Metabolism

The amino-amide and amino-ester local anesthetics are metabolized in very different ways. The aminoester molecules are metabolized via hydrolysis by plasma cholinesterase and excreted in the kidneys, while the amino-amides are metabolized via de-alkylation and hydrolysis by hepatic microsomal enzymes [5]. In addition, lidocaine, prilocaine, and bupivacaine are extracted from the circulatory system by the lungs. The local anesthetics are lipophilic molecules, and therefore less than 5% of the injected dose is cleared by the kidneys [3].

People who are deficient in cholinesterases are at an increased risk of developing toxic levels of aminoester anesthetics, especially chloroprocaine.

Lidocaine is extensively metabolized by the liver and is highly dependent upon hepatic blood flow. Any liver disease or medical conditions which limit blood flow to the liver such as congestive heart failure can impair the clearance of lidocaine from the plasma.

Local anesthetics cross the placenta; however, there is no data to suggest that lidocaine or tetracaine is teratogenic [6]. Local anesthetics are also secreted into breast milk.

Summary: Toxicity

•Local anesthetic toxicity generally occurs from high plasma concentrations of the drugs, or intravascular injection.

•The central nervous and cardiovascular systems are the most vulnerable to excessive plasma levels of local anesthetic.

•Allergic reactions to anesthetics are actually quite rare, and less than 1% of adverse reactions attributed to local anesthetics are considered to be allergic in nature.

•A common preservative in both amino-ester and amino-amide local anesthetics is methylparaben, which, incidentally, is similar in chemical structure to PABA and is known to be associated with type 1 hypersensitivity reactions.

•Local anesthetics can interact with MAO inhibitors, tricyclic antidepressants, phenothiazines, and non-selective beta blockers.

Local anesthetic toxicity generally occurs from high plasma concentrations of the drugs, or intravascular injection [3]. The central nervous and cardiovascular systems are the most vulnerable to excessive plasma levels of local anesthetic [3]. Central nervous system symptoms of local anesthetic toxicity include facial tingling, circumoral numbness, tinnitus, vertigo, and incoherent speech. At the end of this symptomatic spectrum is tonic-clonic seizures [3]. It is believed that the seizures are a result of local anesthetics depressing cortical inhibitory pathways, thereby disinhibiting excitatory pathways [3]. The seizures can lead to metabolic acidosis which can further potentiate the local anesthetic effects upon the CNS.

The cardiovascular system can be affected with high plasma concentrations of local anesthetic because it acts as a vasodilator and can result in profound hypotension [3]. Since the local anesthetics block sodium channels, they can also lead to decreased conduction of electrical impulses in the heart’s conduction system [3]. This can be viewed as an increased P-R interval and widening of the QRS complex on the electrocardiogram [3].

Allergic reactions to anesthetics are actually quite rare, and less than 1% of adverse reactions attributed to local anesthetics are considered to be allergic in nature [3]. Most adverse reactions of local anesthetics are actually a result of instances in which excessive plasma concentrations were reached [3]. Despite this, the amino-ester local anesthetics are known to produce more allergic responses than the amino-amide molecules [3]. This is thought to be due to the hydrolysis of the ester bond resulting in the formation of para-amin- obenzoic acid (PABA). Procaine is known to cause both type 1 and type 4 delayed hypersensitivity reactions. A common preservative in both amino-ester and amino-amide local anesthetics is methylparaben, which is similar in chemical structure to PABA and is known to be associated with type 1 hypersensitivity reactions. Typical symptoms of type 1 hypersensitivity reactions are IgE-mediated, and symptoms include angioedema, hives, bronchospasm, and rhinorrhea [2]. Therefore, if a patient is allergic to a local anesthetic, it must be determined if it is the anesthetic or the preservative in the formulation [3].

Local anesthetics may interact with MAO inhibitors, tricyclic antidepressants, phenothiazine, and nonselective b-blockers. A careful history should ascertain