Local anesthetics
History: For centuries, the Peruvian people have appreciated the pharmacologic actions
of the leaves of the Erythroxylon coca, a shrub growing high in the Andes mountains.
Chewing or sucking these leaves produces a sense of well-being. The plant ash releases
an alkaloid in a form that can be absorbed across mucous membranes. This alkaloid is
more commonly known today as cocaine. The pure alkaloid of cocaine was isolated in
1880, and its pharmacodynamic properties were further investigated. In 1884, cocaine
was used clinically as a local anesthetic in ophthalmology, dentistry, and surgery. In
1905, the first synthetic local anesthetic, procaine, was developed and became the
prototype for these agents. There are currently 16 chemical agents used in local
anesthesia; lidocaine, bupivacaine, and tetracaine are the most commonly used in clinical
practice.
Local anesthetics are used to decrease pain, temperature, touch proprioception, and
skeletal muscle tone. The degree of these actions is dependent on dose and concentrations
of the drug, degree of hydrophobicity, and integrity of the application site. Local
anesthetics are used in a variety of clinical situations, from topical application to the skin
or mucosa membranes to injectable agents used for peripheral, central, or spinal nerve
block. Some agents are used for specific indications in preparations intended for
anorectal or ophthalmic use.
Mechanism of Action: All local anesthetics reversibly block nerve conduction by
decreasing nerve membrane permeability to sodium. This decreases the rate of membrane
depolarization, thereby increasing the threshold for electrical excitability. All nerve fibers
are affected, albeit in a predictable sequence: autonomic, sensory, motor. These effects
diminish in reverse order. Since these drugs can also block sodium channels in
myocardial tissues, an antiarrhythmic action is created. Lidocaine and procainamide are
routinely used as antiarrhythmics. Mexiletine and tocainide, oral congeners of lidocaine,
possess a mechanism of action similar to lidocaine and are also used as antiarrhythmics.
Currently, mexiletine and tocainide are not available in topical or injectable preparations
for local anesthetic purposes. Finally, lidocaine has also been used as an alternative agent
in the treatment of status epilepticus. While the mechanism of this effect is unclear, it is
likely that blockade of neuronal sodium channels may be involved.
Distinguishing Features: Since the mechanism of action is similar, local anesthetics are
selected based on their pharmacodynamic and pharmacokinetic features. Ideally, the
agent should possess low systemic toxicity, have a rapid onset of action, have a duration
of action long enough to complete the intended procedure, and not be irritating to the
tissue.
Local anesthetics are listed according to their basic chemical class. Typically, local
anesthetics are grouped as either "amides" or "esters". The "esters" include the prototype
procaine, and also benzocaine, butamben picrate, chloroprocaine, cocaine, proparacaine,
and tetracaine. These agents are derivatives of paraaminobenzoic acid and are hydrolyzed
by plasma esterases. The "amides" include the prototype lidocaine, and also bupivacaine,
dibucaine, etidocaine, mepivacaine, prilocaine, and ropivacaine. The amides are
derivatives of aniline and are metabolized primarily in the liver, and the metabolites are
then excreted renally. Lidocaine, mepivacaine, and tetracaine also may have some biliary
excretion. Dyclonine and pramoxine do not fit into either chemical classification and
might be suitable alternatives in patients with allergies to amides or esters. Bupivacaine is
commonly used for epidural anesthesia in obstetrics because of its motor-sparing
properties and long duration although its systemic toxicity is greater than less potent
agents such as lidocaine or mepivacaine.
Selection of a local anesthetic is based largely on its pharmacokinetics. The site and route
of administration can influence the characteristics of an agent. Most local anesthetics
have a rapid onset when administered parenterally for infiltrative anesthesia, the fastest
being lidocaine (0.5-1 minute) followed by prilocaine (1-2 minutes). The average onset of
action for the remaining agents is between 3-5 minutes. The exception is tetracaine,
which can take up to 15 minutes. The onset of action is longer with epidural
administration, averaging approximately 5-15 minutes for most local anesthetics.
Procaine (15-25 minutes), tetracaine (20-30 minutes), and bupivacaine (10-20 minutes)
all have slightly slower onsets of action when administered epidurally than the
other agents.
The duration of action of the injectable anesthetic agents is important in their selection
for various procedures. Procaine and chloroprocaine are the shortest-acting agents (0.250.5 hours), followed by lidocaine, mepivacaine, and prilocaine, which have slightly
longer durations of action (0.5-1.5 hours). The longer-acting agents include tetracaine (23 hours), bupivacaine (2-4 hours), etidocaine (2-3 hours), and ropivacaine. Ropivacaine
exhibits a duration of 8-13 hours when used for peripheral nerve block but the effective
analgesia when administered epidurally is only 2.5-6 hours. Epinephrine prolongs the
duration of action of most local anesthetics, however, this is not always a consistent
finding. Spinally administered local anesthetics tend to have a slightly shorter duration of
action compared with other routes of administration.
Applied topically, local anesthetics reach peak effect at different times when applied to
mucous membranes. Benzocaine is the fastest (1 minute), followed by lidocaine =
cocaine < pramoxine < tetracaine < dyclonine and < dibucaine. All of the topical products
have a duration of action ranging from about 30 minutes to an hour. Cocaine's effects can
last up to 2 hours after topical application, and dibucaine has the longest duration of
action at 3-4 hours.
The topical local anesthetics are used for skin and mucous membrane anesthesia. Most
agents are used for both indications, except dibucaine, butamben picrate, and pramoxine,
which are not used on mucous membranes. Pramoxine was found to be too irritating to
the eyes and nose. Dyclonine and cocaine are not used in skin disorders, perhaps because
they are well absorbed through the skin.
Tetracaine and proparacaine are available as ophthalmic preparations. Benzocaine and
pramoxine are also included in a variety of anorectal preparations. Benzocaine candy or
gum is used as a diet aid in combination with dieting. It works by decreasing the ability to
detect degrees of sweetness by altering taste perception.
Adverse Reactions: Systemic absorption of local anesthetics can produce increased serum
concentrations, resulting in toxicity in the CNS or the cardiovascular system. The longer
the duration of action, the higher the potential for toxicity, which can include neurolysis
with sloughing and necrosis of surrounding tissue. Parenteral local anesthetics are often
coadministered epinephrine or other local vasoconstrictor to delay systemic absorption,
prolong duration of action, and promote local hemostasis.
Local hypersensitivity reactions are more likely to occur with the "ester" type of local
anesthetics. The "amide" type of local anesthetics has not demonstrated cross-sensitivity
with the esters. Some of the topical preparations contain tartrazine and sulfites and should
be used with caution in patients with these hypersensitivities.