Cocaine local anesthetic action

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). 

FIGURE 13—3. Icon of cocaine. The main mechanism of action is to block reuptake and cause the release of monoamines, principally dopamine (DA), but also norepinephrine (NE) and serotonin (5HT). There is also a local anesthetic action (caine). 

Therapeutic uses Cocaine has a local anesthetic action that represents the only current rationale for the therapeutic use of cocaine-, cocaine is applied topically as a local anesthetic during eye, ear, nose, and throat surgery. While the local anesthetic action of cocaine is due to a block of voltage-activated sodium channels, an interaction with potassium channels may contribute to cocaine s ability to cause cardiac arrhythmias. [Note Cocaine is the only local anesthetic that causes vasoconstriction. This effect is responsible for the necrosis and perforation of the nasal septum seen in association with chronic inhalation of cocaine powder.]... 

It is found that the free carboxylic acid, benzoyl-eegonine itself, has no local anesthetic action, but that any of its alkyl esters, such as ethyl, propyl, etc., resemble its methyl ester, cocaine, in having this action (2). This applies only to the aliphatic esters, as the aromatic do not appear... 

Tropacocaine resembles cocaine in its stimulant action upon the nerve centers, and also in its local anesthetic action. It differs from cocaine, however, in that it does not cause local constriction of the blood vessels, and that it has very little influence upon the pupil. Sollmann J.A.M.A., 1918, Ixx, 216) has shown that it is approximately equal to cocaine in its anesthetic power and Eggleston and Hatcher that it is distinctly less toxic. It has been used chiefly in the so-called spinal anesthesia and a large number of surgeons have reported favorably upon it. A dose of one grain (0.06 Gm.) is ordinarily recommended, although a number of authors have used larger quantities without evil effects. 

Other tissues The effects of these drugs on the heart are discussed in Chapter 14 (see class I antianhythmic agents). Most local anesthetics also have weak blocking effects on skeletal muscle neuromuscular transmission, but these actions have no clinical application. The mood elevation induced by cocaine probably reflects actions on dopamine or other amine-mediated synaptic transmission in the CNS rather than a local anesthetic action on membranes. 

Erythrophleum alkaloids have cardiac activity (they increase contractile strength) and a very strong local anesthetic action. Although the latter action is more potent than cocaine, it is accompanied by intense irritation at the site of administration. Cassaine (39) inhibits (Na K )-ATPase (Wink, 1993), When the double bond is saturated, almost all biological activity disappears. Erythrophleum bark is used as a cancer remedy in Africa (Suffness and Cordell, 1985). 

The first totally synthetic substitute was eucaine. It was synthesized by Harries in 1918 and retains many of the essential skeletal features of the cocaine molecule. The development of this new anesthetic partly confirmed the portion of the cocaine structure essential for local anesthetic action. The advantage of eucaine over cocaine is that it does not produce mydriasis and is not habit forming. Unfortunately, it is highly toxic. 

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. 

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 action of procaine is mainly as a local anesthetic and xylocaine does not stimulate the reward system of the brain the way that cocaine does. 

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). 

What does cocaine do in the brain First, it binds to sodium ion channels and blocks them from functioning. This action stops the flow of action potentials and prevents neurons from communicating with each other. Cocaine also blocks the conduction of pain signals, which explains why, after it was isolated from the coca plant ((Erythroxylon coca) in 1855, it was used as a local anesthetic, including for the eye and for toothaches. But ultimately, its anesthetic actions would be discovered to have... 

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. 

All local anesthetics including cocaine paralyze the nerve fibers anywhere in their course, wherever they are brought into contact with them. When applied to mucous membranes or hypodermically, they select the portions peripheral to the main trunks, the thinner sheath of the terminal fibrils facilitating its penetration. It is therefore unnecessary to assume selective action on the histological sensory endings. 

Additions of 1/10 to 2 1/2% of urea to dilute procaine solutions increase materially their potency, to ten times, on direct application to nerve trunks, presumably by favoring penetration. The effect is not due to alkalinization. The action of local anesthetics is reported to be increased by intravenous injection of methylene blue, by the local application of caffeine or theophylline, by morphine, and by the antipyretic analgesics. Cocaine anesthesia is said to be ineffective in tissue impregnated with oxalic acid. Inflamed tissues are less susceptible to local anesthesia, probably because of their difficult penetration. 

Cocaine produces vasoconstriction (blanching) probably by sensitizing to sympathetic stimulation. This action is lacking in the other local anesthetics. Procaine has practically no vascular effect alypin, eucaine, and stovaine cause some dilatation. Cocaine decreases capillary hemorrhage procaine, apothesine, and other synthetic anesthetics tend rather to increase bleeding. 

Acute poisoning by local anesthetics is fairly common, especially with cocaine, and is apt to be fatal. Some accidents are due to excessive doses through mistakes or faults of technique, but the susceptibility varies greatly owing to differences of absorption and of destruction, and to varying response to the actions. Fright plays a considerable part. 

The action of norepinephrine is terminated by reuptake mechanisms, two of which have been identified. Biogenic amine Uptake 1 is located in the presynaptic membrane, requires energy for the transport, is sodium and temperature dependent, and is inhibited by ouabain (a cardiac glycoside), cocaine (a local anesthetic), and imipramine (an antidepressant). Biogenic amine Uptake 2 is located extraneuronally in various smooth muscles and glands, requires energy, and is temperature dependent. Approximately 20% of the amine is either taken up by the Uptake 2 mechanism or is metabolized. 

Cocaine is a local anesthetic with a peripheral sympathomimetic action that results from inhibition of transmitter reuptake at noradrenergic synapses (see Chapter 6 Introduction to Autonomic Pharmacology). It readily enters the central nervous system and produces an amphetamine-like effect that is shorter lasting and more intense. The major action of cocaine in the central nervous system is to inhibit dopamine reuptake into neurons in the "pleasure centers" of the brain. These properties and the fact that it can be smoked, "snorted" into the nose, or injected for rapid onset of... 

Novocaine (procaine hydrochloride) is a local anesthetic that is considered to be less toxic than cocaine, and does not have the danger of habituation. It is used frequently in conjunction with a vasoconstrictor such as epinephrine to secure a prolonged anesthetic action. 

Although cocaine can function as a local anesthetic, most of its actions relate to a second mechanism. Cocaine increases synaptic concentrations of catecholamines (i.e., dopamine and norepinephrine) in the brain by blocking their reuptake mechanisms. Normally, when these transmitters are released from nerve terminals, they are rapidly removed from the synaptic cleft by specific energy-dependent transporter proteins that carry them back into the terminal. By blocking these transporter systems, cocaine prolongs the time the catecholamines remain in the synapse and intensifies their actions. This increase in dopamine concentration in the CNS appears to be the basis for the various euphoric and related changes that occur in people who use cocaine. A similar mechanism has been suggested for methamphetamine. 

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