Anesthetics activity

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). 

Chlophedianol [791-35-5] (49) is the most potent antitussive ia a series of compounds originally synthesi2ed as potential antispasmodics. It is about one-third as active as codeiae and has weak antispasmodic and local anesthetic activity. Although the onset of antitussive activity is slow, the duration is prolonged. Chlophedianol can be prepared from 2-chlorophenylphenyLmethanone (67). 

Zipeprol [34758-83-3] (58) is another European antitussive with a wide range of pharmacological effects, including antispasmodic, antihistaminic, and local anesthetic activities (85,86). It has been reported that zipeprol has been abused in Italy because high doses cause hallucinations (87). Spontaneous withdrawal symptoms similar to those of opiates have been observed withdrawal symptoms can also be precipitated by naloxone. Zipeprol can be... 

The finding that the benzoyl ester, tropacocaine (14), possessed local anesthetic activity showed that the carbomethoxy group was not required for activity. 

As shovm above, the attachment of the aromatic ring to the carbon chain bearing the basic nitrogen may be accomplished through an ester or an amide configured in either direction. A simple ether linkage fulfills this function in yet another compound that exhibits local anesthetic activity. Thus, alkylation of the mono potassium salt of hydroquinone with butyl bromide affords the ether (77) alkylation of this with w-C3-chloropropyl)morpholine affords pramoxine (78)... 

The low structural requirements for local anesthetic activity do not maintain in all classes of drugs. Structural requirements for biologic activity in fact follow a full continuum from those cases in which addition of a single carbon atom serves to abolish activity to the case of the local anesthetics that tolerate quite drastic alterations. 

With very few exceptions, the biological activities of synthetic steroids tend to parallel those of the naturally occurring hormones on which they are patterned. Compounds with distant pharmacological activity are, as a rule, quite rare. It is thus intriguing that inclusion of a tertiary amine at the 11 position of a pregnane leads to a compound with activity far removed from its close analogues. The agent in question, minaxalone (47), exhibits anesthetic activity. 

Risocaine (28) manages to retain local anesthetic activity even without having a "basic ester" moiety.10 Its synthesis follows classic lines involving esterification of p-nitrobenzoic acid with thionyl chloride followed by reaction with propanol, and then catalytic reduction to complete the scheme. 

Perivine 25 exhibits an enhanced local anesthetic activity with respect to cocaine in the rabbit-comea test (230). Tabersonine (67) shows 25% of the hypotensive activity of reserpine on cats, ( )-vincadifformine shows 50% activity, whereas (—)-vincadifformine (ent-10) is inactive (231). 

Local anesthetic activity is also shown by uncharged substances, suggesting a binding site in apolar regions of the channel protein or the surrounding lipid membrane. 

The mechanism of action of inhalational anesthetics is unknown. The diversity of chemical structures (inert gas xenon hydrocarbons halogenated hydrocarbons) possessing anesthetic activity appears to rule out involvement of specific receptors. According to one hypothesis, uptake into the hydrophobic interior of the plasmalemma of neurons results in inhibition of electrical excitability and impulse propagation in the brain. This concept would explain the correlation between anesthetic potency and lipophilicity of anesthetic drugs (A). However, an interaction with lipophilic domains of membrane proteins is also conceivable. Anesthetic potency can be expressed in terms of the minimal alveolar concentration (MAC) at which 50% of patients remain immobile following a defined painful stimulus (skin incision). Whereas the poorly lipophilic N2O must be inhaled in high concentrations (>70% of inspired air has to be replaced), much smaller concentrations (<5%) are required in the case of the more lipophilic halothane. 

Cocaine (8), from Erythroxylum coca Lam., besides causing euphoria by inhibiting the dopamine transport protein (DAT) responsible for its recreational and illegal use, exerts a local anesthetic activity through blocking sodium channels and is still used as a probe for this target. 

Stoughton RW, Lamson PD The relative anesthetic activity of the butanes and the pentanes. J Pharmacol Exp Ther 58 74—77, 1936... 

Pharmacology Flecainide has local anesthetic activity and belongs to the membrane stabilizing (Class I) group of antiarrhythmic agents it has electrophysiologic effects... 

B. Anticholinergic agents, such as procainamide and disopyramide, are relatively contraindicated in patients with glaucoma. Procainamide is hypotensive rather than hypertensive. The local anesthetic activity of procainamide would have no adverse interaction with the diabetes mellitus. 

Anesthetic activity. Hot water extract of the rhizome, at a concentration of 1%, was active on the sciatic nerve . Angiotensin-ll inhibition. Methanol extract of the rhizome, at a concentration of 200 (Xg/mL, was inactive on rat liver membrane . ... 

Mechanism of Action An antiarrhythmicthat prevents sodium current across myocardial cell membranes. Has potent local anesthetic activity and membrane stabilizing effects. Slows AV and His-Purkinje conduction and decreases action potential duration and effective refractory period. Therapeutic Effect Suppresses ventricular arrhythmias. 

Similarly, reaction of 2-dimethylaminomethylene-3-oxoalkanoates or 2-di-methylaminomethylene-1,3-cyclohexanediones with 2-phenyl-5(4/7)-oxazolone 146, generated in situ from hippuric acid, affords 6-substituted 3-(benzoyl-amino)-2-oxo-2//-pyran-5-carboxylates 204 and 3-(benzoylamino)-7,8-dihydro-2//-l-benzopyran-2,5(6//)-diones 206, respectively. These compounds showed strong local anesthetic activity (Scheme 7.62). ... 

GNS depressants are drugs that decrease brain activity, resulting in both behavioral and physiological changes. The effects of alcohol on coordination, speech, and cognitive functions are familiar to most people. The effects of barbiturates are similar to alcohol. In low doses, barbiturates act as sedatives increased doses have a hypnotic or sleep-inducing effect and stiU larger doses have anticonvulsant and anesthetic activity, and can lead to respiratory depression, coma, and death. Barbiturate addicts... 

Nadolol is noteworthy for its very long duration of action its spectrum of action is similar to that of timolol. Timolol is a nonselective agent with no local anesthetic activity. It has excellent ocular hypotensive effects when administered topically in the eye. Levobunolol (nonselective) and betaxolol (E -selective) are also used for topical ophthalmic application in glaucoma the latter drug may be less likely to induce bronchoconstriction than nonselective antagonists. Carteolol is a nonselective 13-receptor antagonist. 

The properties and reactions of amino-alcohols, obtained largely by hydrolysis of naturally occurring alkaloids, were investigated primarily for the purposes of structural analysis and the preparation of physiologically active derivatives. Many authors have described acylation of pyrrolizidine alcohols with benzoyl chloride and acetic anhydride (see, e.g., refs. 83 and 101). Trachelanthamidine benzoate and p-aminobenzoate were prepared especially for testing of their physiological activity.102 The p-aminobenzoate was obtained by treatment of trachelanthamidine with p-nitrobenzoyl chloride and subsequent reduction of the nitro group with iron in 20% acetic acid. The compound exhibited an anesthetic activity close to that of cocaine. 

Lidocaine (synonyme lignocaine) was introduced as the first amide in 1944 and is the most commonly used LA today. It has a rapid onset of action with intermediate duration and an intermediate toxicity. The maximum tolerated dose with infiltration or injection is 200 mg (500 mg when combined with adrenaline). Lidocaine is dealkylated in the liver to monoethylglycine xylidide and glycine xylidide which retain local anesthetic activity. It is available in a variety of preparations including creams, gels, patches and solutions, often in combination with adrenaline. 

Courtney, K. R., Strichartz, G. R. Structural elements which determine local anesthetic activity, in Local Anesthetics. Handbook of Experimental Pharmacology 1987, 81, edited by G. R. Strichartz, 53-94, Springer Verlag, Berlin. 

---