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ANTAGONISM OF NEUROMUSCULAR BLOCK BY PHYSOSTIGMINE IN MAN
Br.J. Anaesth. (1978) 50, 1075
ANTAGONISM OF NEUROMUSCULAR BLOCK BY PHYSOSTIGMINE IN MAN A. BARAKA SUMMARY
In 20 adult patients undergoing inguinal herniorrhaphy neuromuscular block was induced with tubocurarine 10 mg. In 10 patients, neostigmine 1-2 mg antagonized the block and restored the twitch response to its baseline value. Physostigmine, up to 4 mg, did not produce significant antagonism of the neuromuscular block.
METHOD
Observations were made on a total of 20 healthy adult patients, in the weight range 60-70 kg undergoing inguinal herniorrhaphy under general anaesthesia. The patients were premedicated with pethidine 100 mg and atropine 0.6 mg injected i.m., 30 min before operation. Anaesthesia was induced with sodium thiopentone 250-350 mg and maintained with halothane 0.5-1% in a mixture of nitrous oxide in oxygen (3 : 2). Ventilation was controlled throughout the procedure and -PaCOi! was maintained in the range 3.33-4.66 kPa. Tubocurarine 10 mg was administered to produce neuromuscular blockade. The ulnar nerve was stimulated supramaximally at the wrist using a Block-Aid monitor which delivers an electrical pulse of approximately 0.2 ms duration at 4-s intervals (Katz, 1965). The stimulus was delivered via a 25-gauge steel hypodermic needle ANIS
BARAKA,
M.D., Department
of
Anesthesiology,
American University of Beirut, Beirut, Lebanon. 0007-0912/78/0050-1075 $01.00
which served as the subcutaneous electrode. The resultant adduction of the thumb was detected by a force displacement transducer FT-03 and recorded on a Grass polygraph with a paper speed of 0.5 mm s"1. When a steady twitch response was obtained, repeated doses of neostigmine 0.5 mg were injected to achieve antagonism (10 patients). The response was compared with that achieved with physostigmine in a group of 10 similar patients. RESULTS
In the first group of 10 patients, neostigmine 1-2 mg antagonized the neuromuscular block produced by tubocurarine 10 mg (fig. 1). The twitch height was restored always to its baseline value and was associated with a sustained response to tetanic stimulation (30 s- 1 ). In the second group of patients, physostigmine 2 mg did not produce any significant antagonism of the neuromuscular block. An increase in the dose of physostigmine up to 4-8 mg was required to initiate antagonism. However, such antagonism was only partial, as demonstrated by incomplete restoration to the baseline twitch response or the presence of tetanic fade or both (fig. 2). DISCUSSION
This report confirms previous experimental investigations which showed that physostigmine is less potent than neostigmine as an antidote to nondepolarizing neuromuscular block (Frank and Mclntyre, 1948). The effects of physostigmine at the neuromuscular junction are considered to be secondary to a pure anti-acetylcholinesterase activity, whereas neostigmine can act both directly by a cholinomimetic mechanism and indirectly by its antiesterase activity (Wescoe and Riker, 1951; Koelle, 1970). Neostigmine is about 50 times as potent as © Macmillan Journals Ltd 1978
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on June 1, 2015
Physostigmine, an antieholinesterase with a tertiary amine structure, can cross the blood-brain barrier and has been used clinically to antagonize the central anticholinergic syndrome produced by hyoscine and other related alkaloids (Duvoisin and Katz, 1968; Greene, 1971; Holzgrafe, Vondrell and Mintz, 1973; Smiler et al., 1973). The drug has been shown in experimental animals to antagonize non-depolarizing neuromuscular block (Frank and Mclntyre, 1948; Wescoe and Riker, 1951). However, it has not been reported that physostigmine, in the doses recommended for the reversal of the central anticholinergic syndrome, can reverse neuromuscular block in man. This report presents data on the ability of physostigmine to antagonize neuromuscular blockade in man, and compares its action with that of neostigmine.
BRITISH JOURNAL OF ANAESTHESIA
107S
t
t t
10 mg
0.5
TUBOCURARINE
1min
0.5 mg
NEOSTIGMINE
FIG. 1. Twitch response to stimulation of the ulnar nerve at 4-s intervals. Neuromuscular block produced by tubocurarine 10 mg. Neostigmine 1 mg restored the control twitch response completely.
t
t
2 mg
2 mg
t
2 mg
PHYSOSTIGMINE
FIG. 2. Twitch response to stimulation of the ulnar nerve at 4-s intervals. Neuromuscular block produced by tubocurarine 10 mg. Physostigmine 2 mg did not antagonize neuromuscular block. Increasing the dose of physostigmine to 4—8 mg was necessary to initiate antagonism.
physostigmine in increasing the endplate potential and prolonging its time to half decay (Wescoe and Riker, 1951). The pharmacological effects of ananticholinesterase agent depend in part on its lipid solubility. In general, a quaternary ammonium compound such as neostigmine does not penetrate cell membranes readily; hence it is excluded by the blood-brain barrier from exerting significant action on the central nervous system, and acts selectively on the neuromuscular junction of skeletal muscles. In contrast, a lipid-soluble tertiary amine compound such as physostigmine can readily cross the blood-brain barrier and act predominantly on the central nervous system (Koelle, 1970). The present report shows that physostigmine does not adequately antagonize neuromuscular block in doses of up to 4mg, which are recommended commonly for the antagonism of the central anticholinergic syndrome. Centrally, physostigmine not only inhibits brain cholinesterase, but can cause also direct excitation of neuronal activity, independent of the response to acetylcholine. The role of acetylcholine in neuromuscular transmission is entirely nicotinic, while cholinergic transmission in the brain is both muscarinic and nicotinic (Bradley, 1968). Therefore, it is not surprising to find that physostig-
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on June 1, 2015
10 mg TUBOCURARINE
mine has mechanisms which vary according to the site of action. REFERENCES
Bradley, P. B. (1968). The effect of atropine and related drugs on the EEG behaviour; in Progress in Brain Research Vol. 28: Antickolinergic Drugs and Brain Functions in Animals and Man. (eds P. B. Bradley and M. Fink), p. 3. Amsterdam: Elsevier Publishing Company. Duvoisin, R. C , and Katz, R. (1968). Reversal of central anticholinergic syndrome in man by physostigmine. J.A.M.A., 206,1963. Frank, M., and Mclntyre, A. (1948). Eserine and neostigmine antagonism to d-tubocurarine. Anesthesiology, 9, 251. Greene, L. T. (1971). Post-operative physostigmine use. Anesth. Analg. (Cleve.), 50, 222. Holzgrafe, R. E., Vondrell, J. J., and Mintz, S. M. (1973). Reversal of post-operative reactions to scopolamine with physostigmine. Anesth. Analg. (Cleve.), 52,921. Katz, R. (1965). A nerve stimulator for the continuous monitoring of muscle relaxant action. Anesthesiology, 26, 832. Koelle, G. B. (1970). Anticholinesterase agents; in The Pharmacological Basis of Therapeutics (eds L. Goodman, and A. Gilman), p. 442. New York: Macmillan. Smiler, B. G., Bartholomew, E. G., Sivak, B. J., Alexander, G. D., and Brown, E. M. (1973). Physostigmine reversal of scopolamine delirium in obstetric patients. Am. J. Obstet. Gynecol, 116,326. Wescoe, W., and Riker, W. jr (1951). The pharmacology of anti-curare agents. Ann. N. Y. Acad. Sci., 54,438.
PHYSOSTIGMINE AND NEUROMUSCULAR BLOCK ANTAGONISME DU BLOCAGE NEUROMUSCULAIRE PAR LA PHYSOSTIGMINE CHEZ L'HOMME RESUME
Sur 20 malades adultes subissant une hemiorraphie inguinale, on a provoque un blocage neuromusculaire a l'aide de 10 mg de tubocurarine. Sur 10 malades, la neostigmine a raison de 1-2 mg a contrarte le blocage et ramene la response de la crispation a sa valeur de base. La physostigmine, essayed jusqu'a raison de 4 nig, n'a produit aucun antagonisme sensible du blockage neuromusculaire.
ZUSAMMENFASSUNG
In 20 erwachsenen Patienten, die sich einer Leistenbruchoperation unterzogen, wurde eine neuromuskulare Blockade
mit 10 mg Tubocurarin erreicht. In 10 Patienten wirkte 1-2 mg Neostigmin gegen die Blockade und brachte den Zuckreflex wieder auf den Ausgangswert zurtick. Physostigmin bis zu 4mg produzierte keine bemerkenswerte Gegenwirkung auf die neuromuskulare Blockade. ANTAGONISMO DEL BLOQUEO NEUROMUSCULAR POR FISOSTIGMINA EN EL HOMBRE SUMARIO
En 20 pacientes adultos sometidos a hemiorafia inguinal se indujo bloqueo neuromuscular con 10 mg de tubocurarina. En 10 pacientes, la neostigmina 1-2 mg result6 antagonica al bloqueo y devolvio la respuesta por sacudida muscular a su valor normal. La fisostigmina, hasta 4 mg, no produjo un antagonismo significativo del bloqueo neuromuscular.
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on June 1, 2015
GEGENWIRKUNG DER NEUROMUSKULAREN BLOCKADE MIT PHYSOSTIGMIN IM MENSCHEN
1077
ANTAGONISM OF NEUROMUSCULAR BLOCK BY PHYSOSTIGMINE IN MAN A. BARAKA SUMMARY
In 20 adult patients undergoing inguinal herniorrhaphy neuromuscular block was induced with tubocurarine 10 mg. In 10 patients, neostigmine 1-2 mg antagonized the block and restored the twitch response to its baseline value. Physostigmine, up to 4 mg, did not produce significant antagonism of the neuromuscular block.
METHOD
Observations were made on a total of 20 healthy adult patients, in the weight range 60-70 kg undergoing inguinal herniorrhaphy under general anaesthesia. The patients were premedicated with pethidine 100 mg and atropine 0.6 mg injected i.m., 30 min before operation. Anaesthesia was induced with sodium thiopentone 250-350 mg and maintained with halothane 0.5-1% in a mixture of nitrous oxide in oxygen (3 : 2). Ventilation was controlled throughout the procedure and -PaCOi! was maintained in the range 3.33-4.66 kPa. Tubocurarine 10 mg was administered to produce neuromuscular blockade. The ulnar nerve was stimulated supramaximally at the wrist using a Block-Aid monitor which delivers an electrical pulse of approximately 0.2 ms duration at 4-s intervals (Katz, 1965). The stimulus was delivered via a 25-gauge steel hypodermic needle ANIS
BARAKA,
M.D., Department
of
Anesthesiology,
American University of Beirut, Beirut, Lebanon. 0007-0912/78/0050-1075 $01.00
which served as the subcutaneous electrode. The resultant adduction of the thumb was detected by a force displacement transducer FT-03 and recorded on a Grass polygraph with a paper speed of 0.5 mm s"1. When a steady twitch response was obtained, repeated doses of neostigmine 0.5 mg were injected to achieve antagonism (10 patients). The response was compared with that achieved with physostigmine in a group of 10 similar patients. RESULTS
In the first group of 10 patients, neostigmine 1-2 mg antagonized the neuromuscular block produced by tubocurarine 10 mg (fig. 1). The twitch height was restored always to its baseline value and was associated with a sustained response to tetanic stimulation (30 s- 1 ). In the second group of patients, physostigmine 2 mg did not produce any significant antagonism of the neuromuscular block. An increase in the dose of physostigmine up to 4-8 mg was required to initiate antagonism. However, such antagonism was only partial, as demonstrated by incomplete restoration to the baseline twitch response or the presence of tetanic fade or both (fig. 2). DISCUSSION
This report confirms previous experimental investigations which showed that physostigmine is less potent than neostigmine as an antidote to nondepolarizing neuromuscular block (Frank and Mclntyre, 1948). The effects of physostigmine at the neuromuscular junction are considered to be secondary to a pure anti-acetylcholinesterase activity, whereas neostigmine can act both directly by a cholinomimetic mechanism and indirectly by its antiesterase activity (Wescoe and Riker, 1951; Koelle, 1970). Neostigmine is about 50 times as potent as © Macmillan Journals Ltd 1978
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on June 1, 2015
Physostigmine, an antieholinesterase with a tertiary amine structure, can cross the blood-brain barrier and has been used clinically to antagonize the central anticholinergic syndrome produced by hyoscine and other related alkaloids (Duvoisin and Katz, 1968; Greene, 1971; Holzgrafe, Vondrell and Mintz, 1973; Smiler et al., 1973). The drug has been shown in experimental animals to antagonize non-depolarizing neuromuscular block (Frank and Mclntyre, 1948; Wescoe and Riker, 1951). However, it has not been reported that physostigmine, in the doses recommended for the reversal of the central anticholinergic syndrome, can reverse neuromuscular block in man. This report presents data on the ability of physostigmine to antagonize neuromuscular blockade in man, and compares its action with that of neostigmine.
BRITISH JOURNAL OF ANAESTHESIA
107S
t
t t
10 mg
0.5
TUBOCURARINE
1min
0.5 mg
NEOSTIGMINE
FIG. 1. Twitch response to stimulation of the ulnar nerve at 4-s intervals. Neuromuscular block produced by tubocurarine 10 mg. Neostigmine 1 mg restored the control twitch response completely.
t
t
2 mg
2 mg
t
2 mg
PHYSOSTIGMINE
FIG. 2. Twitch response to stimulation of the ulnar nerve at 4-s intervals. Neuromuscular block produced by tubocurarine 10 mg. Physostigmine 2 mg did not antagonize neuromuscular block. Increasing the dose of physostigmine to 4—8 mg was necessary to initiate antagonism.
physostigmine in increasing the endplate potential and prolonging its time to half decay (Wescoe and Riker, 1951). The pharmacological effects of ananticholinesterase agent depend in part on its lipid solubility. In general, a quaternary ammonium compound such as neostigmine does not penetrate cell membranes readily; hence it is excluded by the blood-brain barrier from exerting significant action on the central nervous system, and acts selectively on the neuromuscular junction of skeletal muscles. In contrast, a lipid-soluble tertiary amine compound such as physostigmine can readily cross the blood-brain barrier and act predominantly on the central nervous system (Koelle, 1970). The present report shows that physostigmine does not adequately antagonize neuromuscular block in doses of up to 4mg, which are recommended commonly for the antagonism of the central anticholinergic syndrome. Centrally, physostigmine not only inhibits brain cholinesterase, but can cause also direct excitation of neuronal activity, independent of the response to acetylcholine. The role of acetylcholine in neuromuscular transmission is entirely nicotinic, while cholinergic transmission in the brain is both muscarinic and nicotinic (Bradley, 1968). Therefore, it is not surprising to find that physostig-
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on June 1, 2015
10 mg TUBOCURARINE
mine has mechanisms which vary according to the site of action. REFERENCES
Bradley, P. B. (1968). The effect of atropine and related drugs on the EEG behaviour; in Progress in Brain Research Vol. 28: Antickolinergic Drugs and Brain Functions in Animals and Man. (eds P. B. Bradley and M. Fink), p. 3. Amsterdam: Elsevier Publishing Company. Duvoisin, R. C , and Katz, R. (1968). Reversal of central anticholinergic syndrome in man by physostigmine. J.A.M.A., 206,1963. Frank, M., and Mclntyre, A. (1948). Eserine and neostigmine antagonism to d-tubocurarine. Anesthesiology, 9, 251. Greene, L. T. (1971). Post-operative physostigmine use. Anesth. Analg. (Cleve.), 50, 222. Holzgrafe, R. E., Vondrell, J. J., and Mintz, S. M. (1973). Reversal of post-operative reactions to scopolamine with physostigmine. Anesth. Analg. (Cleve.), 52,921. Katz, R. (1965). A nerve stimulator for the continuous monitoring of muscle relaxant action. Anesthesiology, 26, 832. Koelle, G. B. (1970). Anticholinesterase agents; in The Pharmacological Basis of Therapeutics (eds L. Goodman, and A. Gilman), p. 442. New York: Macmillan. Smiler, B. G., Bartholomew, E. G., Sivak, B. J., Alexander, G. D., and Brown, E. M. (1973). Physostigmine reversal of scopolamine delirium in obstetric patients. Am. J. Obstet. Gynecol, 116,326. Wescoe, W., and Riker, W. jr (1951). The pharmacology of anti-curare agents. Ann. N. Y. Acad. Sci., 54,438.
PHYSOSTIGMINE AND NEUROMUSCULAR BLOCK ANTAGONISME DU BLOCAGE NEUROMUSCULAIRE PAR LA PHYSOSTIGMINE CHEZ L'HOMME RESUME
Sur 20 malades adultes subissant une hemiorraphie inguinale, on a provoque un blocage neuromusculaire a l'aide de 10 mg de tubocurarine. Sur 10 malades, la neostigmine a raison de 1-2 mg a contrarte le blocage et ramene la response de la crispation a sa valeur de base. La physostigmine, essayed jusqu'a raison de 4 nig, n'a produit aucun antagonisme sensible du blockage neuromusculaire.
ZUSAMMENFASSUNG
In 20 erwachsenen Patienten, die sich einer Leistenbruchoperation unterzogen, wurde eine neuromuskulare Blockade
mit 10 mg Tubocurarin erreicht. In 10 Patienten wirkte 1-2 mg Neostigmin gegen die Blockade und brachte den Zuckreflex wieder auf den Ausgangswert zurtick. Physostigmin bis zu 4mg produzierte keine bemerkenswerte Gegenwirkung auf die neuromuskulare Blockade. ANTAGONISMO DEL BLOQUEO NEUROMUSCULAR POR FISOSTIGMINA EN EL HOMBRE SUMARIO
En 20 pacientes adultos sometidos a hemiorafia inguinal se indujo bloqueo neuromuscular con 10 mg de tubocurarina. En 10 pacientes, la neostigmina 1-2 mg result6 antagonica al bloqueo y devolvio la respuesta por sacudida muscular a su valor normal. La fisostigmina, hasta 4 mg, no produjo un antagonismo significativo del bloqueo neuromuscular.
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on June 1, 2015
GEGENWIRKUNG DER NEUROMUSKULAREN BLOCKADE MIT PHYSOSTIGMIN IM MENSCHEN
1077