Introduction
Local anesthetics (LAs) form the subset of drugs that provide analgesia and anesthesia by reversible conduction blockade of autonomic, sensory, and motor nerve impulses. The earliest description of “coca leaves” consumption, the derivative of cocaine, dates back to the 16th century when nobles and higher officials primarily used it for recreational purposes. The LAs were used initially by the dentists for a dental procedure and later altered the entire concept of anesthetic as well as surgical practices.
History
Milestones reached in the history of LAs are listed below:
Classification
LAs consist of a hydrophilic amine group and a lipophilic aromatic ring that connect through an intermediate chain. The structural bond in the intermediate chain determines whether the LA belongs to the ester or amide group. LAs may be classified based on the chemical structure, duration of action, or the potency as explained in Tables 11.1 to 11.3.
Anatomy and Physiology of the Peripheral Nerve
Since LAs exert their action by inhibiting the nerve impulses, it is essential to revise the anatomy and physiology related to peripheral nerves. A peripheral nerve usually comprises a bundle of neurons/axons that are generally arranged as one or more fascicles (Fig. 11.1). Each axon consists of an outer connective tissue layer known as endoneurium. The fascicles formed by many axons are surrounded by another connective tissue layer known as perineurium that is similar to the epithelium, and the entire nerve sheath is enclosed exteriorly in a loose sheath known as epineurium (Fig. 11.1). While nonmyelinated nerves have axons enveloped in a single Schwann cell sheath, myelinated nerves (large motor and sensory nerves) are usually encased in myelin, which is the specialized plasma membrane of the Schwann cells that wraps the axons during their growth with periodic interruptions at nodes of Ranvier that form the site for impulse generation. Myelin primarily increases the speed of conduction in the nerves by providing insulation from the exterior environment, thus creating a barrier to the action of various drugs acting on nerves, including LAs. The sodium channels that facilitate the generation as well as the initiation of the nerve impulse are present along the entire length of the nonmyelinated nerve but are concentrated at the nodes of Ranvier in myelinated nerves.
The normal resting potential of the membrane varies between –60 and –90 mV, and it is impermeable to sodium ions and selectively permeable to potassium ions at rest. Energy driven Na-K pump maintains the constant resting membrane potential by a continuous extrusion of the Na ions from the cell interior with the intrusion of K ions to maintain the electrical neutrality. During an action potential, the permeability to Na ions is increased, thus changing the membrane potential momentarily and conducting a unidirectional impulse in one direction. While Na channels open faster and cause further depolarization, it continues till K channels open to balance or inactivates Na channels that lead to repolarization.
Mechanism of Action
Many factors affect the activity of LAs:
pKa: It is the pH at which the ionized and unionized fractions are equal. pKa near to the pH implies more unionized fraction for given pH and faster onset of action and vice versa.
pH: Lower pH, that is, acidic medium, which means the predominance of an ionized fraction of drug and thus lower potency of the LA. This explains the fact that LA has reduced efficacy in conditions like abscess or infection, owing to the acidic milieu.
Protein binding: LAs having higher protein binding have a longer duration of action.
Intermediate chain: The longer the intermediate chain, higher is the potency of the LA; for example, bupivacaine has a longer intermediate chain as compared to lignocaine and, thus, is four times more potent.
The agents usually exert their action by blockade of intracellular fast voltage-gated sodium channels subsequent to the concentration-dependent
action at the site of application, thereby interrupting the initiation and propagation of axonal impulses in the dermatomal distribution of the innervated area. The unionized fraction of the drug crosses the lipid bilayer neuronal membrane and renders the sodium channels inactive and inhibits the conduction of impulse along the peripheral or central nerve. The recovery is governed by the removal of the drug from the site by circulation, tissue binding, and the local hydrolysis of the LA as described under pharmacokinetics.
Factors Affecting Pharmacokinetics of Local Anesthetics
The concentration of LAs in the blood is multifactorial and is determined by:
Absorption
Systemic absorption is determined by the:
Site of injection: LA drug concentrations are higher with intravenous (IV) administration > intercostal nerve blockades > caudal epidural > lumbar epidural > brachial plexus > subarachnoid > subcutaneous tissue. Greater rate of absorption is seen in an area with greater vascularity.
Volume and dosage: Higher the volume and concentration of LA, earlier is the nerve blockade and longer the duration of action.
Use of an additional vasoconstrictor agent and carbonation: Epinephrine decreases the blood flow, slows down the rate of absorption, reduces plasma concentration, thereby increasing the duration of action of LA. The addition of sodium bicarbonate leads to an increase in pH, resulting in a higher unionized fraction of LA and thus leading to the rapid onset of action.
Use of additives/adjuncts: Addition of agents like opioids (morphine, fentanyl,
tramadol), benzodiazepines (midazolam), dexamethasone, α2 agonists (dexmedetomidine, clonidine) to LA have an advantage of reducing the dose of LA and prolong the action of the same. Preservative-free preparations are utilized for neuraxial blocks.
Pharmacological nature of drugs: Intrinsic vasodilatory activity, degree of protein binding, and lipid solubility affect the rate of absorption and distribution of the drug.
Distribution
Some noteworthy points of consideration are:
The plasma concentration of LA is determined by the rate of tissue distribution and clearance of the drug.
Lipid solubility of LA is important in redistribution and is a primary determinant of intrinsic LA potency.
Highly perfused tissues have a higher concentration of LA than less perfused tissues, including skeletal muscles and fat.
The concentration of LA decreases as it passes through pulmonary vasculature due to rapid extraction by the lung tissue.
Clinically significant amounts of transplacental transfer may be seen between the fetus and mother, depending upon the protein binding and hydrolysis of the drug.
Biotransformation and Excretion
Important points to be considered are:
Esters undergo hydrolysis in plasma and, to a lesser extent, in the liver by enzyme pseudocholinesterase, forming benzoic acid and para-aminobenzoic acid (PABA). The enzymatic activity is low at birth and reaches the adult levels by 1 year of age. Cocaine, an ester by exception, undergoes metabolism predominantly by hepatic carboxylesterase.
Amides undergo enzymatic degradation in the liver by oxidative dealkylation with some extrahepatic degradation in the kidney. Articaine, LA, that is widely used in dentistry is an exception to this rule and is inactivated by plasma carboxylesterase-induced cleavage of a methyl ester on the aromatic ring.
Renal clearance of drugs is inversely proportional to protein binding and pH of urine.
More water-soluble ester metabolites such as PABA are excreted in the urine, whereas less than 5% amides appear in the urine unchanged.
Patient Factors
Important patient factors to be borne in mind while administering LAs are:
The patient’s age influences the distribution of LA; newborns have prolonged elimination due to immature hepatic enzymatic biotransformation and decreased alpha-1 acid glycoprotein.
Pregnancy: Increased sensitivity to LA, faster onset, and longer duration of action may be present during pregnancy. Altered protein binding in parturients predisposes them to side effects and toxicity at lower levels, thereby increasing the toxicity potential. The LAs having pKa close to the physiological pH exhibit greater placental transfer. In fetal acidosis, LA becomes ionized after the placental transfer and is unable to reach the maternal circulation, leading to “ion trapping” that may jeopardize fetal well-being.
Higher LA plasma concentration may be encountered in patients with congestive heart failure, hepatic, or renal failure.
Techniques of Administering Local Anesthesia
Topical/Surface Anesthesia
When applied topically, LAs provide an effective but relatively shorter duration of analgesia, which may be increased by longer duration of application. Commonly employed LAs for topical anesthesia are lidocaine, tetracaine, dibucaine and benzocaine (5/10% cream/ointment), eutectic mixture of LAs with 2.5% lidocaine, 2.5% prilocaine (EMLA); tetracaine 0.5%, epinephrine 1:200,000, cocaine 11.8% (TAC); lidocaine 4%, epinephrine 1:20,000, tetracaine 0.5% (LET).
Infiltration Anesthesia
LA is injected directly into the extravascular space in the intradermal or subcutaneous tissues, with immediate onset of action but varying duration of analgesia. The dosage of LA depends on the extent of the surface area to be anesthetized and the duration of the procedure to be performed, for example, lidocaine, bupivacaine, ropivacaine, mepivacaine, prilocaine (Tables 11.1 and 11.2).
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