aid to quitting. It is available in a number of formulations, including chewing gum, transdermal patch, oral and nasal spray. When used casually without special attention to technique, nicotine formulations have proved no better than other aids but, if used carefully and withdrawn as recommended, the accumulated results are almost two times better than in smokers who try to stop without this assistance.27
Restlessness during terminal illness may be due to nicotine withdrawal and go unrecognised; a nicotine patch may benefit a (deprived) heavy smoker. Nicotine transdermal patches may cause nightmares and abnormal dreaming, and skin reactions (rash, pruritus and ‘burning’ at the application site). Immunotherapy, using a vaccine of antibodies specific for nicotine, holds promises to prevent relapse in abstinent smokers or for adolescents to avoid initiation.28
Bupropion
may provide an alternative, or addition, to nicotine. When the drug was being investigated as an antidepressant, researchers noticed that patients gave up smoking, and it was developed as an aid to smoking cessation. Bupropion selectively inhibits neuronal uptake of noradrenaline/norepinephrine and dopamine, and may reduce nicotine craving by an action on the mesolimbic system. Evidence suggests that bupropion may be at least as effective as the nicotine patch, with which it may usefully be combined. It may cause dry mouth and insomnia. It is contraindicated in patients with a history of eating disorder or epilepsy or who are experiencing acute symptoms of alcohol or benzodiazepine withdrawal; where potential for seizure exists, e.g. use of drugs that lower the seizure threshold, this hazard must be weighed against the possible benefits of smoking cessation.
If the patient is heavily tobacco-dependent and severe anxiety, irritability, headache, insomnia and weight gain (about 3 kg) and tension are concomitants of attempts to stop smoking, an anxiolytic sedative (or β-adrenoceptor blocker) may be useful for a short time, but it is important to avoid substituting one drug dependence for another.
Psychodysleptics or hallucinogens
These substances produce mental changes that resemble those of some psychotic states in which the subject experiences hallucinations or illusions, i.e. disturbance of perception with the apparent awareness of sights, sounds and smells that are not actually present.
Experiences with these drugs vary greatly with the subject's expectations, existing frame of mind and personality and environment. Subjects can be prepared so that they are more likely to have a good ‘trip’ than a bad one.
Experiences with psychodysleptics
The following brief account of experiences with LSD (lysergic acid diethylamide, lysergide) in normal subjects will serve as a model. Experiences with mescaline and psilocybin are similar.
Vision may become blurred and there may be hallucinations; these generally do not occur in the blind and are fewer if the subject is blindfolded. Objects appear distorted, and trivial things, e.g. a mark on a wall, may change shape and acquire special significance. Auditory acuity increases, but hallucinations are uncommon. Subjects who do not ordinarily appreciate music may suddenly come to do so. Foods may feel coarse and gritty in the mouth. Limbs may be left in uncomfortable positions. Time may seem to stop or to pass slowly, but usually it gets faster and thousands of years may seem suddenly to go by. The subject may feel relaxed and supremely happy, or may become fearful or depressed. Feelings of depersonalisation and dreamy states occur.
The experience lasts for a few hours, depending on the dose; intervals of normality then occur and become progressively longer.
Somatic symptoms and signs include nausea, dizziness, paraesthesiae, weakness, drowsiness, tremors, dilated pupils, ataxia. Effects on the cardiovascular system and respiration vary and probably reflect fluctuating anxiety.
Lysergide (LSD)
Lysergic acid is a semi-synthetic drug belonging to the ergoline family. An effective oral dose is about 30 micrograms. The t½ is 3 h. (See description of experience, above.) Its mechanisms of action are complex and include agonist effect at pre-synaptic 5-HT receptors in the CNS. Tachyphylaxis (acute tolerance) occurs to LSD. Psychological dependence may occur, but physical dependence does not occur. Serious adverse effects include psychotic reactions (which can be delayed in onset) with suicide.
Mescaline
is an alkaloid from the Mexican peyote cactus. It does not induce serious dependence and the drug has little importance except to members of some North and Central American societies and to psychiatrists and biochemists who are interested in the mechanism of induced psychotic states.
Psilocybin
is derived from varieties of the fungus Psilocybe (‘magic mushrooms’) that grow in many countries. It is related to LSD.
Tenamfetamine
(ecstasy, MDMA: methylenedioxymethamfetamine) is structurally related to both mescaline and amfetamine. It has a t½ of about 8 h. It is popular as a dance drug at ‘rave’ parties. An estimated 5% of the American adult population have used tenamfetamine at least once.29 Popular names reflect the appearance of the tablets and capsules and include White Dove, White Burger, Red and Black, Denis the Menace. Tenamfetamine stimulates central and peripheral α- and β-adrenoceptors; thus the pharmacological effects are compounded by those of physical exertion, dehydration and heat.
In susceptible individuals (poor metabolisers who exhibit the CYP450 2D6 polymorphism) a severe and fatal idiosyncratic reaction may occur with fulminant hyperthermia, convulsions, disseminated intravascular coagulation, rhabdomyolysis, and acute renal and hepatic failure. Treatment includes activated charcoal, diazepam for convulsions, β-blockade (atenolol) for tachycardia, α-blockade (phentolamine) for hypertension, and dantrolene if the rectal temperature exceeds 39°C. In chronic users, positive emission tomographic (PET) brain scans show selective dysfunction of serotonergic neurones, raising concerns that neurodegenerative changes accompany long-term use of MDMA.30
Phencyclidine
(‘angel dust’) is structurally related to pethidine. It induces analgesia without unconsciousness, but with amnesia, in humans (dissociative anaesthesia, see p. 301). It acts as an antagonist at NMDA glutamate receptors. It can be insufflated as a dry powder or smoked (cigarettes are dipped in phencyclidine dissolved in an organics solvent). Phencyclidine overdose can cause agitation, abreactions, hallucinations and psychosis, and if severe can result in seizures, coma, hyperthermia, muscular rigidity and rhabdomyolysis.
Ketamine
(K, special K) has similar effects to those of phencyclidine. It is used as a short-acting general anaesthetic. It can be injected as liquid or inhaled as powder or swallowed as tablet. It is an NMDA antagonist. It induces perceptual changes and hallucinations similar to LSD, and in addition induces dissociative analgesia, with consequent risk of serious injury. Nausea, vomiting and risk of death can result from inhalation of vomitus. It has been used as a date-rape drug. There is increasing evidence that it can cause serious long-term bladder damage.
Methylxanthines (xanthines)
The three xanthines, caffeine, theophylline and theobromine, occur in plants. They are qualitatively similar but differ markedly in potency:
• Tea contains caffeine and theophylline.
• Coffee contains caffeine.
• Cocoa and chocolate contain caffeine and theobromine.
• The cola nut (‘cola’ drinks) contains caffeine.
• Theobromine is weak and of no clinical importance (although responsible for the toxicity of chocolate when ingested by dogs).
Pharmacokinetics
Absorption of xanthines after oral or rectal administration varies with the preparation used. It is generally extensive (> 95%). Caffeine metabolism varies much between individuals (t½ 2–12 h). Xanthines are metabolised (> 90%) by numerous mixed-function oxidase enzymes, and xanthine oxidase. (For further details on theophylline, see Asthma.)
Pharmacodynamics
Caffeine and theophylline have complex and incompletely elucidated actions, which include inhibition of phosphodiesterase (the enzyme that breaks down cyclic AMP, see pp. 465, 474), effects on intracellular calcium distribution, and on noradrenergic function.
Actions on mental performance
Caffeine is more potent than theophylline, but both drugs stimulate mental activity where it is below normal. Thought is more rapid and fatigue is removed or its onset delayed. The effects on mental and physical performance vary according to the mental state and personality of the subject. Reaction time is decreased. Performance that is inferior because of excessive anxiety may become worse. Caffeine can also improve physical performance, both in tasks requiring more physical effort than skill (athletics) and in tasks requiring more skill than physical effort (monitoring instruments and taking corrective action in an aircraft flight simulator). In general, caffeine induces feelings of alertness and well-being, euphoria or exhilaration. Onset of boredom, fatigue, inattentiveness and sleepiness is postponed.
Overdose
will certainly reduce performance (see Chronic overdose, below). Acute overdose, e.g. intravenous aminophylline, can cause convulsions, hypotension, cardiac arrhythmia and sudden death.
Other effects
Respiratory stimulation
occurs with substantial doses.
Sleep
Caffeine affects sleep of older people more than it does that of younger people. Onset of sleep (sleep latency) is delayed, bodily movements are increased, total sleep time is reduced and there are increased awakenings. Tolerance to this effect does not occur, as is shown by the provision of decaffeinated coffee.31
Skeletal muscle
Metabolism is increased, and this may play a part in the enhanced athletic performance mentioned above. There is significant improvement of diaphragmatic function in chronic obstructive pulmonary disease.
Cardiovascular system
Both caffeine and theophylline directly stimulate the myocardium and cause increased cardiac output, tachycardia, and sometimes ectopic beats and palpitations. This effect occurs almost at once after intravenous injection and lasts for half an hour. Theophylline contributes usefully to the relief of acute left ventricular failure. There is peripheral (but not cerebral) vasodilatation due to a direct action of the drugs on the blood vessels, but stimulation of the vasomotor centre tends to counter this.
Changes in the blood pressure are therefore somewhat unpredictable, but caffeine 250 mg (single dose) usually causes a transient rise of blood pressure of about 14/10 mmHg in occasional coffee drinkers (but has no additional effect in habitual drinkers); this effect can be used advantageously in patients with autonomic nervous system failure who experience postprandial hypotension (two cups of coffee with breakfast may suffice for the day). In occasional coffee drinkers two cups of coffee (about 160 mg caffeine) per day raise blood pressure by 5/4 mmHg. Increased coronary artery blood flow may occur but increased cardiac work counterbalances this in angina pectoris.
When theophylline (aminophylline) is given intravenously, slow injection is essential in order to avoid transient peak concentrations which are equivalent to administering an overdose (below).
Smooth muscle
(other than vascular muscle, which is discussed above) is relaxed. The only important clinical use for this action is in reversible airways obstruction (asthma), when the action of theophylline can be a very valuable addition to therapy.
Kidney
Diuresis occurs in normal people chiefly due to reduced tubular reabsorption of sodium, similar to thiazide action, but weaker.
Preparations and uses of caffeine and theophylline
Aminophylline
The most generally useful preparation is aminophylline, which is a soluble, irritant salt of theophylline with ethylenediamine (see Asthma).
Attempts to make non-irritant, orally reliable preparations of theophylline have resulted in choline theophyllinate and numerous variants. Sustained-release formulations are convenient for asthmatics, but they cannot be assumed to be bio-equivalent and repeat prescriptions should adhere to the formulation of a particular manufacturer. Suppositories are available. Aminophylline is used in the following conditions:
• Asthma. In severe asthma (given intravenously) when β-adrenoceptor agonists fail to give adequate response; and for chronic asthma (orally) to provide a background bronchodilator effect.
• Neonatal apnoea; caffeine is also effective.
Caffeine is used as an additional ingredient in analgesic tablets; about 60 mg potentiates the effects of NSAIDs; also as an aid in hypotension of autonomic failure (above) and to enhance oral ergotamine absorption in migraine.
Xanthine-containing drinks (see also above)
Coffee, tea and cola drinks in excess can make people tense and anxious. Epidemiological studies indicate either no, or only slight, increased risk (two- to three-fold) of coronary heart disease in heavy (including decaffeinated) coffee consumers (more than four cups daily) (see Lipids, below). Slight tolerance to the effects of caffeine (on all systems) occurs. Withdrawal symptoms, attributable to psychological and perhaps mild physical dependence, occur in habitual coffee drinkers (five or more cups/day) 12–16 h after the last cup; they include headache (lasting up to 6 days), irritability and jitteriness; they may occur with transient changes in intake, e.g. high at work, lower at the weekend.
Chronic overdose
Excessive prolonged consumption of caffeine causes anxiety, restlessness, tremors, insomnia, headache, cardiac extrasystoles and confusion. The cause can easily be overlooked if specific enquiry into habits is not made, including children regarding cola drinks. Of coffee drinkers, up to 25% who complain of anxiety may benefit from reduction of caffeine intake. An adult heavy user may be defined as one who takes more than 300 mg caffeine per day, i.e. four cups of 150 mL of brewed coffee, each containing 80 ± 20 mg caffeine per cup or five cups (60 ± 20 mg) of instant coffee. The equivalent for tea would be 10 cups at approximately 30 mg caffeine per cup; and of cola drinks about 2 L. Plainly, caffeine drinks brewed to personal taste of consumer or vendor must have an extremely variable concentration according to source of coffee or tea, amount used, method and duration of brewing. There is also great individual variation in the effect of coffee both between individuals and sometimes in the same individual at different times of life (see Sleep, above).
Decaffeinated coffee contains about 3 mg per cup; cola drinks contain 8–13 mg caffeine per 100 mL; cocoa as a drink, 4 mg per cup; chocolate (solid) 6–20 mg/30 g.
In young people high caffeine intake has been linked to behaviour disorders and a limit of 125 mg/L has been proposed for cola drinks.
Blood lipids
Drinking five cups of boiled coffee per day increases plasma total cholesterol by up to 10%; this does not occur with coffee made by simple filtration. Cessation of coffee drinking can reduce plasma cholesterol concentration in hypercholesterolaemic men.
Breast-fed infants may become sleepless and irritable if there is high maternal intake. Fetal cardiac arrhythmias have been reported with exceptionally high maternal caffeine intake, e.g. 1.5 L cola drinks per day.
Cannabis
Cannabis is obtained from the annual plant Cannabis sativa (hemp) and its varieties Cannabis indica and Cannabis americana. The preparations that are smoked are called marijuana (also grass, pot, weed) and consist of crushed leaves and flowers. There is a wide variety of regional names, e.g. ganja (India, Caribbean), kif (Morocco), dagga (Africa). The resin scraped off the plant is known as hashish (hash). The term cannabis is used to include all the above preparations. As most preparations are illegally prepared it is not surprising that they are impure and of variable potency. The plant grows wild in the Americas,32 Africa and Asia. It can also be grown successfully in the open in the warmer southern areas of Britain. Some 27% of the adult UK population report having used cannabis in their lifetime.
Pharmacokinetics
Of the scores of chemical compounds that the resin contains, the most important are the oily cannabinoids, including tetrahydrocannabinol (THC), which is the main psychoactive ingredient. Samples of resin vary greatly in the amounts and proportions of these cannabinoids according to their country of origin. As the sample ages, its THC content declines. THC content of samples can vary from 8% to almost zero. Smoke from a cannabis cigarette (the usual mode of use is to inhale and hold the breath to allow maximum absorption) delivers 25–50% of the THC content to the respiratory tract. THC (t½ 4 days) and other cannabinoids undergo extensive biotransformation in the body, yielding scores of metabolites, several of which are themselves psychoactive. They are extremely lipid-soluble and are stored in body fat from which they are slowly released.33 Hepatic drug-metabolising enzymes are inhibited acutely but may also be induced by chronic use of crude preparations.
Pharmacodynamics
Cannabinoid CB1-receptors (expressed by hypothalamic and peripheral neurones, e.g. sensory terminals in the gastrointestinal tract, and by adipocytes) and CB2-receptors (expressed only in the periphery by immune cells) together with their endogenous ligands (called endocannabinoids) are components of the endocannabinoid neuromodulatory system, which has a role in many physiological processes including food intake and energy homeostasis. Cannabinoids act as agonists at CB1-receptors (mediating addictive effects) and CB2-receptors. Understanding this system offers scope for developing novel drug therapies (see below).
Psychological reactions are very varied, being much influenced by the behaviour of the group. They commence within minutes of starting to smoke and last for 2–3 h. Euphoria is common and is believed to follow stimulation of the limbic system reward pathways causing release of dopamine from the nucleus accumbens (see common mechanism of drugs of dependence). There may be giggling or laughter which can seem pointless to an observer. Sensations become more vivid, especially visual, and contrast and intensity of colour can increase, although no change in acuity occurs. Size of objects and distance are distorted. Sense of time can disappear altogether, leaving a sometimes distressing sense of timelessness. Recent memory and selective attention are impaired; the beginning of a sentence may be forgotten before it is finished. The subject is very suggestible and easily distracted. Psychological tests such as mental arithmetic, digit-symbol substitution and pursuit meter tests show impairment. These effects may be accompanied by feelings of deep insight and truth. Memory defect may persist for weeks after abstinence. Once memory is impaired, concentration becomes less effective, because the object of attention is less well remembered. With this may go an insensitivity to danger or the consequences of actions. A striking phenomenon is the intermittent wavelike nature of these effects which affects mood, visual impressions, time sense, spatial sense and other functions.
The desired effects of cannabinoids, as of other psychodysleptics, depend not only on the expectation of the user and the dose, but also on the environmental situation and personality. Genial or revelatory experiences may indeed occur.
Cannabinoids and skilled tasks
e.g. car driving. General performance in both motor and psychological tests deteriorates, more in naive than in experienced subjects. Effects may be similar to alcohol, but experiments in which the subjects are unaware that they are being tested (and so do not compensate voluntarily) are difficult to do, as with alcohol. In a placebo-controlled trial of airline pilots in a flight simulator, performance was impaired for up to 50 h after the pilots smoked a joint containing THC 20 mg (a relatively low dose by current standards).34
Uses
A therapeutic role has been suggested for cannabinoids in a variety of conditions including chronic pain, migraine headaches, muscle spasticity in multiple sclerosis or spinal cord injury, movement disorders, appetite stimulation in patients with AIDS, nausea and vomiting.
THC is currently available as dronabinol, a synthetic form and as nabilone, a synthetic analogue, and both are approved to alleviate chemotherapy-induced vomiting in patients who have shown inadequate response to conventional antiemetics, and AIDS-related wasting syndrome.
Issues of cannabis and cannabis-based medicines were the subject of a working party report35 whose main conclusions were:
• Inhibition of cannabinoid action can be used to help obese patients to lose weight. The first of a new class of CB1-receptor antagonists, rimonabant, reduced body-weight and improved cardiovascular risk factors (HDL-cholesterol, triglycerides, insulin resistance) in obese patients over 1 year.36 It may cause nausea and depression and is contraindicated in pregnancy.
• In neuropathic pain, i.e. due to damaged neural tissue, data from well-controlled but limited duration trials suggest that THC is similar to codeine in potency, is safe and is not associated with tolerance or dependence.
• Cannabinoids regulate bone mass, and cannabinoid receptor antagonists may have a role in the treatment of osteoporosis.
• Data on the value of cannabis preparations for multiple sclerosis are not conclusive, although there is some support for a therapeutic effect.
Adverse effects
Acute
The psychological effects can be unpleasant, especially in inexperienced subjects. These are: timelessness and the feeling of loss of control of mental processes; feelings of unease, sometimes amounting to anguish and acute panic; ‘flashbacks’ of previously experienced hallucinations, e.g. on LSD. The effect of an acute dose usually ends in drowsiness and sleep. Increase in appetite is commonly experienced. It has been suggested that acute cannabis use might be associated with acute cardiovascular fatality, but this remains unproven.
Chronic
There is tendency to paranoid thinking. Cognitive defect occurs and persists in relation to the duration of cannabis use. High or habitual use can be followed by a psychotic state; this is usually reversible, quickly with brief periods of cannabis use, but more slowly after sustained exposures. Evidence indicates that chronic use may precipitate psychosis in vulnerable individuals.37 Continued heavy use can lead to tolerance, and a withdrawal syndrome (depression, anxiety, sleep disturbance, tremor and other symptoms). Abandoning cannabis is difficult for many users.
In studies of self-administration by monkeys, spontaneous use did not occur but, once use was initiated, drug-seeking behaviour developed. Subjects who have become tolerant to LSD or opioids as a result of repeated dosage respond normally to cannabis but there appears to be cross-tolerance between cannabinoids and alcohol. The term ‘amotivational syndrome’ dignifies an imprecisely characterised state, with features ranging from a feeling of unease and sense of not being fully effective, up to a gross lethargy, with social passivity and deterioration. Yet the reversibility of the state, its association with cannabinoid use, and its recognition by cannabis users make it impossible to ignore. (See Escalation theory, p. 141.)
The smoke produces the usual smoker's cough and delivers much more tar than tobacco cigarettes. In terms of damage to the bronchial epithelium, e.g. squamous metaplasia (a pre-cancerous change), three or four cannabis cigarettes are the equivalent of 20 tobacco cigarettes. Cannabinoids are teratogenic in animals, but effect in humans is unproved, although there is impaired fetal growth with repeated use.
Management of adverse reactions to psychodysleptics
Mild and sometimes even severe episodes (‘bad trips’) can be managed by reassurance including talk, ‘talking the patient down’ and physical contact, e.g. hand-holding (LSD and mescaline). Sedation of anxious or excited subjects can be effected with diazepam (or haloperidol).
Psychostimulants
Cocaine
Cocaine is found in the leaves of the coca plant (Erythroxylum coca), a bush commonly found growing wild in Peru, Ecuador and Bolivia, and cultivated in many other countries. A widespread and ancient practice among South American peasants is to chew coca leaves with lime to release the alkaloid which gives relief from fatigue and hunger, and from altitude sickness in the Andes, experienced even by natives of the area when journeying; it also induces a pleasant introverted mental state. What may have been (or even still may be) an acceptable feature of these ancient stable societies has now developed into a massive criminal business for the manufacture and export of purified cocaine to developed societies, where its use constitutes an intractable social problem. An estimated 1 million people abused cocaine in the UK in 2009. This increase in use has been fuelled by falling street prices.
Pharmacokinetics
Cocaine hydrochloride, extracted from the coca leaves, is a fine white powder. It is metabolised by plasma esterases; the t½ is 50 min. It is taken to obtain the immediate characteristic intense euphoria which is often followed in a few minutes by dysphoria. This leads to repeated use (10–45 min) during ‘runs’ of usually about 12 h. After the ‘run’ there follows the ‘crash’ (dysphoria, irritability, hypersomnia), lasting for hours to days. After the ‘crash’ there may be depression (‘cocaine blues’) and decreased capacity to experience pleasure (anhedonia) for days to weeks.
Route of administration
Cocaine can be snorted, swallowed, smoked (below) or injected. Intranasal use causes mucosal vasoconstriction, anosmia and eventually necrosis and perforation of the nasal septum. Smoking involves converting the non-volatile cocaine HCl into the volatile ‘free base’ or ‘crack’ (by extracting the HCl with alkali).
For use it is vaporised by heat (it pops or cracks) in a special glass ‘pipe’; or mixed with tobacco in a cigarette. Inhalation with breath-holding allows pulmonary absorption that is about as rapid as an intravenous injection. It induces an intense euphoric state. The mouth and pharynx become anaesthetised. (See Local anaesthetic action of cocaine, p. 304.) Intravenous use gives the expected rapid effect (kick, flash, rush). Cocaine may be mixed with heroin (as ‘speedball’).
Mode of action
Cocaine binds to and blocks the dopamine reuptake transporter which plays a key role in controlling entry of dopamine into central nerve terminals after release. Dopamine then accumulates in the synapse and acts on adjacent neurones to produce the characteristic ‘high’. The psychotropic effects of cocaine are similar to those of amfetamine (euphoria and excitement) but briefer. Psychological dependence with intense compulsive drug-seeking behaviour is characteristic of even short-term use. Physical dependence is arguably slight or absent. Tachyphylaxis, acute tolerance, occurs.
Overdose
is common among users. Up to 22% of heavy users report losing consciousness. The desired euphoria and excitement turn to acute fear, with psychotic symptoms, convulsions, hypertension, haemorrhagic stroke, tachycardia, arrhythmias, hyperthermia. Coronary artery vasospasm (sufficient to present as the acute coronary syndrome with chest pain and myocardial infarction) may occur, and acute left ventricular dysfunction.
Treatment is chosen according to the clinical picture (and the known mode of action), from haloperidol (rather than chlorpromazine) for mental disturbance; diazepam for convulsions; a vasodilator, e.g. a calcium channel blocker, for hypertension; glyceryl trinitrate for myocardial ischaemia (but not a β-blocker which aggravates cocaine-induced coronary vasospasm). Fetal growth is retarded by maternal use, but teratogenicity is uncertain.
Cocaine induced coronary artery spasm and myocardial infarction is an increasingly recognised problem and should be suspected in a young person presenting with cardiac chest pain.
Amfetamines
An easily prepared crystalline form of methylamfetamine (known as ‘crystal meth’ or ‘ice’) is in widespread illicit use as a psychostimulant. Amfetamine is a racemic compound: the laevo form is relatively inactive but dexamfetamine (the dextro isomer) finds use in medicine. Amfetamine will be described, and structurally related drugs only in the ways in which they differ.
Pharmacokinetics
Amfetamine (t½ 12 h) is readily absorbed by any usual route and is largely eliminated unchanged in the urine. Urinary excretion is pH dependent; being a basic substance, elimination will be greater in an acid urine. As well as oral use, intravenous administration (with the pleasurable ‘flash’ as with opioids) is employed. Interactions are as expected from mode of action, e.g. antagonism of antihypertensives; severe hypertension with MAOIs and β-adrenoceptor blocking drugs.
Mode of action
Amfetamine acts centrally by releasing dopamine stored in nerve endings and peripherally by α- and β-adrenoceptor actions common to indirectly acting sympathomimetics. As with all drugs acting on the CNS, the psychological effects vary with mood, personality and environment, as well as with dose. Subjects become euphoric and fatigue is postponed. Although physical and mental performance may improve, this cannot be relied on. Subjects may be more confident and show more initiative, and be better satisfied with a more speedy performance that has deteriorated in accuracy. There may be anxiety and a feeling of nervous and physical tension, especially with large doses, and subjects develop tremors and confusion, and feel dizzy. Time seems to pass with greater rapidity. The sympathomimetic effect on the heart, causing palpitations, may intensify discomfort or alarm. Amfetamine increases the peripheral oxygen consumption and this, together with vasoconstriction and restlessness, leads to hyperthermia in overdose, especially if the subject exercises.
Dependence
on amfetamine and similar sympathomimetics is chiefly psychological. There is a withdrawal syndrome, suggesting physical dependence. Tolerance occurs. Severe dependence induces behaviour disorders, hallucinations, even florid psychosis, which can be controlled by haloperidol. Withdrawal is accompanied by lethargy and sleep, desire for food, and sometimes severe depression, which leads to an urge to resume the drug.
Acute poisoning
is manifested by excitement and peripheral sympathomimetic effects. Convulsions may occur in acute or chronic overuse; a state resembling hyperactive paranoid schizophrenia with hallucinations develops. Hyperthermia occurs with cardiac arrhythmias, vascular collapse, intracranial haemorrhage and death. Treatment is chlorpromazine with added antihypertensive, e.g. labetalol, if necessary; these provide sedation and β-adrenoceptor blockade (but not a β-blocker alone, see p. 408), rendering unnecessary the optional enhancement of elimination by urinary acidification.
Chronic overdose
can cause a psychotic state mimicking schizophrenia. A vasculitis of the cerebral and/or renal vessels can occur, possibly due to release of vasoconstrictor amines from both platelets and nerve endings. Severe hypertension can result from the renal vasculitis.
Structurally related drugs include dexamfetamine, used for narcolepsy and in attention-deficit hyperactivity disorder (ADHD) (see p. 345), methylphenidate (used for ADHD), tenamfetamine (Ecstasy, see p. 153), phentermine, diethylpropion and pemoline.
Khat
The leaves of the khat shrub (Catha edulis) contain alkaloids (cathinine, cathine, cathidine) that are structurally like amfetamine and produce similar effects. They are chewed fresh (for maximal alkaloid content). The habit was confined to geographical areas favourable to the shrub (Arabia, East Africa) until modern transportation allowed wider distribution. Use in the UK has been increasingly reported. It has been banned in the USA and Canada. Khat chewers (mostly male) became euphoric, loquacious, excited, hyperactive and even manic. As with some other drug dependencies, subjects may give priority to their drug needs above personal, family, and other social and economic responsibilities. Cultivation takes up serious amounts of scarce arable land and irrigation water.
Volatile substance abuse
Seekers of the ‘self-gratifying high’ also inhale any volatile substance that may affect the CNS. These include adhesives (‘glue sniffing’), lacquer-paint solvents, petrol, nail varnish, any pressurised aerosol, butane liquid gas (which latter especially may ‘freeze’ the larynx, allowing fatal inhalation of food, drink, gastric contents, or even the liquid itself to flood the lungs). Even solids, e.g. paint scrapings, solid shoe polish, may be volatilised over a fire.
These substances are particularly abused by the young (13–15 years), no doubt largely because they are accessible at home and in ordinary shops, and these children cannot easily buy alcohol or ‘street’ drugs (although this may be changing as dealers target the youngest).
CNS effects include confusion and hallucinations, ataxia, dysarthria, coma, convulsions, respiratory failure. Liver, kidney, lung and heart damage occur. Sudden cardiac death may be due to sensitisation of the heart to endogenous catecholamines. If the substance is put in a plastic bag from which the user takes deep inhalations, or is sprayed in a confined space, e.g. cupboard, there is particularly high risk.
A 17-year-old boy was offered the use of a plastic bag and a can of hair spray at a beach party. The hair spray was released into the plastic bag and the teenager put his mouth to the open end of the bag and inhaled … he exclaimed, ‘God, this stuff hits ya fast!’ He got up, ran 100 yards, and died.38
Signs of frequent volatile substance abuse include perioral eczema and inflammation of the upper respiratory tract.
Guide to further reading
Aubin H.J., Karila L., Reynaud M. Pharmacotherapy for smoking cessation: present and future. Curr. Pharm. Des.. 2011;17(14):143–150.
Clark S. Personal account: on giving up smoking. Lancet. 2005;365:1855.
Doll R. One for the heart. Br. Med. J.. 1997;315:1664–1668.
Edwards R. The problem of tobacco smoking. Br. Med. J.. 2004;328:217–219. (and subsequent articles in this series on the ‘ABC of Smoking Cessation’)
Fergusson D.M., Poulton R., Smith P.F., Boden J.M. Cannabis and psychosis. Br. Med. J.. 2006;322:172–176.
Flower R. Lifestyle drugs: pharmacology and the social agenda. Trends Pharmacol. Sci.. 2004;25(4):182–185.
Gerada C. Drug misuse: a review of treatments. Clin. Med. (Northfield Il). 2005;5(1):69–73.
Gordon R.J., Lowy F.D. Bacterial infections in drug users. N. Engl. J. Med.. 2005;353(18):1945–1954.
Jamrozik K. Estimate of deaths attributable to passive smoking among UK adults: database analysis. Br. Med. J.. 2005;330:812–815.
Kahan M., Srivastava A., Ordean A., Cirone S. Buprenorphine: new treatment of opioid addiction in primary care. Can. Fam. Physician. 2011;57(3):281–289.
Kosten T.R., O'Connor P.G. Management of drug and alcohol withdrawal. N. Engl. J. Med.. 2003;348(18):1786–1795.
Lange R.A., Hillis L.D. Cardiovascular complications of cocaine use. N. Engl. J. Med.. 2001;345(5):351–358.
Malaiyandi V., Sellers E.M., Tyndale R.F. Implications of CYP2A6 genetic variation for smoking behaviours and nicotine dependence. Clin. Pharmacol. Ther.. 2005;77(3):145–158.
Minozzi S., Amato L., Vecchi S., et al. Oral naltrexone maintenance treatment for opioid dependence. Cochrane Database Syst. Rev.. 2011;13:4.
Nutt D., King L.A., Saulsbury W., Blakemore C. Development of a rational scale to assess the harm of drugs of potential misuse. Lancet. 2007;369:1047–1053.
Ricaurte G.A., McCann U.D. Recognition and management of complications of new recreational drug use. Lancet. 2005;365:2137–2145. (see also p. 2146, the anonymous Personal Account: GHB – sense and sociability)
Snead O.C., Gibson K.M. γ-hydroxybutyric acid. N. Engl. J. Med.. 2005;352(26):2721–2732.
1 MacDonald R, Das A 2006 UK classification of drugs of abuse: an un-evidence-based mess. Lancet 368:559–561.
2 Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Association 2007.
3 Bourne P 1976 Acute Drug Abuse Emergencies. Academic Press, New York.
4 See Department of Health 1999 Drug Misuse and Dependence – Guidelines on Clinical Management. The Stationery Office, London (3rd impression 2005).
5 A 49-year-old man became ill after an international flight. An abdominal radiograph showed a large number of spherical packages in his gastrointestinal tract, and body-packing was suspected. As he had not defaecated, he was given liquid paraffin. He developed ventricular fibrillation and died. Post-mortem examination showed that he had ingested more than 150 latex packets, each containing 5 g cocaine, making a total of almost 1 kg (lethal oral dose 1–3 g). The liquid paraffin may have contributed to his death as the mineral oil dissolves latex. Sorbitol or lactulose with activated charcoal should be used to remove ingested packages, or surgery if there are signs of intoxication. (Visser L, Stricker B, Hoogendoorn M, Vinks A 1998 Do not give paraffin to packers. Lancet 352:1352.)
6 A highly sensitive technique that can identify minor differences between molecules. It is based on the principle that ions passing at high velocity through an electrical field at right angles to their motion will deviate from a straight line according to their mass and charge; the heaviest will deviate least, the lightest most.
7 An arrested man was told, in a police station by a doctor, that he was drunk. The man asked, ‘Doctor, could a drunk man stand up in the middle of this room, jump into the air, turn a complete somersault, and land down on his feet?’ The doctor was injudicious enough to say, ‘Certainly not’ – and was then and there proved wrong (Worthing C L 1957 British Medical Journal i:643). The introduction of the breathalyser, which has a statutory role only in road traffic situations, has largely eliminated such professional humiliations.
8 Approximately equivalent to 35 micrograms alcohol in 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 variability and instrumental error. Urine concentrations are little used as the urine is accumulated over time and does not provide the immediacy of blood and breath.
9 In 1990 Sweden lowered the limit to 20 mg/100 mL, which has been approached by ingestion of glucose which becomes fermented by gut flora in some people – the ‘autobrewery’ syndrome.
10 Report of an Inter-Departmental Working Group 1995 Sensible Drinking. Department of Health, London.
11 Stampfer M J, Kang J H, Chen J et al 2005 Effects of moderate alcohol consumption on cognitive function in women. New England Journal of Medicine 352:245–253.
12 Ruitenberg A, van Swieten J C, Witteman J C M et al 2002 Alcohol consumption and the risk of dementia: the Rotterdam study. Lancet 359:281–286.
13 Rimm E B, Williams P, Fosher K et al 1999 Moderate alcohol intake and lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic factors. British Medical Journal 319:1523–1528.
14 Mukherjee R A S, Hollins A, Turk J 2006 Fetal alcohol spectrum disorder: an overview. Journal of the Royal Society of Medicine 99:298–302.
15 For pictures see Streissguth A P, Clarren S K, Jones K L 1985 Natural history of the fetal alcohol syndrome: a 10-year follow-up of eleven patients. Lancet ii:85–91.
16 After the French diplomat, Jean Nicot de Villemain, who introduced tobacco to Europe.
17 Dickson S A 1954 Panacea or Precious Bane. Tobacco in 16th Century Literature. New York Public Library, New York. Quoted in: Charlton A 2004 Medicinal uses of tobacco in history. Journal of the Royal Society of Medicine 97:292–296.
18 Doll R, Hill A B 1954 The mortality of doctors in relation to their smoking habits. British Medical Journal i:1451–1455.
19 Peto R, Lopez A D, Boreham A et al 1996 Mortality from smoking worldwide. British Medical Bulletin 52:12–21.
20 Environmental Protection Agency (EPA 1992A/600/6–90/006 F).
21 Law M R, Morris J K, Wald N J 1997 Environmental tobacco smoke exposure and ischaemic heart disease: an evaluation of the evidence. British Medical Journal 315:973–988.
22 Tobacco Advisory Group, Royal College of Physicians 2000 Nicotine Addiction in Britain. Royal College of Physicians, London.
23 Fatal nicotine poisoning has been reported from smoking, from swallowing tobacco, from tobacco enemas, from topical application to the skin and from accidental drinking of nicotine insecticide preparations. In 1932 a florist sat down on a chair, on the seat of which a 40% free nicotine insecticide solution had been spilled. Fifteen minutes later he felt ill (vomiting, sweating, faintness and respiratory difficulty, followed by loss of consciousness and cardiac irregularity). He recovered in hospital over about 24 h. On the fourth day he was deemed well enough to leave hospital and was given his clothes, which had been kept in a paper bag. He noticed the trousers were still damp. Within 1 h of leaving hospital he had to be readmitted, suffering again from poisoning due to nicotine absorbed transdermally from his still contaminated trousers. He recovered over 3 weeks, apart from persistent ventricular extrasystoles (Faulkner J M 1933 Journal of the American Medical Association 100:1663).
24 The metabolic rate at rest accounts for about 70% of daily energy expenditure.
25 Peto R, Darby S, Deo H et al 2000 Smoking, smoking cessation and lung cancer in the UK since 1950: combination of national statistics with two case–control studies. British Medical Journal 321:323–329.
26 Smoking and Reproductive Life: The Impact of Smoking on Sexual, Reproductive and Child Health. Available at: http://www.bma.org.uk (accessed 27 October 2011).
27 Lancaster T, Stead L, Silagy C, Sowden A 2000 Effectiveness of interventions to help people to stop smoking: findings from the Cochrane Library. British Medical Journal 321:355–358.
28 Le Houezec J 2005 Why a nicotine vaccine? Clinical Pharmacology and Therapeutics 78:453–455.
29 Roehr B 2005 Half a million Americans use methamfetamine every week. British Medical Journal 332:476.
30 In an extreme usage, a man was estimated to have taken about 40 000 tablets of ecstasy between the ages of 21 and 30 years. At maximum he took 25 pills per day for 4 years. At age 37 years, and after 7 years off the drug, he was experiencing paranoia, hallucinations, depression, severe short-term memory loss, and painful muscle rigidity around the neck and jaw. Several of these features were thought to be permanent. (Kouimtsidis C 2006 Neurological and psychopathological sequelae associated with a lifetime intake of 40 000 ecstasy tablets. Psychosomatics 47:86–87.)
31 The European Union regulations define ‘decaffeinated’ as coffee (bean) containing 0.3% or less of caffeine (normal content 1–3%).
32 The commonest pollen in the air of San Francisco, California, is said to be that of the cannabis plant, illegally cultivated.
33 When a chronic user discontinues, cannabinoids remain detectable in the urine for an average of 4 weeks and it can be as long as 11 weeks before 10 consecutive daily tests are negative (Ellis G M, Mann M A, Judson B A et al 1985 Excretion patterns of cannabinoid metabolites after last use in a group of chronic users. Clinical Pharmacology and Therapeutics 38(5):572–578).
34 Yesavage J A, Leirer V O, Denari M, Hollister L E 1985 ‘Hangover’ effects of marijuana intoxication in airline pilots. American Journal of Psychiatry 142:1325–1328.
35 Working Party Report 2005 Cannabis and Cannabis-Based Medicines: Potential Benefits and Risks to Health. Royal College of Physicians, London.
36 Van Gaal L F, Rissanen A M, Scheen A J et al 2005 Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 365:1389–1397.
37 Henquet C, Murray R, Linszen D, van Os J 2005 Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people. British Medical Journal 330:11–14.
38 Bass M 1970 Sudden sniffing death. Journal of the American Medical Association 212:2075.