- Email: [email protected]
TOXICITY OF QUINIDINE
1184
made for educating the children in both plans, since I consider that special schooling for the disturbed child is an important part of the therapeutic regime. Department of Child Psychiatry, Clatterbridge Hospital, Bebington, Wirral, Cheshire.
DAVID ZAUSMER.
PARTNERSHIP
-
SIR,-Dr. Frears (Nov. 21) mistakes the symptoms for the disease. Partnership is not a cause of N.H.S. malaise: it is one way (possibly a bad one) of lightening the onerous duties of present-day general practice. It is a self-defence mechanism to solve the impossible-to-sustain situation of being on duty 24 hours a day, 365 days a year. As proof, the paucity of partnerships in the Ilford area can be quoted. Ilford has had an effective rota system since the appointed day with complete cover for half-days, weekends, and a month’s holiday each year. I would like to hear of even one doctor who took on a partner to enable him to name his successor, except to ensure the practice for his son or other relative or friend. Gidea Park, Romford, Essex.
LEON M. SHIRLAW.
PARTNERSHIP—BENIGN OR MALIGNANT ?
SIR,-In your annotation last week you say, in reference to our superannuation scheme, that present arrangements have proved workable. " Workable " is a vague term. How valuable the scheme has been for general practitioners cannot be precisely measured, since no accounts for this section of the scheme have ever been published. This is the more surprising, because from 1948 to 1961 the cost of the employers’ contribution was deducted from our central fund. One may hope that the Government Actuary in his report on the valuation made in 1962 will be less reticent than he was in his previous report. Until then we should reserve
judgment.
Nottingham.
RUSSELL E. FREARS.
TOXICITY OF QUINIDINE SIR,-Dr. Oram and Dr. Davieshave drawn attention to the danger of quinidine prophylaxis against return of atrial fibrillation after (electrical) reversion, and we are prompted to report our own unhappy experience in this context.
400 mg. t.d.s.) was given to the first with atrial fibrillation in whom we were able to patients restore sinus rhythm with Lown’s ’Cardioverter ’. None of these patients showed signs of intolerance to quinidine when given a test dose (200 mg.) the day before reversion, or during the first full day’s treatment with the standard dose. 1 of these patients began to have paroxysms of ventricular tachycardia, at least three of which provoked syncope with convulsions, on the first post-reversion day, and these recurred until the quinidine Three of these paroxysms was stopped on the third day. further D.c. shocks to terminate them. Another patient required (who had experienced benign paroxysmal tachycardia occasionally before reversion) suddenly became unconscious during the second full day’s quinidine prophylaxis; she recovered spontaneously on this occasion, but died next day in a similar attack shown (by E.C.G.) to be due to ventricular fibrillation. A third patient died suddenly at home while taking prophylactic quinidine after her second successful electrical reversion. No similar episodes have been seen in 66 patients with atrial fibrillation (and a few other arrhythmias) not given quinidine after successful or attempted reversion by D.c. shock. In the light of this experience, and of reports describing ventricular fibrillation2 and sudden death3 during
Quinidine (usually
38
1. Oram, S., Davies, J. P. H. Lancet, 1964, 2. Selzer, A. Circulation, 1964, 30, 17. 3. Thomson, G. W. ibid. 1956, 14, 757.
quinidine therapy (without prior electrical treatment), we have concluded that quinidine is too dangerous a drug for routine use. It may still have a place in the emergency treatment of ventricular tachycardia, but, as facilities for synchronised D.c. shock become universally available, even this indication for quinidine therapy should ultimately disappear.
i, 1294.
Queen Elizabeth Hospital, Birmingham, 15.
-
O. BRENNER P. H. DAVISON D. W. EVANS.
EFFECTS OF (3-SYMPATHETIC BLOCKADE ON NON-ESTERIFIED-FATTY-ACID AND CARBOHYDRATE METABOLISM AT REST AND DURING EXERCISE Muir and his coworkers (Oct. 31) have not SIR,-Dr.
drawn a distinction between the metabolic substrate level.
rate
and
a
I do not see how it can be postulated that carbohydrate metabolism does not increase. If a fixed amount of work is to be performed, then a fixed number of calories must be provided from metabolic substrates. If a decreased utilisation of one of the substrates, fat, is proposed, it must follow that a comparable increase in utilisation of the other substrate-carbohydrate-takes place to compensate for this. One would therefore expect to find a rise in respiratory quotient. I agree that pronethalol prevents release of nonesterified fatty acids (N.E.F.A.) from adipose tissue, and, since no limitations on cell permeability of N.E.F.A. have been demonstrated, it can be postulated that the adipose-tissue] glucose/fatty-acid cycle is interfered with by pronethalol. The glucose/fatty-acid cycle, as propounded by Randle et al.1 ordinarily provides a basic regulatory method whereby N.E.F.A. release is controlled by the availability of oc-glycerophosphate (from glucose) and hence is related to the bloodglucose level. N.E.F.A. is preferentially utilised by muscle tissue and its rate of oxidation is a function of its concentration in the medium.2 N.E.F.A. is the preferred substrate due to its inhibition directly and indirectly of glycogen degradation and some stages in glycolysis. Bearing this system in mind, with a decrease in N.E.F.A. release there is likely to be not only increased glucose utilisation by muscle but also increased glucose release from the liver. There need therefore be no change in blood-glucose during exercise either with or without pronethalol. Equally, on the alternative hypothesis, in the control group the increase in fat metabolism with exercise may tend to maintain the plasma/pyruvate at a constant level, its increased production being prevented by the inhibition of glycolysis above, while increased concentrations of acetyl coA below (due to increased fat metabolism) inhibit further pyruvate metabolism.3 Thus the plasma-pyruvate level remains constant in a watertight bulkhead ", whereas in the controls the level remains constant but the rate of flow through the pathway is increased. Similarly, in man the production of lactate during exercise has been shown to depend on the severity but not on the duration of exercise, since lactate production corresponds to the initial anaerobic stage of muscular activity before the capillary bed has opened up, after which the lactate level falls.4 "
According to the alternative hypothesis suggested here, a fall in blood-glucose would, however, have been found had the controls undergone long-continued exercise in the fasting state. Although it seems unlikely that by decreasing the liberation of N.E.F.A. (and hence increasing carbohydrate metabolism) pronethalol administration in the absence of sufficient carbohydrate stores could contribute to serious hypoglycsemia, this possibility should be investigated. Catechol amines increase the liberation of N.E.F.A. and 1. Randle, P. J., Garland, P. B., Hales, C. N., Newsholme, E. A. Lancet, 2. 3. 4.
1963, i, 785. Fritz, J. B., Davis, D. G., Hatrop, R. H., Dundee, H. Amer. J. Physiol. 1958, 194, 379. Garland, P. B., Randle, P. J. Biochem. J. 1964, 91, 6C. Bang, O. Skand. Arch. Physiol. 1936, 74, suppl. 10, 51.
made for educating the children in both plans, since I consider that special schooling for the disturbed child is an important part of the therapeutic regime. Department of Child Psychiatry, Clatterbridge Hospital, Bebington, Wirral, Cheshire.
DAVID ZAUSMER.
PARTNERSHIP
-
SIR,-Dr. Frears (Nov. 21) mistakes the symptoms for the disease. Partnership is not a cause of N.H.S. malaise: it is one way (possibly a bad one) of lightening the onerous duties of present-day general practice. It is a self-defence mechanism to solve the impossible-to-sustain situation of being on duty 24 hours a day, 365 days a year. As proof, the paucity of partnerships in the Ilford area can be quoted. Ilford has had an effective rota system since the appointed day with complete cover for half-days, weekends, and a month’s holiday each year. I would like to hear of even one doctor who took on a partner to enable him to name his successor, except to ensure the practice for his son or other relative or friend. Gidea Park, Romford, Essex.
LEON M. SHIRLAW.
PARTNERSHIP—BENIGN OR MALIGNANT ?
SIR,-In your annotation last week you say, in reference to our superannuation scheme, that present arrangements have proved workable. " Workable " is a vague term. How valuable the scheme has been for general practitioners cannot be precisely measured, since no accounts for this section of the scheme have ever been published. This is the more surprising, because from 1948 to 1961 the cost of the employers’ contribution was deducted from our central fund. One may hope that the Government Actuary in his report on the valuation made in 1962 will be less reticent than he was in his previous report. Until then we should reserve
judgment.
Nottingham.
RUSSELL E. FREARS.
TOXICITY OF QUINIDINE SIR,-Dr. Oram and Dr. Davieshave drawn attention to the danger of quinidine prophylaxis against return of atrial fibrillation after (electrical) reversion, and we are prompted to report our own unhappy experience in this context.
400 mg. t.d.s.) was given to the first with atrial fibrillation in whom we were able to patients restore sinus rhythm with Lown’s ’Cardioverter ’. None of these patients showed signs of intolerance to quinidine when given a test dose (200 mg.) the day before reversion, or during the first full day’s treatment with the standard dose. 1 of these patients began to have paroxysms of ventricular tachycardia, at least three of which provoked syncope with convulsions, on the first post-reversion day, and these recurred until the quinidine Three of these paroxysms was stopped on the third day. further D.c. shocks to terminate them. Another patient required (who had experienced benign paroxysmal tachycardia occasionally before reversion) suddenly became unconscious during the second full day’s quinidine prophylaxis; she recovered spontaneously on this occasion, but died next day in a similar attack shown (by E.C.G.) to be due to ventricular fibrillation. A third patient died suddenly at home while taking prophylactic quinidine after her second successful electrical reversion. No similar episodes have been seen in 66 patients with atrial fibrillation (and a few other arrhythmias) not given quinidine after successful or attempted reversion by D.c. shock. In the light of this experience, and of reports describing ventricular fibrillation2 and sudden death3 during
Quinidine (usually
38
1. Oram, S., Davies, J. P. H. Lancet, 1964, 2. Selzer, A. Circulation, 1964, 30, 17. 3. Thomson, G. W. ibid. 1956, 14, 757.
quinidine therapy (without prior electrical treatment), we have concluded that quinidine is too dangerous a drug for routine use. It may still have a place in the emergency treatment of ventricular tachycardia, but, as facilities for synchronised D.c. shock become universally available, even this indication for quinidine therapy should ultimately disappear.
i, 1294.
Queen Elizabeth Hospital, Birmingham, 15.
-
O. BRENNER P. H. DAVISON D. W. EVANS.
EFFECTS OF (3-SYMPATHETIC BLOCKADE ON NON-ESTERIFIED-FATTY-ACID AND CARBOHYDRATE METABOLISM AT REST AND DURING EXERCISE Muir and his coworkers (Oct. 31) have not SIR,-Dr.
drawn a distinction between the metabolic substrate level.
rate
and
a
I do not see how it can be postulated that carbohydrate metabolism does not increase. If a fixed amount of work is to be performed, then a fixed number of calories must be provided from metabolic substrates. If a decreased utilisation of one of the substrates, fat, is proposed, it must follow that a comparable increase in utilisation of the other substrate-carbohydrate-takes place to compensate for this. One would therefore expect to find a rise in respiratory quotient. I agree that pronethalol prevents release of nonesterified fatty acids (N.E.F.A.) from adipose tissue, and, since no limitations on cell permeability of N.E.F.A. have been demonstrated, it can be postulated that the adipose-tissue] glucose/fatty-acid cycle is interfered with by pronethalol. The glucose/fatty-acid cycle, as propounded by Randle et al.1 ordinarily provides a basic regulatory method whereby N.E.F.A. release is controlled by the availability of oc-glycerophosphate (from glucose) and hence is related to the bloodglucose level. N.E.F.A. is preferentially utilised by muscle tissue and its rate of oxidation is a function of its concentration in the medium.2 N.E.F.A. is the preferred substrate due to its inhibition directly and indirectly of glycogen degradation and some stages in glycolysis. Bearing this system in mind, with a decrease in N.E.F.A. release there is likely to be not only increased glucose utilisation by muscle but also increased glucose release from the liver. There need therefore be no change in blood-glucose during exercise either with or without pronethalol. Equally, on the alternative hypothesis, in the control group the increase in fat metabolism with exercise may tend to maintain the plasma/pyruvate at a constant level, its increased production being prevented by the inhibition of glycolysis above, while increased concentrations of acetyl coA below (due to increased fat metabolism) inhibit further pyruvate metabolism.3 Thus the plasma-pyruvate level remains constant in a watertight bulkhead ", whereas in the controls the level remains constant but the rate of flow through the pathway is increased. Similarly, in man the production of lactate during exercise has been shown to depend on the severity but not on the duration of exercise, since lactate production corresponds to the initial anaerobic stage of muscular activity before the capillary bed has opened up, after which the lactate level falls.4 "
According to the alternative hypothesis suggested here, a fall in blood-glucose would, however, have been found had the controls undergone long-continued exercise in the fasting state. Although it seems unlikely that by decreasing the liberation of N.E.F.A. (and hence increasing carbohydrate metabolism) pronethalol administration in the absence of sufficient carbohydrate stores could contribute to serious hypoglycsemia, this possibility should be investigated. Catechol amines increase the liberation of N.E.F.A. and 1. Randle, P. J., Garland, P. B., Hales, C. N., Newsholme, E. A. Lancet, 2. 3. 4.
1963, i, 785. Fritz, J. B., Davis, D. G., Hatrop, R. H., Dundee, H. Amer. J. Physiol. 1958, 194, 379. Garland, P. B., Randle, P. J. Biochem. J. 1964, 91, 6C. Bang, O. Skand. Arch. Physiol. 1936, 74, suppl. 10, 51.