AMPHETAMINES AND OTHER STIMULANTS
CLINICAL USE
OTHER EUPHORIANT DRUGS
SIDE-EFFECTS
TREATMENT OF OBESITY
THE USE OF BARBITURATES
2. The use of barbiturates as hypnotics 2
TABLE I. Barbiturate Hypnotics
SIDE-EFFECTS
Pages: 43 to 46
Creation Date: 1969/01/01
The following notes are extracted from the series "Today's Drugs" published in the British Medical Journal and are reproduced here by permission of the Editor.
Amphetamine was introduced into clinical practice in 1935, at first for the treatment of narcolepsy. The drug's stimulating effect on the central nervous system and the transitory euphoria induced led to its use in depressive illness.
Pharmacologically its properties are not fully worked out, but its stimulant effect is probably due to its ability to release noradrenaline from its binding sites, and this has been shown to hold for brain as well as peripheral sites [ 1] , [ 2] . Reserpine, which also releases noradrenaline from binding sites, but which results in the animal becoming "depressed", seems to release the noradrenaline intracellularly, where it is metabolized by monoamine oxidase. Amphetamine, which stimulates the animal, releases the noradrenaline on to receptor sites, where it is metabolized by catechol-o-methyl transferase.
The amphetamines have limited value in the treatment of endogenous depression. Apart from their having little effect in other than very mild depressive states with symptoms mainly of fatigue, their action is short-lasting and may be followed by an even deeper depression. For this reason they are almost always used only when the depression is limited to one part of the day - for example, early morning - or perhaps to counteract the depressing effect of the major tranquillizers.
They are much more effective in the "neurotic" or neurasthenic states secondary to an inadequate personality, where the patient is unable to cope with everyday tensions, is mildly and chronically depressed, and constantly complains of lethargy and apathy. Unfortunately, because of the nature of the condition, such patients are likely to become dependent on the drugs. Furthermore, if other than small doses are used tolerance may occur, with increasing doses having to be used to obtain the same effect.
For these reasons stimulant drugs should be used only after giving the matter very careful thought, and even then the doctor should prescribe the drugs only in short courses to tide the patient over a particular crisis or with a definite aim such as a return to work. The drugs are best used in a delayed release form, when the stimulant effect is not so dramatic, the "let down" effect is less pronounced, and the danger of habituation and tolerance is decreased.
Amphetamine has side-effects which reflect sympathetic overactivity: dryness of mouth, sweating, tremor, tachycardia, hyper-reflexia, insomnia, and diminution of appetite. Dextroamphetamine (Dexedrine) tends to cause fewer side-effects than amphetamine, and is therefore preferable - in fact amphetamine itself is now seldom used. Dextroamphetamine can be prescribed in combination with amylobarbitone (Drinamyl), and experimental evidence supports the clinical impression that such a combination is more effective than either drug given separately [ 3] .
Methylamphetamine (Methedrine) can be given orally in 5-10 mg. doses as an alternative to dexamphetamine. Its main use, however, is by intravenous injection with or without a barbiturate to produce an abreaction in tense, obsessional patients. Such patients often have difficulty in ventilating resentment and hostility, but with the aid of intravenous methylamphetamine their feelings may be released with considerable relief of tension and any associated somatic symptoms.
Methylphenidate (Ritalin) has a similar but weaker action than the amphetamines. It is given orally in doses of 10-40 mg.
Phenmetrazine (Preludin) is used mainly for its anorexic effects, but many obese patients are mildly depressed or have inadequate personalities, and habituation is not uncommon.
Addiction. Habituation or psychological dependence is not uncommon in "neurotic" depressed patients with inadequate personalities. True addiction with tolerance to the drugs is likely to occur if doses in excess of 30 mg.day of dexamphetamine are used. In such cases the intake may rapidly increase, and the patient may end up by taking the tablets in handfuls to obtain an effect. Surprisingly, the side-effects are few and limited to sympathomimetic effects, such as sweating, palpitation, and dry mouth. The patient can be taken off the drug abruptly, as withdrawal effects are minimal or non-existent, but this is best done in the disciplined environment of a hospital, as relapse is common unless the underlying condition is treated or alternative arrangements are made to support an underlying inadequate personality.
Toxic psychosis. A syndrome resembling paranoid schizophrenia may occur with any of the amphetamines, and though it is commonest in addicts or patients taking large doses of the drug, it may occur after single doses of one or two tablets. Anxiety, restlessness, ideas of reference, and paranoid delusions occur together with visual and auditory hallucinations in a setting of clear consciousness [ 4] . The symptoms rapidly clear up within ten days of stopping the drugs, though occasionally the drugs seem to set off a true schizophrenic illness. Similar toxic psychoses have been described with phenmetrazine and pipradol, though not apparently with methylphenidate, though this may be due more to the relative rarity with which the drug can be obtained for irresponsible use than to its innate properties.
Use with monoamine oxidase inhibitors. The monoamine oxidase inhibitors cause an accumulation of noradrenaline in storage sites all over the body. One of the actions of the amphetamines and other stimulant drugs is to release noradrenaline from these storage sites, and if large amounts are released suddenly into the blood stream there is a consequent sharp rise in blood pressure with severe occipital headache, occasional collapse, and, rarely, a cerebral haemorrhage. Theoretically amphetamines should never be given to patients taking monoamine oxidase inhibitors, but in fact reactions are extremely rare if the drug is given orally, and several experienced psychiatrists regularly prescribe these drugs in combination. Intravenous amphetamine(for example, methylamphetamine) is, however, highly dangerous and absolutely contra-indicated in patients who have taken a monoamine oxidase inhibitor drug in the preceding four weeks.
It is much easier for a doctor to prescribe a low calorie diet than it is for the patient to stick to it. As part of a general regimen of regular support and encouragement, moderate exercise, and possibly the addition of methyl cellulose to provide bulk in the diet, amphetamines may be useful in alleviating hunger.
This anorexic effect only occurs in some patients and to a variable degree, the action occurring 1½-2 hours after an oral dose of 10-15 mg. dexamphetamine. To prevent habituation, the amphetamines should be used once, or at the most twice, a day to counter the periods of greatest hunger and never continued for more than four weeks at a time. The drug can be prescribed again after an interval of a month.
Many amphetamine - related compounds have been introduced for the treatment of anorexia, some, such as diethylpropion (Tenuate) and fenfluramine (Ponderax), having less stimulant effects and yet demonstrating definite anorexic properties in controlled trials. However, all have similar side-effects and all are potentially apt to produce drug dependence. Selection of drug in the management of obesity will be considered in a later article in this series.
The barbiturates in the treatment of psychoneurosis 1
In many cases the barbiturates are still unsurpassed in their ability to relieve anxiety, and they are far cheaper than tranquillizers. But they are apt to cause addiction in predisposed personalities, and a suicidal attempt with a barbiturate is more likely to succeed than with a tranquillizer.
In an acute panic attack a barbiturate in high dosage is probably the most effective treatment - for an adult 400 to 600 mg. of amylobarbitone sodium by mouth, with 100 mg. chlorpromazine if necessary, will produce deep prolonged sleep in 20 to 30 minutes. Subsequent treatment will depend on the circumstances.
1British Medical Journal, 1968, vol. 2, Nos. 5600 and 5602.
The so-called medium-acting barbiturates, such as quinalbarbitone and amylobarbitone sodium, are the most useful both as hypnotics and as sedatives. They are particularly effective in the chronically tense individual with a reasonable personality. An effective se- dative for an anxious or phobic patient is 50 to 100 mg. of amylobarbitone sodium up to three times a day. As tension is relieved it is sometimes replaced by a mild sense of euphoria. It is as well, therefore, to avoid giving barbiturates to a patient liable to become addicted. Some chronically tense patients may need to continue on such a dose continuously or intermittently for years. A number of phobic patients can be helped merely by the knowledge that they have 50 mg. of amylobarbitone sodium in their pockets to use in an emergency.
Longer acting barbiturates such as phenobarbitone are sometimes useful in the treatment of chronic anxiety states in patients who have always reacted to minor stresses with excessive anxiety. But acute anxiety does not respond well to phenobarbitone. The drug should not be used as a hypnotic. Phenobarbitone is a depressing drug, and its use is therefore contra-indicated if there are signs of depression, particularly in older patients. Phenobarbitone is useful in children as a temporary means of reducing excessive excitement and hyperactivity and also as a hypnotic. Unlike adults, young children and infants will often sleep soundly on a small dose of phenobarbitone.
Compared with adults, children can tolerate relatively large doses of barbiturates, but they are not effective in children who are severely disturbed. A phenothiazine derivative such as promethazine (Phenergan), or one of the diazepine tranquillizers, is usually a better choice.
A common symptom of anxiety is difficulty in getting to sleep. Sometimes treatment of this symptom alone will effect an all-round improvement. Some patients displace all their anxiety on to difficulty in getting to sleep and work themselves into a state of panic as bedtime approaches. A hypnotic which ensures a good night's rest will break this pattern and lead to a lessening of anxiety; 200 mg. amylobarbitone sodium, or the equivalent dose of another medium-acting barbiturate, may be most satisfactory for this purpose. But sometimes a non-barbiturate hypnotic, such as diazepam (Valium) 10-15 mg., or glutethimide (Doriden) 250-750 mg., is more satisfactory. Where there is a tendency to waken frequently the hypnotic can be potentiated by adding chlorpromazine 50-100 mg. Promethazine is also a useful hypnotic in a dose of 25-75 mg. for an adult. It is also valuable when given as an elixir to a child.
The barbiturates have been in clinical use for about 50 years, and in that time they have become among the most used and probably also the most misused of the drugs of the twentieth century. According to Ministry of Health statistics about 10% of all prescriptions are for hypnotics and 66% of deaths from accidental overdosage of a drug are due to barbiturates. None the less, barbiturates must still take pride of place in any consideration of hypnotics because none of the other drugs, with the possible exception of chloral hydrate, has stood the test of time, and to date none has been proved to be convincingly superior.
2Note by the Editor: The original articles in the British Medical Journal used propietary names for referring to the various barbituric substances; these have been replaced here by the international non-proprietary names.
The barbiturates are derivatives of barbituric acid. A large number of compounds which have some therapeutic value have been synthesized, but only a few are in general clinical use. They may be used as the acids themselves or as the salts, which are more soluble. Usually it is the sodium salts which are prescribed, but in the case of cyclobarbital it is the calcium salt which is the official preparation.
It is customary to divide the barbiturates into long-, medium-, short-, and very short-acting drugs. The long-acting ones such as phenobarbital are thought of mainly as sedatives and the very short-acting ones, such as thiopental, as anaesthetics. Only the medium- and shortacting barbiturates (table I) are regarded as hypnotics. This classification is based upon pharmacological studies mainly in animals, and its relevance to the therapeutic use of these drugs in man is doubtful. Patients, particularly sick patients, vary much more in their sensitivity to drugs than do experimental animals; and, though it may well be true that in a healthy individual the rate of absorption, metabolism, and excretion of the various barbiturates varies considerably, clinical experience suggests that all of those in common use if given in equivalent dosage will induce sleep after about the same interval and of similar duration. For example, phenobarbital, which is usually regarded as a sedative rather than as a hypnotic, when given in a dose equivalent to that of the so-called medium-acting barbiturates - that is, 200 mg. - has a similar hypnotic effect and does not cause any greater degree of hangover.
Official Name |
ProprietaryName |
Dose(mg.) |
---|---|---|
Allobarbital
|
Dial
|
50-200
|
Amylobarbital
*
|
Amytal
|
100-200
|
Aprobarbital
|
Allonal
|
50-100
|
Bntobarbital
*
|
MonodormSoneryl
|
100-200
|
Cyclobarbital
*
|
PhanodormRapidal
|
200-400
|
Heptabarbital
|
Medomin
|
200-400
|
Pentobarbital
*
|
Nembutal
|
100-200
|
Quinalbarbital
*
|
Seconal
|
100-200
|
* British National Formulary.
There is no convincing evidence that any one barbiturate is a better hypnotic than any other, and nothing to suggest that the newer compounds - for example, heptabarbital - are superior to the well-established drugs such as cyclobarbital or quinalbarbital. Nor are there good reasons for believing that propietary preparations which contain more than one barbiturate are any more efficacious than a single drug. The occurrence of residual sedation or hangover is frequently held up as a disadvantage of the barbiturates. Its occurrence is unpredictable and varies greatly from patient to patient. No barbiturate is completely free from this effect; if used in high therapeutic dosage they will all cause some hangover.
There are few contra-indications to the use of the barbiturates as hypnotics. It is frequently said that they should not be used in patients with renal disease or liver disease. The fate in the body of those barbiturates which are used as hypnotics is not determined by renal excretion, so that there is no good reason why they should not be given to patients with renal disease. On the other hand, they are metabolized in the liver, so there is theoretical justification for caution regarding their use in patients with hepatic disorders. In at least one good study, however, it was shown that patients with cirrhosis of the liver were no more susceptible to the effects of barbiturates than non-cirrhotics. Barbiturates depress the sensitivity of the respiratory centre to the action of carbon dioxide, and they should therefore be used with care in patients with respiratory depression, especially those who are also receiving oxygen. A definite history of a previous sensitivity reaction to a barbiturate and acute intermittent por- phyria are probably the only two absolute contraindications.
When one considers how widely the barbiturates are used, the incidence of side-effects and toxicity from therapeutic doses is extremely low. Rashes are the most common side-effect, and because of their pleomorphic nature they may be very difficult to diagnose; they are more commonly seen with phenobarbital than with the shorter-acting barbiturates. Confusional states in the elderly are often attributed to barbiturates; this is probably not a direct toxic effect but merely the elderly patient's reaction to the sensation of unreality that often accompanies the half-awake state which is prolonged by sedation, and may be very alarming to an elderly patient who is in an unfamiliar environment. Tolerance, habituation, and even addiction to the barbiturates do occur but are less of a danger when these drugs are used as hypnotics than when they are used as daytime sedatives. The physician should be on his guard, however, if he finds that a patient who cannot get to sleep is using progressively larger doses of a barbiturate, or if a patient continues to ask for the drug after the apparent indication for its use has passed. One peculiar danger of the use of barbiturates as hypnotics is the phenomenon of unconscious repetition of the dose; the patient takes his hypnotic dose at the correct time, falls asleep, wakens, thinks he has forgotten to take his tablets, and repeats the dose. This risk can be minimized by advising the patient never to keep the tablets at the bedside.
J. Glowinski and J. Axelrod, J. Pharmacol. exp. Ther ., 1965, 149, 43.
002J. Glowinski, J. Axelrod and L. L. Iversen, J. Pharmacol. exp . Ther., 1966, 153, 30.
003H. Steinberg, The scientific Basis of Drug Therapy in Psychiatry , ed. J. Marks and C. M. B. Pare, Oxford, 1965, p. 25.
004P. H. Connell, Amphetamine Psychosis, 1958, London.
(British Medical Journal , 1968, vol. 1, No. 5594, pp. 753-754.)