Hydrolysis of procaine

Scheme 9.1 Metabolic hydrolysis of procaine, 2. Esterases convert 2 into two inactive fragments 2a and 2b. Since this process is very rapidly accomplished in the body by these ubiquitous enzymes, procaine exhibits an ultra-short duration of action (USA) after intravenous administration.

Acetylchohnesterase inhibitors inhibit the hydrolysis of procaine and concomitant use can cause procaine toxicity (3). 

Dmgs that contain ester linkages include acetylsalicylic acid (aspirin), physostigmine, methyldopate, tetracaine and procaine. Ester hydrolysis is usually a bimolecular reaction involving acyl-oxygen cleavage. For example, the hydrolysis of procaine is shown in Scheme 4.2. 

T. Yotsuyanagi, T. Hamada, H. Tomida, and K. Ikeda, Hydrolysis of procaine in liposomal suspension, Acta Pharm. Suec. 16,271-280(1979). 

Kinetic studies of the alkaline hydrolysis of procaine, 4-NH2-C6H4C02CH2CH2NEt2, an anaesthetic, in the presence of various surfactants showed that both cationic and anionic micelles inhibited the reaction, the latter more so than the former. ... 

SKF 525-A inhibits the in vitro metabolism of several barbiturates, meperidine, aminopyrine, and codeine, the formation of morphine glucuronide, and the hydrolysis of procaine and ethylglycinexylidide. However, SKF 525-A has no significant effect on the microsomal N-demethylation of monomethyl-4-aminoantipyrine, N-methylaniline or 3-methyl-4-monomethylaminoazobenzene, the O-dealkylation of phenacetin, the hydroxylation of acetanilide, or the sulphoxidation of chlorpro-mazine. 

Relatively small increases in stability of chloramphenicol in polysorbate 80, Myrj 59, polysorbate 20 and Brij 35 have been observed on autoclaving [134]. Selection of a suitable concentration of polysorbate 80 and adjustment of solutions to pH 4.6 reduced to half the autoxidative degradation of methyl-prednisolone even in the presence of oxygen [135]. Contrary to electrostatic theories of stabilization the base-catalysed hydrolysis of procaine was inhibited by non-ionic, anionic and cationic micelles as shown in Table 11.10. The order of inhibition of hydrolysis was NaLS > CTAB > PLE > NDB the order of partition coefficients (P ) was found to be NaLS > CTAB > NDB > PLE (see table for abbreviations). 

The observed rate constants for hydrolysis of procaine in various surfactant... 

Figure 8.35 Hydrolysis of procaine by plasma esterases and the metabolism of procainamide.

A good example to illustrate the difference in the rates of hydrolysis of esters and amides is to compare the metabolism of procaine and procainamide because the only difference between the two drugs is that one is an ester and the other is an amide (Fig. 6.2). Procaine has a half-life of about 1 minute due to the rapid hydrolysis of the ester, whereas... 

Several drugs, in particular neuropharmacological agents, feature a car-boxylate group esterified to an aminoalkyl moiety. As a rule, such lipophilic compounds are good substrates for hydrolases, and their duration of action is influenced by their rate of hydrolysis (see also Sect. 7.3.4). A simple example is that of procaine (7.56), which is rapidly inactivated by hydrolysis [41] [76a], Various hydrolases catalyze the reaction, in particular plasma cholinesterase and cellular carboxylesterases. As often reported, atropine and scopolamine are rapidly hydrolyzed by plasma carboxylesterases in rabbits (with very large differences between individual animals), but are stable in human plasma [1] [75] [76a] [110]. 

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. 

These enzymes [EC 3.1.1.1] (also referred to as ali-ester-ase, B-esterase, monobutyrase, cocaine esterase, methyl-butyrase, and procaine esterase) catalyze the hydrolysis of a carboxylic ester to yield a carboxylate anion and an alcohol. They exhibit a broad specificity, even acting on vitamin A esters. 

The metabolic degradation of local anesthetics depends on whether the compound has an ester or an amide linkage. Esters are extensively and rapidly metabolized in plasma by pseudochoUnesterase, whereas the amide linkage is resistant to hydrolysis. The rate of local anesthetic hydrolysis is important, since slow biotransformation may lead to drug accumulation and toxicity. In patients with atypical plasma cholinesterase, the use of ester-linked compounds, such as chloroprocaine, procaine and tetracaine, has an increased potential for toxicity. The hydrolysis of all ester-linked local anesthetics leads to the formation of paraaminobenzoic acid (PABA), which is known to be allergenic. Therefore, some people have allergic reactions to the ester class of local anesthetics. 

Kosheleva et al. have reported a compleximetric method for the determination of procaine in the presence of its hydrolysis products [91]. 

Figure 4.43 (A) Hydrolysis of the ester procaine. (B) Hydrolysis of the amide procainamide.

Combining these two pioneer drugs, namely 1 for its efficacy and 2 for its ultra-short duration, resulted in the double ABDD target compound 3. By analogy to procaine, it was anticipated that metabolic hydrolysis of the ester within 3 would fragment the requisite beta-blocker pharmacophore (see Chapter 11-8) and thus rapidly deactivate such compounds. This unique, ABDD-related situation is depicted in Scheme 9.2. 

Scheme 4.2 Hydrolysis of llie ester group of procaine.

Amides are hydrolyzed slowly in comparison to esters. Consequently, hydrolysis of the amide bond of procainamide is relatively slow compared with hydrolysis of the etster linkage in procaine. Drugs in which amide cieavage has been reported to occur, to some extent, include lidocaine. carbainazepine. indomethacin. and prazosin (Mini-... 

Another good example of hydrolysis reaction is the anesthetic procaine, which is prone to specific acid-catalyzed decomposition (of the protonated form) at a pH value below 2.5, a specific base-catalyzed hydrolysis between pH 5.5 and 8.5, titration around pH 8.5-11.0 and finally, the base-catalyzed hydrolysis of the free base at a pH value above 12.0. Maximum stability occurs at pH 3.5. 

Commercial preparations of procaine are limited to injectable forms. As water is the solvent of choice for injectable drugs, procaine can be protected from hydrolysis by increasing the solubility of procaine in a nonaqueous environment and protecting (shielding) the drug from hydrolysis by employing surfactants to micellize the drug. 

The foregoing studies have dealt chiefly with model substrates in vitro. Several of the early papers by Augustinsson, referred to in Section 4.1.1, considered substrate specificity from the viewpoint of species variations. It is also important to recognize that plasma cholinesterase may be associated with the hydrolysis, in vivo, of a large number of drugs (K4, LI, L4) that contain ester bonds susceptible to enzymic hydrolysis. Apart from succinylcholine (Section 3.1), cholinesterase is known to be responsible in man for the hydrolysis of cocaine (S40), procaine (K2), and other esters with local anesthetic properties. Whether enzymatic hydrolysis terminates the pharmacologic effect depends on the whole mechanism of action of the particular drug. 

Bll. Becker, C. E., Cholinesterase genotype and hydrolysis of choline esters, procaine and tetracaine. Hum. Hered. 23, 394-399 (1973). 

The amidase-catalysed hydrolysis of amides is rather slower than that of esters. Thus, unlike procaine, the analogue procainamide is not hydrolysed in the plasma at all, the hydrolysis in vivo being carried out by enzymes in other tissues (figure 4.42). 

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