80
mines; and lately there has also been alarm about their long-term effect on the atmosphere which might increase risks of skin cancer. Reviewing the toxicity of C.F.C.S, McLean2 concludes that the main risk is associated with misuse among "sniffers", who inhale them for kicks and may die with cardiac dysrhythmias. There seems to be no hazard in household use ofc.F.c. propellants in spray cans, nor does there seem to be an increased risk of sudden death among workers who make refrigerators, frozen food, or foam plastic. There has been a report of palpitations among pathology staff preparing frozen sections3 but the inhaled-air concentration of the particular c.F.c. was many times lower than that required to produce experimental dysrhythmias in animals: this matter needs prospective investigation. The possibility that industrial pollutants might influence ozone concentrations in the stratosphere cannot be dismissed but, as McLean points out, there is probably greater cause for concern about the oxides of nitrogen in the air, to which we are subjected and about which we do not hear so much. Furthermore, there has already been a great reduction in the use of c..c. propellants in aerosol cans. A good manufacturer will exclude any unnecessary ingredient of a preparation, especially if that ingredient is suspected of an undesirable effect. Most of us, no doubt, had come to accept that aerosol preparations of drugs for inhalation required some propellant or vehicle for satisfactory delivery. The introduction of the ’Spinhaler’ for delivery of disodium cromoglycate in the form of ’Intal’ showed that this was not true. Now a device which delivers salbutamol as a drug powder in a lactose base for inhalation has been described,4 and first clinical trials5.6 show that it is well tolerated with bronchodilator properties similar to those of the conventional pressurised aerosol. If further controlled studies confirm these results with salbutamol, then the onus will be on the manufacturers of other such drugs to produce preparations free of c.F.c. propellants. As McLean concludes : "Economic disruption that would be caused by a sudden ban on CFC spray cans would be unjustified, but the replacement of CFC spray cans by alternatives over the next three years would seem practical and desirable." INTRAVENOUS VERSUS INHALED SALBUTAMOL AN uncomfortable hiatus in the management of acute asthma often occurs shortly after admission, whilst the beneficial effects of corticosteroids are awaited. During this time, other agents such as aminophylline and beta agonists play a vital role. Selective j3 agonists such as salbutamol and terbutaline are now available for both parenteral and inhaled use, and the choice between these routes of administration may sometimes pose problems. Williams and Seatonhave compared the effects of salbutamol given intravenously and by inhalation during the first few days of hospital admission for acute severe asthma. Patients were first given salbutamol 5 mg by positive-pressure nebulisation and severe
1. Lancet, 1975, , 1073. 2. McLean, A. E M. Br. J. clin. Pharmac. 1977, 4, 663. 3. Speizer, F. E., Wegman, D. H., Ramirez, A. New Engl. 624. 4 Hallworth, G W. Br. J. clin. Pharmac. 1977, 4, 689. 5. Duncan, D , et al. ibid. p. 669. 6 Hartley, J. P. R. ibid. p. 673. 7. Williams, S., Seaton, A. Thorax, 1977, 32, 555.
J.
Med.
1975, 293,
flow response was measured over the next twenty minutes. Salbutamol 200 ;ag was then injected intravenously and any further response was recorded. The procedure was repeated each day. It transpired that inhaled salbutamol was often totally ineffective during the first phase of an acute severe asthmatic attack, whereas intravenous salbutamol almost always produced useful bronchodilatation. However, once patients began to cough and to raise their sputum, inhaled salbutamol proved just as effective as intravenous. One simple mechanical explanation for this failure of inhaled salbutamol is that the drug does not penetrate small airways, which in severe asthma are plugged with viscid mucus and narrowed by oedema and smoothmuscle spasm. Another possibility is that acute asthma is accompanied by partial p-receptor blockade-the hypothesis advanced by Cookson and Reed8 and elaborated by Szentivanyi.9 In fact, the p-blockade hypothesis receives no support from the latest work since intravenous salbutamol was useful even in the early stages of acute asthma. Moreover, further work from the Cardiff group showed that asthmatics during severe attacks were nevertheless able to mount a normal metabolic response to intravenous salbutamol, with appropriate rise in free fatty acids and insulin levels, again arguing
peak
against generalised p-receptor blockade. 10 These investigations support the use of intravenous salbutamol as an alternative to aminophylline in the early stages of acute severe asthma." The ideal dose has not been established, but 4 fLg/kg by slow intravenous infusion over 10 minutes achieved good bronchodilatation without harmful side-effects. CAROTID BODIES IT is about fifty years since Corneel Heymans stumbled on the chemical sensitivity of the carotid body, if stumbled is the right word to use when a vigorous and vigilant observer deliberately embarks on an eccentric experiment to see what will happen.12 He injected a tiny dose of cyanide into each carotid artery of an ancesthetised dog; one carotid body happened to have been previously denervated, and only the injection on the other side provoked panting. The carotid body behaves as an hypoxia sensor and so, under hypoxic conditions, instead of simply dying like normal aerobic tissues, it generates an increased impulse traffic which serves as an index of the partial pressure of oxygen in the arterial bloodthough also reflecting in part the concentration of hxmoglobin, the pH, and the PC02. Further, the impulse traffic does not change only as a final warning in extreme hypoxia; it changes all the way down from pressures as high as 200 mm Hg (28 kPa)-pressures presumably never naturally encountered by any mammal." How this unusual feat is performed is not yet agreed. Besides two main types of cell, the carotid body contains both efferent and afferent nerve-endings, but uncertainty persists about which are which, and the electron microscope does not reveal conclusively which way transmission occurs between a cell and a nerve-ending8. Cookson, D. U., Reed, C. E. Am. Rev. resp. Dis. 1963, 88, 636. 9. Szentivanyi, A. J. Allergy, 1968, 42, 203. 10. Nogrady, S. G., Hartley, J. P. R., Seaton, A. Thorax, 1977, 32, 559. 11 Williams, S. J., Parrish, R. W., Seaton, A. Br. med. J. 1975, iv, 685. 12. Neil, E. Archs int Pharmacodyn. Ther. 1973, 202, suppl. p. 283. 13. Biscoe, T. J. Am Rev. resp. Dis. 1977, 115, no. 6, part 2, p. 189.
mines; and lately there has also been alarm about their long-term effect on the atmosphere which might increase risks of skin cancer. Reviewing the toxicity of C.F.C.S, McLean2 concludes that the main risk is associated with misuse among "sniffers", who inhale them for kicks and may die with cardiac dysrhythmias. There seems to be no hazard in household use ofc.F.c. propellants in spray cans, nor does there seem to be an increased risk of sudden death among workers who make refrigerators, frozen food, or foam plastic. There has been a report of palpitations among pathology staff preparing frozen sections3 but the inhaled-air concentration of the particular c.F.c. was many times lower than that required to produce experimental dysrhythmias in animals: this matter needs prospective investigation. The possibility that industrial pollutants might influence ozone concentrations in the stratosphere cannot be dismissed but, as McLean points out, there is probably greater cause for concern about the oxides of nitrogen in the air, to which we are subjected and about which we do not hear so much. Furthermore, there has already been a great reduction in the use of c..c. propellants in aerosol cans. A good manufacturer will exclude any unnecessary ingredient of a preparation, especially if that ingredient is suspected of an undesirable effect. Most of us, no doubt, had come to accept that aerosol preparations of drugs for inhalation required some propellant or vehicle for satisfactory delivery. The introduction of the ’Spinhaler’ for delivery of disodium cromoglycate in the form of ’Intal’ showed that this was not true. Now a device which delivers salbutamol as a drug powder in a lactose base for inhalation has been described,4 and first clinical trials5.6 show that it is well tolerated with bronchodilator properties similar to those of the conventional pressurised aerosol. If further controlled studies confirm these results with salbutamol, then the onus will be on the manufacturers of other such drugs to produce preparations free of c.F.c. propellants. As McLean concludes : "Economic disruption that would be caused by a sudden ban on CFC spray cans would be unjustified, but the replacement of CFC spray cans by alternatives over the next three years would seem practical and desirable." INTRAVENOUS VERSUS INHALED SALBUTAMOL AN uncomfortable hiatus in the management of acute asthma often occurs shortly after admission, whilst the beneficial effects of corticosteroids are awaited. During this time, other agents such as aminophylline and beta agonists play a vital role. Selective j3 agonists such as salbutamol and terbutaline are now available for both parenteral and inhaled use, and the choice between these routes of administration may sometimes pose problems. Williams and Seatonhave compared the effects of salbutamol given intravenously and by inhalation during the first few days of hospital admission for acute severe asthma. Patients were first given salbutamol 5 mg by positive-pressure nebulisation and severe
1. Lancet, 1975, , 1073. 2. McLean, A. E M. Br. J. clin. Pharmac. 1977, 4, 663. 3. Speizer, F. E., Wegman, D. H., Ramirez, A. New Engl. 624. 4 Hallworth, G W. Br. J. clin. Pharmac. 1977, 4, 689. 5. Duncan, D , et al. ibid. p. 669. 6 Hartley, J. P. R. ibid. p. 673. 7. Williams, S., Seaton, A. Thorax, 1977, 32, 555.
J.
Med.
1975, 293,
flow response was measured over the next twenty minutes. Salbutamol 200 ;ag was then injected intravenously and any further response was recorded. The procedure was repeated each day. It transpired that inhaled salbutamol was often totally ineffective during the first phase of an acute severe asthmatic attack, whereas intravenous salbutamol almost always produced useful bronchodilatation. However, once patients began to cough and to raise their sputum, inhaled salbutamol proved just as effective as intravenous. One simple mechanical explanation for this failure of inhaled salbutamol is that the drug does not penetrate small airways, which in severe asthma are plugged with viscid mucus and narrowed by oedema and smoothmuscle spasm. Another possibility is that acute asthma is accompanied by partial p-receptor blockade-the hypothesis advanced by Cookson and Reed8 and elaborated by Szentivanyi.9 In fact, the p-blockade hypothesis receives no support from the latest work since intravenous salbutamol was useful even in the early stages of acute asthma. Moreover, further work from the Cardiff group showed that asthmatics during severe attacks were nevertheless able to mount a normal metabolic response to intravenous salbutamol, with appropriate rise in free fatty acids and insulin levels, again arguing
peak
against generalised p-receptor blockade. 10 These investigations support the use of intravenous salbutamol as an alternative to aminophylline in the early stages of acute severe asthma." The ideal dose has not been established, but 4 fLg/kg by slow intravenous infusion over 10 minutes achieved good bronchodilatation without harmful side-effects. CAROTID BODIES IT is about fifty years since Corneel Heymans stumbled on the chemical sensitivity of the carotid body, if stumbled is the right word to use when a vigorous and vigilant observer deliberately embarks on an eccentric experiment to see what will happen.12 He injected a tiny dose of cyanide into each carotid artery of an ancesthetised dog; one carotid body happened to have been previously denervated, and only the injection on the other side provoked panting. The carotid body behaves as an hypoxia sensor and so, under hypoxic conditions, instead of simply dying like normal aerobic tissues, it generates an increased impulse traffic which serves as an index of the partial pressure of oxygen in the arterial bloodthough also reflecting in part the concentration of hxmoglobin, the pH, and the PC02. Further, the impulse traffic does not change only as a final warning in extreme hypoxia; it changes all the way down from pressures as high as 200 mm Hg (28 kPa)-pressures presumably never naturally encountered by any mammal." How this unusual feat is performed is not yet agreed. Besides two main types of cell, the carotid body contains both efferent and afferent nerve-endings, but uncertainty persists about which are which, and the electron microscope does not reveal conclusively which way transmission occurs between a cell and a nerve-ending8. Cookson, D. U., Reed, C. E. Am. Rev. resp. Dis. 1963, 88, 636. 9. Szentivanyi, A. J. Allergy, 1968, 42, 203. 10. Nogrady, S. G., Hartley, J. P. R., Seaton, A. Thorax, 1977, 32, 559. 11 Williams, S. J., Parrish, R. W., Seaton, A. Br. med. J. 1975, iv, 685. 12. Neil, E. Archs int Pharmacodyn. Ther. 1973, 202, suppl. p. 283. 13. Biscoe, T. J. Am Rev. resp. Dis. 1977, 115, no. 6, part 2, p. 189.
