37
schizophrenics
has been
going
on
all
over
the world for
more
than twenty years. Further details, relating to this fluphenazine-treated sample to all schizophrenics in the base population, and to defaulters, will be published. Psychiatry Department, Hope Hospital, Eccles Old Road,
Salford M6 8HD.
HUGH FREEMAN
ABUSE OF NON-AMPHETAMINE APPETITE SUPPRESSANTS
SIR,-Although the abuse potential of amphetamines and related drugs is widely appreciated, there is still need for caution in the use of appetite suppressants which are supposedly non-euphoriant. During the past 18 months I have been seeing an increase in the abuse of diethylpropion, especially the slow-release preparation ’Tenuate Dospan’. This has prompted me to ask around among "experienced" drug addicts attending the St Giles’ Hospital drug-dependence clinic and Guy’s. The addicts confirmed my impression that this particular preparation seems to have a bigger abuse potential than I had previously thought. Patients who abuse it as a preferred drug may often take surprisingly high doses. One such patient, a 22-year-old woman, had been taking over 200 tenuate dospan a week. These were all prescribed for her by her doctor for the treatment of a "weight problem". She would frequently take 20 or more at a time, and after a first admission to Guy’s Hospital she was transferred to the drug-dependence unit at Bexley Hospital, where she has had several readmissions. In each instance she presents with extreme restlessness, sweating profusely, and with severe persistent tachycardia which can be only slightly reduced with exprenolol. Usually the tachycardia takes up to ten days to settle. Her mental state is usually characterised by perplexity, incoherent thinking, and severe visual and auditory hallucinosis. Admittedly, she is an extreme example, but she does illustrate that diethylpropion can be abused, and I suspect that it is a drug that may be being misused a good deal more widely than we realise, since its euphoriant action must be greater than had at first been thought. It is possible that people may be using this drug as a substitute for the amphetamines. Other newer appetite suppressants may also be suspect. Two patients have reported to me that mazindol (’Teronac’) is an effective hallucinogen. On the other hand, I would suggest that, despite the apparent cardiovascular hazard of fenfluramine, it is probably the appetite suppressant with the lowest abuse potential. Patients of mine who have abused it felt so unwell that they never repeated the experience. Incidentally, may I add that self-reporting of mind-altering effects by patients is an excellent early-warning system. Department of Psychological Medicine, Guy’s Hospital, London SE1.
J. H. WILLIS
SALBUTAMOL AEROSOL IN PREMATURE LABOUR
SiR,-Dr Hastwell’s findings’ that oral salbutamol 4-8 mg taken every 4-6 h can effectively postpone premature labour for at least a week is not unexpected in view of previous results obtained by Liggins and Vaughan2and others3 with the same drug given by intravenous infusion. Although there is a wide variation in dosage, many patients in these two studies received about 40 g/min, and most needed 14-43 g/rnin to 1. Hastwell, G. B. Lancet, 1975, ii, 1212. 2. Liggins, G. C., Vaughan, G. S. J. Obst Gynœc. Br. Commonw. 1973, 80, 29. 3. Sen, D. K., Ng, K. H. Med. J. Malaysia, 1974, 28, 191.
prevent uterine contractions. Since oral salbutamol is well absorbed from the alimentary tract over a period of 2-3 h, the average gross rate of delivery of drug after an 8 mg dose is about 50 g/min, but up to half of it is metabolised in the gut and/or liver during and immediately after its absorption.4I The blood-levels after the oral drug are, therefore, somewhat lower and less precise than those after intravenous infusion, but are of an order that might be expected to be pharmacologi-
cally active in the uterus. Hastwell’s use of ’Ventolin’ inhaler to "top up" blood levels achieved by the oral drug cannot be sound because at most an additional 0-8 of drug is delivered over a 20 min period. At least 80% of this material is swallowed after being deposited in the mouth and throat6 and is, therefore, simply a small supplement to the oral dose. The 0-15mg which finds its way into the respiratory tract is more slowly absorbed than the swallowed portion, because the duration of action of the drug is at least 4 h after two puffs of the inhaler (200 µg) are given by inhalation to asthmatic patients, compared with 3-4 hs after 4 mg of the drug given by mouth. Thus a maximum rate of absorption of drug from the lungs in Hastwell’s dosage schedule is about 1 µg/min, an irrelevant amount when one considers the total drug intake in his patients. The use of ventolin inhaler for the management of premature labour is, therefore, irrational and should not be encouraged. Obstetricians should also be aware that the use of oral salbutamol in premature labour has not been approved by the Licensing Authority nor is it recommended by the manufacturers mainly because they feel that the precision of intravenous dosage is desirable for this indication. Medical Division, Allen & Hanbury’s Research Priory Street,
Ware,
Hertfordshire SG12 0DJ.
Ltd, D. M. HARRIS
REVERSAL BY PHYSOSTIGMINE OF CLOZAPINE-INDUCED DELIRIUM
SIR,-Clozapine is an antipsychonc drug with strong sedative action but with a low incidence of extrapyramidal sideeffects.7 8 It resembles the tricyclic antidepressants in structure and has been reported to be similar in anticholinergic potency to benztropine.9 10 Treatment with clozapine can cause a delirium which occurs also in younger patients with no evidence of previous brain damage.8 We describe here the antagonism of a clozapine-induced delirium by physostigmine. A 25-year-old woman with mania was admitted and treated with 100 mg clozapine (’Leponex’) three times a day. The patient was sedated but then developed signs of central anticholinergic toxicity, became confused and agitated, had dysarthria, and was in delirium with visual and auditory hallucinations on the morning of the third day of treatment. The patient developed hypersalivation, which is a frequent side-effect of clozapine, and had a pulse-rate of 140-150/min. 2 mg physostigmine was given at 10 A.M. by slow intravenous injection with an immediate improvement of her delirium, which lasted for about 30 min, and during this time she had unchanged symptoms of her mania. Her pulse-rate dropped to 100/min, and the clozapine-induced hypersalivation remained unchanged. Physostigmine treatment was repeated at 12.30 with the same reversal of her delirium as before, lasting for about 30 min. 4.
Martin, L. E., Hobson, J. C., Page, Jean, A., Harrison, C. Eur. J. Phar-
mac. 1971, 14, 183. 5 Evans, Marion E., Walker, S. R., Brittain, R T., Patterson, J. W. Xenobiotica, 1973, 3, 113 6. Dollery, C. T., Davies, D. S., Conolly, M. E. Ann. N. Y. Acad. Sci. 1971,
7. 8 9. 10
179, 108. Angst, J., and others Pharmacopsychiatry, 1971, 4, 201. Gross, H. Langner, E. Int. Pharmacopsychiat. 1970, 4, 220. Miller, R. J., Hiley, C. R. Nature, 1975, 248, 596. Snyder, S. H., Greenberg, D., Yamamura, H. I. Archs gen. Psychiat, 1974, 31, 58.
schizophrenics
has been
going
on
all
over
the world for
more
than twenty years. Further details, relating to this fluphenazine-treated sample to all schizophrenics in the base population, and to defaulters, will be published. Psychiatry Department, Hope Hospital, Eccles Old Road,
Salford M6 8HD.
HUGH FREEMAN
ABUSE OF NON-AMPHETAMINE APPETITE SUPPRESSANTS
SIR,-Although the abuse potential of amphetamines and related drugs is widely appreciated, there is still need for caution in the use of appetite suppressants which are supposedly non-euphoriant. During the past 18 months I have been seeing an increase in the abuse of diethylpropion, especially the slow-release preparation ’Tenuate Dospan’. This has prompted me to ask around among "experienced" drug addicts attending the St Giles’ Hospital drug-dependence clinic and Guy’s. The addicts confirmed my impression that this particular preparation seems to have a bigger abuse potential than I had previously thought. Patients who abuse it as a preferred drug may often take surprisingly high doses. One such patient, a 22-year-old woman, had been taking over 200 tenuate dospan a week. These were all prescribed for her by her doctor for the treatment of a "weight problem". She would frequently take 20 or more at a time, and after a first admission to Guy’s Hospital she was transferred to the drug-dependence unit at Bexley Hospital, where she has had several readmissions. In each instance she presents with extreme restlessness, sweating profusely, and with severe persistent tachycardia which can be only slightly reduced with exprenolol. Usually the tachycardia takes up to ten days to settle. Her mental state is usually characterised by perplexity, incoherent thinking, and severe visual and auditory hallucinosis. Admittedly, she is an extreme example, but she does illustrate that diethylpropion can be abused, and I suspect that it is a drug that may be being misused a good deal more widely than we realise, since its euphoriant action must be greater than had at first been thought. It is possible that people may be using this drug as a substitute for the amphetamines. Other newer appetite suppressants may also be suspect. Two patients have reported to me that mazindol (’Teronac’) is an effective hallucinogen. On the other hand, I would suggest that, despite the apparent cardiovascular hazard of fenfluramine, it is probably the appetite suppressant with the lowest abuse potential. Patients of mine who have abused it felt so unwell that they never repeated the experience. Incidentally, may I add that self-reporting of mind-altering effects by patients is an excellent early-warning system. Department of Psychological Medicine, Guy’s Hospital, London SE1.
J. H. WILLIS
SALBUTAMOL AEROSOL IN PREMATURE LABOUR
SiR,-Dr Hastwell’s findings’ that oral salbutamol 4-8 mg taken every 4-6 h can effectively postpone premature labour for at least a week is not unexpected in view of previous results obtained by Liggins and Vaughan2and others3 with the same drug given by intravenous infusion. Although there is a wide variation in dosage, many patients in these two studies received about 40 g/min, and most needed 14-43 g/rnin to 1. Hastwell, G. B. Lancet, 1975, ii, 1212. 2. Liggins, G. C., Vaughan, G. S. J. Obst Gynœc. Br. Commonw. 1973, 80, 29. 3. Sen, D. K., Ng, K. H. Med. J. Malaysia, 1974, 28, 191.
prevent uterine contractions. Since oral salbutamol is well absorbed from the alimentary tract over a period of 2-3 h, the average gross rate of delivery of drug after an 8 mg dose is about 50 g/min, but up to half of it is metabolised in the gut and/or liver during and immediately after its absorption.4I The blood-levels after the oral drug are, therefore, somewhat lower and less precise than those after intravenous infusion, but are of an order that might be expected to be pharmacologi-
cally active in the uterus. Hastwell’s use of ’Ventolin’ inhaler to "top up" blood levels achieved by the oral drug cannot be sound because at most an additional 0-8 of drug is delivered over a 20 min period. At least 80% of this material is swallowed after being deposited in the mouth and throat6 and is, therefore, simply a small supplement to the oral dose. The 0-15mg which finds its way into the respiratory tract is more slowly absorbed than the swallowed portion, because the duration of action of the drug is at least 4 h after two puffs of the inhaler (200 µg) are given by inhalation to asthmatic patients, compared with 3-4 hs after 4 mg of the drug given by mouth. Thus a maximum rate of absorption of drug from the lungs in Hastwell’s dosage schedule is about 1 µg/min, an irrelevant amount when one considers the total drug intake in his patients. The use of ventolin inhaler for the management of premature labour is, therefore, irrational and should not be encouraged. Obstetricians should also be aware that the use of oral salbutamol in premature labour has not been approved by the Licensing Authority nor is it recommended by the manufacturers mainly because they feel that the precision of intravenous dosage is desirable for this indication. Medical Division, Allen & Hanbury’s Research Priory Street,
Ware,
Hertfordshire SG12 0DJ.
Ltd, D. M. HARRIS
REVERSAL BY PHYSOSTIGMINE OF CLOZAPINE-INDUCED DELIRIUM
SIR,-Clozapine is an antipsychonc drug with strong sedative action but with a low incidence of extrapyramidal sideeffects.7 8 It resembles the tricyclic antidepressants in structure and has been reported to be similar in anticholinergic potency to benztropine.9 10 Treatment with clozapine can cause a delirium which occurs also in younger patients with no evidence of previous brain damage.8 We describe here the antagonism of a clozapine-induced delirium by physostigmine. A 25-year-old woman with mania was admitted and treated with 100 mg clozapine (’Leponex’) three times a day. The patient was sedated but then developed signs of central anticholinergic toxicity, became confused and agitated, had dysarthria, and was in delirium with visual and auditory hallucinations on the morning of the third day of treatment. The patient developed hypersalivation, which is a frequent side-effect of clozapine, and had a pulse-rate of 140-150/min. 2 mg physostigmine was given at 10 A.M. by slow intravenous injection with an immediate improvement of her delirium, which lasted for about 30 min, and during this time she had unchanged symptoms of her mania. Her pulse-rate dropped to 100/min, and the clozapine-induced hypersalivation remained unchanged. Physostigmine treatment was repeated at 12.30 with the same reversal of her delirium as before, lasting for about 30 min. 4.
Martin, L. E., Hobson, J. C., Page, Jean, A., Harrison, C. Eur. J. Phar-
mac. 1971, 14, 183. 5 Evans, Marion E., Walker, S. R., Brittain, R T., Patterson, J. W. Xenobiotica, 1973, 3, 113 6. Dollery, C. T., Davies, D. S., Conolly, M. E. Ann. N. Y. Acad. Sci. 1971,
7. 8 9. 10
179, 108. Angst, J., and others Pharmacopsychiatry, 1971, 4, 201. Gross, H. Langner, E. Int. Pharmacopsychiat. 1970, 4, 220. Miller, R. J., Hiley, C. R. Nature, 1975, 248, 596. Snyder, S. H., Greenberg, D., Yamamura, H. I. Archs gen. Psychiat, 1974, 31, 58.
