Local anesthetics

Physiochemical properties

The potency and duration of action of local anesthetic agents are dependent on the lipophilicity of the local anesthetic molecule, the degree of ionization (pK _a ), the pH of the preparation and of the tissue, the degree of protein binding, the intrinsic vasoconstrictor properties of the drug, and the temperature ( ). Lipophilicity determines the affinity of the molecule for lipid membranes and increases the potency and the duration of action. Lipophilicity is increased by increasing the size of the alkyl substitution on the aromatic ring or on or near the tertiary amine ( ).

The pK _a of a drug is the hydrogen ion concentration (pH) at which 50% of the drug exists in its ionized hydrophilic form (i.e., in equilibrium with its un-ionized lipophilic form). All local anesthetic agents are weak bases. At physiologic pH, the lower the pK _a , the greater the lipophilicity will be. The pH of the site where the local anesthetic is placed determines the degree of ionization and thus the activity of the drug. Sodium bicarbonate can be used clinically to speed the onset by raising the pH of a local anesthetic solution, thereby increasing the un-ionized fraction (lipophilicity).

Bupivacaine, mepivacaine, and ropivacaine—but not lidocaine—have an asymmetric carbon atom that allows these drugs to exist as different isomers or S ⁻ and R ⁺ enantiomers. A racemic mixture contains equal amounts of the S ⁻ and R ⁺ enantiomers. Bupivacaine is a racemic mixture of equiosmolar amounts of R ⁺ bupivacaine and S ⁻ bupivacaine ( ).

The pharmacokinetic properties of enantiomers are essentially the same, but their stereospecificity influences the protein binding and pharmacodynamics ( ; ; ). Ropivacaine and levobupivacaine are pure S ⁻ enantiomers that have less cardiac toxicity and a greater sensory motor differential ( ; ; ; ; ). This differential effect is poorly understood but may be related to the length of spread along the nerve, to selective inhibition of the Na ⁺ and K ⁺ channels that are present in different proportions in different nerve types, or to preferential blockade of the tetrodotoxin-resistant sodium channels ( ; ).

The intrinsic vasoconstrictor properties of a local anesthetic agent influence the initial rate of uptake from the site of injection into the central circulation (T _max ) and the duration of action. It may also influence the peak plasma concentration (C _max ). Some local anesthetic agents have a biphasic effect on the blood vessels; for example, ropivacaine at low concentrations vasoconstricts, but at higher concentrations it has vasodilator effects ( ).

Finally, the duration of action of local anesthetic agents is shorter in neonates and infants despite the use of larger weight-scaled doses for both central and peripheral nerve blockade ( ). This may be the result of age-related differences in the pharmacodynamic responses, the degree of myelination of the nerves that increases with age, spacing of the nodes of Ranvier, the length of nerve exposed, tissue barriers, and other factors, including pharmacogenetic variation ( ).

Mechanisms of action

Local anesthetics are reversible sodium channel blockers with marked stereospecificity that influences their action. They interfere with nerve cell membrane excitation and subsequent conduction of action potentials in excitable tissue. They bind to the inner vestibule of the voltage-gated sodium channel after passing through the cell membrane. Various subtypes of sodium channels exist that are tetrodotoxin sensitive or resistant in different nerve fibers ( ; ; ). Nerve fibers vary in their sensitivity to local anesthetic agents. Small myelinated axons, Aγ motor axons, and Aδ sensory axons are the most sensitive, followed by the large myelinated Aα and Aβ fibers. The least susceptible are the slow-conducting fibers, the small unmyelinated C-fibers.

The local anesthetic agents enter the sodium channels in the “active” or “open” state and render them “inactive” or “closed.” The membrane is thus stabilized, and propagation of a depolarizing wave is prevented. The affinity of the local anesthetic drug to the sodium channel varies with the gating state of the channel. Their affinity is high when the sodium channel is open and activated (during sensory transmission, motor activity, or tachydysrhythmias of the myocardium), and their affinity is low at slow excitation rates or when the sodium channel is inactivated or closed ( ). Neonates have a higher heart rate than adults and may thus be more prone to myocardial toxicity. Hypoxia, acidosis, hypothermia, and electrolyte disorders increase the risk of toxicity ( ; ).

Local anesthetic agents also inhibit the K2P channel, blocking repolarization and delaying recovery after depolarization. This effectively prolongs the action potential and adds to risk of toxicity (i.e., convulsions or dysrhythmias) ( ). The distribution of Na ⁺ and K ⁺ ions in the channel varies from one nerve type to another and may explain the differential blockade of sensory and motor nerves by individual local anesthetic agents ( ).

Local anesthetic agents may also have beneficial systemic actions on inflammatory cells and in chronic pain by interaction with G-protein receptors ( ).

Systemic absorption

When local anesthetics are used to perform a nerve block, they are injected into a specific space (e.g., spinal, caudal, or epidural) or location (e.g., peripheral nerve block, skin infiltration, topical). The speed of absorption is a function of the site of injection, the speed of injection, the amount and concentration of the local anesthetic injected, the intrinsic vasoconstrictor properties of the drug, the blood supply to the site, lipid solubility, absorption into the surrounding tissue, and the pH of the tissue.

Local diffusion into the nerve at the site of injection produces regional anesthesia. Diffusion into the bloodstream produces blood concentrations that can be measured. After a single shot injection, the rate of absorption and the volume of distribution determine the rate at which peak plasma levels are reached. Clearance has little impact, but on the other hand, clearance is the major factor that impacts steady-state plasma concentrations during continuous infusions.

Highly vascular areas are more prone to rapid local anesthetic uptake and, consequently, toxicity. The rate of absorption is greatest from the intercostal space and trachea, intermediate from the caudal and epidural spaces, and lowest following skin infiltration. The order of site absorption from highest to lowest is intercostal, intratracheal, caudal, epidural, brachial plexus, and subcutaneous.

Absorption from the epidural space is considered biphasic ( ). The buffering properties of the epidural space are important, and the epidural fat acts as a store where the injected drug can accumulate. The slow release is responsible for a longer terminal half-life. Epidural fat in neonates and infants is less abundant, and the peak plasma concentration occurs earlier in this age group ( ).

In young patients, the endoneurium is loose and is easily traversed by local anesthetics in both directions, resulting in more rapid onset but a shorter duration of action. As the child matures, the connective tissue fibers within the endoneurium increase, causing both latency (onset) and duration of action to increase with age.

The systemic effects of local anesthetics are a function of dose, rapidity of injection, site of injection, and ultimately the rate of rise and the plasma concentration reached. Toxic effects involving either the CNS or the heart are directly related to the free (unbound) drug concentration. In general, CNS toxicity occurs at lower plasma concentrations than cardiac toxicity in infants and young children.

Cardiac output also has an influence. A higher cardiac output increases the uptake, producing higher initial plasma concentrations and decreasing the duration of action. Ropivacaine is considered a better agent than bupivacaine for epidural infusions because the vasoconstrictor properties of ropivacaine slow the absorption of the drug into the blood, decreasing the peak plasma levels. ) have shown that after 2 mg/kg of either caudal ropivacaine or bupivacaine, ropivacaine undergoes slower systemic absorption from the caudal space, but the peak venous plasma concentrations are comparable.

Vasoconstrictors may also be used to reduce the absorption of local anesthetic into the systemic circulation. In the un-ionized form, local anesthetics cross the endothelium of capillaries at the site of injection relatively freely. Because the cardiac output and local blood flow in infants is two to three times greater than in adults, the systemic absorption is increased accordingly. The efficacy of epinephrine in slowing absorption varies with age but also the vascularity at the site of injection. Epinephrine prolongs the duration of bupivacaine and ropivacaine by approximately 50% in neonates, 25% in infants younger than 4 years old, and 10% in older children ( ; ).

Distribution

The volume of distribution is difficult to evaluate and is largely unknown in children. Pharmacokinetic analysis after extravascular injection is difficult. In conventional pharmacokinetic modeling, it is assumed that elimination is longer than absorption and that the terminal phase occurs when absorption is almost totally completed ( ). If absorption is longer than elimination, such as when local anesthetic agents are injected extravascularly, the terminal half-life represents the complex absorption process as well as elimination. It is thus impossible to accurately calculate the volume of distribution, but the total body clearance can be calculated accurately if sampling is long enough. A further confounding factor is that clearance also varies with time ( ).

Local anesthetic agents are water soluble and are affected by changes in the water compartment volumes. The distribution volumes of all agents are thus markedly increased in the very young. Tissue binding is another important factor because the local anesthetic agents are widely distributed outside the blood. Furthermore, the extracellular fluid volume in newborns and young infants is almost twice that of an adult. Theoretically, volume of distribution should be much larger in neonates and infants.

Protein binding and volume of distribution influence the C _max of a drug. The peak plasma C _max of ropivacaine is delayed in infants and children compared with adults. The time to C _max decreases from 90 to 120 minutes in infants younger than 6 months of age to 30 minutes in adults and children older than 8 years of age.

In infants and children, the pharmacokinetics of ropivacaine has been reported after caudal, epidural, and ilioinguinal blocks ( ; ; ). showed that infants between the ages of 0 and 3 months have higher free ropivacaine concentrations than infants who are 3 to 12 months of age, and for both these groups of infants, the free drug concentrations were within the concentrations reported for adults. However, noted that infants had higher peak plasma concentrations than toddlers aged 1 to 5 years, with the peak concentration occurring at 60 minutes in both groups. In a dosing study of children 4 to 12 years of age, noted that single-shot caudals in doses of 1 to 3 mg/kg resulted in peak plasma levels of free ropivacaine that increased proportionately with increasing doses.

The lungs may also influence the plasma levels. The lungs slow the rate of rise and influence the peak plasma concentration. The lung extraction ratio for amide local anesthetic agents is high (approximately 0.8), resulting in a difference between mixed venous and arterial concentrations. Infants with right-to-left cardiac shunts may therefore be at greater risk of toxicity. demonstrated higher plasma lidocaine levels in the systemic circulation in animals with right-to-left shunts.