Local anesthetics development

Ziconotide, a novel non-opioid, non-local anesthetic, developed for the treatment of severe chronic pain. Ziconotide CK GKGAKCSR LMYDCCTGSC RSGKCa (disulfide bonds C -C, C -C , also previously referred to as Prialt , Cl 1009, or SNX-111, is the synthetic equivalent of the cone snail peptide... 

Procaine (its hydrochloride is marketed as Novocaine ) was one of the first local anesthetics developed for infiltration and regional anesthesia. It is synthesized by the following Fischer esterification ... 

The NF and reagent grades are employed in the pharmaceutical industry which makes use of benzyl alcohol s local anesthetic, antiseptic, and solvent properties (17—20). It also finds use in cough symps and drops ophthalmic solutions bum, dental (21), and insect repeUant solutions and ointments and dermatological aerosol sprays. It is used in nail lacquers and as a color developer in hair dyes by the cosmetics industry (22), and in acne treatment preparations (23). 

The Class I antiarrhythmic agents inactivate the fast sodium channel, thereby slowing the movement of Na" across the cell membrane (1,2). This is reflected as a decrease in the rate of development of phase 0 (upstroke) depolarization of the action potential (1,2). The Class I agents have potent local anesthetic effects. These compounds have been further subdivided into Classes lA, IB, and IC based on recovery time from blockade of sodium channels (11). Class IB agents have the shortest recovery times (t1 ) Class lA compounds have moderate recovery times (t 2 usually <9 s) and Class IC have the longest recovery times (t 2 usually >9 s). 

The line of reasoning that leads from morphine to the 4-phenyl-piperidines is so clear—if unhistoric—as to demand exposition in an integral chapter. The chronologically oriented chapter on the development of the local anesthetics is included specifically to give the reader some appreciation of one of the first approaches to drug development. 

The ion-channel blocking mechanism has been widely tested and found to be important in both pharmacology and physiology. Examples are the block of nerve and cardiac sodium channels by local anesthetics, or block of NMDA receptor channels by Mg2+ and the anesthetic ketamine. The channel-block mechanism was first used quantitatively to describe block of the squid axon K+ current by tetraethylammonium (TEA) ions. The effects of channel blockers on synaptic potentials and synaptic currents were investigated, particularly at the neuromuscular junction, and the development of the single-channel recording technique allowed channel blockages to be observed directly for the first time. 

One of the first pharmacological classes to be studied by medicinal chemists was local anesthetics. Many of the guiding principles which are used to this day, for example, molecular dissection, side chain substitution and inversion, and the like, were first developed in the course of those early researches. 

Epidural anesthesia This term is understood to be an introduction of local anesthetic into the spinal cord membrane of the intervertebral space. It is used during obstetrical and gynecological interventions that do not require a fast development of anesthesia. Drugs such as lidocaine, mepivacaine, bupivacaine, ethidocaine, and chloroprocaine are used for this purpose. 

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. 

Historically, local anesthetics have been known for many years. Cocaine, the first such agent, was isolated in 1860 and introduced for clinical application in 1884. Procaine was developed as a synthetic analog of cocaine in 1905 and lidocaine was synthesized in 1943. The development of new chemical entities as putative local anesthetics remains an ongoing activity in medicinal chemistry. 

The development of newer agents continues because it is relatively easy to synthesize chemicals with local anesthetic properties. Unfortunately, it is difficult to reduce the toxicity of these compounds because the common side effects of local anesthetics represent extensions of their therapeutic effects. New research into the mechanisms of local anesthetic-induced cardiac and spinal toxicity and identification of alternative drug targets for spinal analgesia (eg, opioid receptors, [Pg.560]

An anatomic circumstance that sometimes creates exceptions to the above rules for differential nerve block is the location of the fibers within the peripheral nerve bundle. In large nerve trunks, fibers located circumferentially are the first to be exposed to the local anesthetic when it is administered into the tissue surrounding the nerve. In the extremities, proximal sensory fibers are located in the outer portion of the nerve trunk, whereas the distal sensory innervation is located in the central core of the nerve. Thus, during infiltration block of a large nerve, sensory analgesia first develops proximally and then spreads distally as the drug penetrates deeper into the core of the nerve. 

Whiteside, J. B. and Wildsmith, J. A. W. Developments in local anesthetic drugs, Brit. J. Anesth. 2001,... 

The pharmaceutical industry makes use of benzyl alcohol s local anesthetic, antiseptic, and solvent properties. It is used in nail lacquers and as a color developer in hair dyes by the cosmetics industry, and in acne treatment preparations. 

A frequently cited example of an important natural-product-derived drag is the neuromuscular blocker d-tubocurarine, derived from the South American plant curare, which was used by South American Indians as an arrow poison (see Chapter 26). Tubocurarine led to the development of decamethonium, which, although structurally dissimilar to tubocurarine, was nevertheless synthesized based on the then prevalent presumption that tubocurarine contained two quaternary nitrogens. Similarly, synthetic local anesthetics, such as lidocaine, benzocaine, and dibucaine, were synthesized to mimic the nerve-blocking effect of cocaine, a natural alkaloid obtained from the leaves of Coca eroxylum, but without the adverse side effects that have led to its abuse. 

The leaves of Erythroxylon coca, the divine plant of the Incas, contain a local anesthetic and a psychostimulant. Erythroxylaceae is a very small family, represented by two genera, the more important of which is Erythroxylon. They are mostly tropical shrubs with entire leaves and 5-merous flowers, and the fruit is a 1-seeded, reddish drupe resembling that of dogwood. The anatomy of the plants of this family closely resembles that of the Linaceae. Of special interest is the development of papillae on the dorsal surface of the leaves. This is found in most species of Erythroxylon. 

A need was seen for a synthetic and less toxic anesthetic. In 1905, Procaine was synthesized and became the prototype for synthesized anesthetics for the next 50 years. In 1948, Lidocaine was developed and is now the most commonly used local anesthetic. Other synthesized local anesthetics include bupivacaine and tetracaine. 

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