Para-aminobenzoic acid esters

Procaine, a para-aminobenzoic acid ester, was the first synthetic LA synthesized in 1904. It has a slow onset of action and a short duration and hence low toxicity. Due to its extremely low binding to plasma proteins (only 6 %) procaine is rapidly hydrolyzed by plasma cholinesterases to diethylaminoethanol and para-aminobenzoic acid, which inhibit the actions of salicylates and sulfonamides (Tetzlaff, 2000). 

Likewise, in a series of para-aminobenzoic acid esters the length of the alkyl chain is directly proportional to the local anaesthetic activity, and... 

Para-aminobenzoic acid (PABA) and its esters, benzophenones IX Acne preparations... 

Tetracaine, an ester of para-aminobenzoic acid, has a slow onset, very short plasma half-life of 2.5 to 4 min and a long duration of action. Toxic effects are rare and only in the case of vascular absorbance from mucous membranes. 

Esters of para-aminobenzoic acid Procaine Chloroprocaine Tetracaine Benoxinate... 

Tetracaine, an ester of para-aminobenzoic acid (PABA), has been widely used for topical anesthesia of the eye. It is currently available in a 0.5% solution. Its onset, intensity, and duration of anesthesia are comparable with those of proparacaine and benoxinate (Figure 6-2). Onset of anesthesia sufficient to permit tonometry or other minor procedures involving the superficial cornea and conjimc-tiva is 10 to 20 seconds, and duration of anesthesia is 10 to 20 minutes. It has been reported, however, that the 1% solution produces anesthesia lasting nearly an hour. Tetracaine 1% has also been used successfully to provide anesthesia during phacoemulsification cataract surgery and intraocular lens implantation. 

Benzocaine is a poorly soluble local anesthetic, an ester of para-aminobenzoic acid. It is used in many countries as a component of some free-sale formulations for topical use, for example in skin creams, as a dry powder for skin ulcers, as throat lozenges, and as teething formulations for young children. It is also used in aerosol sprays when anesthetizing the oropharynx. Relatively high concentrations of local anesthetic are required to be effective topically, increasing tissue penetration and the risk of subsequent toxicity. Benzocaine formulations are available in concentrations of 1-20%. 

Oxybuprocaine is an ester of para-aminobenzoic acid. It is a popular local anesthetic for use in ophthalmology. 

The sulfonamides have a bacteriostatic rather than a bactericidal action. Many local anesthetics used in the eye are esters of para-aminobenzoic acid, and such drugs will interfere with the action of sulfonamides. Thus, to obtain the maximum effect from instillation of sulfonamide eye-drops, these drugs should not be used until the effect of the local anesthesia disappears. 

Procaine (novocain), the first synthetic local anesthetic, is an amino ester (see Figure 14-1) with low potency, slow onset, and short duration of action. Its use now is confined to infiltration anesthesia and occasionally for diagnostic nerve blocks. Its hydrolysis in vivo produces para-aminobenzoic acid which inhibits the action of sulfonamides. Thus, large doses should not be administered to patients taking sulfonamide drugs. 

Amide-type Ester-type (ester of benzoic acid) Ester-type (ester of para-aminobenzoic acid) ... 

Lindsey and Maxwell, 1949) phosphoric acid 0.005% (Eckey, 1934, 1935 Kraybill and Beadle, 1948) thiodipropionic acid 0.01% and its esters (O Leary, 1946) and lecithin in any amount (Evans, 1935 Olcott and Mattill, 1936). Many other compounds have been reported to have synergistic activity, including normal constituents of meat such as amino acids (Clausen et cd., 1947), ascorbic acid (Golumbic and Mattill, 1941 Calkins and Matthill, 1944), nicotinic acid (Taub and Simone, 1947), and para-aminobenzoic acid (Norris, 1949). 

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... 

Synera is contraindicated in patients with a known history of sensitivity to lidocaine, tetracaine, or local anesthetics of the amide or ester type. Synera is also contraindicated in patients with para-aminobenzoic acid (PABA) hypersensitivity. 

The occurrence of photoallergy to esters of / -aminobenzoic acid was described in the discussion of photoallergic topical drugs (Sect. P.IX). Ordinary contact sensitization is more frequent, described as early as 1949 by Meltzer and Baer (1949). Cross-reactions to other para compounds such as paraphenylenediamine-de-rived hair dyes, azo and aniline dyes, local anesthetics (procaine, benzocaine), sulfonamides, and / -aminosalicylic acid occur. The spectrum of cross-reactions varies from patient to patient (Fisher et al. 1958). Fisher (1977) has emphasized the importance of recognizing impurities in a compound as responsible for certain crossreactions, i.e., benzocaine in glyceryl-/7-aminobenzoic acid (Escalol 106),... 

Fife et al. have reported intramolecular GB-assisted ester hydrolysis. The pseudo-first-order rate constants (k bj.) are pH-independent from pH 8 to pH 4. The triflnoroethyl, phenyl, and p-nitrophenyl esters of 2-aminobenzoic acid hydrolyze with similar rate constants in the pH-independent reactions, and the rates of these water reactions are twofold slower in D2O than in HjO. The most likely mechanism involves the intramolecular GB assistance by the neighboring amino group. The rate enhanc ents in the pH-independent reaction in comparison with the pH-indepen-dent hydrolysis of the corresponding para-substituted esters are 50- to 100-fold. 

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