Drug dependence

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Chapter 11 Drug dependence

Stephen Haydock

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

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 Also cannabis, magic mushrooms
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

Between 2007/8 and 2008/9

None

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 spectrometry ⁶ 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) GABA_A-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
People of Asian origin (particularly Japanese) develop flushing, headache and nausea after what are small doses
May be due to slow metabolism of toxic acetaldehyde by variant forms of alcohol dehydrogenase

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) GABA_A 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

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 Chronic administration induces metabolism and reduces efficacy
Anticonvulsants	phenytoin	Acute alcohol ingestion increases availability and side effect profile Chronic administration induces metabolism and can increase seizure frequency
Anaesthetics	propofol	Chronic alcohol ingestion results in resistance to effects of anaesthetic agents such that increased doses are required. Chronic consumption may increase risk of liver damage from halothane and enflurane
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 GABA_A–benzodiazepine receptor complex (see p. 339 and Fig. 20.5) and all readily induce tolerance and dependence.

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 t_½ 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 t_½ 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 t_½ (20 h).

Pharmacodynamics

Large doses ²³

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.

• 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

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 t_½ 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 t_½ 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.