Procaine, hydrolysis

Because the ester group of procaine is hydrolyzed relatively rapidly by serum esterases (enzymes that catalyze ester hydrolysis), procaine has a short half-life. Therefore, compounds with less easily hydrolyzed amide groups were synthesized (Section 17.6). In this way, lidocaine, one of the most widely used injectable anesthetics, was discovered. The rate at which lidocaine is hydrolyzed is further decreased by its two orthomethyl substituents, which provide steric hindrance to the vulnerable carbonyl group. 

Specific Local Anesthetic Agents. Clinically used local anesthetics and the methods of appHcation are summarized in Table 5. Procaine hydrochloride [51-05-8] (Novocain), introduced in 1905, is a relatively weak anesthetic having along onset and short duration of action. Its primary use is in infiltration anesthesia and differential spinal blocks. The low potency and low systemic toxicity result from rapid hydrolysis. The 4-arninobenzoic acid... 

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. 

Additional information Procaine is formulated in injections and thus susceptible to aqueous phase hydrolysis, in simple solution its degradation is first order (Fig. 2.9). 

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]. 

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. 

Metabolism of the local anesthetic procaine provides an example of esterase action, as shown in Figure 4.43. This hydrolysis may be carried out by both a plasma esterase and a microsomal enzyme. 

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

Thus, unlike procaine, the analogue procainamide is not hydrolyzed in the plasma at all, the hydrolysis in vivo being carried out by enzymes in other tissues (Fig. 4.43). 

Most local anesthetic agents consist of a lipophilic group (frequently an aromatic ring) connected by an intermediate chain (commonly including an ester or amide) to an ionizable group (usually a tertiary amine Table 26-1). In addition to the general physical properties of the molecules, specific stereochemical configurations are associated with differences in the potency of stereoisomers for a few compounds, eg, bupivacaine, ropivacaine. Since ester links (as in procaine) are more prone to hydrolysis than amide links, esters usually have a shorter duration of action. 

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 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). 

Ellis PP, Littlejohn K. Effects of topical anticholinesterases on procaine hydrolysis. Am J Ophthalmol 1974 77(l) 71-5. 

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. 

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-... 

The first two of these reactions are equally relevant for biotransformation process. Amides are often more stable to enzymatic hydrolysis than the corresponding esters with similar structures. For example, phenyl-acetate is hydrolyzed much faster than acetanilide. In addition, CarbE can hydrolyze therapeutically useful drug esters, such as chloramphenicol succinate, prednisolone succinate, procaine, and methylparaben. 

---