Local anesthetics esters

Contraindications Hypersensitivityto ester local anesthetics, sulfites, PABA, patients on anticoagulant therapy, and in patients with coagulopathy, infection, thrombocytopenia, Should not be given via intra-arterial, intrathecal, or intravenous routes. 

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. 

Benzocaine is an ester local anesthetic with a moderate onset of action and short duration. It is minimally absorbed and therfore relatively free from systemic adverse effects (toxic range of total dose 200 to 300 mg Tetzlaff, 2000). 

Reduced pseudocholinesterase activity has been described both in pregnancy and with magnesium therapy. As most ester local anesthetics (with the exception of cocaine) are metabolized by this enzyme, caution should be exercised when using ester local anesthetics in pregnancy, especially with the increasing use of magnesium sulfate in this field. 

There have been two reports of patients scheduled for tonometry who developed periorbital dermatitis following the topical instillation of local anesthetic eye drops (4). The first patient reacted strongly positive on patch testing to Thilorbin AT (oxybuprocaine, fluorescein, phenylmercuric borate, polysorbate 20, mannitol) and also to oxybuprocaine alone. The second reacted to Conjucain EDO (oxybuprocaine, sorbitol, sodium hydroxide) and to oxybuprocaine alone. The authors believed these to be the only described cases of a delayed hjrpersensitivity reaction to oxybuprocaine, an ester local anesthetic commonly used for topical anesthesia in the eye. 

Benzocaine, an ester local anesthetic (20% topical gel), is indicated as a local anesthetic for dental pain or dental procedures and as a local anesthetic for pruritic dermatoses, pruritis, or other irritations. 

Chloroprocaine (nesacaine), an ester local anesthetic, is a chlorinated derivative of procaine with rapid onset, short duration of action, and reduced acute toxicity due to rapid metabolism (plasma tj 25 seconds). A higher-than-expected incidence of muscular back pain following epidural anesthesia with 2-chloroprocaine has been reported this back pain is thought to be due to tetany in the paraspinus muscles, which may be a consequence of binding by the EDTA included as... 

Tetracaine (pontocaine), a long-acting amino ester, is significantly more potent and has a longer duration of action than procaine. Tetracaine may exhibit increased systemic toxicity because it is more slowly metabolized than the other commonly used ester local anesthetics. It is widely used in spinal anesthesia when a drug of long duration is needed. Tetracaine also is incorporated into several topical anesthetic preparations. Tetracaine is rarely used in peripheral nerve blocks because of the large doses often necessary, its slow onset, and its potential for toxicity. 

Metabolism of ester local anesthetics is carried out by plasma cholinesterases and may be rapid. Procaine and chloroprocaine have half-lives of only 1-2 minutes. The amides are hydrolyzed in the liver and have half-lives from 1.8 hours to 6 hours. Bupivacaine and ropiva-caine are very lipid-soluble and long-acting local anesthetics. Liver dysfunction may increase the elimination half-life of amide local anesthetics. 

Uses sun-screening agent in cosmetics, moisturizers, shampoos, hair-care products, nail polish, lipstick, lip balms, oral vitamin supplements manufacture of various esters (local anesthetics), folic acid and azo dyes in sunburn preventatives used in laboratories as sulfonamide antagonist antirickettsial Cross para groups of compounds. PA PABA A... 

Inactivation of LA clinical effect occurs by diffusion away from the neuronal Na+ channels and by uptake into the vas nervorum and into the systemic circulation. It is here that metabolic inactivation of the linkage between the aromatic ring and tertiary amine can occur. The mechanism and site are very different for the amide and ester local anesthetics. 

An allergic reaction to specific agents is an obvious contraindication. Allergy to para-aminobenzoic acid (PABA) is a contraindication to use of ester local anesthetics due to the fact that PABA is a metabolic product of ester metabolism. Methylparaben is a common preservative chemically similar to PABA and likewise can cause an allergic reaction. Metabisulfite is a commonly used preservative that may also cause allergic reactions but more notably is neurotoxic when used intrathecally. Local anesthetics containing any preservative should not be used intrathecally. Ester local... 

Situations which affect the level or efficacy of pseudocholinesterase can significantly alter the duration of action and toxicity of ester local anesthetics. This is more likely in premature infants, individuals with atypical pseudocholinesterase production or advanced liver disease. 

Allergic reactions are very rare, but occur more commonly with the ester local anesthetics. Ester local anesthetics should be avoided in known PABA-allergic patients. Other allergic reactions may be due to the preservative methylparaben, which is chemically similar to PABA. 

Sorbitan sesquioleate emulsions of petrolatum and wax are used as ointment vehicles in skin treatment. In topical appHcations, the inclusion of both sorbitan fatty esters and their poly(oxyethylene) derivatives modifies the rate of release and promotes the absorption of antibiotics, antiseptics, local anesthetics, vasoconstrictors, and other medications from suppositories, ointments, and lotions. Poly(oxyethylene(20)) sorbitan monooleate, also known as Polysorbate 80 (USP 23), has been used to promote absorption of ingested fats from the intestine (245). 

Some active 5-pyrazolone derivatives (707) and (708) in which the 1-phenyl substituent of antipyrine was replaced by 2 -, 3 - and 4 -pyridyl groups have been prepared (66HCA272). A series of aminoesters substituted at the nitrogen atom of the ester grouping with an antipyryl residue (709) were found to possess local anesthetic properties (69MI40400). 

The finding that the benzoyl ester, tropacocaine (14), possessed local anesthetic activity showed that the carbomethoxy group was not required for activity. 

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. 

As shovm above, the attachment of the aromatic ring to the carbon chain bearing the basic nitrogen may be accomplished through an ester or an amide configured in either direction. A simple ether linkage fulfills this function in yet another compound that exhibits local anesthetic activity. Thus, alkylation of the mono potassium salt of hydroquinone with butyl bromide affords the ether (77) alkylation of this with w-C3-chloropropyl)morpholine affords pramoxine (78)... 

The low structural specificity in the local anesthetic sell cs is perhaps best illustrated by phenacalne (91), a local an-I -.lhetic that lacks not only the traditional ester or amide func-I ion but the basic aliphatic nitrogen as well. First prepared at I lie turn of the century, a more recent synthesis starts by con-ili iusation of p-ethoxyaniline with ethyl orthoacetate to afford I he imino ether (90), Reaction of that intermediate with a sec-I liil mole of the aniline results in a net displacement of ethanol, iiobably by an addition-elimination scheme. There is thus ob-I.lined the amidine, 91, phenacalne. 

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]. 

Moore, D.C. (1986). Ester or amide local anesthetics in malignant hyperthermia— Who knows Anesthesiology 54, 294-296. 

Single-substituent polymers, such as the procaine derivative shown as compound 24, are insoluble in water. In principle, the bioerosion characteristics can be modified by the presence of amino acid ester, glyceryl, or glucosyl (see later) cosubstituents, and this offers the possibility of a long-term release of a local anesthetic at a targeted site in the body. 

Risocaine (28) manages to retain local anesthetic activity even without having a "basic ester" moiety.10 Its synthesis follows classic lines involving esterification of p-nitrobenzoic acid with thionyl chloride followed by reaction with propanol, and then catalytic reduction to complete the scheme. 

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 answer is c. (Hardman, p 340. Katzung, p 437.) Of the listed agents, only bupivacaine is an amide. Allergy to amide-type local anesthetics is much less frequent than with ester-type local anesthetics, such as benzo-caine patients who demonstrate an allergy to one such drug will be allergic to all of them... 

The answer is a. (Hardman, p 338. Katzung, pp 438-439.) Ester-type local anesthetics are mainly hydrolyzed by pseudocholinesterases. Amide-type local anesthetics are hydrolyzed by microsomal enzymes in the liver. Of the listed agents, only lidocaine is an amide and can be influenced by liver dysfunction. 

The answer is d. (Hardman, p T36J The addition of a vasoconstrictor, such as epinephrine or phenylephrine, to certain short-acting, local anesthetics is a common practice in order to prevent the rapid systemic absorption of the local anesthetics, to prolong the local action, and to decrease the potential systemic reactions. Some local anesthetics cause vasodilation, which allows more compound to escape the tissue and enter the blood. Procaine is an ester-type local anesthetic with a short duration of action due to rather rapid biotransformation in the plasma by cholinesterases. The duration of action of the drug during infiltration anesthesia is greatly increased by the addition of epinephrine, which reduces the vasodilation caused by procaine. 

The contribution of pseudocholinesterase, also known simply as cholinesterase, to drug metabolism is much greater as it possesses considerably broader substrate selectivity. In addition to acetylcholine, it will hydrolyze other choline esters like the muscle relaxant succinylcholine. It will also hydrolyze non-choline-containing drugs like the local anesthetic procaine and the anti-inflammatory agent aspirin (Fig. 6.5). Cholinesterases, particularly... 

Mannich, C. Krosche, W. Arch. Pharm. 1912, 250, 647. Carl U. F. Mannich (1877-1947) was bom in Breslau, Germany. After receiving a Ph.D. at Basel in 1903, he served on the faculties of Gottingen, Frankfurt and Berlin. Mannich synthesized many esters of p-aminobenzoic acid as local anesthetics. 

The special case of the endogenous transmitter acetylcholine illustrates well the high velocity of ester hydrolysis. Acetylcholine is broken down at its sites of release and action by acetylcholinesterase (pp. 100,102) so rapidly as to negate its therapeutic use. Hydrolysis of other esters catalyzed by various esterases is slower, though relatively fast in comparison with other biotransformations. The local anesthetic, procaine, is a case in point it exerts its action at the site of application while being largely devoid of undesirable effects at other locations because it is inactivated by hydrolysis during absorption from its site of application. 

Clinically used local anesthetics are either esters or amides. This structural element is unimportant for efficacy even drugs containing a methylene bridge, such as chlorpromazine (p. 236) or imipramine (p. 230), would exert a local anesthetic effect with appropriate application. Ester-type local anesthetics are subject to inactivation by tissue es-Ltillmann, Color Atlas of Pharmacology... 

The amide type local anesthetic lidocaine is broken down primarily in the liver by oxidative N-dealkylation. This step can occur only to a restricted extent in prilocaine and articaine because both carry a substituent on the C-atom adjacent to the nitrogen group. Articaine possesses a carboxymethyl group on its thiophen ring. At this position, ester cleavage can occur, resulting in the formation of a polar -COO group, loss of the amphiphilic character, and conversion to an inactive metabolite. 

---