Local anesthetics nature

Many 1,2,3,5-benzenetetrol derivatives are used mediciaaHy. For example, khellin [82-02-0] (65), which is a naturally occurring benzopyranone, is used as a coronary vasodilator and bronchodilator (233). Derivatives of khellin are effective local anesthetics and antiarrythmics (234). Similarly, amine derivatives (68) that are prepared from khellinone oxime (66) exhibit hypnotic, sedative, anticonvulsant, antiinflammatory, cardiac analeptic, diuretic, and antiulcerous activity (235) (see Analgesics, antipyretics, and antiinflammatory agents). 

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]. 

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]. 

This subsection is devoted to the metabolic reactivity of the amide bond in anilides, i.e., compounds whose amino moiety is attached to an aromatic ring. Based on the nature of the acyl moiety, a number of classes of anilides exist, three of which are of particular interest here, namely arylacetamides, acylani-lides, and aminoacylanilides. The first group contains several analgesic-antipyretic drugs, the second A4-acyl derivatives of sulfonamides, and the third a number of local anesthetics. Particular attention will be paid to structure-metabolism relationships in the hydrolysis of these compounds. Cases where hydrolysis leads to toxification will be summarized in the last part of the chapter. 

Like procainamide, lidocaine is an amide with local anesthetizing action. Lidocaine is usually administered intravenously for short-term therapy of ventricular extrasystole, tachycardia, especially in the severe phase of myocardial infarction, arrhythmia of natural cause, and for arrhythmia that can originate in the heart during surgical manipulations. Synonyms of this drug are lidopen, xylocaine, xylocard, and others. 

Flecainide, as with other local anesthetics, is used for naturally occurring ventricular arrhythmia. A synonym of this drug is tambocor. 

The local anesthetics can be broadly categorized on the basis of the chemical nature of the linkage contained within the intermediate alkyl chain group. The amide local anesthetics include lidocaine (7.5), mepivacaine (7.6), bupivacaine (7.7), etidocaine (7.8), prilocaine (7.9), and ropivacaine (7.10) the ester local anesthetics include cocaine (7.11), procaine (7.12), benzocaine (7.13), and tetracaine (7.14). Since the pharmacodynamic interaction of both amide and ester local anesthetics with the same Na" channel receptor is essentially idenhcal, the amide and ester functional groups are bioisosterically equivalent. However, amide and ester local anesthetics are not equal from a pharmacokinetic perspective. Since ester links are more susceptible to hydrolysis than amide links. 

The method of drug administration or exposure to a poison may impart selectivity to a xenbiotic. For example, atropine can be applied directly to the eye for the dilation of the pupils. Note that eventual absorption into the blood stream from this site will cause systemic effects. Another example would be the topical (skin) application of a local anesthetic such as benzocaine. Monoclonal antibodies, which are specific for chemical functional groups, are tissue and cell-specific natural agents to which drugs can be chemically bonded. 

The natural alkaloid cocaine was introduced as the first local anesthetic drug in clinical surgery... 

One of the more notorious and abused stimulants is cocaine, a natural product isolated from the South American coca plant, shown in Figure 14.25. Once in the bloodstream, cocaine produces a sense of euphoria and increased stamina. It is also a powerhd local anesthetic when applied topically. Within a few decades of its first isolation from plant material in 1860, cocaine was used as a local anesthetic for eye surgery and dentistry—a practice that stopped once safer local anesthetics were discovered in the early 1900s. 

The use of terpenoids, usually as mixtures prepared from plants, dates from antiquity. The several essential oils produced by distillation of plant parts contained the plant essences. These oils have been employed in die preparation of perfumes, flavorings, and medidnals. Examples are oils of clove (local anesthetic in toothache), lemon (flavoring), lavender (perfume), and juniper (diuretic). Usually essential oil production depends on a simple technology which often involves steam distillation of plant material The perfume industry of Soudiem France uses somewhat more sophisticated procedures in the isolation of natural flower oils since these oils are heat sensitive. The separation of oils from citrus fruit residues m California and Florida is done by machine. 

Esters, which contain the C 0 C functional group, have many uses in medicine, industry, and living systems. In medicine, a number of important pharmaceutical agents, including aspirin and the local anesthetic benzocaine, are esters. In industry, polyesters such as Dacron and Mylar are used to make synthetic fibers and films. In nature, many simple esters are responsible for the fragrant odors of fruits and flowers. For example, pentyl acetate is found in bananas, and octyl acetate is found in oranges. 

Finally, therapists may work with patients who are receiving central neural blockade in the form of an epidural or spinal injection. These procedures are common during natural and caesarean childbirth and in some other surgical procedures. Administration of local anesthetics into the spaces around the spinal cord are also used to treat individuals with severe and chronic pain—that is, patients recovering from extensive surgery, patients who have cancer, or patients with other types of intractable pain. In these situations, therapists may notice that an indwelling catheter has been placed in the patient s epidural or subarachnoid space to allow repeated or sustained administration of the spinal anesthesia. 

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. 

A third role of natural products is their utility as prototypes or models for synthetic drugs possessing physiological activities similar to the original drug. Procaine and similar local anesthetics are commonly cited representatives of this category. 

Tab. 5.1 Relative blocking potency of local anesthetics on natural membranes and various physicochemical effects of local anesthetics on artificial phospholipid membranes. (Reprinted from Tab. 1 of ref.

Local anesthetic agents can affect the function of any organs in which electrical impulse transmi.ssion occurs. The nature and the extent of the.se unwanted side effects depend on the drug u.sed, the concentration of the drug in circulation, the site of application, and the technique used. The. secondary effects of local ane.sthelic agents in lhe.se situations are discussed in this. section. 

There are numerous natural substances that have useful therapeutic properties as well as other undesirable properties. From these starting points, medicinal chemists have improved on nature. For example, while extremely useful in the treatment of infection, penicillin is not available by the oral route this shortcoming is overcome in the analogue ampicillin (Figure 8.3A). Similarly, the obvious deleterious effects of cocaine have been eliminated in the local anesthetic procaine (Figure 8.3B). The short activity and weak steroid progesterone is converted to a stronger... 

Extension of Tropine Alkaloids. Here again, medicinal chemists have gone beyond nature by molecular modification. While cocaine possesses topical anesthetic activity but no local infiltration value as an anesthetic, a number of very useful, local anesthetic agents such as procaine and lidocaine have been derived from our knowledge of the structure of cocaine. Chemists have broadened the scope of usefulness of the cocaine structure. 

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