Competition Between Acetylcholine and a Nondepolarizing Muscle Relaxant for Binding to the Postsynaptic Receptors at the Motor End Plate: Simulation of Twitch Strength and Neuromuscular Block

Nigrovic, V.; Amann, Anton

doi:10.1023/a:1023245409315

Cited by 12 publications

(43 citation statements)

References 15 publications

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“…The free molecules of ACh bind to 2 sites on the postsynaptic receptors ([R] synaptic cleft = 7.75 Â 10 -5 mol/L) and are rapidly hydrolyzed (the first-order rate constant for hydrolysis k hydrolysis = 12000 s -1 ). The details of the interaction between ACh and the receptors were presented earlier (Nigrovic and Amann 2003) and are briefly summarized here: The equilibrium dissociation constants for site 1 and site 2 were K A1 = 10 -5 and K A2 = 10 -4 mol/L, whereas the association rate constants were identical for both sites, k aasocA1 = k assocA2 = 1.35 Â 10 8 molÁL -1 Ás -1 . The dissociation rate constants were calculated from k dissocA = K DA Â k assocA .…”

Section: Methodsmentioning

confidence: 91%

“…Twitch strength, defined as the force of muscle contraction after a single supramaximal stimulus of the motor nerve, was calculated using the model of neuromuscular transmission (Nigrovic and Amann 2003). The model simulates the events in the synaptic cleft after the stimulusinduced release of acetylcholine (ACh).…”

Section: Methodsmentioning

confidence: 99%

“…We assumed that a muscle fiber contracts when peak [ARA] reaches or surpasses threshold [ARA] for that fiber (Nigrovic and Amann 2003). Accordingly, the number of simultaneously contracting fibers determines the strength of contraction of the whole muscle.…”

Section: Methodsmentioning

confidence: 99%

“…where A represents the distribution of threshold [ARA] in the muscle and [ARA 50 ] is the median threshold [ARA] (Nigrovic and Amann 2003). We used the previously derived values: A = 4.732 and [ARA 50 ] = 9.524 Â 10 -9 mol/L (Nigrovic and Amann 2003).…”

Section: Methodsmentioning

confidence: 99%

“…We used the previously derived values: A = 4.732 and [ARA 50 ] = 9.524 Â 10 -9 mol/L (Nigrovic and Amann 2003).…”

Section: Methodsmentioning

confidence: 99%

See 4 more Smart Citations

Onset–potency relationship of nondepolarizing muscle relaxants: a reexamination using simulations

Bhatt

Amann

Nigrovic

2007

Can. J. Physiol. Pharmacol.

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Nondepolarizing muscle relaxants (MRs) display an inverse onset-potency relationship, that is, less potent MRs display a more rapid onset. We have conducted the current investigation to estimate the impact of variable pharmacokinetic or pharmacodynamic properties of the MRs on potency and onset time, and on the onset-potency relationship. Using a model of neuromuscular transmission, we changed either the affinity of MRs for the postsynaptic receptors or the pharmacokinetic properties of the MRs. The elimination rate constant, k(10), which defines the systemic clearance, was assigned one of 9 values and the transport rate constant, k(12), one of 5 values. The transport rate constant into the effect compartment was constant (k(e1) = 0.2 min(-1)). Only one parameter was altered at a time. With constant pharmacokinetics, a 100-fold decrease in affinity caused a proportional decrease in potency, but little change (0.02 min) in onset time. With constant affinity, increasing the clearance from 1 to 250 mL x kg(-1) x min(-1) shortened the onset time from 7.2 to 0.7 min and decreased the potency 12-fold. In a double logarithmic plot, the onset-potency relationship was linear. Lesser affinities produce a nearly parallel rightward shift of the regression lines. The inverse onset-potency relationship may be explained by the pharmacokinetic factors producing changes in both the potency and onset times.

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Section: Methodsmentioning

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…We used the previously derived values: A = 4.732 and [ARA 50 ] = 9.524 Â 10 -9 mol/L (Nigrovic and Amann 2003).…”

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Onset–potency relationship of nondepolarizing muscle relaxants: a reexamination using simulations

Bhatt

Amann

Nigrovic

2007

Can. J. Physiol. Pharmacol.

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Myasthenia gravis and myasthenic syndrome: Simulation of twitch strength with or without therapy

2005

Self Cite

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To examine the quantitative relationship between indirectly evoked twitch and decreases in the number of either postsynaptic receptors or acetylcholine molecules released by a single stimulus, we studied these variables in a computer-simulated model of neuromuscular transmission. Twitch strength decreased if the number of receptors decreased to below 30% of normal or the number of acetylcholine molecules released by a stimulus decreased to below 80%. Inhibition of acetylcholine hydrolysis to 50% restored twitch strength in the presence of a decreased number of receptors. However, twitch strength was more easily restored to normalcy by augmenting the release of acetylcholine, if the release was diminished by disease. The simulations mimic the clinically known therapeutic outcomes in certain disorders of neuromuscular transmission. These results provide useful quantitative insights into the relationship between acetylcholine receptors or the stimulus-induced release of acetylcholine and muscle function in myasthenia gravis or Lambert-Eaton myasthenic syndrome.

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Pharmacokinetic–Pharmacodynamic Modelling of Anesthetic Drugs

Proost

2017

Total Intravenous Anesthesia and Target Controlled Infusions

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Competition Between Acetylcholine and a Nondepolarizing Muscle Relaxant for Binding to the Postsynaptic Receptors at the Motor End Plate: Simulation of Twitch Strength and Neuromuscular Block

Cited by 12 publications

References 15 publications

Onset–potency relationship of nondepolarizing muscle relaxants: a reexamination using simulations

Onset–potency relationship of nondepolarizing muscle relaxants: a reexamination using simulations

Myasthenia gravis and myasthenic syndrome: Simulation of twitch strength with or without therapy

Pharmacokinetic–Pharmacodynamic Modelling of Anesthetic Drugs

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