Structural Elements which Determine Local Anesthetic Activity

Courtney, Kenneth R.; Strichartz, Gary R.

doi:10.1007/978-3-642-71110-7_3

Cited by 52 publications

(36 citation statements)

References 84 publications

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“…Most of normal Na + currents in GH3 cells can be easily converted to the BTX-modified current after <5-10 rain of repetitive stimulations. Using these neuronal cells, we have now demonstrated that in normal Na + channels the LA stereoselectivity is indeed weak, as reported in other preparations (for review, see Courtney and Strichartz, 1987), whereas in BTX-modified Na + channels the LA stereoselectivity is relatively high as in muscle, brain, and cardiac BTX-modified Na + channels incorporated into planar bilayers (Wang, 1990). One noteworthy abnormality is that (-)bupivacaine is more potent than (-)cocaine in normal and BTX-modified Na + channels from rat neuronal GH3 cells, whereas the reverse is true in BTX-modified Na + channels from rabbit skeletal muscle (this report vs. Wang, 1990).…”

Section: Different La Stereoselectivity In Normal and Btx-raodified Nsupporting

confidence: 75%

“…First, we speculated that there may be more than one LA receptor in Na + channels as reported before (e.g., Mrose and Ritchie, 1978;Huang and Ehrenstein, 1981; for review, see Courtney and Strichartz, 1987). Second, we speculated that the open channel conformation may have different stereoselectivity than the closed channel conformation.…”

Section: What Is the Underlying Mechanism For The Altered Stereoselecmentioning

confidence: 66%

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Altered stereoselectivity of cocaine and bupivacaine isomers in normal and batrachotoxin-modified Na+ channels.

Wang

1992

The Journal of General Physiology

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The inhibitory effects of local anesthetics (LAs) of cocaine and bupivacaine optical isomers on Na + currents were studied in clonal GH3 cells under whole-cell patch clamp conditions. At holding potential of-100 mV, all four isomers inhibited peak Na ÷ currents when the cell was stimulated infrequently. The dose-response curves of this tonic block of peak Na + currents by (-)/(+) cocaine and (-)/(+) bupivacaine were well fitted by the Langmuir isotherm, suggesting that one LA isomer blocked one Na + channel. Each pair of isomers showed no greater than a twofold difference in stereoselectivity toward Na + channels. Additional block of Na + currents occurred when the cell was stimulated at 2 Hz. This use-dependent block was also observed in all four isomers, which again displayed little stereoselectivity. The voltage dependence of the use-dependent block produced by cocaine isomers did not overlap with the activation of Na ÷ channels but did overlap with the steady-state inactivation (h®), indicating that cocaine can bind directly to the inactivated state of Na ÷ channels before channel opening. In comparison, the peak batrachotoxin (BTX)-modified Na ÷ currents were little inhibited by cocaine and bupivacaine isomers. However, the maintained BTX-modified Na ÷ currents were highly sensitive toward the (-) form of cocaine and bupivacaine isomers during a prolonged depolarization. As a result, a profound time-dependent block of BTXmodified Na + currents was evident in the presence of these LA isomers. The estimated values of the equilibrium dissociation constant (KD in micromolar) at +50 mV were 35.8, 661, 7.0, and 222 for (-)/(+) cocaine and (-)/(+) bupivacaine, respectively. Although chloramine-T (CT) also modified the fast inactivation of Na ÷ channels and gave rise to a maintained Na + current during a prolonged depolarization, LA isomers showed no greater stereoselectivity in blocking this maintained current than in blocking the normal transient Na + current. We conclude that (a) cocaine and bupivacaine isomers exhibit only weak stereoselectivity toward the LA receptor in normal and CT-treated Na + channels, (b) BTX drastically modifies the configuration of the LA binding site so that the LA stereoselectivity of the open Na + channels is altered by an order of magnitude, and (c) the (-) forms of cocaine and bupivacaine interact strongly with the open state of BTX-modified Na + channels but Address reprint requests to Dr.

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Section: Different La Stereoselectivity In Normal and Btx-raodified Nsupporting

confidence: 75%

Section: What Is the Underlying Mechanism For The Altered Stereoselecmentioning

confidence: 66%

Altered stereoselectivity of cocaine and bupivacaine isomers in normal and batrachotoxin-modified Na+ channels.

Wang

1992

The Journal of General Physiology

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“…In parallel experiments, the histamine release induced by 30 MM spantide, a widely used tachykinin receptor antagonist (Folkers et al, 1984), was 61.9 ± 10.2% (n = 3); this result is consistent with a previous report (Schultheiss & H6rig, 1985). electrically-evoked compound action potentials generated in the frog sciatic nerve, a preparation previously shown to be sensitive to local anaesthetics (Courtney & Strichartz, 1987) (data not shown).…”

Section: Effects Of Fkmentioning

confidence: 79%

Investigation of the specificity of FK 888 as a tachykinin NK₁ receptor antagonist

Wang¹,

Tung²,

Strichartz³

et al. 1994

British J Pharmacology

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“…This produces blockade of the sodium ion channel, thereby decreasing sodium ion conductance and preventing depolarization of the cell memberane. 19 Hydrophobicity appears to be a primary determinant of intrinsic anesthetic potency because the anesthetic molecules must penetrate the nerve membrane and must bind at a partially hydrophobic site on the sodium channel. [20][21][22][23] Clinically this may not be true as in all circumstances as vasodilatation and tissue redistribution properties also affect the potency.…”

Section: Fig 5: Sedation Score Distribution In Study Groupmentioning

confidence: 99%

Efficacy of Adding Fentanyl to Lignocaine – Adrenaline Combination in Supraclavicular Brachial Plexus Block for Upper Limb Orthopedic Surgeries a Multi - Center Study

Varkey¹,

Alexander²,

C³

2015

jemds

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BACKGROUND:Brachial plexus block is a suitable alternative to general anesthesia for surgeries of upper limb and it can be performed even in patients who are not adequately fit for general anesthesia. The significance of brachial plexus block has increased in recent years due to renewed interest in day care surgery. Lignocaine hydrochloride has been used extensively for brachial plexus block and it has the disadvantage of having short duration of action. Opioids when added to anesthetic mixtures may improve and prolong the action of local anesthetics during peripheral nerve blocks. Such postoperative pain control can reduce both narcotic requirements and narcotic induced side effects. Studies have shown the efficacy of opioids as analgesic adjuvants in prolonging the duration of brachial plexus block. With this background in mind, this study was conducted to compare the onset and duration of sensory and motor block produced by a mixture of lignocaine and adrenaline with that produced by a mixture of fentanyl, lignocaine and adrenaline. Aims: To assess the effectiveness of addition of fentanyl to a mixture of lignocaine and adrenaline in prolonging the duration of analgesia and motor block for upper limb orthopedic surgeries. MATERIALS AND METHODS:This multi-center randomized control study was conducted in two tertiary care centers in 80 patients underwent elective upper limb orthopedic surgeries and they were allocated into two groups of 40 each group L and group F. the classical approach of supraclavicular brachial plexus block. Drug used were 30ml of lignocaine 1.5%+adrenaline 5mcg/ml +0.5ml normal saline in group L and 30ml of lignocaine 1.5% + adrenaline 5mcg/ml + fentanyl 50mcg in group F. Adequacy of block was assessed by the pin prick test and temperature test. Motor power was assessed by the modified Lowett scale. Sedation was monitored using the modified Ramsay scale. An assessment was made for onset of analgesia, onset of motor block, duration of analgesia, duration of motor block and occurrence of any side effects during the first 24 hours of the postoperative period. Subjective assessment of post-operative analgesia was done by direct questioning of the patient and by a five point pain scores. Data's were analyzed using computer software, Statistical Package for Social Science (SPSS) 16th version. OBSERVATION AND RESULTS: The mean onset of sensory block in the lignocaine group was 6.6±1.52 and in the lignocaine-fentanyl group 10.22±2.58. The mean onset of motor block was 8±1.97 in the lignocaine group and 11.39±3.57 in lignocaine-fentanyl group. The mean duration of sensory block was 105.73±9.45 in lignocaine group and 170.28±12.28 in lignocaine-fentanyl group. The mean duration of motor block motor block was 95.93±10.65 in lignocaine group and 178.33±12.37 in the lignocaine-fentanyl group. CONCLUSION: Addition of fentanyl to lignocaine-adrenaline in brachial plexus blocks will significantly delay the onset of sensory and motor block and significantly prolongs the duration of sensory and mo...

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Structural Elements which Determine Local Anesthetic Activity

Cited by 52 publications

References 84 publications

Altered stereoselectivity of cocaine and bupivacaine isomers in normal and batrachotoxin-modified Na+ channels.

Altered stereoselectivity of cocaine and bupivacaine isomers in normal and batrachotoxin-modified Na+ channels.

Investigation of the specificity of FK 888 as a tachykinin NK₁ receptor antagonist

Efficacy of Adding Fentanyl to Lignocaine – Adrenaline Combination in Supraclavicular Brachial Plexus Block for Upper Limb Orthopedic Surgeries a Multi - Center Study

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Structural Elements which Determine Local Anesthetic Activity

Cited by 52 publications

References 84 publications

Altered stereoselectivity of cocaine and bupivacaine isomers in normal and batrachotoxin-modified Na+ channels.

Altered stereoselectivity of cocaine and bupivacaine isomers in normal and batrachotoxin-modified Na+ channels.

Investigation of the specificity of FK 888 as a tachykinin NK1 receptor antagonist

Efficacy of Adding Fentanyl to Lignocaine – Adrenaline Combination in Supraclavicular Brachial Plexus Block for Upper Limb Orthopedic Surgeries a Multi - Center Study

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Investigation of the specificity of FK 888 as a tachykinin NK₁ receptor antagonist