Anesthetics cocaine

Local anesthetics with an amide linkage (and one ester-lined anesthetic, cocaine) are almost completely metabolized by the liver before excretion. However, the total dose administered and the degree of drug accumulation resulting from the initial and subsequent doses are still a concern. 

Local anesthetics are used extensively on the mucous membranes in the nose, mouth, tracheobronchial tree, and urethra. The vasoconstriction produced by some local anesthetics, cocaine especially, adds a very important advantage to their use in the nose by preventing bleeding and inducing tissue shrinkage. Topical anesthesia permits many diagnostic procedures in the awake patient, and when it is combined with infiltration techniques, excellent anesthesia may be obtained for many... 

The effects of temperature on local anesthesia of frog s nerve differ for various types of anesthetics cocaine, salicylamide, and monacetine are more effective on cooled nerves, whereas... 

Procaine hydrochloride was first synthesized by Einhorn in 1905 as a substitute for cocaine, the first local anesthetic. Cocaine, an alkaloid obtained from the leaves of the coca plant, Erythroxylon coca, is highly addictive and toxic. Procaine hydrochloride replaced cocaine as a local anesthetic because it is much less toxic, cheaper and easier to produce, and it is easier to sterilize. In contrast to cocaine, it is not addictive because it is less stimulating to the central nervous system. 

The observation that very significant parts of the cocaine molecule could be deleted from synthetic analogs without loss of biologic activity led to the search for the minimal structural feature consistent with activity. This exercise, sometimes referred to as molecular dissection, not only led to great simpli-fi cation of the structure of local anesthetics but resulted fi-tially in the preparation of active molecules that bear only the remotest structural relation to the prototype, cocaine. 

A chance observation made some time prior to the full structural elucidation of cocaine in fact led to one of the more important lasses of local anesthetics. It was found that the simple ethyl e. ter of p-aminobenzoic acid, benzocaine (25), showed activity. 1-. a local anesthetic. It is of interest to note that this drug, I 1rst introduced in 1903, is still in use today. Once the struc-iiire of cocaine was established, the presence of an alkanolamine iiiniety in cocaine prompted medicinal chemists to prepare esters "I aminobenzoic acids with acyclic alkanolamines. Formula 26 11 presents the putative relationship of the target substances with cocaine. 

Thus, acylation of 3(W,iV-dibutylamino)propanol (39) with p-nitrobenzoyl chloride affords the intermediate, 40. Reduction of the nitro group gives butacaine (41), an agent equipotent as cocaine as a topical anesthetic. 

The simplification of the local anesthetic phaimacophore of cocaine to an aryl substituted ester of ethanolamine has been described previously. Atropine (S2) is a structurally closely related natural product whose main biologic action depends on inhibition of the parasympathetic nervous system. Among its many other actions, the compound exerts useful spasmolytic effects. 

Esters of tropine have a venerable place in medicinal chemistry. One such compound, cocaine, the object of some current interest, was the natural product lead which led eventually to most of today s local anesthetics. A distantly related analogue is prepared by reaction of tropine (132) with 3,5-dimethylbenzoyl chloride. This leads to an ester structurally related to another ]ii ominent natural product, atropine (133). The product, tropanaerin (134), is described as an iinti.serotonergic agent intended for antimigraine use [34]. 

Many alkaloids have pronounced biological properties, and a substantial number of the pharmaceutical agents used today are derived from naturally occurring amines. As a few examples, morphine, an analgesic agent, is obtained from the opium poppy Papaver somnifemm. Cocaine, both an anesthetic and a central nervous system stimulant, is obtained front the coca bush Erythroxylon coca, endemic to upland rain forest areas of Colombia, Ecuador, Peru, Bolivia, and western Brazil. Reserpine, a tranquilizer and antihypertensive, comes from powdered roots of the semitropical plant Rauwolfia serpentina. Ephedrine, a bronchodilator and decongestant, is obtained front the Chinese plant Ephedra sinica. 

Toluene, volatile nitrites, and anesthetics, like other substances of abuse such as cocaine, nicotine, and heroin, are characterized by rapid absorption, rapid entry into the brain, high bioavailability, a short half-life, and a rapid rate of metabolism and clearance (Gerasimov et al. 2002 Pontieri et al. 1996, 1998). Because these pharmacokinetic parameters are associated with the ability of addictive substances to induce positive reinforcing effects, it appears that the pharmacokinetic features of inhalants contribute to their high abuse liability among susceptible individuals. 

Several topically applied local anesthetics are routinely used by the eye care specialist in certain routine diagnostic procedures and for various relatively simple surgical procedures such as insertion of punctal plugs and surgical vision correction. The first of these to be used was cocaine, in concentrations ranging from 1 to 4% [30]. More modern local anesthetics, however, such as tetracaine hydrochloride and proparacaine hydrochloride, have replaced cocaine as drugs of choice in these procedures. For surgical procedures of a more complex nature, lidocaine hydrochloride and similar local anesthetics as retrobulbar injections have been used [31]. 

The answer is local anesthetic properties it can block the initiation or conduction of a nerve impulse. It is biotransformed by plasma esterases to inactive products. In addition, cocaine blocks the reuptake of norepinephrine. This action produces CNS stimulant effects including euphoria, excitement, and restlessness Peripherally, cocaine produces sympathomimetic effects including tachycardia and vasoconstriction. Death from acute overdose can be from respiratory depression or cardiac failure Cocaine is an ester of benzoic acid and is closely related to the structure of atropine. 

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). 

Once the cocaine has been legally produced from the coca leaf, it is exported to various countries for medicinal use, basically as a topical local anesthetic (applied to the surface, not injected, only treating a particular area). In the United States the crystalline powder is imported to pharmaceutical companies who process and package the cocaine for medical use. Merck Pharmaceutical Company and Mallinckrodt Chemical Works distribute cocaine in crystalline form (Hydrochloride Salt) in dark colored glass bottles to pharmacies and hospitals throughout the United States. Cocaine, in the alkaloid form (base drug containing no additives such as hydrochloride in the crystalline form) is rarely used for medicinal purposes. Cocaine hydrochloride crystals or flakes come in Vs, A and 1 ounce bottles from the manufacturer and has a wholesale price of approximately 20 to 25 per ounce (100% pure). 

Cocaine is still a drug of choice among many physicians as a topical local anesthetic because the drug has vasoconstrictive qualities (shrinks and stops the flow of blood). Synthetic local anesthetics such as novacaine and xylocaine (lidocaine) have also been discovered and used extensively as a local anesthetic. 

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]. 

Na+ channels Cocaine is an antagonist of voltage-gated Na-i- channels, reducing axonal conduction and acting as a local anesthetic. This effect will be discussed at greater length in chapter 8. Cocaine s blockade of Na-i- channels as a contribution to its psychotropic effects is possible but has not been examined. 

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