Chapter 11: Local Anesthetics

CLINICAL PHARMACOLOGY

Pharmacokinetics

A. ABSORPTION

Absorption after topical application depends on the site. Most mucous membranes (eg, tracheal or oropharyngeal mucosa) provide a minimal barrier to local anesthetic penetration, leading to a rapid onset of action. Intact skin, on the other hand, requires topical application of an increased concentration of lipid-soluble local anesthetic base to ensure permeation and analgesia. Depth of analgesia (usually <0.5 cm), duration of action (usually <2 h), and amount of drug absorbed depend on application time, dermal blood flow, and total dose administered.

Systemic absorption of injected local anesthetics depends on blood flow, which in turn is determined by the site of injection, the presence of additives, and the local anesthetic agent selected.

1. Site of injection—The rates of local anesthetic systemic absorption and rise of local anesthetic concentrations in blood are related to the vascularity of the site of injection and generally follow this rank order: intravenous (or intraarterial) > tracheal (transmucosal) > intercostal > paracervical > epidural > brachial plexus > sciatic > subcutaneous.

2. Presence of additives—The addition of epinephrine causes vasoconstriction at the site of administration, leading to some or all of the following: reduced peak local anesthetic concentration in blood, facilitated neuronal uptake, enhanced quality of analgesia, prolonged duration of analgesia, and reduced toxic side effects. For example, the addition of epinephrine to lidocaine usually extends the duration of anesthesia by at least 50%, but epinephrine has a limited effect on the duration of bupivacaine peripheral nerve blocks. Epinephrine and clonidine may also augment analgesia through the activation of α₂-adrenergic receptors. Coadministration of dexamethasone or other steroids with local anesthetics can prolong blocks by up to 50%. Mixtures of local anesthetics (eg, ropivacaine and mepivacaine) produce nerve blocks with onset and duration that are intermediate between the two parent compounds.

3. Local anesthetic agent—More lipid-soluble local anesthetics that are highly tissue-bound are also more slowly absorbed than less lipid-soluble agents.

B. DISTRIBUTION

Distribution depends on organ uptake, which is determined by the following factors:

1. Tissue perfusion—The highly perfused organs (brain, lung, liver, kidney, and heart) are responsible for the initial rapid removal of local anesthetics from blood, which is followed by a slower redistribution to a wider range of tissues. In particular, the lung extracts significant amounts of local anesthetic during the “first pass”; consequently, patients with right-to-left cardiac shunts are more susceptible to toxic side effects of lidocaine injected as an antiarrhythmic agent.

2. Tissue/blood partition coefficient—Increasing lipid solubility is associated with greater plasma protein binding and also greater tissue uptake of local anesthetics from an aqueous compartment.

3. Tissue mass—Muscle provides the greatest reservoir for the distribution of local anesthetic agents in the bloodstream because of its large mass.

C. BIOTRANSFORMATION AND EXCRETION

1. Esters—Ester local anesthetics are ...