Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 12B) pdf

10 NONMEDICAL USE OF DRUGS Chronic consumption For benefits of chronic alcohol consumption, see page 187. Central nervous system. The development of dependence on alcohol appears to involve alterations in central nervous system neurotransmission. The acute effect of alcohol is to block NMDA receptors for which the normal agonist is glutamate, the main excitatory transmitter in the brain. Chronic exposure increases the number of NMDA receptors and also 'L type' calcium channels, while the action of the (inhibitory) GABA 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). Malnutrition. With heavy continuous drinking, subjects take all the calories they need from alcohol, cease to eat adequately and develop deficiency of B group vitamins particularly. The malnutrition complicates the long-term effects of alcohol itself. Organ damage. Chronic heavy alcohol use is associated with: hepatic cirrhosis, deteriorating brain function (psychotic states, dementia, seizures, Wernicke's encephalopathy, episodes of loss of memory); peripheral neuropathy and, separately, myopathy (including cardiomyopathy); cancer of the upper alimentary and respiratory tracts (many alcoholics also smoke heavily, and this contributes), hepatic carcinoma and breast cancer in women; chronic pancreatitis; cardiomyopathy; bone marrow depression, including megaloblastosis (due to the alcohol and to alcohol-induced folate deficiency); deficiency of vitamin K-dependent blood clotting factors (due to liver injury); psoriasis; multiple effects on the hypothalamic/pituitary/endocrine system (endocrine investigations should be interpreted cautiously); Dupuytren's contracture. Hypertension. Heavy chronic use of alcohol is an important cause of hypertension and this should always be considered in both diagnosis and management. Cessation of use may be sufficient to eliminate or reduce the need for drug therapy. But even social drinking can raise blood pressure, and hypertensives should be told this. In general, 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, France, in the 1939-45 war, deaths from hepatic cirrhosis dropped to about one-sixth the previous level; 5 years after the war they had regained their former level. Blood lipoproteins. Moderate intake of alcoholic drinks may increase high density lipoprotein and diminish low density lipoprotein, which may account for the observed protective effect against ischaemic heart disease (see below). Alcohol dependence syndrome 32 General aspects of dependence are discussed earlier in this chapter. Dependence (chronic alcoholism) varies from social drinkers for whom companionship is the principal factor, through individuals who take a drink at the end of a working (or indeed any) day, who feel a need and who would be reluctant to give it up, to the person who is overcome by need, who cannot resist and whose whole life is dominated by the quest for alcohol. The major factors determining physical dependence are dose, frequency of dosing, and duration of abuse. 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 h and an acute psychotic attack (del- irium tremens) and seizures (at 72 h). Withdrawal should be supervised in hospital with the patient receiving chlordiazepoxide by mouth 32 A World Health Organization report prefers this term to 'alcoholism'. 184 CHRONIC CONSUMPTION 10 Fig. 10.4 Features of alcohol dependence. 10-50 mg qid, gradually reducing over 7-10 d. Longer exposure to chlordiazepoxide should be avoided as it has the potential to induce depend- ence. A B-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 i.v. glucose unaccompanied by thiamine may precipitate Wernicke's encephalopathy. Treatment of alcohol dependence Psychosocial support is more important than drugs, which nevertheless may help. Acamprosate bears a structural resemblance to both glutamate and GABA and appears to reduce the effect of excitatory amino acids such as glutamate, and modifies GABA neurotransmission. Taken for 1 year (accompanied by counselling and psycho- social support), acamprosate increases the number 185 10 NONMEDICAL USE OF DRUGS of alcohol-free days and also the chance of sub- sequent complete abstinence. The benefit may last for 1 year after stopping treatment. Acamprosate may cause gastrointestinal adverse effects, and cutaneous eruptions. Disulfiram (Antabuse). In alcoholics who are well and motivated, an attempt may be made to dis- courage drinking by inducing immediate unpleas- antness. Disulfiram inhibits the enzyme aldehyde dehydrogenase so that acetaldehyde (toxic meta- bolite of alcohol) accumulates. The objective of administering disulfiram is that patients will find the experience so unpleasant that they will avoid alcohol. 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. It 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; they may last several hours. Some advocate the use of a test dose of alcohol under supervision (after the fifth day), so that patients can be taught what to expect and also to induce an aversion from alcohol. SAFE LIMITS FOR CHRONIC CONSUMPTION These cannot be accurately defined. But both patients and nonpatients 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): men, not more than 21 units per week (and not more than 4 units in any one day), and women, 14 units per week (and not more than 3 units in any one day). 33 Consistent drinking more than these amounts carries a progressive risk to health (see also Alcoholic drinks and mortality, below). 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. It has long been thought that total con- sumption accumulated over time was the crucial factor for cirrhosis. 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). A standard human cannot metabolise more than about 170 g per day. People whose intake is con- centrated at the weekend allow their livers time for repair and have a lower risk of liver injury than do those who consume the same total on an even daily basis. Pregnancy, the fetus and lactation Pregnancy is unlikely to occur in severely alcoholic women (who have amenorrhoea secondary to liver injury). The spontaneous miscarriage rate in the second trimester is doubled by consumption of 1-2 units/day. Fetal injury can occur in early pregnancy (fetal alcohol syndrome). It may be due to the metabolite, acetaldehyde, and so acute (binge) consumption is more hazardous than similar total intake on a daily basis. The vulnerable period of pregnancy is at 4-10 weeks. Because of this, prevention cannot be reliably achieved after diagnosis of pregnancy (usually 3-8 weeks). There is no level of maternal consumption that can be guaranteed safe for the fetus. But it is plainly unrealistic to leave the matter there, and it has been suggested that if the ideal of total abstinence is unachievable then women who are pregnant or are thinking of becoming pregnant should not drink more than 1-2 units of alcohol per week and should avoid periods of intoxication. 34 In addition to the fetal alcohol syndrome there is general fetal/embryonic growth retardation (1% for 33 Report of an Inter-Departmental Working Group, 1995 Sensible Drinking. Department of Health. 34 Report of an Inter-Departmental Working Group, 1995 Sensible Drinking. Department of Health. 186 10 every 10 g alcohol per day) and this is not 'caught up' later. Fetal alcohol syndrome includes the following characteristics: microcephaly, mental retardation with irritability in infancy low body weight and length, poor coordination, hypotonia, small eyeballs and short palpebral fissures, lack of nasal bridge. 35 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 much 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. Alcoholic drinks and mortality The curve that relates mortality (vertical axis) to alcoholic drink consumption (horizontal axis) is J- shaped; i.e. as consumption rises above zero the all- cause mortality declines, then levels off, and finally rises. The benefit is largely a reduction of deaths due to cardio- and cerebrovascular disease for regular drinkers of 1-2 units/d for men over 40 years and postmenopausal women. Consumption over 2 units/d does not provide any major additional health benefit. The mechanism may be an improve- ment in lipoprotein (HDL/LDL) profiles and perhaps a reduction in platelet aggregation. The effect appears to be due mainly to ethanol itself but nonethanol ingredients (antioxidants, phenols, flavinoids) may contribute (see below). 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). Whether the cardioprotective effect differs between classes of alcoholic drink remains an open issue. Suggestion that wine confers greater advan- 35 For pictures see Streissguth A P et al 1985 Lancet 2: 85-91. ALCOHOL AND OTHER DRUGS tage than spirits was not supported by a review of 12 ecological, 3 case-control and 10 prospective cohort studies. 36 The social importance of alcohol combined with the very substantial scientific problems posed by these studies (including the problem of unreliably reported intakes) render the whole matter controversial. Alcohol and other drugs All cerebral depressants (hypnotics, tranquillisers, antiepileptics, antihistamines) can either potentiate or synergise with alcohol, and this can be important at ordinary doses in relation to car driving. But, when supplies of hypnotics or tranquillisers are given to patients known to drink heavily, they should be warned to omit the drugs when they have been drinking. Deaths have occurred from these combinations. Alcohol-dependent people with a physical toler- ance are relatively tolerant of some other cerebral depressant drugs (hydrocarbon anaesthetics), but of course the synergism with these drugs still occurs. There is no significant acquired cross-tolerance with opioids. A disulfiram-like reaction occurs with metro- nidazole, griseofulvin, cefamandole, chlorpropamide, procarbazine and (possibly) tinidazine. Oral anticoagulants. Control may be disturbed by alcohol inhibiting hepatic metabolism acutely, or enhancing it by enzyme induction; moderate drinking is unlikely to cause trouble. Antiepilepsy drugs can be metabolised faster due to enzyme induction and this contributes to its well-known adverse effect on epilepsy. Monoamine oxidase inhibitors (MAOIs). Some alco- holic (and de-alcoholised) drinks contain tyramine, sufficient to cause a hypertensive crisis in a patient taking a MAOI. Miscellaneous uses of alcohol. Alcohol precipitates protein and is used to harden the skin in bedridden 36 Rimm E B et al. 1996 Review of moderate alcohol consumption and reduced risk of coronary heart disease: is the effect due to beer, wine or spirits? British Medical Journal 312: 731-741. 187 10 NONMEDICAL USE OF DRUGS patients. Local application also reduces sweating and may allay itching. 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). Psychodysleptics or hallucinogens These substances produce mental changes that resemble those of some psychotic states. They are used by people seeking a new experience or escape. 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. The experience lasts a few hours, depending on the dose; intervals of normality then occur and become progressively longer. Somatic symptoms include nausea, dizziness, paraesthesiae, weakness, drowsiness, tremors, dilated pupils, ataxia. Effects on the cardiovascular system and respiration vary and probably reflect fluc- tuating anxiety. There is no shortage of sensational accounts of experience with psychodysleptics, because there has been a vogue amongst intellectuals, begun by Mr Aldous Huxley, 37 for publishing their experiences. Subsequent accounts are tedious to most except their authors and to those who would do the same; they have little pharmacological importance and reveal more about the author's egocentricity than about pharmacology. The same applies to published accounts of what it is like to be a drug addict. Individual substances 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 less if the subject is blind- folded. 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. LYSERGIDE (LSD) Lysergic acid provides the nucleus of the ergot alkaloids and it was during a study of derivatives of this in a search for an analeptic that in 1943 a Swiss worker investigating LSD (which structurally resem- bles nikethamide) felt peculiar and had visual hallucinations. This led him to take a dose of the substance and so to discover its remarkable potency, an effective oral dose being about 30 microgams. The t l / 2 is 3 h. (See description of experience, above.) Mechanisms of action are complex and include agonist effect at presynaptic 5-HT receptors in the CNS. Tachyphylaxis (acute tolerance) occurs to LSD. Psychological dependence may occur; physical dependence does not. Serious adverse effects include psychotic reactions (which can be delayed in onset) with suicide. LSD has curious effects in animals: green sunfish become aggressive, Siamese fighting fish float nose up, tail down and goats walk in unaccustomed stereotyped patterns. The elephant exhibits episod- 37 Huxley A1964 The doors of preception. Chatto and Windus, London. 188 INDIVIDUAL SUBSTANCES 10 ically a form of sexual or delinquent behaviour known as 'musth'. Mescaline is an alkaloid from the Mexican peyote cactus (derived from the Indian word peyotl, meaning 'divine messenger'), the top of which is cut off and dried and used as 'mescal buttons' in religious ceremonies. Mescaline 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. Tenamfetamine ('ecstasy', MDMA: methylenedioxy- methamphetamine) is structurally related to mesca- line as well as to amphetamine. It was originally patented in 1914 as an appetite suppressant and has recently achieved widespread popularity as a dance drug at 'rave' parties (where it is deemed necessary to keep pace with the beat and duration of the music; 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 a- and (3-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, (3-blockade (atenolol) for tachycardia, a- 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 neuro- degenerative changes accompany long-term use of MDMA. Phencyclidine ('angel dust') was made in a search for a better intravenous anaesthetic. It is structurally related to pethidine. Phencyclidine was found to induce analgesia without unconsciousness, but with amnesia, in man (dissociative anaesthesia). The postoperative course, however, was complicated by psychiatric disturbance. As the interest of anaesthetists waned, so that of psychiatrists grew and the drug has been used in experimental therapy. Ketamine originated from this work. Overdose can cause agitation, abreactions, hallu- cinations and psychosis, and if severe can result in seizures, coma, hyperthermia, muscular rigidity, and rhabdomyolysis. Psilocybin is derived from varieties of the fungus Psilocybe ('magic mushrooms') that grow in many countries. It is related to LSD. CANNABIS Cannabis is obtained from the annual plant Cannabis saliva (hemp) and its varieties Cannabis indica and Cannabis americana. The preparations that are smoked are called marijuana (grass, pot, weed, etc.) 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. Since most preparations are illegally prepared it is not surprising that they are impure and of variable potency. The plant grows wild in the Americas, 38 Africa and Asia. It can also be grown successfully in the open in the warmer southern areas of Britain. Pharmacokinetics Of the scores of chemical compounds that the resin contains, the most important are the oily cannabinoids, including tetrahydrocannabinol (THC), which is the chief cause of the psychic action. 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. As a result, the THC content of samples can vary from almost zero to 8%. 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. 38 The commonest pollen in the air of San Francisco, California is said to be that of the cannabis plant, illegally cultivated. 189 10 NONMEDICAL USE OF DRUGS THC (t 1 /, 4 d) and other cannabinoids undergo extensive biotransformation in the body, yielding scores of metabolites, several of which are them- selves psychoactive. They are extremely lipid- soluble and are stored in body fat from which they are slowly released. 39 Hepatic drug metabolising enzymes are inhibited acutely but may also be induced by chronic use of crude preparations. Pharmacodynamics The discovery of cannabinoid CBj-receptors (expressed by central and peripheral neurones) and CB 2 -receptors (expressed by immune cells) and the presence of endogenous agonists will point the way to identifying its mechanisms of action, although these are as yet not well understood. Psychological reactions are very varied, being much influenced by the behaviour of the group. They commence within minutes of starting to smoke and last 2-3 h. Euphoria is common, though not invariable, with 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 time- lessness. Recent memory and selective attention are impaired; the beginning of a sentence may be forgotten before it is finished, and 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, since 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 wave- like 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 expec- tation of the user and the dose, but also on the environmental situation and personality. Genial or revelatory experiences may indeed occur, e.g. 'Haschich Fudge'. 40 (which anyone can whip up on a rainy day). This is the food of Paradise euphoria and brilliant storms of laughter, ecstatic reveries and extension of one's personality on several simultaneous planes are to be complacently expected. Almost anything St Teresa 41 did, you can do better But this cannot be relied on. The effects can be unpleasant, especially in inexperienced subjects, particularly timelessness and the feeling of loss of control of mental processes. Feelings of unease, sometimes amounting to anguish and acute panic occur as well as 'flashbacks' of previously experienced hallucinations, e.g. on LSD. There is also, especially in the habitual user, a tendency to paranoid thinking. 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 suggests that chronic use may precipitate schizophrenia in vulnerable individuals. The effect of an acute dose usually ends in drowsiness and sleep. It is claimed that death has not occurred. Tolerance, with continued heavy use, and a with- drawal syndrome occur (depression, anxiety, sleep disturbance, tremor and other symptoms). Many users find it very difficult to abandon cannabis. In studies of self-administration by monkeys, sponta- neous 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 39 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 et al 1986 Clinical Pharmacology and Therapeutics 38: 572). 40 From The Alice B Toklas cook book 1954 Michael Joseph, London. The author was companion to Gertrude ('rose is a rose is a rose') Stein (1874-1946). 41 St Teresa of Avila (1515-82) was noted for her power of levitation. 190 INDIVIDUAL SUBSTANCES _10 there appears to be cross-tolerance between cannabinoids and alcohol. 'Amotivational syndrome'. This term dignifies an imprecisely characterised state, ranging from a feeling of unease and sense of not being fully effective, up to a gross lethargy, with social passivity and deterioration. It is difficult to assess, when personal traits and intellectual rejection of techno- logical civilisation are also taken into account. Yet the reversibility of the state, its association with cannabinoid use, and its recognition by cannabis users make it impossible to ignore. (Escalation theory, see p. 171.) Cannabinoids and skilled tasks, e.g. car driving. General performance in both motor and psycho- logical 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. Some scientists claim the effects are negligible but this view has been 'put in proper perspective' by a commentator 42 who asked how these scientists 'would feel if told that the pilot of their international jet taking them to a psychologists' conference, was just having a reefer or two before opening up the controls'. Other effects. Cannabis smoked or taken by mouth produces reddening of the eyeballs (probably the forerunner of the general dilatation of blood vessels and fall of blood pressure with higher doses), unsteadiness (particularly for precise movements), and tachycardia. The smoke produces the usual smoker's cough and delivers much more tar than tobacco cigarettes; the tar from reefer cigarettes is as carcinogenic in animal experiments as cigarette tobacco tar. Increase in appetite is commonly experienced. Cannabinoids are teratogenic in animals, but effect in humans is unproved, although there is impaired fetal growth with repeated use. A therapeutic role has been suggested for cannabi- noids in a variety of conditions including chronic 42 Dr G Milner. pain, migraine headaches, muscle spasticity in multiple sclerosis or spinal cord injury, movement disorders, appetite stimulation in AIDS patients and nausea and vomiting. One systematic review concluded that cannabinoids were no more effective that codeine for acute or chronic pain although most of the trials were conducted in the 1970s. 43 A further review concluded that cannabinoids protected against nausea and vomiting induced by chemo- therapy but the studies were conducted mainly in the 1980s, i.e. before the introduction of the (highly effective) serotonin receptor antagonists. 44 Clinical trials now in progress will clarify the value of individual cannabinoids in such conditions, their profile of adverse effects and comparison with other drug and non-drug therapies. MANAGEMENT OF ADVERSE REACTIONS 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). The objective is to help patients relate their experience to reality and to appreciate that the mental experiences are drug-induced and will abate. Because short-term memory is disrupted the treatment can be very time- consuming since therapists cannot absent themselves without risking relapse. But with phencyclidine such intervention may have the opposite effect, i.e. overstimulation. It is therefore appropriate to sedate all anxious or excited subjects with diazepam (or haloperidol). With sedation the 'premorbid ego' may be rapidly re-established. If the user's 'bad trip' is due to overdose of an antimuscarinic drug, natural or synthetic, then diazepam is specially preferred, or a neuroleptic with no or minimal antimuscarinic effects, e.g. haloperidol. A dose of an anticholinesterase that penetrates the central nervous system (physostig- 43 Campbell FA et al 2001 Are cannabinoids an effective and safe treatment option in the management of pain? A quantitative systematic review. British Medical Journal 323: 13-16. 44 Tramer MR et al 2001 Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. British Medical Journal 323:16-20. 191 10 NONMEDICAL USE OF DRUGS mine, tacrine) is effective in severe reaction to an antimuscarinic. Stimulants COCAINE Cocaine (see also Local anaesthetics, p. 422) use is a widespread and ancient practice amongst South American peasants who chew coca leaves with lime to release the alkaloid. It is claimed to give relief from fatigue and hunger; from altitude sickness in the Andes, experienced even by natives when journeying by car or other 'fast' trans- portation; and also to induce a pleasant introverted mental state. Remarkable feats of endurance attributed to chewing coca leaves have been reported, but there is no sound scientific confirmation of them. A United Nations enquiry into coca-leaf chewing reported that there was psychological but no physical dependence. It also reported that its use caused physical exhaustion rather than the reverse, and advocated gradual suppression in the interest of the populations concerned. But 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, not for leaf chewing, but for the manufacture and export of purified cocaine to supply an eager and lucrative demand from unhappy but economically richer societies where its use constitutes an intractable social problem. These economically developed societies, which cannot control social demand and importation, seek to eliminate the drug at its source in peasant societies that have come to rely on it for economic subsistence. When coca plantations are destroyed great distress to local populations ensues by a combination of economic deprivation and removal of the coca leaf, which, when used in the traditional way, helps to make tolerable lives of deprivation. Cocaine (snow) is used as snuff (snorting), swallowed, smoked (below) or injected i.v. 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 hours to days. After the 'crash' there may be depression ('cocaine blues') and decreased capacity to experience pleasure (anhedonia) for days to weeks. Psychological dependence with intense compul- sive drug-seeking behaviour is characteristic of even short-term use, but physical dependence is arguably slight or absent. Tachyphylaxis, acute tolerance, occurs. The psychotropic effects of cocaine are similar to those of amfetamine (euphoria and excitement) but briefer and are due to blockade of the reuptake of dopamine at central nervous system synapses, which increases its concentration at receptors and produces the characteristic 'high'. Intranasal use causes mucosal vasoconstriction, anosmia and eventually necrosis and perforation of the nasal septum. Smoking involves converting the nonvolatile HC1 into the volatile 'free base' or 'crack' (by extracting the HC1 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 i.v. injection. It induces an intense euphoric state. The mouth and pharynx become anaesthetised. Intravenous use gives the expected rapid effect (kick, flash, rush). Cocaine may be mixed with heroin (as 'speedball'). Cocaine is metabolised by plasma esterases; the i l / 2 is 50 min. Overdose is common amongst users (up to 22% of heavy users report losing consciousness). The desired euphoria and excitement turns to acute fear, with psychotic symptoms, convulsions, hypertension, haemorrhagic storke, tachycardia, arrhythmias, hyperthermia; coronary 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 amongst, e.g. haloperidol (rather than chlorpromazine) for mental disturbance; diazepam for convulsions; a vasodilator, e.g. a calcium channel blocker, for hypertension; glyceryl trinirrate for myocardial ischaemia (but not a P- 192 STIMULANTS 10 blocker which aggravates cocaine-induced coronary vasospasm). Fetal growth is retarded by maternal use, but teratogenicity is uncertain. AMFETAMINES Amfetamine has had multifarious uses. It is now obsolete for depression and as an appetite suppres- sant, and its use in sport is abuse (see before). There is concern that its illicit use as a psychostimulant is widespread. Amfetamine is a racemic compound: the laevo-form is relatively inactive but dexamphet- amine (the dextro- isomer) finds use in medicine. Amfetamine will be described, and structurally- related drugs only in the ways in which they differ. Mode of action. Amfetamine acts by releasing noradrenaline (norepinephrine) stored in nerve endings in both the CNS and the periphery. As with all drugs acting on the central nervous system, the psychological effects vary with mood, personality and environment, as well as with dose. Subjects become euphoric and fatigue is post- poned. 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. On the other hand 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 con- sumption and this, together with vasoconstriction and restlessness, leads to hyperthermia in overdose, especially if the subject exercises. Dependence on amfetamine and similar sympa- thomimetics occurs; it is chiefly psychological, but there is a withdrawal syndrome, suggesting physical dependence; tolerance occurs. Mild dependence on prescribed amfetamines became common, particularly amongst people with unstable personalities, depressives and tired, lonely housewives. In the 1960s, adolescents began to turn to amfetamines for occasional use to keep awake to have 'fun' and then as an aid to the challenges normal to that stage of life. Unfortunately, drugs provide only the temporary solution of avoidance and postponement of such challenges, retarding rather than assisting progress to maturity. As well as oral use, i.v. administration (with the pleasurable 'flash' as with opioids) is employed. Severe dependence induces behaviour disorders, hallucinations and even florid psychosis, which can be controlled by haloperidol. Withdrawal is accompanied by lethargy, sleep, desire for food and sometimes severe depression, which leads to an urge to resume the drug. Pharmacokinetics. Amfetamine (i l / 2 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. Interactions are as expected from mode of action, e.g. antagonism of antihypertensives; severe hyper- tension with MAOIs and (3-adrenoceptor blocking drugs. Acute poisoning is manifested by excitement and peripheral sympathomimetic effects; convulsions may occur; also, in acute or chronic overuse, a state resembling hyperactive paranoid schizophrenia with hallucinations develops. Hyperthermia occurs with cardiac arrhythmias, vascular collapse and death. Treatment is chlorpromazine with added antihypertensive, e.g. labetalol, if necessary; these provide sedation and a- and (3-adrenoceptor blockade (not a p-blocker alone), rendering unnecessary the 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 dexamfet- amine (used for narcolepsy and in attention defi- cit hyperactivity disorder (ADHD) see p. 387), methylphenidate (used for ADHD), tenamfetamine (Ecstasy, see p. 189), phentermine, diethylpropion, and pemoline. 193 [...]... 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 is of no clinical importance Mode of action Caffeine and theophylline have complex and incompletely elucidated actions, which include inhibition of phosphodiesterase (the enzyme that breaks down cyclic AMP, see... 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 . before 10 consecutive daily tests are negative (Ellis G M et al 1986 Clinical Pharmacology and Therapeutics 38: 572). 40 From The Alice B Toklas. importance and reveal more about the author's egocentricity than about pharmacology. The same applies to published accounts of what it is like