Local anesthetics metabolism

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... 

This subsection is devoted to the metabolic reactivity of the amide bond in anilides, i.e., compounds whose amino moiety is attached to an aromatic ring. Based on the nature of the acyl moiety, a number of classes of anilides exist, three of which are of particular interest here, namely arylacetamides, acylani-lides, and aminoacylanilides. The first group contains several analgesic-antipyretic drugs, the second A4-acyl derivatives of sulfonamides, and the third a number of local anesthetics. Particular attention will be paid to structure-metabolism relationships in the hydrolysis of these compounds. Cases where hydrolysis leads to toxification will be summarized in the last part of the chapter. 

Amide-type agents include articaine, lidocaine, bupivacaine, prilocaine, mepivacain and ropiva-caine. These are metabolized in the liver by microsomal enzymes with amidase activity. The amide group is preferred for parenteral and local use. If by accident rapidly administered intravascularly these agents, especially bupivacaine but also lidocaine, can produce serious and potentially lethal adverse effects including convulsions and cardiac arrest. They can more easily accumulate after multiple administrations. Intravenous lidocaine is sometimes used for regional anesthesia, for infiltration procedures, for the induction of nerve blockade and for epidural anesthesia. However, it is also used as an antiarrhythmic. Bupivacaine is a long-acting local anesthetic used for peripheral nerve blocks and epidural anesthesia. 

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. 

Local anesthetics with an amide linkage (and one ester-lined anesthetic, cocaine) are almost completely metabolized by the liver before excretion. However, the total dose administered and the degree of drug accumulation resulting from the initial and subsequent doses are still a concern. 

Mechanism of Action An amide-type local anesthetic that shortens the action potential duration and decreases the effective refractory period and automaticity in the His-Purkinje system of the myocardium by blocking sodium transport across myocardial cell membranes. Therapeutic Effect Suppresses ventricular arrhythmias. Pharmacokinetics Very rapidly and completely absorbed following PO administration, Protein binding 10%, Metabolized in liver. Excreted in urine. Half-life 15 hr. 

Local anesthetics are frequently coadministered with vasoconstrictor molecules such as epinephrine. Normally, they are applied or injected locally and then taken up by local blood vessels into the systemic circulation, ultimately leading to their metabolic breakdown. The co-administration of a vasoconstrictor decreases the systemic absorption of the local anesthetic, thereby increasing its effective half-life in the area of administration and decreasing the probability of systemic toxicity (i.e., cardiac toxicity) secondary to systemic distribution. 

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. 

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. 

Local anesthetics generally have only slight endocrine and metabolic adverse effects, without clinical repercussions. 

Local anesthetics are usually eliminated by hydrolyzing or breaking apart the drug molecule. This metabolic hydrolysis is catalyzed by hepatic enzymes or enzymes circulating in the plasma (e.g., the plasma cholinesterase). Once metabolized, the kidneys excrete the polar drug metabolites. 

The ester-containing local anesthetics become metabolized to p-aminobenzoic acid derivatives, which have a potential for causing hypersensitivity reactions. Allergic reactions to amide are... 

The action of norepinephrine is terminated by reuptake mechanisms, two of which have been identified. Biogenic amine Uptake 1 is located in the presynaptic membrane, requires energy for the transport, is sodium and temperature dependent, and is inhibited by ouabain (a cardiac glycoside), cocaine (a local anesthetic), and imipramine (an antidepressant). Biogenic amine Uptake 2 is located extraneuronally in various smooth muscles and glands, requires energy, and is temperature dependent. Approximately 20% of the amine is either taken up by the Uptake 2 mechanism or is metabolized. 

The only other anesthetic to cause serious toxicity for which a metabolic drug interaction has been reasonably well characterized is the local anesthetic and antiarrhythmic agent lidocaine. Amiodarone decreased lidocaine systemic clearance in a patient (primarily by inhibition of CYP3A4 N-dealkylation of lidocaine) and yielded concentrations of lidocaine that led to seizures (78,79). 

Kharasch ED, Ibrahim AE. Volatile, intravenous, and local anesthetics. In Levy RH, Thummel KE, Trager WF, et al., eds. Metabolic Dmg Interactions. Philadelphia Lippincott Williams and Wilkins, 2000 271-295. 

Local anesthetics containing an amide linkage are metabolized principally by the liver.Thus, patients with hepatic disease may be more likely to exhibit toxic effects from the injectable anesthetics. Local tissue infiltration or nerve blocks should be avoided or performed using minimally effective anesthetic doses in patients with hepatitis, cirrhosis, extrahepatic obstruction (e.g., lithiasis), or other clinically significant hepatic dysfunction. 

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