Local anesthetics amides

Prilocaine hydrochloride [1786-81-8] is also similar in profile to Hdocaine, although prilocaine has significantly less vasodilator activity. Prilocaine is the least toxic of the amino amide local anesthetics. However, its tendency to cause methemoglobinemia, especially in newborns, has eliminated its use in obstetric surgery. 

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

J. E., Peray, P.A., Desch, G., Sassine, A. and Eledjam, J.J. (1996) Comparative electrophysiologic and hemodynamic effects of several amide local anesthetic drugs in anesthetized dogs. Anesthesia and Analgesia, 82, 648—656. 

Hypersensitivity to amide local anesthetics Stokes-Adams syndrome Wolff-Parkinson-White syndrome severe degrees of sinoatrial, atrioventricular (AV), or intraventricular block in the absence of an artificial pacemaker. 

Malignant hyperthermia Amide local anesthetic administration has been associated with acute onset of fulminant hypermetabolism of skeletal muscle known as malignant hyperthermic crisis. Recognition of early unexplained signs of tachycardia. 

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. 

Some pharmacokinetic properties of the commonly used amide local anesthetics are summarized in Table 26-2. The pharmacokinetics of the ester-based local anesthetics have not been extensively studied owing to their rapid breakdown in plasma (elimination half-life < 1 minute). Local anesthetics are usually administered by injection into dermis and soft tissues around nerves. Thus, absorption and distribution are not as important in controlling the onset of effect as in determining the rate of offset of local analgesia and the likelihood of CNS and cardiac toxicity. Topical application of local anesthetics (eg, transmucosal or transdermal) requires drug diffusion for both onset and offset of anesthetic effect. However, intracavitary (eg, intra-articular, intraperitoneal) administration is associated with a more rapid onset and shorter duration of local anesthetic effect. 

Table 26-2 Pharmacokinetic Properties of Several Amide Local Anesthetics. ...

The amide local anesthetics are widely distributed after intravenous bolus administration. There is also evidence that sequestration can occur in lipophilic storage sites (eg, fat). After an initial rapid distribution phase, which consists of uptake into highly perfused organs such as the brain, liver, kidney, and heart, a slower distribution phase occurs with uptake into moderately well-perfused tissues, such as muscle and the gastrointestinal tract. As a result of the extremely short plasma half-lives of the ester type agents, their tissue distribution has not been extensively studied. 

The amide linkage of amide local anesthetics is hydrolyzed by liver microsomal cytochrome P450 isozymes. There is considerable variation in the rate of liver metabolism of individual amide compounds, with prilocaine (fastest)... 

The ester-type local anesthetics are metabolized to p-aminobenzoic acid derivatives. These metabolites are responsible for allergic reactions in a small percentage of the patient population. Amides are not metabolized to p-aminobenzoic acid, and allergic reactions to amide local anesthetics are extremely rare. 

Ropivacaine, which is an (S)-enantiomer, is a new long-lasting amide local anesthetic drug that has been produced in order to address the... 

Table 26-1. Structure and Properties of Some Ester and Amide Local Anesthetics.

Feldman HS, Covino BG (1988) Comparative motor-blocking effects of bupivacaine and ropivacaine, a new amino amide local anesthetic, in the rat and dog. Anesth Analg 67 1047-1052... 

Malamed SF, Gagnon S, Leblanc D. Articaine hydrochloride a study of the safety of a new amide local anesthetic. J Am Dent Assoc 2001 132(2) 177-85. 

Levobupivacaine is the levorotatory isomer, 5(—)-bupiva-caine, of bupivacaine, an amide local anesthetic. 

Australia and several showed cross-reactivity with other amide local anesthetics, such as bupivacaine, mepivacaine, and prilocaine (46). 

Minasian A, Yagiela JA. The use of amide local anesthetics in patients susceptible to mahgnant hyperthermia. Oral Surg Oral Med Oral Pathol 1988 66(4) 405-15. 

However, some sensitized patients do cross-react with various related local anesthetic agents or chemically similar compounds, including some muscle relaxants (SEDA-15, 117). On the other hand, cross-reactivity between aminoesters and aminoamides seems unlikely and does not appear to be on record. Although crossreactivity between amide local anesthetics is uncommon, it has been reported. 

Lidocaine (lignocaine) is an amide local anesthetic that is approved (2% solution, 20mg/ml) for use in horses. This agent is also used widely in humans and is available as 1% and 2% solutions also in combination with epinephrine (adrenaline) at a concentration of 1 in 200 000. 

Table 1 Pharmacokinetic, physiochemical characteristics, and maximal recommended doses of some commonly used amide local anesthetics...

Allergies to local anesthetics (LAs) are rare, and the term allergy is often used to describe numerous problems that are more likely an overdose or a vagal reaction. Publications report that the frequency of allergic reactions to LAs is no more than 1% of aU the side-effects met with. Lidocaine is an amide local anesthetic that does not cause many allergies. 

Bupivacaine, an amide local anesthetic, is indicated in the production of local or regional anesthesia or analgesia, for oral surgery, for surgery, for diagnostic procedures, or for obstetrical anesthesia. 

Lidocaine (Xylocaine, others), an aminoethylamide is the prototypical amide local anesthetic. Lidocaine produces faster, more intense longer lasting, and more extensive anesthesia than does an eqnal concentration of procaine. Lidocaine is an alternative choice for individuals sensitive to ester-type local anesthetics. 

Udocaine (XYIOCAINE, others), an aminoethylamide (Figure I4-I), is the prototypical amide local anesthetic. 

Esters and Amides Local anesthetics that are esters have just one "i" in their names (e.g., procaine, cocaine) amide local anesthetics have more than one "i" (e.g., lidocaine, bupivacaine). 

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. 

The most important effect of inadvertent IV administration of a large dose of an amide local anesthetic is... 

Long-acting amide local anesthetic prototype Tox greater cardiovascular toxicity than most local anesthetics. 

Occupational problems with topically applied local anesthetics, particularly ester derivatives, have been known for many years (Altomare et al. 1992). Contact allergy to procaine used to be a typical professional disease of dentists due to direct handling (Kanerva et al. 1994). Other affected professions include ophthalmologists and veterinary surgeons. There is an extensive cross-reactivity between all p-amino benzoic acid derivatives, such as procaine, benzocaine and tetracaine, but not to amide derivatives, such as lidocaine. Since the less allergenic amide local anesthetics are used today, the number of occupational cases has declined. The intravenous anesthetic propanidid, a derivative of eugenol (Castelain and Piriou 1980), has caused sensitization in anesthesists by direct and probably also airborne contact (Altomare et al. 1992). 

Following the first description of allergy to a local anesthetic over 90 years ago, there was initially a steady stream of reports of reactions to the drugs consisting mainly of erythema or edema. With the introduction of the amide local anesthetics, the number of hypersensitivity reactions tapered off significantly, indicating that ester compounds were less well tolerated. Even today, however, reports of adverse reactions to local anesthetics occasionally appear, but the nature of the reactions cannot always be described... 

Fuzier R, Lapeyre-Mestre M, Mertes PM, et al. Immediate-and delayed-type aUeigic reactions to amide local anesthetics clinical features and skin testing. Pharmacoepidemiol Drug Saf. 2009 18 595-601. 

Like all amide local anesthetics, ropivacaine is metabolized extensively in the liver via aromatic hydroxyla-tion mediated by cytochrome P4501A. The metabohte is 3-hydroxy ropivacaine. 

Lidocaine is the most widely used and first synthesized amide local anesthetic. Nils Lofgren, a Swedish chemist who later became a professor of organic chemistry at the University of Stockholm, synthesized the chemical in 1943 and named it xylocaine. His coworker Bengt Lundqvist first tested the chemical on himself via injection prior to marketing the drug in 1948 [1-3]. 

Patients with hypersensitivity reactions to amide local anesthetics should not receive lidocaine. Lidocaine should be used with caution in patients with severe hepatic dysfunction or congestive heart failure, both of which may impair hepatic metabolism and lead to toxic serum levels of the drug. 

Known history of methemoglobinemia or in patients with a known history of sensitivity to amide local anesthetics. 

---