Cocaine anesthetic properties

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. 

The first clinical uses of a local anesthetic agent occurred in 1884, when cocaine was employed as a topical agent for eye surgery and to produce a nerve block. These events inaugurated a new era, that of regional anesthesia. New applications were developed, including spinal, epidural, and caudal anesthesia. The search for a better local anesthetic led to chemical synthesis of a number of other compounds that have more selective local anesthetic properties and few systemic side effects. 

Cocaine (Fig. 13—3) has two major properties it is both a local anesthetic and an inhibitor of monoamine transporters, especially dopamine (Fig. 13—4). Cocaine s local anesthetic properties are still used in medicine, especially by ear, nose, and throat specialists (otolaryngologists). Freud himself exploited this property of cocaine to help dull the pain of his tongue cancer. He may have also exploited the second property of the drug, which is to produce euphoria, reduce fatigue, and create a sense of mental acuity due to inhibition of dopamine reuptake at the dopamine transporter. Cocaine also has similar but less important actions at the norepinephrine and the serotonin transporters (Fig. 13—3). Cocaine may do more than merely block the transporter—it may actually release dopamine (or norepinephrine or serotonin) by reversing neurotransmitter out of the presynaptic neuron via the monoamine transporters (Fig. 13—4). 

One of the earliest examples of this SAR approach was the development of synthetic local anesthetic agents. These drugs were developed based upon the structure of cocaine, whose local anesthetic property was championed by Carl Roller, who introduced cocaine into clinical practice in 1884 for ophthamological surgery. The many local anesthetics used in clinical practice today all emanate from these early observations. 

Death from cocaine often occurs within 2-3 minutes, suggesting direct cardiac toxicity, fatal dysrhythmias, and depression of medullary respiratory centers as common causes of death (11,12). Thus, cocaine s local anesthetic properties can contribute additional hazards when high doses are used, reminiscent of deaths reported in the era when it was used as a mucous membrane paste for nasopharyngeal surgery (13). 

The importance of cocaine in surgery has led to the study of its chemical constitution and to the preparation, by synthetic methods, of analogous compounds having the beneficial anesthetic properties... 

This compound possesses anesthetic properties and is less toxic than cocaine. It is irritating when injected into the body and is now replaced by beta-eucaine which is a similar compound derived from acetaldehyde di-acetone amine, vinyl di-acetone amine. 

Experimental evidence shows that stimulants actually may impair one s ability to learn complex tasks (Fischman, 1984). Considerable anecdotal evidence suggests that stimulants may impair performance in complex reasoning. Consider the case of William Halstead. Halstead became known as the father of modern surgery for his pioneering work in the early 1900s. But later in his career, while studying the anesthetic properties of cocaine, he was probably the first American to become addicted to the... 

Thus truxilline (3) (isatropyl-cocaine) has no anesthetic action, but is a strong cardiac poison, and Ehrlich (4) found that, of several different cocaine derivatives, such as isatropyl-cocaine, valeryl-cocaine hydriodide, and phenylacetyl-cocaine hydriodide, the last named was the only one which had anesthetic properties, but to a less degree than cocaine. All of these have a characteristic toxic effect on the liver, and differ from cocaine only in having the benzoyl group replaced by the one named. 

The foregoing studies have dealt chiefly with model substrates in vitro. Several of the early papers by Augustinsson, referred to in Section 4.1.1, considered substrate specificity from the viewpoint of species variations. It is also important to recognize that plasma cholinesterase may be associated with the hydrolysis, in vivo, of a large number of drugs (K4, LI, L4) that contain ester bonds susceptible to enzymic hydrolysis. Apart from succinylcholine (Section 3.1), cholinesterase is known to be responsible in man for the hydrolysis of cocaine (S40), procaine (K2), and other esters with local anesthetic properties. Whether enzymatic hydrolysis terminates the pharmacologic effect depends on the whole mechanism of action of the particular drug. 

Cocaine (Figure 14-1) is an ester of benzoic acid and methylecgonine. The clinically desired actions of cocaine are the blockade of nerve impulses, as a consequence of its local anesthetic properties, and local vasoconstriction, secondary to inhibition of local norepinephrine reuptake. Toxicity and its potential for abuse have steadily decreased the clinical utility of cocaine. Its high toxicity is due to reduced catecholamine uptake in both the central and peripheral nervous systems. 

Its euphoric properties are due primarily to inhibition of catecholamine uptake, particularly dopamine, in the CNS. Other local anesthetics do not block the uptake of norepinephrine and do not produce the sensitization to catecholamines, vasoconstriction, or mydriasis characteristic of cocaine. Currently, cocaine is used primarily for topical anesthesia of the upper respiratory tract, where its combination of both vasoconstrictor and local anesthetic properties provide anesthesia and shrinking of the mucosa. Because of its abuse potential, cocaine is listed as a schedule II drug by the U.S. Drug Enforcement Agency. 

Because of its ability to block pain, cocaine became widely used as a local anesthetic to deaden nerves during various medical procedures, but it was not an ideal anesthetic owing to its undesired side effects. For example, in eye surgery it produces mydriasis, or dilation of the pupil It also has powerful addictive properties and exhibits dangerous effects on the central nervous system. Medicinal chemists thus began a search for substances related to cocaine that would retain its valuable anesthetic properties but would not produce its side effects. 

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. 

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]. 

D. Epinephrine is by far the most commonly employed vasoconstrictor. Phenylephrine is occasionally used with procaine for dental procedures. Levonordefrin is also used rarely in dental procedures. Dopamine has no vasoconstrictor activity. Cocaine is itself a local anesthetic with some vasoconstrictor properties. However, cocaine, because of its abuse potential and toxicity, is seldom used. Its only use is topical. 

Cocaine differs from the other local anesthetics with respect to its cardiovascular effects. Cocaine s blockade of norepinephrine reuptake results in vasoconstriction and hypertension, as well as cardiac arrhythmias. The vasoconstriction produced by cocaine can lead to local ischemia and, in chronic abusers who use the nasal route, ulceration of the mucous membrane and damage to the nasal septum have been reported. The vasoconstrictor properties of cocaine can be used clinically to decrease bleeding from mucosal damage or surgical trauma in the nasopharyneal region. 

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. 

Many substances of widely different chemical structure abolish the excitability of nerve fibers on local application in concentrations that do not cause permanent injury and that may not affect other tissues. Sensory nerve fibers are most susceptible, so that these agents produce a selective sensory paralysis, which is utilized especially to suppress the pain of surgical operation. This property was first discovered in cocaine, but because of its toxicity and addiction liability, it has been largely displaced by synthetic chemicals. The oldest of these, procaine (novocaine), is still the most widely used. Its relatively low toxicity renders it especially useful for injections, but it is not readily absorbed from intact mucous membranes and is therefore not very effective for them. Many of its chemical derivatives are also used. They differ in penetration, toxicity, irritation, and local injury as well as in duration of action and potency. Absolute potency is not so important for practical use as is its balance with the other qualities. If cocaine is absorbed in sufficient quantity, it produces complex systemic actions, involving stimulation and paralysis of various parts of the CNS. These are mainly of toxicological and scientific interest. Its continued use leads to the formation of a habit, resembling morphinism. This is not the case with the other local anesthetics. 

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