M.P. McLeod • S. Choudhary

Department of Dermatology and Cutaneous Surgery, University of Miami Leonard M. Miller School of Medicine,

Miami, FL, USA

Y.A. Alqubaisy

Department of Dermatology and Cutaneous Surgery,

University of Miami Hospital,

Miami, FL, USA

K. Nouri (*)

Department of Dermatology and Cutaneous Surgery,

University of Miami Leonard M. Miller School of Medicine,

Miami, FL, USA

Sylvester Comprehensive Cancer Center, University of Miami

Hospital and Clinics,

Miami, FL, USA

e-mail: knouri@med.miami.edu

Summary: Introduction

•Local anesthesia is a loss in the perception of pain in a small or localized area of the body.

•Regional anesthesia is also defined as a loss in sensation, but encompasses a larger area, or region, of tissue, and is usually achieved in a pharmacological and temporary fashion.

5.1Introduction

Local anesthesia is a loss in the perception of pain over a small or localized area of the body. It is usually achieved by pharmacologically manipulating the electrochemical activity of peripheral nerves in a temporary fashion with the end result being to decrease impulse propagation or generation. Regional anesthesia is also defined as a loss in sensation, but encompasses a larger area, or region, of tissue, and is also usually achieved in a pharmacological and temporary fashion [1].

Summary: History

•The first known anesthetic was derived from the leaves of the coca plant in South America.

•The first prototype of injectable local anesthetic was procaine; a derivative of paraaminobenzoic acid (PABA).

•Lidocaine was developed in 1948 as the first amino-amide local anesthetic and is associated with less allergic reactions than its ester predecessors.

5.2History

The first known anesthetic was derived from the leaves of the coca plant in South America and was extracted in 1860. However, the purified product of the coca plant was not used for medicinal purposes until 1884 when Freud and Koller used it as a topical agent [2]. Shortly thereafter, Halsted and Hall used cocaine for regional anesthesia by intravenously infusing it into the brachial vein [2]. The first prototype of injectable local anesthetic was procaine [3], which consists of an aromatic head, a hydrocarbon chain, and a terminal amine tail [3]. It is a derivative of para-aminobenzoic acid (PABA) and is a type of amino-ester.

Lidocaine was developed in 1948 [3], as the first amino-amide local anesthetic [3]. Its aromatic head and hydrocarbon chain are attached by an amide bond [3]. Lidocaine is associated with considerably less allergic reactions than its ester predecessors [3], because the amide bond is much more stable than the ester bond. Therefore, the highly allergenic aromatic

acid does not get cleaved as in esters and stimulate an allergic response [3]. Numerous other amino-amide local anesthetics were later developed as a result of this advantageous property [3]. The chemical structure of amino-amide local anesthetics consists of an aromatic portion, and a tertiary amine which are connected by a hydrocarbon chain [4].

Summary: Pharmacology

•Local anesthetics are thought to bind to the sodium channels during their inactivated and activated states with more affinity than the resting state.

•Repeated depolarizations result in more effective anesthetic binding to the sodium channels.

•When the neuron becomes excited to a certain threshold, the membrane becomes depolarized with an inward rush of sodium ions.

•Local anesthetics target the cytoplasmic side of the receptor.

•The lower the pKa, the greater the proportion of unionized molecules for a given pH.

•Approximately, 25% of the epinephrine is degraded per week in neutral solution.

•Most local anesthetics are vasodilators.

•One way to increase the time duration by which local anesthetics exert their effect is to mix a vasoconstrictor with the local anesthetic.

5.3Pharmacology

The resting membrane potential (RMP) of neurons is −90 mV. When the neuron becomes excited to a threshold, the membrane becomes depolarized with an inward rush of sodium ions, followed by an outward flow of potassium ions that brings the membrane potential back into equilibrium. The local anesthetics achieve their effects by inhibiting the sodium channels of neurons, thereby making it more difficult for a membrane potential to reach the threshold required for depolarization [3]. They achieve their effects on the cytoplasmic side of the receptor. In addition, it is the charged form of the local anesthetic that binds to the receptor. The charged form of the molecule cannot pass through the membrane; it can only pass through the membrane in its uncharged form. Following its

passage though the membrane, the molecule must become protonated to its active form so that it can interact with the sodium channels.

Local anesthetics are thought to bind to the sodium channels during their inactivated and activated states with more affinity then the resting state [3]. They dissociate from the inactivated state of the sodium channels at a much lower rate compared to the activated state. Therefore, repeated depolarizations result in more effective anesthetic binding to the sodium channels [3]. This concept is termed the “use-dependent” or “frequency-dependent” effect of local anesthesia [3]. Nerves that are more active are more likely to become anesthetized compared to inactive nerves.

A basic understanding of how pH affects local anesthetics is important to their clinical use. The HendersonHasselbalch equation:

pH = PKa + long [base]/ [acid]

is useful to determine if a local anesthetic exists as a charged or uncharged molecule [3]. The lower the pKa, the greater the proportion of unionized molecules for a given pH [3]. Any acidic conditions such as an infective process may lead to a delay in the onset of anesthesia (see Table 5.1). Most local anesthetics have an alkaline to neutral pH. Epinephrine is rapidly degraded in an alkaline solution. Approximately, 25% of the epinephrine is degraded per week in neutral solution. Therefore, most commercial preparations of local anesthetics, such as lidocaine, are kept in an acidic solution [2]. Unfortunately, the acidic local anesthetic solution causes more pain than when a basic or neutral local anesthetic solution is injected [2]. This can be countered by adding sodium bicarbonate in a 1:10 ratio or 1 mL of 8.4% bicarbonate for every 9 mL of lidocaine [5].

Most local anesthetics are vasodilators; however, there are some exceptions. Notably, the S (−) enantiomer of ropivacaine has some vasoconstrictive activity in comparison to its R (+) enantiomer, and cocaine is a vasoconstrictor. One way to increase the time duration by which local anesthetics exert their effect is to mix a vasoconstrictor with the local anesthetic. Epinephrine is commonly used for this purpose at doses of 5 mg/mL. Care should be taken in patients who have hypertension or any predisposition to cardiac arrhythmias. It is also recommended that epinephrine not be used in areas with poor collateral flow, such as the digits.

Summary: Pharmacokinetics

•The circulatory system “washes away” the anesthetic from its local site.

•Local anesthetics that are highly lipophilic and have a high affinity for protein binding tend to stay localized to one area longer than local anesthetics that are highly hydrophilic and do not have a high affinity for protein binding.

5.4Pharmacokinetics

Local anesthetics are unique drugs in that the circulatory system does not distribute the drug to its intended target. Instead, the circulatory system actually “washes away” the anesthetic from its local site, thereby curtailing its effect on the local tissue. The uptake of the local anesthetic via the blood can also lead to its toxicity. Local anesthetics that are highly lipophilic and have a high affinity for protein

binding tend to stay localized to one area longer than local anesthetics that are highly hydrophilic and do not have a high affinity for protein binding.

Summary: Regional Anesthesia

•Regional anesthesia most often takes the form of nerve blocks.

•The advantages of regional anesthesia include: no tissue distortion at the operative site, and a much larger area can be anesthetized with less anesthetic agent.

•The anesthetic should be injected in the vicinity of the nerve, not the nerve itself, and not into a nearby blood vessel.

5.5Regional Anesthesia

Regional anesthesia most often takes the form of nerve blocks. The most common nerve blocks performed in dermatologic surgery take place at the digital and trigeminal nerves [6]. There are some important advantages associated with regional anesthesia: there is no tissue distortion at the operative site, and a much larger area can be anesthetized with less anesthetic. Despite the advantages, there are also a number of serious complications that can occur with a nerve block, namely, physical nerve damage, hematoma, and intravascular injection. The anesthetic should be injected in the vicinity of the nerve, not the

nerve itself, and should also not be injected in a nearby blood vessel. The technique may be assisted by the use of an ultrasound and muscle stimulator to help visualize proximity of the needle to vital structures and localize the correct location for injecting anesthetic.

5.6Peripheral Nerve Fibers

Peripheral nerve fibers are classified by their diameter and the presence or absence of myelin [3]. The larger the diameter of a nerve, the faster the conduction velocity. The presence of myelin also leads to a faster conduction velocity among nerves. The spaces between each myelin sheath, i.e., unmyelinated areas, are known as nodes of Ranvier. The electrical flow of current “jumps” between the nodes of Ranvier due to the insulating property of the nodes.

When a local anesthetic is injected near a nerve, it infiltrates the nervous tissue from the outside toward the inside of the nerve; therefore, nerve fibers near the outside or mantle of a nerve are anesthetized first. Generally, the nervous fibers running along the outside of a nerve innervate more proximal anatomical structures, while those running deep innervate more distal structures [3]. The smaller nerve fibers become anesthetized before the larger nerve fibers. The nocioceptive C fibers are usually blocked before the nerves carrying pressure information, so a patient usually does not feel pain but may still perceive pressure [5].

Summary: Peripheral Nerve Fibers

•Peripheral nerve fibers are classified by their diameter and the presence or absence of myelin.

•The larger the diameter of a nerve, the faster the conduction velocity.

•When local anesthetics are injected near a nerve, they infiltrate the nervous tissue from the outside toward the inside; therefore, nerve fibers near the outside or mantle of a nerve are anesthetized first.

•The nervous fibers running along the outside of a nerve innervate more proximal anatomical structures, while those running deeply innervate more distal structures.

Summary: Metabolism

•The amino-ester molecules are metabolized via hydrolysis, while the amino-amides are metabolized via hepatic microsomal enzymes.

•Lidocaine, prilocaine, and bupivacaine are extracted from the circulatory system by the lungs.

•People who are deficient in cholinesterases are at an increased risk of developing toxic levels of amino-ester anesthetics, especially chloroprocaine.

•Lidocaine is extensively metabolized by the liver and is highly dependent upon hepatic blood flow.