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TOXICITY OF TRANQUILLISERS
270 In all patients with evidence of cerebrovascular disease the " dilution curve " was broadened. The circulation-time was particularly prolonged where the injected artery was occluded or stenosed. The circulationtime was shorter between one carotid and the ipsilateral jugular bulb than the contralateral jugular bulb. A general fall in blood-pressure further slowed the circulation-time, supporting the view of Meyer and Denny-Brown 23 that collateral circulation is particularly sensitive to variations in the systemic blood-pressure, a fall in which will render inadequate a pial blood-flow which suffices at normal pressures. With four main arteries of supply and a complex, dividing, venous outflow, the dilution curve represents an integration of several component curves. The mathematical formulas by which the blood-flow and the bloodpool of the brain are derived have not been perfected: different methods of calculating the blood-pool in the brain in the same individual may yield values differing by 100%. Nevertheless estimation of circulation-time alone proved sufficiently sensitive to show changes in circulation-time in cerebrovascular disease when no other method would do so; and Nylin et al. conclude that it may be feasible to determine this time by an external counter without puncturing the jugular bulb. Such a measurement could be made in conjunction with angiography. If indeed labelled erythrocytes give different information from a water-soluble dye, this type of investigation may have practical value.
time.
TOXICITY OF
and administration of central stimulants. Gastric lavage is often necessary as an overdose of phenothiazines hinders the induction of vomiting. Noradrenaline should be administered to counteract hypotension due to phenothiazines .21 Barbiturates control the convulsions and extrapyramidal symptoms of phenothiazine intoxication, Chlorpromazine is bound to plasma-proteins, and in children exchange transfusion may be indicated to remove most of the circulating drug.
TRANQUILLISERS
KNOWLEDGE of the toxic effects of drugs introduced into psychiatric treatment emerges only after extensive clinical use. In preliminary animal experiments over-
dosage is intentionally applied to establish the minimum lethal dose, therapeutic margin, and toxicity; but the findings are not necessarily applicable to man. Information on accidental poisoning with these drugs, such as the 280 cases collected in the U.S.A. by the National Clearing-house for Poison Control Centres,24 is therefore particularly valuable. The largest group consisted of 112 cases of overdosage with meprobamate or other drugs with a similar actionreflecting the widespread use of such preparations in the U.S.A. The remaining cases were due almost equally to rauwolfia alkaloids and phenothiazine derivatives, of which chlorpromazine was the most commonly involved. In many cases the exact amount of the drug ingested could not be established. Nearly two-thirds of all cases in children under 5 years of age. Toxic manifestations occurred in 45% of cases of overdosage reported; their incidence was about three times higher in adults than in children. Meprobamate overdosage was associated with drowsiness, ataxia, coma, hypotension, convulsions, and muscular flaccidity. The signs of reserpine overdosage were mild; flushing secondary to release of vasomotor control 25 was the commonest. Drowsiness, hypotension, convulsions, and extrapyramidal symptoms followed overdosage with phenothiazines-in particular prochlorperazine, perphenazine, and promazine. were
Treatment is on the lines usually followed with depressants of the central nervous system: removal of the offending substance, maintenance of pulmonary ventilation, 23. 24. 25.
Meyer, J. S., Denny-Brown, D. Neurology, 1957, 7, 447. Cann, H. M., Verhulst, H. L. New Engl. J. Med. 1960, 263, 719. Costa, E. Int. Rev. Neurobiol. 1960, 2, 175.
DEGLUTITION
OUR understanding of the normal mechanism of swallowing has increased considerably, primarily as a result of extensive cineradiographic studies. 27-33 The behaviour of the tongue and epiglottis and the mechanism of pharyngeal expression have been described, but many details await investigation : for instance, biting and mastication34 have only recently been considered. But with existing knowledge it is now possible to study dysphagia and to understand abnormalities of deglutition much
fully. Cineradiography should not yield just a film record of a fluoroscopic examination, but should provide information difficult or impossible to obtain by other methods. A scheme for examination has been described by Ardran and Kemp.35 Information may be obtained as to tongue, soft palate, and nasopharyngeal-sphincter function; the effectiveness of the pharyngeal expressor mechanism; the competence of the laryngeal sphincter; and the cause of material entering the airway. The function of the cricopharyngeus, oesophagus, and lower cesophageal sphincter can also be studied. Thus a considerable amount of information may be obtained beyond that concerning filling defects or strictures which can be demonstrated by routine methods. In examining very ill patients (e.g., those with relatively severe bulbar palsy) only small quantities of fluid barium are used, with the patient in the horizontal position, and if necessary with bedside cinefluorographic apparatus.36 As apparatus and skilled workers become available, the cineradiographic method will be increasingly used. But this method is unnecessary for the investigation of every patient with difficulty in swallowing : it should be reserved for ill patients and those in whom the routine methods do not give a clear-cut answer. (It must not be forgotten that symptoms and signs may arise in the cervical region from lesions in the lower oesophagus.) Clinical application
more
of this method owes much to the work of Shedd et al.1138 and of Ardran and Kemp.39 Operative treatment of swallowing defects due to causes other than neoplasm and of defects resulting from surgery is still in its infancy; but in selected cases of pharyngeal palsy Kaplan’s operation 40 for division of the cricopharyngeus has proved of value. Foster, C. A., O’Mullane, E. J., Gaskell, P., Churchill-Davidson, H. C. Lancet, 1954, ii, 614. 27. Rushmer, R. F., Hendron, J. A. J. appl. Physiol. 1951, 3, 622. 28. Ardran, G. M., Kemp, F. H. Brit. J. Radiol. 1952, 25, 406 29. Ardran, G. M., Kemp, F. H. Acta pœdiat., Stockh. 1959, 48, 261. 30. Ramsey, G. H., Watson, J. S., Gramiak, M. D., Weinberg, S. A. Radiology, 1955, 64, 498. 31. Saunders, J. B. DeC. M., Davis, C., Miller, E. R. Ann. Otol., &c., St. Louis, 1951, 60, 897. 32. Bosma, J. F. Physiol. Rev. 1957, 37, 275. 33. Roberts, R. I. Brit. J. Radiol. 1957, 30, 449. 34. Ardran, G. M., Kemp, F. H. Dent. Practit. 1960, 11, 23. 35. Ardran, G. M., Kemp, F. H. Acta radiol., Stockh. 1956, 46, 446. 36. Ardran, G. M., Wyatt, D. G. Brit. J. Radiol. 1957, 30, 52. 37. Shedd, D. P., Kirchner, J. A., Scatliff, J. H. Surg. Gynec. Obstet. 1960, 110, 69. 38. Shedd, D. P., Scatliff, J. H., Kirchner, J. A. Surgery, 1960, 48, 846. 39. Ardran, G. M., Kemp, F. H. Brit. J. Radiol. 1957, 30, 169. 40. Kaplan, S. Ann. Surg. 1951, 133, 572.
26.
time.
TOXICITY OF
and administration of central stimulants. Gastric lavage is often necessary as an overdose of phenothiazines hinders the induction of vomiting. Noradrenaline should be administered to counteract hypotension due to phenothiazines .21 Barbiturates control the convulsions and extrapyramidal symptoms of phenothiazine intoxication, Chlorpromazine is bound to plasma-proteins, and in children exchange transfusion may be indicated to remove most of the circulating drug.
TRANQUILLISERS
KNOWLEDGE of the toxic effects of drugs introduced into psychiatric treatment emerges only after extensive clinical use. In preliminary animal experiments over-
dosage is intentionally applied to establish the minimum lethal dose, therapeutic margin, and toxicity; but the findings are not necessarily applicable to man. Information on accidental poisoning with these drugs, such as the 280 cases collected in the U.S.A. by the National Clearing-house for Poison Control Centres,24 is therefore particularly valuable. The largest group consisted of 112 cases of overdosage with meprobamate or other drugs with a similar actionreflecting the widespread use of such preparations in the U.S.A. The remaining cases were due almost equally to rauwolfia alkaloids and phenothiazine derivatives, of which chlorpromazine was the most commonly involved. In many cases the exact amount of the drug ingested could not be established. Nearly two-thirds of all cases in children under 5 years of age. Toxic manifestations occurred in 45% of cases of overdosage reported; their incidence was about three times higher in adults than in children. Meprobamate overdosage was associated with drowsiness, ataxia, coma, hypotension, convulsions, and muscular flaccidity. The signs of reserpine overdosage were mild; flushing secondary to release of vasomotor control 25 was the commonest. Drowsiness, hypotension, convulsions, and extrapyramidal symptoms followed overdosage with phenothiazines-in particular prochlorperazine, perphenazine, and promazine. were
Treatment is on the lines usually followed with depressants of the central nervous system: removal of the offending substance, maintenance of pulmonary ventilation, 23. 24. 25.
Meyer, J. S., Denny-Brown, D. Neurology, 1957, 7, 447. Cann, H. M., Verhulst, H. L. New Engl. J. Med. 1960, 263, 719. Costa, E. Int. Rev. Neurobiol. 1960, 2, 175.
DEGLUTITION
OUR understanding of the normal mechanism of swallowing has increased considerably, primarily as a result of extensive cineradiographic studies. 27-33 The behaviour of the tongue and epiglottis and the mechanism of pharyngeal expression have been described, but many details await investigation : for instance, biting and mastication34 have only recently been considered. But with existing knowledge it is now possible to study dysphagia and to understand abnormalities of deglutition much
fully. Cineradiography should not yield just a film record of a fluoroscopic examination, but should provide information difficult or impossible to obtain by other methods. A scheme for examination has been described by Ardran and Kemp.35 Information may be obtained as to tongue, soft palate, and nasopharyngeal-sphincter function; the effectiveness of the pharyngeal expressor mechanism; the competence of the laryngeal sphincter; and the cause of material entering the airway. The function of the cricopharyngeus, oesophagus, and lower cesophageal sphincter can also be studied. Thus a considerable amount of information may be obtained beyond that concerning filling defects or strictures which can be demonstrated by routine methods. In examining very ill patients (e.g., those with relatively severe bulbar palsy) only small quantities of fluid barium are used, with the patient in the horizontal position, and if necessary with bedside cinefluorographic apparatus.36 As apparatus and skilled workers become available, the cineradiographic method will be increasingly used. But this method is unnecessary for the investigation of every patient with difficulty in swallowing : it should be reserved for ill patients and those in whom the routine methods do not give a clear-cut answer. (It must not be forgotten that symptoms and signs may arise in the cervical region from lesions in the lower oesophagus.) Clinical application
more
of this method owes much to the work of Shedd et al.1138 and of Ardran and Kemp.39 Operative treatment of swallowing defects due to causes other than neoplasm and of defects resulting from surgery is still in its infancy; but in selected cases of pharyngeal palsy Kaplan’s operation 40 for division of the cricopharyngeus has proved of value. Foster, C. A., O’Mullane, E. J., Gaskell, P., Churchill-Davidson, H. C. Lancet, 1954, ii, 614. 27. Rushmer, R. F., Hendron, J. A. J. appl. Physiol. 1951, 3, 622. 28. Ardran, G. M., Kemp, F. H. Brit. J. Radiol. 1952, 25, 406 29. Ardran, G. M., Kemp, F. H. Acta pœdiat., Stockh. 1959, 48, 261. 30. Ramsey, G. H., Watson, J. S., Gramiak, M. D., Weinberg, S. A. Radiology, 1955, 64, 498. 31. Saunders, J. B. DeC. M., Davis, C., Miller, E. R. Ann. Otol., &c., St. Louis, 1951, 60, 897. 32. Bosma, J. F. Physiol. Rev. 1957, 37, 275. 33. Roberts, R. I. Brit. J. Radiol. 1957, 30, 449. 34. Ardran, G. M., Kemp, F. H. Dent. Practit. 1960, 11, 23. 35. Ardran, G. M., Kemp, F. H. Acta radiol., Stockh. 1956, 46, 446. 36. Ardran, G. M., Wyatt, D. G. Brit. J. Radiol. 1957, 30, 52. 37. Shedd, D. P., Kirchner, J. A., Scatliff, J. H. Surg. Gynec. Obstet. 1960, 110, 69. 38. Shedd, D. P., Scatliff, J. H., Kirchner, J. A. Surgery, 1960, 48, 846. 39. Ardran, G. M., Kemp, F. H. Brit. J. Radiol. 1957, 30, 169. 40. Kaplan, S. Ann. Surg. 1951, 133, 572.
26.