Why does tubocurarine block muscle contraction

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Password Error: Please enter Password. Forgot Password? Pop-up div Successfully Displayed This div only appears when the trigger link is hovered over. Please Wait. This site uses cookies to provide, maintain and improve your experience. Neuromuscular paralysis that results from persistent depolarization of the end plate eg, by succinylcholine.

A phase of blockade by a depolarizing blocker during which the end plate repolarizes but is less than normally responsive to agonists acetylcholine or succinylcholine.

Hyperthermia that results from massive release of calcium from the sarcoplasmic reticulum, leading to uncontrolled contraction and stimulation of metabolism in skeletal muscle. Nondepolarizing blockade. Neuromuscular paralysis that results from pharmacologic antagonism at the acetylcholine receptor of the end plate eg, by tubocurarine.

A drug that reduces abnormally elevated muscle tone spasm without paralysis eg, baclofen, dantrolene. This factor has clinical significance; the effect of such NMBDs is potentiated in acidotic patients. The two quaternary ammonium groups are separated by a bridging structure that is lipophilic and varies in size.

The bridging structure varies with different series of NMBDs and is a major determinant of their potency. NMBDs are classified as depolarizing and non-depolarizing drugs according to their action at the postjunctional nicotinic receptor.

Depolarizing drugs are agonists at ACh receptors. Succinylcholine is the only depolarizing NMBD in clinical use. It is effectively two ACh molecules joined through the acetate methyl groups. When voltage-sensitive sodium channels sense membrane depolarization as a result of activation of the ACh receptors , they first open Fig. The membrane potential must be reset before the sodium channels can be reactivated Fig. This is a very rapid process with ACh 1 ms , as it is hydrolysed by acetylcholinesterase AChE within the synaptic cleft.

However, succinylcholine is not metabolized by AChE, so a prolonged activation of the ACh receptors is produced. The sodium receptors at the end-plate and the perijunctional zone remain inactivated Fig. The muscle becomes flaccid. A Sketch of the sodium channel. The bars v and t represent parts of the molecule that act as gates. Gate v is voltage-dependent, and gate t is time-dependent. This state is maintained as long as the surrounding membrane is depolarized. The channel reverts to the resting state a when the membrane repolarizes.

B Several states of nicotinic acetylcholine receptors. Upper left to right : resting; resting with agonist bound to recognition sites but channel not yet opened; and active with open channel allowing ion flow. Lower left to right : desensitized without agonist; desensitized with agonist bound to recognition site. Both are non-conducting. All conformations are in dynamic equilibrium. Reproduced, with permission of Elsevier, from Standaert FG. Neuromuscular physiology and pharmacology.

In: Miller RD ed Anesthesia , 4th edn. New York: Churchill Livingstone, ; — Depolarization block is also called Phase I or accommodation block and is often preceded by muscle fasciculation.

This is probably the result of the prejunctional action of succinylcholine, stimulating ACh receptors on the motor nerve, causing repetitive firing and release of neurotransmitter. Recovery from Phase I block occurs as succinylcholine diffuses away from the neuromuscular junction, down a concentration gradient as the plasma concentration decreases.

It is metabolized by plasma cholinesterase previously called pseudocholinesterase. Prolonged exposure of the neuromuscular junction to succinylcholine can result in i desensitization block or ii Phase II block. Desensitization occurs when ACh receptors are insensitive to the channel-opening effects of agonists, including ACh itself. Receptors are in a constant state of transition between resting and desensitized states, whether or not agonists are present Fig. Agonists do promote the transition to a desensitized state or trap receptors in that state, as desensitized receptors have a high affinity for them.

Normally, ACh is hydrolysed so rapidly that it has no potential for causing desensitization. Desensitization block may be a safety mechanism that prevents overexcitation of the neuromuscular junction. Phase II block differs from desensitization block. It occurs after repeated boluses or a prolonged infusion of succinylcholine. In patients with atypical plasma cholinesterase, Phase II block can develop after a single dose of the drug.

The block is characterized by fade of the train-of-four TOF twitch response, tetanic fade and post-tetanic potentiation, which are all features of competitive block. After the initial depolarization, the membrane potential gradually returns towards the resting state, even though the neuromuscular junction is still exposed to the drug.

Neurotransmission remains blocked throughout. Possible explanations for the development of Phase II block include presynaptic block reducing the synthesis and mobilization of ACh; postjunctional receptor desensitization; and activation of the sodium—potassium ATPase pump by initial depolarization of the postsynaptic membrane, which repolarizes it.

Inhalation anaesthetic drugs accelerate the onset of Phase II block. Anticholinesterase drugs can be used to antagonize it, but the response is difficult to predict.

Therefore, it is advisable to allow spontaneous recovery. The dose of succinylcholine required for tracheal intubation in adults is 1. This dose produces profound block within 60 s, which is faster than any other NMBD presently available Table 1. Neuromuscular block starts to recover within 3 min and is complete within 12—15 min. Plasma cholinesterase has an enormous capacity to hydrolyse succinylcholine, such that only a small fraction of the injected dose actually reaches the neuromuscular junction.

Succinylcholine has several undesirable side-effects which limit its use. It stimulates muscarinic and nicotinic receptors as does ACh.

Stimulation of muscarinic receptors in the sino-atrial node produces bradycardia, especially in patients with a high vagal tone e. In adults, bradycardia is seen more commonly after repeated increments. Anticholinergic drugs e. Nodal rhythm or ventricular arrhythmias may develop. Muscle pain is most often experienced the day after surgery and is worse in ambulatory patients. It is more common in the young and healthy with a large muscle mass. Children, elderly and pregnant women complain less frequently.

The pain is thought to be a result of the initial fasciculations and occurs in unusual sites, such as the diaphragm, intercostal muscles and between the scapulae. The pain is not relieved by conventional analgesics. Various preventive measures have been recommended, but none is effective in all cases. These include precurarization, whereby a small dose of a non-depolarizing NMBD is given 2—3 min before the administration of succinylcholine e. This technique reduces the potency of succinylcholine, requiring a larger dose to produce the same effect.

Other drugs that have been used include benzodiazepines, lidocaine, calcium, magnesium and repeated doses of thiopental. Administration of succinylcholine 1. This effect is thought to be a result of muscle fasciculation, but it is not abolished by precurarization. A similar increase occurs in patients with renal failure, but these patients may already have an increased serum potassium concentration, and the further increase may precipitate cardiac arrhythmias.

There are several conditions in which the release of potassium may be exaggerated. These include burns, muscular dystrophies particularly relevant in undiagnosed paediatric patients , and paraplegia.

The underlying mechanism may be increased release of potassium from swollen or damaged muscle cells or due to proliferation of extrajunctional receptors. Fatal hyperkalaemia after succinylcholine has also been reported in patients with muscle wasting secondary to chronic arterial insufficiency, prolonged immobilization, severe trauma and closed head injury.

Succinylcholine is a recognized trigger factor for malignant hyperthermia and may also precipitate muscle contracture in patients with myotonic dystrophies. Hypersensitivity reactions occur with all NMBDs. However, unlike the non-depolarizing drugs which produce non-immunologically mediated anaphylactoid reactions, succinylcholine reactions generally represent classic Type 1 anaphylaxis IgE-antibody mediated and are more common after repeated exposure to the drug.

The incidence is estimated to be 1 in administrations. The average increase in intra-ocular pressure after succinylcholine 1. The increase occurs promptly after intravenous injection, peaking at 1—2 min and lasting as long as the neuromuscular block. The cause is multifactorial, including increases in choroidal blood volume, extra-ocular muscle tone and aqueous humour outflow resistance. There is concern that the increased intra-ocular pressure may be sufficient to cause expulsion of vitreal contents in the patient with a penetrating eye injury.

This is unlikely. Succinylcholine-induced increase in intragastric pressure is thought to be a result, in part, of the fasciculation of abdominal muscles and a direct increase in vagal tone. The increase in intragastric pressure is highly variable. To calculate m o in individual junctions, — consecutive stimuli were delivered to the motor nerve. Excised rat hemidiaphragm and EDL muscles were pinned in the silicone-lined organ bath with the aid of mini pins.

A careful dissection was performed under the microscope to isolate small muscle strips containing the endplate regions. These strips were immediately frozen until use for determining nAChR ligand binding sites. A total of 10 or 20 mg of the junctional region of rat diaphragm and EDL muscles were prepared in 1 ml of Krebs-Ringer solution containing 0. Total binding was obtained after 3 h of incubation with 2. The tissue samples were washed first for 3 h in cold buffer and then overnight.

Experiments were made in triplicate. The number of separate experiments in different muscle is indicated. Comparison of data between the diaphragm and the EDL was performed using the Wilcoxon test. A concentation-response study was conducted in each preparation investigated to compare the activity of d-tubocurarine in the rat hemidiaphragm and the EDL muscle.

As shown in figure 1 , higher concentrations of d-tubocurarine were needed to block nerve-evoked muscle twitches in the diaphragm than in the EDL muscles. Concentration-response curves for d-tubocurarine in isolated rat Extensor digitorum longus EDL; white circles and hemidiaphragm DIA; black circles.

Figure 2 shows the results obtained in 30 hemidiaphragm and EDL junctions from eight rats. The median value of the mean quantal content of endplate potentials in the hemidiaphragm was 0. Each point represents data obtained in a single junction. No specific binding was found in excised muscle strips devoid of endplates. Table 1. In addition, we have demonstrated that both the mean quantal content of endplate potentials, which provides an indication of evoked quantal transmitter release, and the nAChR-specific binding sites are in higher numbers in the diaphragm than in EDL muscles of the rat.

The different potency of d-tubocurarine presently observed in vitro in the rat between the diaphragm and the EDL corroborates our previous findings in the mice. This difference can probably be explained by differences between the in vivo and in vitro conditions. To the best of our knowledge, no studies have been reported comparing quantal transmitter release between rat diaphragm and peripheral muscles. Differences in quantal transmitter release have been reported between nerve terminals innervating rat fast and slow muscles.

Although this method has some limitations, it is useful for comparing relative values of the quantal content of endplate potentials between muscles. In contrast to the results of our study, Ibebunjo et al. Ibebunjo et al. Another difference may be due to the different species studied, as Ibebunjo et al. The 3. A higher acetylcholine release at the neuromuscular junction of the diaphragm will diminish the neuromuscular blocking effect of nondepolarizing NMBA.

Increase in receptor density will decrease the neuromuscular blocking effect of competitive agents. Among skeletal muscles, the diaphragm differs by its rate of activation. The ratio of active to inactive times i. It was stated that the resistance of the diaphragm to NMBA was due to the greater safety margin of its neuromuscular junction, 10 but this statement was not supported by an electrophysiological analysis.

Our study provides an explanation to these phenomena and will require further investigations to complete the present findings. In conclusion, by comparing the neuromuscular junction of the rat diaphragm and a limb muscle, we observed that the mean quantal content of endplate potentials and the number nAChR binding sites were greater in the diaphragm muscle.