Anesthetic action

Although most anesthetics are achiral or are adininistered as racemic mixture, the anesthetic actions are stereoselective. This property can define a specific, rather than a nonspecific, site of action. Stereoselectivity is observed for such barbiturates as thiopental, pentobarbital, and secobarbital. The (3)-enantiomer is modestly more potent (56,57). Additionally, the volatile anesthetic isoflurane also shows stereoselectivity. The (3)-enantiomer is the more active (58). Further evidence that proteins might serve as appropriate targets for general anesthetics come from observations that anesthetics inhibit the activity of the enzyme luciferase. The potencies parallel the anesthetic activities closely (59,60). 

The onset of action is fast (within 60 seconds) for the intravenous anesthetic agents and somewhat slower for inhalation and local anesthetics. The induction time for inhalation agents is a function of the equiUbrium estabUshed between the alveolar concentration relative to the inspired concentration of the gas. Onset of anesthesia can be enhanced by increasing the inspired concentration to approximately twice the desired alveolar concentration, then reducing the concentration once induction is achieved (3). The onset of local anesthetic action is influenced by the site, route, dosage (volume and concentration), and pH at the injection site. 

Benzonatate [104-31 ] (46) is a unique compound which appears to have both central and peripheral antitussive effects. Stmcturally it is a derivative of ji)-aminoben2oic acid and contains a long poly(ethylene glycol) side chain. The peripheral effects ate the result of local anesthetic action on the pulmonary stretch receptors. Clinical activity was first reported in 1955 (65). 

In conjunction with local anesthetics to prolong anesthetic action in medicine and dentistry. 

It has been generally accepted that anesthetics interact with membrane lipids as a primary step of anesthesia. The detailed mechanism of the anesthetic action is, however, still controversial. This is mainly due to the absence of specific information on delivery sites in membranes. The NMR data for the delivery site of drugs in membranes are of great use. 

It should be emphasized that the ester carbonyl group in the interfacial zone II is most crucial and susceptible to the anesthetic action of the drugs. In our NMR study, we have found that the ester carbonyl site in zone II is particularly susceptible to the extent of hydration [51]. Above the G/LC transition temperature, the carbonyl is the innermost site where the water can penetrate. The strong perturbation of the NMR signal of the... 

Although the contribution is rather small, the partial discharging of the anesthetics in membranes can be important in the mechanism of the anesthetic action. The most plausible mechanism can be summarized as only a small portion of the cationic species are neutralized (deprotonated) at the bilayer surface and the neutral species are deeply penetrated and widely distributed in the hydrophobic bilayer interior, while the cationic species still remain at the hydrophilic bilayer surface where the hydration is significant. 

The tropane alkaloids are a well-recognized group of structurally related natural products. Long before elucidation of the structures, the mydriatic and anesthetic action of several compounds was exploited (6). The very extensive literature covering the pharmacological properties of the tropane alkaloids will be considered only briefly in this chapter. Readers with a deeper interest in the subject are referred to other publications (7-14) and to the references given in Section VII. 

Further, the removal of benzodiazepine sensitivity in a selective a subunit in a mouse using the gene knockin technique has established that the al subunit plays a major role in the sedative and amnesiac effects of benzodiazepines, part of the anticonvulsant effect and little of the anxiolytic effect the latter effects are more importantly mediated by the a2 subunit [5, 6], The 0 subunit selectivity for the drugs loreclezole (an anxiolytic) and etomidate (an anesthetic) allowed determination that a single residue in the M2 domain could account for this selectivity (02 = 03 >01). When a mouse knockin selectively removed the etomidate sensitivity of the 02 subunit, the animals showed reduced sensitivity to sedative effects of etomidate but no reduction of the true anesthetic effects. In contrast, mutation of the 03 subunit to negate etomidate sensitivity of that subunit alone resulted in a mouse with no sensitivity to the anesthesia produced by etomidate. This proved that the GABA receptor is the target of at least this one anesthetic (etomidate) and, furthermore, that the specific locations in the brain of 03 subunits are important for anesthetic action, while the... 

Cocaine is another example of a dmg with a complex pharmacological profile responsible for different properties probably concurring due to QT prolongation. It has a local anesthetic action (and therefore shares the pharmacological properties mentioned above), but recent reports also indicate the blockade of hERG K+ currents [47-49]. Thus, it is not unexpected that cocaine has been associated with QT prolongation and occurrence of TdP [50-53]. 

The local anesthetic actions of cocaine are independent of its well-known actions on monoamines. Rather, the local anesthetic effects occur as a consequence of its interaction with voltage-gated Na-i-channels (Matthews and Collins 1983). Cocaine s cerebral vasoconstrictor effects occur through local anesthetic rather than sympathomimetic mechanisms (Albuquerque and Kurth 1993). 

Sell AB, Carlini EA. (1976). Anesthetic action of methyleugenol and other eugenol derivatives. Pharmacology. 14(4) 367-77. 

Unlike barbiturates, benzodiazepine derivatives administered orally lack a general anesthetic action cerebral activity is not globally inhibited (respiratory paralysis is virtually impossible) and autonomic functions, such as blood pressure, heart rate, or body temperature, are unimpaired. Thus, benzodiazepines possess a therapeutic margin considerably wider than that of barbiturates. 

The wide variation in structure, ranging from complex steroids to the inert monatomic gas xenon, led to several theories of anesthetic action. The mechanism by which inhalation anesthetics manifest their effect is not exactly known. Since they do not belong to one chemical class of compounds, the correlations between structure and activity are also not known. Inhalation anesthetics are nonspecific and therefore there are not specific antagonists. Interaction of inhalation anesthetics with cellular structures can only be described as van der Waals interactions. There are a number of hypotheses that have been advanced to explain the action of inhalation anesthetics however, none of them can adequately describe the entire spectrum of effects caused by inhalation anesthetics. 

A mechanism of local anesthetic action in which they serve as sodium channel blockers has been proposed. According to this mechanism, the molecular targets of local anesthetic action are the voltage-requiring sodium channels, which are present in all the neurons. The process of local anesthesia by respective drugs can be schematically represented in the following manner. 

Like procainamide, lidocaine is an amide with local anesthetizing action. Lidocaine is usually administered intravenously for short-term therapy of ventricular extrasystole, tachycardia, especially in the severe phase of myocardial infarction, arrhythmia of natural cause, and for arrhythmia that can originate in the heart during surgical manipulations. Synonyms of this drug are lidopen, xylocaine, xylocard, and others. 

Labetalol produces equilibrium-competitive antagonism at p-receptors but does not exhibit selectivity for Pi- or P2-receptors. Like certain other p-blockers (e.g., pindolol and timolol), labetalol possesses some degree of intrinsic activity. This intrinsic activity, or partial ago-nism, especially at P2-receptors in the vasculature, has been suggested to contribute to the vasodilator effect of the drug. The membrane-stabilizing effect, or local anesthetic action, of propranolol and several other p-blockers, is also possessed by labetalol, and in fact the drug is a reasonably potent local anesthetic. 

Because of its anticholinergic properties, disopyramide should not be used in patients with glaucoma. Urinary retention and benign prostatic hypertrophy are also relative contraindications to disopyramide therapy. Patients with myasthenia gravis may have a myasthenic crisis after disopyramide administration as a result of the drug s local anesthetic action at the neuromuscular junction. The elderly patient may exhibit increased sensitivity to the anticholinergic actions of disopyramide. 

Flecainide (Tambocor) is a fluorinated aromatic hydrocarbon examined initially for its local anesthetic action and subsequently found to have antiarrhythmic effects. Flecainide inhibits the sodium channel, leading to conduction slowing in all parts of the heart, but most notably in the His-Purkinje system and ventricular myocardium. It has relatively minor effects on repolarization. Flecainide also inhibits abnormal auto-maticity. 

Meyer and Overton discover effect of lipid solubility on anesthetic action Fischer and von Mering identify hypnotic properties of barbiturates (see 1882)... 

Selectivity Partial Agonist Activity Local Anesthetic Action Lipid Solubility Elimination Half-life Approximate Bioavailability... 

Most of the effects of these drugs are due to occupation and blockade of 13 receptors. However, some actions may be due to other effects, including partial agonist activity at 13 receptors and local anesthetic action, which differ among the 13 blockers (Table 10-2). 

Local anesthetic action, also known as "membrane-stabilizing" action, is a prominent effect of several 3 blockers (Table 10-2). This action is the result of typical local anesthetic blockade of sodium channels (see Chapter 26) and can be demonstrated experimentally in isolated neurons, heart muscle, and skeletal muscle membrane. However, it is unlikely that this effect is important after systemic administration of these drugs, since the concentration in plasma usually achieved by these routes is too low for the anesthetic effects to be evident. These membrane-stabilizing 3 blockers are not used topically on the eye, where local anesthesia of the cornea would be highly undesirable. Sotalol is a nonselective 3-receptor antagonist that lacks local anesthetic action but has marked class III antiarrhythmic effects, reflecting potassium channel blockade (see Chapter 14). 

Drugs with local anesthetic action block sodium channels and reduce the sodium current, INa. They are the oldest group of antiarrhythmic drugs and are still widely used. 

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