The Time-Concentration Curve of Local Anesthetics.

Ehrenberg, L.; Öbrink, Karl Johan; Laaksonen, Terttu

doi:10.3891/acta.chem.scand.02-0063

Cited by 31 publications

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“…This observation has been confir me d by ma ny investigators with the same conclusion (32,43,78,86) . Howe ve r, there is not close agreement be tween the observed minimum eff ective concentration at different va lues of pH ( Fig.…”

Section: The Active Form Of Local Anestheticssupporting

confidence: 59%

“…A more reasonable approach is that of LOfgren (61) and Ehrenberg (32) who assumed that the activity coefficient of the uncharged molecule is constant, and is equal to unity, whereas that of the charged cation (fBH+ may vary. The corresponding relation to Equation 1 then becomes…”

Section: The Active Form Of Local Anestheticsmentioning

confidence: 99%

“…In fact, if the pH in the vicinity of the receptors remains constant with variation of external pH, the amount of cation must always change in parallel with that of the uncharged molecule. The mere experimental obser vation, therefore, that less anesthetic is required in more alkaline solutions does not permit any conclusion concerning the active form [see also (32)]. …”

Section: The Active Form Of Local Anestheticsmentioning

confidence: 99%

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On the Mode of Action of Local Anesthetics

Ritchie¹,

Greengard²

1966

Annu. Rev. Pharmacol.

236

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Local anesthetics possess the specific ability to bl ock conduction in nerve in a reversible ma nner and in low concentration. The reactions that occur in the ner ve membrane that allow local anesthetics to achieve this effect are still not clearly defi ned. Howe ver , with the re cent increa se in our knowledge of the nature of the nerve impul se , some idea of the mode of action of local anesthetics is be ginning to form. Measurements of me m brane potentials and ionic move me nt s have strong ly suggested that local anesthetics block cond uct ion by inter fe ring with the sodium and potassium conductance cha ng es that are fundamental to the generation of the nerve impulse . Other studies have indicated that local anesthetic molecule s achieve this conduction block in the form of ca ti ons. Furthermore, studies of structure-activity relations have suggeste d someth ing of the chemical na ture of the re ce ptor in the nerve membrane and the method of interac tion of this receptor with the local anesthetic molecule . Finally, studies of the be ha vior of loca l anesthetics in model systems have suggested a phys icochemical ba sis for the mode of action of local anesthetics on the ne rve membrane. These various aspects of local anesthetic action will be g iven particular emphasis in this review. Many other, perhaps equally important, aspects will be neglected, and the interested reader is there fore referred to the many comprehensive reviews on local anesthetics that have appeared in the last decade (4,14,24,25,56,73,94,104,106,108). ELECTROPHYSIOLOGICAL EFFECTS OF LOCAL ANESTHETICSThe work of Hodgkin, Huxley, Keynes, and ot hers [see (52)] has led in recent year s to a better under standing of the nature of the nerve im pulse . In consequence , it is now possible to expla in the action of local an esthet ics within the fra me wor k of the ionic theory of nervous act ivity .Active nerve membrane.-Local anesthetics increase the threshold for ele ctr ical excitat ion in nerve , slow pr opagation of the impul se, reduce the rate of rise of the action pote nt ial, and eventually bl ock conduct ion [e.g. (85)]. They do this by inter fer ing with the pr oce ss fundamental to the gen eration of the nerve action pote ntial, name ly the large transient rise in the permeability of the me mbrane to sodium ions that is produced by a slight de pola rization of the me mbrane. Taylor (99), Shanes et al. (85), and, more re ce ntly, Blaustein & Goldman (19) used the voltage-clamp me thod to study 1 The survey of th e literature pertaining to this review was concluded in Octo ber 1965. 405 Annu. Rev. Pharmacol. 1966.6:405-430. Downloaded from www.annualreviews.org Access provided by Queens University -Kingston (Canada) on 03/08/15. For personal use only. Quick links to online content Further ANNUAL REVIEWS

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Section: The Active Form Of Local Anestheticssupporting

confidence: 59%

Section: The Active Form Of Local Anestheticsmentioning

confidence: 99%

Section: The Active Form Of Local Anestheticsmentioning

confidence: 99%

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On the Mode of Action of Local Anesthetics

Ritchie¹,

Greengard²

1966

Annu. Rev. Pharmacol.

236

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“…Previous experimental studies suggest that this MEGX concentration would produce some antiarrhythmic effect. MEGX was reported to have about one-third the equimolar potency of lidocaine for antifibrillatory action in chloroform-exposed mice, one-half the potency for premature ventricular contraction suppression in dogs after coronary ligation, full potency for suppression of ouabain-toxic atrial arrhythmias in guinea pigs, and one-fourth the potency for block of frog sciatic nerve (Ehrenberg, 1948;Smith and Duce, 1971;Burney et al, 1974). In comparison, we found that the level of V max block immediately after action potential repolarization was one-third of the block with lidocaine at 30 tiu concentration, similar to the reported potency ratios for nerve block and suppression of ventricular arrythmia.…”

Section: Discussionmentioning

confidence: 99%

Lipid solubility modulates pH potentiation of local anesthetic block of Vmax reactivation in guinea pig myocardium.

Broughton¹,

Grant²,

Starmer³

et al. 1984

Circulation Research

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SUMMARY. Current theories envision recovery from local anesthetic block of sodium channels via slow hydrophilic and fast hydrophobic paths. Extracellular pH reduction which increases cationic/neutral anesthetic form should especially prolong recovery kinetics of highly lipid soluble compounds that could readily exit via the hydrophobic pathway at normal extracellular pH. To test this hypothesis, we compared the effects of three related compounds with similar pKa on the time course of V max reactivation in guinea pig papillary muscle at pH<, 7.4 and 6.95. The compounds were lidocaine and its two desethylation products, monoethylglycinexylidide and glycinexylidide. Judged from the octanol:water partition coefficient, lidocaine was the most lipid soluble (log partition coefficient 2.39 ± 0.10), followed by monoethylglycinexylidide (log partition coefficient 1.32 ± 0.09) and glycinexylidide was the least lipid soluble (log partition coefficient 0.41 ± 0.09). At 30 MM and pHo 7.4, the potency order for W mix depression at zero diastolic interval was lidocaine (53 ± 6%), monoethylglycinexylidide (17 ± 3%), and then glycinexylidide (7.8 ± 1.9%). The decay of V^ block appeared monoexponential, and the time constant of recovery was dose independent. Most important is the fact that there were significant differences in the r r increase with extracellular pH reduction (P < 0.05; Scheffe contrasts). The increase was greatest with lidocaine [73 ± 28% (mean ± SD)], less with monoethylglycinexylidide (42 ± 15%), and least with glycinexylidide (13 ± 17%). The simplest interpretation of the differences in extracellular pHdependence of recovery kinetics was that recovery from block due to the neutral form of these ionizable local anesthetics depended on lipid solubility, whereas recovery from block due to the protonated form depended on molecular weight. (Circ Res 55: 513-523, 1984)

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“…The efficiency of a local anaesthetic determined by this method will largely be determined by its physico-chemical properties such as pKa, lipid solubility and ability of the base to penetrate to the site of action in the nerve. The importance of these factors for the local anaesthetic effect has been discussed by Trevan & Boock (1927) and later by Ehrenberg (1948), Brown & Luduena (1953), Skou (1954) and Rud (1957). Determinations of certain physico-chemical properties of L 67 and lignocaine would therefore possibly offer an explanation for the lower activity of L 67 as observed on the isolated nerve preparation.…”

Section: Discussionmentioning

confidence: 99%

SOME PHARMACOLOGICAL PROPERTIES OF o‐METHYL‐α‐PROPYLAMINOPROPIONANILIDE, A NEW LOCAL ANAESTHETIC

Åström¹,

Persson²

1961

British Journal of Pharmacology and Chemotherapy

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The anaesthetic action of o-methyl-a-propylaminopropionanilide (L 67, Astra) has been studied and compared with lignocaine in different in vitro and in vivo tests.Procaine and amethocaine (tetracaine) were also included in several of the comparisons. In nerve block on the isolated frog sciatic nerve L 67 is somewhat less effective than lignocaine. In all in vivo conditions, however, L 67 is quite comparable to lignocaine as to duration, latency and frequency of anaesthesia. As a spinal anaesthetic in rabbits 2 to 4% solutions of L 67 give a longer duration of anaesthesia than lignocaine. Toxicity in mice and rabbits and respiratory and circulatory effects in cats have also been evaluated. L 67 is almost twice as well tolerated as lignocaine. It is concluded that L 67 may prove to be a useful anaesthetic in certain clinical applications.

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The Time-Concentration Curve of Local Anesthetics.

Cited by 31 publications

References 0 publications

On the Mode of Action of Local Anesthetics

On the Mode of Action of Local Anesthetics

Lipid solubility modulates pH potentiation of local anesthetic block of Vmax reactivation in guinea pig myocardium.

SOME PHARMACOLOGICAL PROPERTIES OF o‐METHYL‐α‐PROPYLAMINOPROPIONANILIDE, A NEW LOCAL ANAESTHETIC

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