Applied anatomy

The typical nerve cell has been traditionally described in terms of having a cell body (perikaryon), multiple dendrites, and a single axon (Fig. 3.1). Sensory neurons are classified as unipolar; that is, they have an axon that divides to extend a branch to both the spinal cord and the periphery. Motor neurons are classified as multipolar because, in addition to an axon, they possess many dendrites. Impulses arriving via the dendrites and cell body are integrated at the axon hillock, a specialized area of the cell body. Summation of excitatory and inhibitory impulses occurs at the axon hillock and determines whether impulses are generated or not.

Figure 3.1 The nerve cell. Sensory neuron with a cell body (perikaryon) and an axon with long peripheral and short central branches (unipolar nerve cell); interneuron with numerous dendrites, a cell body, and one short axon (multipolar nerve cell); motor neuron with a great many dendrites, a cell body, and a long peripheral axon (multipolar).

(From Ref. 1, Strichatz GR. Neural Physiology and Local Anesthetic Action. In: Cousins MJ, Bridenbaugh PO (eds). Neural blockade in clinical anesthesia and management of pain, 3rd edn. Philadelphia: © Lippincott-Raven; 1998.)

The axon is always enclosed within a nutriprotective Schwann cell envelope. Most are further invested in a myelin sheath formed by a single Schwann cell wrapped many times around the axon and interrupted periodically at the nodes of Ranvier. Many unmyelinated nerves, on the other hand, may have their axons enclosed within the folds of a single Schwann cell (Fig. 3.2).

Figure 3.2 The axon. Myelinated axon in longitudinal section (A), showing the relation of the myelin sheath to the nodes of Ranvier, and transverse section (B), showing how the Schwann cell wraps around one axon many times to form the multiple layers of the myelin sheath. A Schwann cell and its group of unmyelinated axons (C); many unmyelinated axons are embedded in the folds of a single Schwann cell.

(From Ref. 1, Strichatz GR. Neural physiology and local anesthetic action. In: Cousins MJ, Bridenbaugh PO (eds). Neural blockade in clinical anesthesia and management of pain, 3rd edn. Philadelphia: © Lippincott-Raven; 1998.)

The nerve cell membrane, in common with all cells of the body, comprises a phospholipid bilayer traversed by proteins that selectively regulate the influx and efflux of ions and molecules, act as hormone and transmitter receptors, are involved in cell-to-cell interactions, and enhance the structural integrity of the membrane (Fig. 3.3). It is the specialized nature of some of these proteins that is responsible for the unique character of nerve cells.²

Figure 3.3 The axonal membrane. A phospholipid bilayer traversed by proteins. Carbohydrate molecules attached to proteins and lipids on the extracellular surface of the membrane form a ‘cell coat’. The lipid bilayer consists of densely packed phospholipids. Integral proteins and peripheral proteins only on the cytoplasmic surface are associated with enzymatic and receptor functions.

(From Strichatz GR. Neural Physiology and Local Anesthetic Action. In Cousins MJ, Bridenbaugh PO (eds). Neural blockade in clinical anesthesia and management of pain, 3rd edn. Philadelphia: © Lippincott-Raven; 1998.)

Ionic basis of conduction

A special membrane protein, the Na⁺–K⁺ ATPase pump, is responsible for the transmembrane concentration gradient of these ions peculiar to nerve cells. It transports sodium out of the cell and potassium into it.³ At rest, the membranse is selectively permeable to K⁺, resulting in an efflux of positive charge. Thus, the interior of the cell is negatively charged relative to the exterior; this resting membrane potential is in the order of 70–80 mV. Because of its chemical and electrical gradient, there is a tendency for Na⁺ to enter the cell.

Temporal and spatial summation of excitatory and inhibitory potentials occurs at the axon hillock. Small net depolarizations of 15–20 mV will raise the membrane potential to −55 mV, resulting in a voltage-dependent opening of Na⁺ channels and a rapid change in transmembrane potential to +40 mV.^4–6 This is shortly followed by the opening of K⁺ channels, and the subsequent outward flow of K⁺ returns the membrane potential to normal and beyond (the refractory period where it is more difficult to stimulate the nerve).³ The Na⁺−K⁺ pump then serves to restore the chemical gradient to its initial state. These changes in transmembrane potential account for the familiar action potential (Fig. 3.4). The electrical changes occurring during the action potential serve to open adjacent voltage-dependent Na⁺ channels, and so the action potential is propagated along the axon. Because the area immediately preceding the action potential is in the refractory period, the action potential is propagated in one direction only.

Figure 3.4 A propagating action potential and the membrane currents that produce it. See text for details. I_K+, outward K⁺ current; I_Na+, inward Na⁺ current; I_i, net ionic current across the membrane.

(From Strichatz GR. Neural Physiology and Local Anesthetic Action. In: Cousins MJ, Bridenbaugh PO (eds). Neural blockade in clinical anesthesia and management of pain, 3rd edn. Philadelphia: © Lippincott-Raven; 1998.)

Physiochemical properties of local anesthetics

Local distribution

The local distribution of local anesthetics is affected by the physiochemical properties of the agent; the site of injection; the volume, mass, and concentration injected; and the presence or absence of vasoconstrictor substances.

The mass movement or bulk flow of an agent is a physical process and as such depends on the volume of drug injected, the rate of injection, and the physical barrier of the surrounding fibrous and fatty tissue.

Fick’s Law explains the relations between the various factors affecting diffusion of a substance through a membrane:

where dQ/dT is the rate of passive diffusion; D the diffusion coefficient of the drug in the membrane; A the area of the membrane; K the aqueous membrane partition coefficient of the drug; ΔC the concentration gradient; and δ the thickness of the membrane.

Local clearance of drug depends on the vascularity of the injection site and the degree of tissue binding. Therefore a rich capillary bed and little surrounding fatty tissue coupled with a low water:oil partition coefficient favors systemic absorption. The rate of absorption, and hence initial plasma concentrations as a function of site of injection, vary as follows: spinal < plexus block < epidural < caudal < intercostal < intrapleural (Fig. 3.6).

Figure 3.6 Systemic absorption of mepivacaine in humans after various regional block procedures as indicated by mean (± SEM) maximum plasma drug concentrations. IC: intercostal block; C: caudal block; E: epidural block; BP: brachial plexus block; SF: sciatic or femoral block; w/o: solution without epinephrine; w: with epinephrine. 1 : 200 000 (shaded).

(From Tucker et al 1972,²⁹ with permission.)

Following absorption into the systemic circulation, local anesthetics are subjected to substantial sequestration by the lungs.^30,31 This is because of a high lung:blood partition coefficient and ion trapping of drug secondary to the low extravascular pH of the lungs. The drugs also bind plasma proteins, showing high affinity and low capacity for alpha₁-acid glycoprotein, and low affinity and high capacity for albumin. This binding is increased in the presence of cancer, trauma, chronic pain, and inflammatory disease, as well as in the postoperative period; it is significantly decreased in neonates because of their low plasma concentrations of alpha₁-acid glycoprotein. Further binding of drug takes place in the tissue. The long-acting group of amide local anesthetics are bound in plasma and tissue to a greater extent than the short-acting ones.^32–37

The distribution of local anesthetics obeys the laws governing a three-compartment model of distribution and elimination. This can be described by:

The volume of distribution in a steady state (VD_ss) is based on unbound plasma concentrations and reflects net tissue binding.

The half-life of elimination can be calculated following the intravenous injection of a bolus of drug. It allows one to anticipate the risk of drug accumulation in case of reinjection. For example, lidocaine has an elimination half-life of 96min and bupivacaine 210 min.¹⁴ Therefore as a rough guide one may readminister half the initial dose 1.5 and 3.5h following the first injection, and in this way avoid drug accumulation.

Metabolism and excretion

Amide local anesthetics are metabolized in the liver and their elimination depends on their hepatic clearance. They can be divided into two groups, depending on whether their hepatic extraction ratio is high (e.g. lidocaine, >50%) or low (e.g. bupivacaine, <40%). Those drugs with a high ratio have, therefore, perfusion-dependent clearance; those with a low ratio are subject to induction and inhibition of hepatic enzyme systems.³⁸

As stated above, the ester drugs are rapidly hydrolyzed by plasma and other esterases, limiting their potential for toxicity.^8,9,11,39,40 Renal excretion of local anesthetics is of little importance, accounting for less than 6% of the dose. This may be increased, however, to 20% following acidification of the urine.⁴¹

Nerve fibers

Nerve fibers have been categorized into A, B, and C fibers. A fibers have been further divided into α, β, γ, and δ fibers. The important features of each category of nerve fiber are outlined in Table 3.2. A fibers are myelinated somatic nerves, B fibers are myelinated preganglionic autonomic nerves, and C fibers are unmyelinated nerves. The susceptibility of nerves to local anesthetics, in general, depends on their caliber, degree of myelination, and speed of conduction. However, as outlined below, further factors also come into play.

Minimum blocking concentration

The minimum blocking concentration (C_m) is the lowest concentration of a local anesthetic agent that will block conduction in a nerve in vitro. In vivo, the drug is injected in and about nerve trunks, fibrous sheaths, fatty tissue, and blood vessels. Therefore, before reaching a nerve, it is subject to dilution, dispersion, fixation, destruction, and systemic absorption. Under these conditions, the minimum concentration necessary to block a nerve is much greater than the C_m. Consequently, lidocaine 1% is necessary to block a mixed somatic nerve that has a C_m for lidocaine of approximately 0.07%.⁴²

Differential nerve block

Within a single peripheral nerve, one may observe complete block of pain fibers (Aδ and C) while motor and touch (Aα and Aβ) are spared. This is known as differential nerve block. A number of possible explanations for this phenomenon have been postulated. First, the time taken for a drug to diffuse into and along the course of a nerve, and so affect various fibers, may result in the clinical features observed. Second, the presence or absence of a myelin sheath may affect local anesthetic activity and penetration. Third, not all axons have the same sensitivity to local anesthetic agents because of variations in Na⁺ channel and membrane lipid content.^43,44

Nerve penetration

Peripheral nerves are organized so that the fibers innervating the distal portions of a limb are in the center of the nerve trunk and the more proximal structures are supplied from the outer layers of the trunk. Following deposition of the drug, one may therefore observe anesthesia of the more proximal limb structures before the distal ones (Fig. 3.7).

Figure 3.7 Somatopic distribution in peripheral nerve. Axons in large nerve trunks are arranged so that the outer fibers innervate the more proximal structures. The inner fibers innervate the more distal parts of a limb.

(From Ref. 45, de Jong RH. Physiology and pharmacology of local anesthesia. Springfield, IL, 1970. Courtesy of Charles C. Thomas Publishers, Ltd, Springfield, Illinois, USA.)

Regression of block is primarily dependent on diffusion from the nerve and absorption into the local vasculature. Drugs with high lipophilic solubility diffuse slowly from local tissues for reasons stated earlier, while the addition of adrenaline to local anesthetics results in local vasoconstriction and an increase of up to 50% in block duration.^46–48