Summary
Cocaine, derived from the coca leaf indigenous to South America, was the first drug to be utilized as a topical local anesthetic by Dr. Carl Koller for glaucoma surgery in 1884. Dr. William Stewart Halstead and Dr. Richard John Hall were the first to demonstrate nerve blockade with cocaine for dental surgery later in that same year. Due to the undesirable effects of cocaine, novocaine and subsequent other local anesthetics were developed.
Introduction
Cocaine, derived from the coca leaf indigenous to South America, was the first drug to be utilized as a topical local anesthetic by Dr. Carl Koller for glaucoma surgery in 1884. Dr. William Stewart Halstead and Dr. Richard John Hall were the first to demonstrate nerve blockade with cocaine for dental surgery later in that same year. Due to the undesirable effects of cocaine, novocaine and subsequent other local anesthetics were developed.
Local anesthetics function through nerve conduction blockade and provide surgical or perioperative analgesia. Local anesthetics may be administered in a variety of routes, including local subcutaneous infiltration, topical, neuraxial, or peripheral nerve blockade, or intravenously. Each delivery method should be chosen based on the clinical situation or the provider’s skill set.
Basics of Local Anesthetics
Structure
The basic structure of local anesthetics includes a lipophilic aromatic ring and a hydrophilic tertiary amine linked by either an amide or an ester linkage (see Figure 7.1). Local anesthetic types are therefore divided into ester local anesthetics and amide local anesthetics, depending on their linkage. Ester local anesthetics are rapidly metabolized by pseudocholinesterase in plasma, whereas amide local anesthetics are metabolized by hepatic microsomal enzymes. Examples of ester and amide local anesthetics are shown in Table 7.1.
Figure 7.1 Structure of local anesthetics, including an aromatic ring group linked to a tertiary amine via an amide or ester linkage.
Table 7.1 Common ester and amide local anesthetics with associated characteristics
| Speed of onset | Duration of action | Maximum dose (mg kg−1) | Maximum dose (with epinephrine) (mg kg−1) | |
|---|---|---|---|---|
| Esters | ||||
| Cocaine | +++ | + | 1.5 (topical) | − |
| Benzocaine | +++ | + | − | − |
| Procaine | + | + | 7 | 10 |
| Chloroprocaine | +++ | + | 11 | 14 |
| Amides | ||||
| Prilocaine | ++ | + | 6 | 8 |
| Lidocaine | ++ | ++ | 4.5 | 7 |
| Mepivacaine | ++ | ++ | 5 | 7 |
| Bupivacaine | + | +++ | 3 | − |
| Ropivacaine | + | +++ | 3 | − |
Maximum doses reported in the literature are shown, but it is important to consider the route and location of administration when calculating the maximum dosages of local anesthetics.
+, least; +++, most.
Mechanism of Action
In order to understand the mechanism of action of local anesthetics at the level of the nerves, it is important to understand the physiology of nerve signals. Signal conduction in the nervous system relies on propagation of an action potential via depolarization of neuronal cell membranes. Depolarization can occur with the opening of voltage-gated sodium channels in the neuronal membrane; these voltage-gated sodium channels can exist in one of three states: resting, open, or inactive. Voltage-gated sodium channels are in the resting state at the neuron’s resting state (−70 mV). Initial depolarization occurs when sodium channels are in the open state, leading to an influx of sodium ions into the cell. Upon reaching a threshold potential (−55 mV), an action potential fires and a signal is propagated down the nerve’s axon (see Figure 7.2). Following an action potential, the sodium channel repolarizes and the voltage-gated sodium channels temporarily revert to an inactive state. This inactive state is responsible for the refractory period in which a nerve signal cannot be sent until the sodium channels return to their resting state.
Figure 7.2 Depolarization of a nerve to the threshold potential leading to firing of an action potential (grey). Local anesthetic limits the nerve’s ability to reach the threshold potential (black). Following a successful action potential, the refractory period leads to hyperpolarization of the nerve prior to returning to the resting potential of −90 mV.
Local anesthetics reversibly inhibit voltage-gated sodium channels and prevent propagation of action potentials by preventing depolarization to the threshold potential. Binding of local anesthetics to voltage-gated sodium channels results in a sustained inactivated state. Voltage-gated sodium channels are most susceptible to inhibition by local anesthetics when in the open or inactivated state. Because of this preference for the open or inactivated state, nerves which fire more often are more susceptible to local anesthetic effects.
Nerve Fiber Sensitivity and Differential Blockade
Local anesthetics do not affect all nerve fiber types identically. Differential blockade refers to varied susceptibility to local anesthetic effects among different nerve fibers and may be responsible for pain signal blockade without motor signal blockade. Typically, smaller nerves and myelinated nerves are more susceptible to blockade by local anesthetics. Myelinated fibers have small gaps along their axons called the nodes of Ranvier. Three consecutive nodes of Ranvier must be blocked to reliably block nerve signal conduction.
Autonomic nerves (C- and B-type fibers) are often the first to be blocked by local anesthetics, followed by sensory and motor nerves. Resolution of blockade follows the inverse of this pattern.
Pharmacodynamics
Onset of action for local anesthetics is dependent on the proportion of drug in the unionized form, as this form is able to cross the neuronal membrane to bind the cytoplasmic side of the target sodium channel (see Figure 7.3). This balance of unionized to ionized local anesthetic is dependent on the drug’s pKa and the pH of the environment in which the drug is located. The pKa is defined as the pH at which 50% of the drug is in the unionized form and the remaining 50% in the ionized form. Most local anesthetics are weak bases with a pKa of 7.5–9.0, while physiologic pH is generally 7.35–7.45. The closer a drug’s pKa is to physiologic pH, the more the drug is in the unionized form, which leads to a faster onset of action. The exception to this is for drugs such as chloroprocaine, which has a higher pKa of 9.0 but is rapid-acting due to the concentration at which it is administered (3%).
