Pharmacology_Katzung

Pharmacology_Katzung. became sufficiently rare for it to remain a widely used anesthetic for nearly every regional technique in modern clinical practice. Nonetheless, this inherent cardiotoxicity would drive developmental work leading to the introduction of two recent additions to the anesthetic armamen-tarium, levobupivacaine and ropivacaine. The former is the S(–) enantiomer of bupivacaine, which has less affinity for cardiac sodium channels than its R(+) counterpart. Ropivacaine, another S(–) enantiomer, shares this reduced affinity for cardiac sodium channels, while being slightly less potent than bupivacaine or levobupivacaine.


Pharmacology_Katzung

Pharmacology_Katzung. Thus, pKa can be seen as an effective way to consider the tendency for compounds to exist in a charged or uncharged form, ie, the lower the pKa, the greater the percentage of uncharged weak bases at a given pH. Because the pKa of most local anesthetics is in the range of 7.5–9.0, the charged, cationic form will constitute the larger percentage at physiologic pH. A glaring exception is benzocaine, which has a pKa around 3.5, and thus exists solely as the nonionized base under normal physiologic conditions.


Pharmacology_Katzung

Pharmacology_Katzung. This issue of ionization is of critical importance because the cationic form is the most active at the receptor site. However, the story is a bit more complex, because the receptor site for local anesthetics is at the inner vestibule of the sodium channel, and the charged form of the anesthetic penetrates biologic membranes poorly. Thus, the uncharged form is important for cell penetration. After penetration into the cytoplasm, equilibration leads to formation and binding of the charged cation at the sodium channel, and hence the production of a clinical effect (Figure 26–1). Drug may also reach the receptor laterally through what has been termed the hydrophobic pathway. As a clinical consequence, local anesthetics are less effective when they are injected into infected tissues because the low extracellular pH favors the charged form, with less of the neutral base available for diffusion across the membrane. Conversely, adding bicarbonate to a local anesthetic—a strategy sometimes


Pharmacology_Katzung

Pharmacology_Katzung. the low extracellular pH favors the charged form, with less of the neutral base available for diffusion across the membrane. Conversely, adding bicarbonate to a local anesthetic—a strategy sometimes used in clinical practice—will raise the effective concentration of the nonionized form and thus shorten the onset time of a regional block.


Pharmacology_Katzung

Pharmacology_Katzung. When local anesthetics are used for local, peripheral, and central neuraxial anesthesia—their most common clinical applications—systemic absorption, distribution, and elimination serve only to diminish or terminate their effect. Thus, classic pharmacokinetics plays a lesser role than with systemic therapeutics, yet remains important to the anesthetic’s duration and critical to the potential development of adverse reactions, specifically cardiac and CNS toxicity. Some pharmacokinetic properties of the commonly used amide local anesthetics are summarized in Table 26–2. The pharmacokinetics of the ester-based local anesthetics have not been extensively studied owing to their rapid breakdown in plasma (elimination half-life < 1 minute).


Pharmacology_Katzung

Pharmacology_Katzung. ExtracellularIntracellularSodiumchannel+LA+HLAH+LA+H+LAH+LAFIGURE 26–1 Schematic diagram depicting paths of local anesthetic (LA) to receptor sites. Extracellular anesthetic exists in equilib-rium between charged and uncharged forms. The charged cation penetrates lipid membranes poorly; intracellular access is thus achieved by passage of the uncharged form. Intracellular re-equilibration results in formation of the more active charged species, which binds to the receptor at the inner vestibule of the sodium channel. Anesthetic may also gain access more directly by diffusing laterally within the membrane (hydrophobic pathway). A. Absorption


Pharmacology_Katzung

Pharmacology_Katzung. A. Absorption Systemic absorption of injected local anesthetic from the site of administration is determined by several factors, including dosage, site of injection, drug-tissue binding, local tissue blood flow, use of a vasoconstrictor (eg, epinephrine), and the physicochemical properties of the drug itself. Anesthetics that are more lipid soluble are generally more potent, have a longer duration of action, and take longer to achieve their clinical effect. Extensive protein binding also serves to increase the duration of action.


Pharmacology_Katzung

Pharmacology_Katzung. Application of a local anesthetic to a highly vascular area such as the tracheal mucosa or the tissue surrounding intercostal nerves results in more rapid absorption and thus higher blood levels than if the local anesthetic is injected into a poorly perfused tissue such as subcutaneous fat. When used for major conduction blocks, the peak serum levels will vary as a function of the specific site of injection, with intercostal blocks among the highest, and sciatic and femoral among the lowest (Figure 26–2). When vasoconstrictors are used with local anesthetics, the resultant reduction in blood flow serves to reduce the rate of systemic absorption and thus diminishes peak serum levels. This effect is generally most evident with the shorter-acting, less potent, and less lipid-soluble anesthetics. B. Distribution 1.


Pharmacology_Katzung

Pharmacology_Katzung. Localized—As local anesthetic is usually injected directly at the site of the target organ, distribution within this compartment plays an essential role with respect to achievement of clinical effect. For example, anesthetics delivered into the subarachnoid space will be diluted with cerebrospinal fluid (CSF) and the pattern of distribution will be dependent upon a host of factors, among the most critical being the specific gravity relative to that of CSF and the patient’s position. Solutions are termed hyperbaric, isobaric, and hypobaric, and will respectively descend, remain relatively static, or ascend, within the subarachnoid space due to gravity when the patient sits upright. A review and analysis of relevant literature cited 25 factors that have been invoked as determinants of spread of local anesthetic in CSF, which can be broadly classified as characteristics of the anesthetic solution, CSF constituents, patient characteristics, and techniques of injection. Somewhat similar


Pharmacology_Katzung

Pharmacology_Katzung. of local anesthetic in CSF, which can be broadly classified as characteristics of the anesthetic solution, CSF constituents, patient characteristics, and techniques of injection. Somewhat similar considerations apply to epidural and peripheral blocks.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Systemic—The peak blood levels achieved during major conduction anesthesia will be minimally affected by the concentration of anesthetic or the speed of injection. The disposition of these agents can be well approximated by a two-compartment model. The initial alpha phase reflects rapid distribution in blood and highly perfused organs (eg, brain, liver, heart, kidney), characterized by a steep exponential decline in concentration. This is TABLE 26–2 Pharmacokinetic properties of several amide local anesthetics. CL, clearance; Vdss, volume of distribution at steady state per 70 kg body weight.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 26–2 Pharmacokinetic properties of several amide local anesthetics. CL, clearance; Vdss, volume of distribution at steady state per 70 kg body weight. FIGURE 26–2 Comparative peak blood levels of several local anesthetic agents following administration into various anatomic sites. (Adapted, with permission, from Covino BD, Vassals HG: Local Anesthetics: Mechanism of Action in Clinical Use. Grune & Stratton, 1976. Copyright Elsevier.) followed by a slower declining beta phase reflecting distribution into less well perfused tissue (eg, muscle, gut), and may assume a nearly linear rate of decline. The potential toxicity of the local anesthetics is affected by the protective effect afforded by uptake by the lungs, which serve to attenuate the arterial concentration, though the time course and magnitude of this effect have not been adequately characterized. C. Metabolism and Excretion


Pharmacology_Katzung

Pharmacology_Katzung. C. Metabolism and Excretion The local anesthetics are converted to more water-soluble metabolites in the liver (amide type) or in plasma (ester type), which are excreted in the urine. Since local anesthetics in the uncharged form diffuse readily through lipid membranes, little or no urinary excretion of the neutral form occurs. Acidification of urine promotes ionization of the tertiary amine base to the more water-soluble charged form, leading to more rapid elimination. Ester-type local anesthetics are hydrolyzed very rapidly in the blood by circulating butyrylcholinesterase to inactive metabolites. For example, the half-lives of procaine and chloroprocaine in plasma are less than a minute. However, excessive concentrations may accumulate in patients with reduced or absent plasma hydrolysis secondary to atypical plasma cholinesterase.


Pharmacology_Katzung

Pharmacology_Katzung. The amide local anesthetics undergo complex biotransformation in the liver, which includes hydroxylation and N-dealkylation by liver microsomal cytochrome P450 isozymes. There is considerable variation in the rate of liver metabolism of individual amide compounds, with prilocaine (fastest) > lidocaine > mepivacaine > ropivacaine ≈ bupivacaine and levobupivacaine (slowest). As a result, toxicity from amide-type local anesthetics is more likely to occur in patients with hepatic disease. For example, the average elimination half-life of lidocaine may be increased from 1.6 hours in normal patients (t½, Table 26–2) to more than 6 hours in patients with severe liver disease. Many other drugs used in anesthesia are metabolized by the same P450 isozymes, and concomitant administration of these competing drugs may slow the hepatic metabolism of the local anesthetics. Decreased hepatic elimination of local anesthetics would also be anticipated in patients with reduced hepatic blood flow. For


Pharmacology_Katzung

Pharmacology_Katzung. competing drugs may slow the hepatic metabolism of the local anesthetics. Decreased hepatic elimination of local anesthetics would also be anticipated in patients with reduced hepatic blood flow. For example, the hepatic elimination of lidocaine in patients anesthetized with volatile anesthetics (which reduce liver blood flow) is slower than in patients anesthetized with intravenous anesthetic techniques. Delayed metabolism due to impaired hepatic blood flow may likewise occur in patients with heart failure.


Pharmacology_Katzung

A. Mechanism of Action 1.

Pharmacology_Katzung. A. Mechanism of Action 1.


Pharmacology_Katzung

Pharmacology_Katzung. Membrane potential—The primary mechanism of action of local anesthetics is blockade of voltage-gated sodium channels (Figure 26–1). The excitable membrane of nerve axons, like the membrane of cardiac muscle (see Chapter 14) and neuronal cell bodies (see Chapter 21), maintains a resting transmembrane potential of –90 to –60 mV. During excitation, the sodium channels open, and a fast, inward sodium current quickly depolarizes the membrane toward the sodium equilibrium potential (+40 mV). As a result of this depolarization process, the sodium channels close (inactivate) and potassium channels open. The outward flow of potassium repolarizes the membrane toward the potassium equilibrium potential (about –95 mV); repolarization returns the sodium channels to the rested state with a characteristic recovery time that determines the refractory period. The transmembrane ionic gradients are maintained by the sodium pump. These ionic fluxes are similar to, but simpler than, those in heart muscle,


Pharmacology_Katzung

Pharmacology_Katzung. recovery time that determines the refractory period. The transmembrane ionic gradients are maintained by the sodium pump. These ionic fluxes are similar to, but simpler than, those in heart muscle, and local anesthetics have similar effects in both tissues.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Sodium channel isoforms—Each sodium channel consists of a single alpha subunit containing a central ion-conducting pore associated with accessory beta subunits. The pore-forming alpha subunit is actually sufficient for functional expression, but the kinetics and voltage dependence of channel gating are modified by the beta subunit. A variety of different sodium channels have been characterized by electrophysiologic recording, and subsequently isolated and cloned, while mutational analysis has allowed for identification of the essential components of the local anesthetic binding site. Nine members of a mammalian family of sodium channels have been so characterized and classified as Nav1.1–Nav1.9, where the chemical symbol represents the primary ion, the subscript denotes the physiologic regulator (in this case voltage), the initial number denotes the gene, and the number following the period indicates the particular isoform.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Channel blockade—Biologic toxins such as batrachotoxin, aconitine, veratridine, and some scorpion venoms bind to receptors within the channel and prevent inactivation. This results in prolonged influx of sodium through the channel and depolarization of the resting potential. The marine toxins tetrodotoxin (TTX) and saxitoxin have clinical effects that largely resemble those of local anesthetics (ie, block of conduction without a change in the resting potential). However, in contrast to the local anesthetics, the toxin binding site is located near the extracellular surface. The sensitivity of these channels to TTX varies, and subclassification based on this pharmacologic sensitivity has important physiologic and therapeutic implications. Six of the aforementioned channels are sensitive to nanomolar concentration of this biotoxin (TTX-S), while three are resistant (TTX-R). Of the latter, Nav1.8 and Nav1.9 appear to be exclusively expressed in dorsal root ganglia nociceptors, which


Pharmacology_Katzung

Pharmacology_Katzung. to nanomolar concentration of this biotoxin (TTX-S), while three are resistant (TTX-R). Of the latter, Nav1.8 and Nav1.9 appear to be exclusively expressed in dorsal root ganglia nociceptors, which raises the developmental possibility of targeting these specific neuronal subpopulations. Such fine-tuned analgesic therapy has the theoretical potential of providing effective analgesia, while limiting the significant adverse effects produced by nonspecific sodium channel blockers.


Pharmacology_Katzung

Pharmacology_Katzung. When progressively increasing concentrations of a local anesthetic are applied to a nerve fiber, the threshold for excitation increases, impulse conduction slows, the rate of rise of the action potential declines, action potential amplitude decreases, and, finally, the ability to generate an action potential is completely abolished. These progressive effects result from binding of the local anesthetic to more and more sodium channels. If the sodium current is blocked over a critical length of the nerve, propagation across the blocked area is no longer possible. In myelinated nerves, the critical length appears to be two to three nodes of Ranvier. At the minimum dose required to block propagation, the resting potential is not significantly altered.


Pharmacology_Katzung

Pharmacology_Katzung. The blockade of sodium channels by most local anesthetics is both voltage and time dependent: Channels in the rested state, which predominate at more negative membrane potentials, have a much lower affinity for local anesthetics than activated (open state) and inactivated channels, which predominate at more positive membrane potentials (see Figure 14–10). Therefore, the effect of a given drug concentration is more marked in rapidly firing axons than in resting fibers (Figure 26–3). Between successive action potentials, a portion of the sodium channels will recover from the local anesthetic block (see Figure 14–10). The recovery from drug-induced block is 10–1000 times slower than the recovery of channels from normal inactivation (as shown for the cardiac membrane in Figure 14–4). As a result, the refractory period is lengthened and the nerve conducts fewer action potentials.


Pharmacology_Katzung

Pharmacology_Katzung. Elevated extracellular calcium partially antagonizes the action of local anesthetics owing to the calcium-induced increase in the surface potential on the membrane (which favors the low-affinity rested state). Conversely, increases in extracellular potassium depolarize the membrane potential and favor the inactivated state, enhancing the effect of local anesthetics.


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 26–3 Effect of repetitive activity on the block of sodium current produced by a local anesthetic in a myelinated axon. A series of 25 pulses was applied, and the resulting sodium currents (downward deflections) are superimposed. Note that the current produced by the pulses rapidly decreased from the first to the 25th pulse. A long rest period after the train resulted in recovery from block, but the block could be reinstated by a subsequent train. nA, nanoamperes. (Adapted, with permission, from Courtney KR: Mechanism of frequency-dependent inhibition of sodium currents in frog myelinated nerve by the lidocaine derivative GEA. J Pharmacol Exp Ther 1975;195:225.) 4. Other effects—Currently used local anesthetics bind to the sodium channel with low affinity and poor specificity, and there are multiple other sites for which their affinity is nearly the same as that for sodium channel binding. Thus, at clinically relevant concentrations, local anesthetics are potentially active at


Pharmacology_Katzung

Pharmacology_Katzung. there are multiple other sites for which their affinity is nearly the same as that for sodium channel binding. Thus, at clinically relevant concentrations, local anesthetics are potentially active at countless other channels (eg, potassium and calcium), enzymes (eg, adenylyl cyclase, carnitine-acylcarnitine translocase), and receptors (eg, N-methyl-d-aspartate [NMDA], G protein-coupled, 5-HT3, neurokinin-1 [substance P receptor]). The role that such ancillary effects play in achievement of local anesthesia appears to be important but is poorly understood. Further, interactions with these other sites are likely the basis for numerous differences between the local anesthetics with respect to anesthetic effects (eg, differential block) and toxicities that do not parallel anesthetic potency, and thus are not adequately accounted for solely by blockade of the voltage-gated sodium channel.


Pharmacology_Katzung

Pharmacology_Katzung. The actions of circulating local anesthetics at such diverse sites exert a multitude of effects, some of which go beyond pain control, including some that are also potentially beneficial. For example, there is evidence to suggest that the blunting of the stress response and improvements in perioperative outcome that may occur with epidural anesthesia derive in part from an action of the anesthetic beyond its sodium channel block. Circulating anesthetics also demonstrate antithrombotic effects having an impact on coagulation, platelet aggregation, and the microcirculation, as well as modulation of inflammation. B. Structure-Activity Characteristics of Local Anesthetics


Pharmacology_Katzung

Pharmacology_Katzung. B. Structure-Activity Characteristics of Local Anesthetics The smaller and more highly lipophilic local anesthetics have a faster rate of interaction with the sodium channel receptor. As previously noted, potency is also positively correlated with lipid solubility. Lidocaine, procaine, and mepivacaine are more water soluble than tetracaine, bupivacaine, and ropivacaine. The latter agents are more potent and have longer durations of local anesthetic action. These long-acting local anesthetics also bind more extensively to proteins and can be displaced from these binding sites by other protein-bound drugs. In the case of optically active agents (eg, bupivacaine), the R(+) isomer can usually be shown to be slightly more potent than the S(–) isomer (levobupivacaine). C. Neuronal Factors Affecting Block 1.


Pharmacology_Katzung

Pharmacology_Katzung. Differential block—Since local anesthetics are capable of blocking all nerves, their actions are not limited to the desired loss of sensation from sites of noxious (painful) stimuli. With central neuraxial techniques (spinal or epidural), motor paralysis may impair respiratory activity, and autonomic nerve blockade may promote hypotension. Further, while motor paralysis may be desirable during surgery, it may be a disadvantage in other settings. For example, motor weakness occurring as a consequence of epidural anesthesia during obstetrical labor may limit the ability of the patient to bear down (ie, “push”) during delivery. Similarly, when used for postoperative analgesia, weakness may hamper ability to ambulate without assistance and pose a risk of falling, while residual autonomic blockade may interfere with bladder function, resulting in urinary retention and the need for bladder catheterization. These issues are particularly problematic in the setting of ambulatory (same-day)


Pharmacology_Katzung

Pharmacology_Katzung. may interfere with bladder function, resulting in urinary retention and the need for bladder catheterization. These issues are particularly problematic in the setting of ambulatory (same-day) surgery, which represents an ever-increasing percentage of surgical caseloads.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Intrinsic susceptibility of nerve fibers—Nerve fibers differ significantly in their susceptibility to local anesthetic blockade. It has been traditionally taught, and still often cited, that local anesthetics preferentially block smaller diameter fibers first because the distance over which such fibers can passively propagate an electrical impulse is shorter. However, a variable proportion of large fibers are blocked prior to the disappearance of the small fiber component of the compound action potential. Most notably, myelinated nerves tend to be blocked before unmyelinated nerves of the same diameter. For example, preganglionic B fibers are blocked before the smaller unmyelinated C fibers involved in pain transmission (Table 26–3).


Pharmacology_Katzung

Pharmacology_Katzung. Another important factor underlying differential block derives from the stateand use-dependent mechanism of action of local anesthetics. Blockade by these drugs is more marked at higher frequencies of depolarization. Sensory (pain) fibers have a high firing rate and relatively long action potential duration. Motor fibers fire at a slower rate and have a shorter action potential duration. As type A delta and C fibers participate in high-frequency pain transmission, this characteristic may favor blockade of these fibers earlier and with lower concentrations of local anesthetics. The potential impact of such effects mandates cautious interpretation of non-physiologic experiments evaluating intrinsic susceptibility of nerves to conduction block by local anesthetics.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Anatomic arrangement—In addition to the effect of intrinsic vulnerability to local anesthetic block, the anatomic organization of the peripheral nerve bundle may impact the onset and susceptibility of its components. As one would predict based on the necessity of having proximal sensory fibers join the nerve trunk last, the core will contain sensory fibers innervating the most distal sites. Anesthetic placed outside the nerve bundle will thus reach and anesthetize the proximal fibers located at the outer portion of the bundle first, and sensory block will occur in sequence from proximal to distal.


Pharmacology_Katzung

Pharmacology_Katzung. Local anesthetics can provide highly effective analgesia in well-defined regions of the body. The usual routes of administration include topical application (eg, nasal mucosa, wound [incision site] margins), injection in the vicinity of peripheral nerve endings (perineural infiltration) and major nerve trunks (blocks), and injection into the epidural or subarachnoid spaces surrounding the spinal cord (Figure 26–4). TABLE 26–3 Relative size and susceptibility of different types of nerve fibers to local anesthetics.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 26–3 Relative size and susceptibility of different types of nerve fibers to local anesthetics. Caudal block Spinal block Subarachnoid space in spinal canal Base of spinal cord (Conus medullaris) Dura Epidural space T12 L1 L2 L3 L4 L5 S1 S2Epidural space in caudal canal Filum terminale Cauda equina Epidural block FIGURE 26–4 Schematic diagram of the typical sites of injection of local anesthetics in and around the spinal canal. When local anesthet-ics are injected extradurally, it is referred to as an epidural block. A caudal block is a specific type of epidural block in which a needle is inserted into the caudal canal via the sacral hiatus. Injections around peripheral nerves are known as perineural blocks (eg, paravertebral block). Finally, injection into cerebrospinal fluid in the subarachnoid (intrathecal) space is referred to as a spinal block.


Pharmacology_Katzung

Pharmacology_Katzung. In clinical practice, there is generally an orderly evolution of block components beginning with sympathetic transmission and progressing to temperature, pain, light touch, and finally motor block. This is most readily appreciated during onset of spinal anesthesia, where a spatial discrepancy can be detected in modalities, the most vulnerable components achieving greater dermatomal (cephalad) spread. Thus, loss of the sensation of cold (often assessed by a wet alcohol sponge) will be roughly two segments above the analgesic level for pinprick, which in turn will be roughly two segments rostral to loss of light touch recognition. However, because of the anatomic considerations noted earlier for peripheral nerve trunks, onset with peripheral blocks is more variable, and proximal motor weakness may precede onset of more distal sensory loss. Additionally, anesthetic solution is not generally deposited evenly around a nerve bundle, and longitudinal spread and radial penetration into the


Pharmacology_Katzung

Pharmacology_Katzung. may precede onset of more distal sensory loss. Additionally, anesthetic solution is not generally deposited evenly around a nerve bundle, and longitudinal spread and radial penetration into the nerve trunk are far from uniform.


Pharmacology_Katzung

Pharmacology_Katzung. With respect to differential block, it is worth noting that “successful” surgical anesthesia may require loss of touch, not just ablation of pain, as some patients will find even the sensation of touch distressing during surgery, often fearing that the procedure may become painful. Further, while differences may exist in modalities, it is not possible with conventional techniques to produce surgical anesthesia without some loss of motor function. A. Effect of Added Vasoconstrictors


Pharmacology_Katzung

Pharmacology_Katzung. Several benefits may be derived from addition of a vasoconstrictor to a local anesthetic. First, localized neuronal uptake is enhanced because of higher sustained local tissue concentrations that can translate clinically into a longer duration block. This may enable adequate anesthesia for more prolonged procedures, extended duration of postoperative pain control, and lower total anesthetic requirement. Second, peak blood levels will be lowered as absorption is more closely matched to metabolism and elimination, and the risk of systemic toxic effects is reduced. Moreover, when incorporated into a spinal anesthetic, epinephrine may not only contribute to prolongation of the local anesthetic effect via its vasoconstrictor properties, but also exert a direct analgesic effect mediated by postsynaptic α2 adrenoceptors within the spinal cord. Recognition of this potential has led to the clinical use of the α2 agonist clonidine as a local anesthetic adjuvant for spinal anesthesia.


Pharmacology_Katzung

Pharmacology_Katzung. Conversely, inclusion of epinephrine may also have untoward effects. The addition of epinephrine to anesthetic solutions can potentiate the neurotoxicity of local anesthetics used for peripheral nerve blocks or spinal anesthesia. Further, the use of a vasoconstrictor agent in an area that lacks adequate collateral flow (eg, digital block) is generally avoided, although some have questioned the validity of this proscription. B. Intentional Use of Systemic Local Anesthetics


Pharmacology_Katzung

Pharmacology_Katzung. Although the principal use of local anesthetics is to achieve anesthesia in a restricted area, these agents are sometimes deliberately administered systemically to take advantage of suppressive effects on pain processing. In addition to documented reductions in anesthetic requirement and postoperative pain, systemic administration of local anesthetics has been used with some success in the treatment of chronic pain, and this effect may outlast the duration of anesthetic exposure. The achievement of pain control by systemic administration of local anesthetics is thought to derive, at least in part, from the suppression of abnormal ectopic discharge, an effect observed at concentrations of local anesthetic an order of magnitude lower than those required for blockade of propagation of action potentials in normal nerves. Consequently, these effects can be achieved without the adverse effects that would derive from failure of normal nerve conduction. Escalating doses of anesthetic appear


Pharmacology_Katzung

Pharmacology_Katzung. potentials in normal nerves. Consequently, these effects can be achieved without the adverse effects that would derive from failure of normal nerve conduction. Escalating doses of anesthetic appear to exert the following systemic actions: (1) low concentrations may preferentially suppress ectopic impulse generation in chronically injured peripheral nerves; (2) moderate concentrations may suppress central sensitization, which would explain therapeutic benefit that may extend beyond the anesthetic exposure; and (3) higher concentrations will produce general analgesic effects and may culminate in serious toxicity.


Pharmacology_Katzung

Pharmacology_Katzung. Local anesthetic toxicity derives from two distinct processes: (1) systemic effects following inadvertent intravascular injection or absorption of the local anesthetic from the site of administration; and (2) neurotoxicity resulting from local effects produced by direct contact with neural elements. A. Systemic Toxicity


Pharmacology_Katzung

Pharmacology_Katzung. A. Systemic Toxicity The dose of local anesthetic used for epidural anesthesia or high-volume peripheral blocks is sufficient to produce major clinical toxicity, even death. To minimize risk, maximum recommended doses for each drug for each general application have been promulgated. The concept underlying this approach is that absorption from the site of injection should appropriately match metabolism, thereby preventing toxic serum levels. However, these recommendations do not consider patient characteristics or concomitant risk factors, nor do they take into account the specific peripheral nerve block performed, which has a significant impact on the rate of systemic uptake (Figure 26–2). Most importantly, they fail to afford protection from toxicity induced by inadvertent intravascular injection (occasionally into an artery, but more commonly a vein).


Pharmacology_Katzung

Pharmacology_Katzung. 1. CNS toxicity—All local anesthetics have the ability to produce sedation, light-headedness, visual and auditory disturbances, and restlessness when high plasma concentrations result from rapid absorption or inadvertent intravascular administration. An early symptom of local anesthetic toxicity is circumoral and tongue numbness and a metallic taste. At higher concentrations, nystagmus and muscular twitching occur, followed by tonic-clonic convulsions. Local anesthetics apparently cause depression of cortical inhibitory pathways, thereby allowing unopposed activity of excitatory neuronal pathways. This transitional stage of unbalanced excitation (ie, seizure activity) is then followed by generalized CNS depression. However, this classic pattern of evolving toxicity has been largely characterized in human volunteer studies (which are ethically constrained to low doses) and by graded administration in animal models. Deviations from such classic progression are common in clinical


Pharmacology_Katzung

Pharmacology_Katzung. characterized in human volunteer studies (which are ethically constrained to low doses) and by graded administration in animal models. Deviations from such classic progression are common in clinical toxicity and will be influenced by a host of factors, including patient vulnerability, the particular anesthetic administered, concurrent drugs, and rate of rise of serum drug levels. A recent literature review of reported clinical cases of local anesthetic cardiac toxicity found prodromal signs of CNS toxicity in only 18% of cases.


Pharmacology_Katzung

Pharmacology_Katzung. When large doses of a local anesthetic are required (eg, for major peripheral nerve block or local infiltration for major plastic surgery), premedication with a parenteral benzodiazepine (eg, diazepam or midazolam) will provide some prophylaxis against local anesthetic-induced CNS toxicity. However, such premedication will have little, if any, effect on cardiovascular toxicity, potentially delaying recognition of a life-threatening overdose. Of note, administration of a propofol infusion or general anesthesia accounted for 5 of the 10 cases presenting with isolated cardiovascular toxicity in the aforementioned literature review of reported clinical cases.


Pharmacology_Katzung

Pharmacology_Katzung. If seizures do occur, it is critical to prevent hypoxemia and acidosis, which potentiate anesthetic toxicity. Rapid tracheal intubation can facilitate adequate ventilation and oxygenation, and is essential to prevent pulmonary aspiration of gastric contents in patients at risk. The effect of hyperventilation is complex, and its role in resuscitation following anesthetic overdose is somewhat controversial, but it likely offers distinct benefit if used to counteract metabolic acidosis. Seizures induced by local anesthetics should be rapidly controlled to prevent patient harm and exacerbation of acidosis. A recent practice advisory from the American Society of Regional Anesthesia advocates benzodiazepines as first-line drugs (eg, midazolam, 0.03–0.06 mg/kg) because of their hemodynamic stability, but small doses of propofol (eg, 0.25–0.5 mg/kg) were considered acceptable alternatives, as they are often more immediately available in the setting of local anesthetic administration. The


Pharmacology_Katzung

Pharmacology_Katzung. but small doses of propofol (eg, 0.25–0.5 mg/kg) were considered acceptable alternatives, as they are often more immediately available in the setting of local anesthetic administration. The motor activity of the seizure can be effectively terminated by administration of a neuromuscular blocker, though this will not diminish the CNS manifestations, and efforts must include therapy directed at the underlying seizure activity.


Pharmacology_Katzung

Pharmacology_Katzung. 2.


Pharmacology_Katzung

Pharmacology_Katzung. Cardiotoxicity—The most feared complications associated with local anesthetic administration result from the profound effects these agents can have on cardiac conduction and function. In 1979, an editorial by Albright reviewed the circumstances of six deaths associated with the use of bupivacaine and etidocaine. This seminal publication suggested that these relatively new lipophilic and potent anesthetics had greater potential cardiotoxicity and that cardiac arrest could occur concurrently or immediately following seizures and, most importantly, in the absence of hypoxia or acidosis. Although this suggestion was sharply criticized, subsequent clinical experience unfortunately reinforced Albright’s concern—within 4 years, the US Food and Drug Administration (FDA) had received reports of 12 cases of cardiac arrest associated with the use of 0.75% bupivacaine for epidural anesthesia in obstetrics. Further support for enhanced cardiotoxicity of these anesthetics came from animal studies


Pharmacology_Katzung

Pharmacology_Katzung. cases of cardiac arrest associated with the use of 0.75% bupivacaine for epidural anesthesia in obstetrics. Further support for enhanced cardiotoxicity of these anesthetics came from animal studies demonstrating that doses of bupivacaine and etidocaine as low as two thirds of those producing convulsions could induce arrhythmias, while the margin between CNS and cardiac toxicity was less than half that for lidocaine. In response, the FDA banned the use of 0.75% bupivacaine in obstetrics. In addition, incorporation of a test dose became ingrained as a standard of anesthetic practice, along with the practice of fractionated administration of local anesthetic.


Pharmacology_Katzung

Pharmacology_Katzung. Although reduction in bupivacaine’s anesthetic concentration and changes in anesthetic practice did much to reduce the risk of cardiotoxicity, the recognized differences in the toxicity of the stereoisomers comprising bupivacaine created an opportunity for the development of potentially safer anesthetics (see Chapter 1). Investigations demonstrated that the enantiomers of the racemic mixture bupivacaine were not equivalent with respect to cardiotoxicity, the S(–) enantiomer having better therapeutic advantage, leading to the subsequent marketing of levobupivacaine. This was followed shortly thereafter by ropivacaine, a slightly less potent anesthetic than bupivacaine. It should be noted, however, that the reduction in toxicity afforded by these compounds is only modest and that risk of significant cardiotoxicity remains a very real concern when these anesthetics are administered for high-volume blocks. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Reversal of bupivacaine toxicity—Recently, a series of clinical events, serendipitous observations, systematic experimentation, and astute clinical decisions have identified a relatively simple, practical, and apparently effective therapy for resistant bupivacaine cardiotoxicity using intravenous infusion of lipid. Furthermore, this therapy appears to have applications that extend beyond bupivacaine cardiotoxicity to the cardiac or CNS toxicity induced by an overdose of any lipid-soluble drug (see Box: Lipid Resuscitation).


Pharmacology_Katzung

Pharmacology_Katzung. B. Localized Toxicity 1. Neural injury—From the early introduction of spinal anesthesia into clinical practice, sporadic reports of neurologic injury associated with this technique raised concern that local anesthetic agents were potentially neurotoxic. Following injuries associated with Durocaine—a spinal anesthetic formulation containing procaine—initial attention focused on the vehicle components. However, experimental studies found 10% procaine alone induced similar injuries in cats, whereas the vehicle did not. Concern for anesthetic neurotoxicity reemerged in the early 1980s with a series of reports of major neurologic injury occurring with the use of chloroprocaine for epidural anesthesia. In these cases, there was evidence that anesthetic intended for the epidural space was inadvertently administered intrathecally. As the dose required for spinal anesthesia is roughly an order of magnitude less than for epidural anesthesia, injury was apparently the result of excessive


Pharmacology_Katzung

Pharmacology_Katzung. inadvertently administered intrathecally. As the dose required for spinal anesthesia is roughly an order of magnitude less than for epidural anesthesia, injury was apparently the result of excessive exposure of the more vulnerable subarachnoid neural elements.


Pharmacology_Katzung

Pharmacology_Katzung. With changes in vehicle formulation and in clinical practice, concern for toxicity again subsided, only to reemerge a decade later with reports of cauda equina syndrome associated with continuous spinal anesthesia (CSA). In contrast to the more common single-injection technique, CSA involves placing a catheter in the subarachnoid space to permit repetitive dosing to facilitate adequate anesthesia and maintenance of block for extended periods. In these cases, the local anesthetic was evidently administered to a relatively restricted area of the subarachnoid space; in order to extend the block to achieve adequate surgical anesthesia, multiple repetitive doses of anesthetic were then administered. By the time the block was adequate, neurotoxic concentrations had accumulated in a restricted area of the caudal region of the subarachnoid space. Most notably, the anesthetic involved in the majority of these cases was lidocaine, a drug most clinicians considered to be the least toxic of


Pharmacology_Katzung

Pharmacology_Katzung. area of the caudal region of the subarachnoid space. Most notably, the anesthetic involved in the majority of these cases was lidocaine, a drug most clinicians considered to be the least toxic of agents. This was followed by reports of neurotoxic injury occurring with lidocaine intended for epidural administration that had inadvertently been administered intrathecally, similar to the cases involving chloroprocaine a decade earlier. The occurrence of neurotoxic injury with CSA and subarachnoid administration of epidural doses of lidocaine served to establish vulnerability whenever excessive anesthetic was administered intrathecally, regardless of the specific anesthetic used. Of even more concern, subsequent reports provided evidence for injury with spinal lidocaine administered at the high end of the recommended clinical dosage, prompting recommendations for a reduction in maximum dose. These clinical reports (as well as concurrent experimental studies) served to dispel the concept


Pharmacology_Katzung

Pharmacology_Katzung. end of the recommended clinical dosage, prompting recommendations for a reduction in maximum dose. These clinical reports (as well as concurrent experimental studies) served to dispel the concept that modern local anesthetics administered at clinically relevant doses and concentrations were incapable of inducing neurotoxic injury.


Pharmacology_Katzung

Pharmacology_Katzung. Based on a case of apparent cardiotoxicity from a very low dose of bupivacaine in a patient with carnitine deficiency, G. L. Weinberg postulated that this metabolic derangement led to enhanced toxicity due to the accumulation of fatty acids within the cardiac myocyte. He hypothesized that administration of lipid would similarly potentiate bupivacaine cardiotoxicity, but experiments performed to test this hypothesis demonstrated exactly the opposite effect. Accordingly, he began systematic laboratory investigations, which clearly demonstrated the poten-tial efficacy of an intravenous lipid emulsion (ILE) for resuscita-tion from bupivacaine cardiotoxicity. Clinical confirmation came 8 years later with the report of the successful resuscitation of a patient who sustained an anesthetic-induced (bupivacaine plus mepivacaine) cardiac arrest refractory to standard advanced cardiac life support procedures (ACLS). Numerous similar reports of successful resuscitations soon followed, extending


Pharmacology_Katzung

Pharmacology_Katzung. (bupivacaine plus mepivacaine) cardiac arrest refractory to standard advanced cardiac life support procedures (ACLS). Numerous similar reports of successful resuscitations soon followed, extending this clinical experience to other anesthetics including levobupivacaine and ropivacaine, anesthetic-induced CNS toxicity, as well as toxicity induced by other classes of compounds, eg, bupropion-induced cardiovascular collapse and multiform ventricular tachycardia provoked by haloperidol. Laboratory investigations have like-wise provided evidence of efficacy for treatment of diverse toxic challenges (eg, verapamil, clomipramine, and propranolol). The mechanism by which lipid is effective is incompletely understood, but almost certainly some of its effect is related to its ability to extract a lipophilic drug from aqueous plasma, thus reducing its effective concentration at tissue targets, a mecha-nism termed “lipid sink.” However, the extent of this extraction does not appear adequate to


Pharmacology_Katzung

Pharmacology_Katzung. lipophilic drug from aqueous plasma, thus reducing its effective concentration at tissue targets, a mecha-nism termed “lipid sink.” However, the extent of this extraction does not appear adequate to account for the magnitude of clini-cal effect, suggesting that other mechanisms at least contribute to the efficacy of lipid rescue. For example, bupivacaine has been shown to inhibit fatty acid transport at the inner mitochondrial membrane, and lipid might act by overcoming this inhibition serving to restore energy to the myocardium or derive benefit via elevation of intramyocyte calcium concentration. Although numerous questions remain, the evolving evidence is sufficient to warrant administration of lipid in cases of systemic anesthetic toxicity. Its use has been promulgated by a task force of the American Society of Regional Anesthesia (http://www.asra.com/ checklist-for-local-anesthetic-toxicity-treatment-1-18-12.pdf ), and administration of lipid has been incorporated into the most


Pharmacology_Katzung

Pharmacology_Katzung. of the American Society of Regional Anesthesia (http://www.asra.com/ checklist-for-local-anesthetic-toxicity-treatment-1-18-12.pdf ), and administration of lipid has been incorporated into the most recent revision of ACLS guidelines for Cardiac Arrest in Special Situations. Importantly, propofol cannot be administered for this purpose, as the relatively enormous volume of this solu-tion required for lipid therapy would deliver lethal quantities of propofol.


Pharmacology_Katzung

Pharmacology_Katzung. The mechanism of local anesthetic neurotoxicity has been extensively investigated in cell culture, isolated axons, and in vivo models. These studies have demonstrated myriad deleterious effects including conduction failure, membrane damage, enzyme leakage, cytoskeletal disruption, accumulation of intracellular calcium, disruption of axonal transport, growth cone collapse, and apoptosis. It is not clear what role these factors or others play in clinical injury. It is clear, however, that injury does not result from blockade of the voltage-gated sodium channel per se, and thus clinical effect and toxicity are not tightly linked.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Transient neurologic symptoms (TNS)—In addition to the very rare but devastating neural complications that can occur with neuraxial (spinal and epidural) administration of local anesthetics, a syndrome of transient pain or dysesthesia, or both, has been recently linked to use of lidocaine for spinal anesthesia. Although these symptoms are not associated with sensory loss, motor weakness, or bowel and bladder dysfunction, the pain can be quite severe, often exceeding that induced by the surgical procedure. TNS occurs even at modest doses of anesthetic and has been documented in as many as one third of patients receiving lidocaine, with increased risk associated with certain patient positions during surgery (eg, lithotomy) and with ambulatory anesthesia. Risk with other anesthetics varies considerably. For example, the incidence is only slightly reduced with procaine or mepivacaine but appears to be negligible with bupivacaine, prilocaine, and chloroprocaine. The etiology and


Pharmacology_Katzung

Pharmacology_Katzung. varies considerably. For example, the incidence is only slightly reduced with procaine or mepivacaine but appears to be negligible with bupivacaine, prilocaine, and chloroprocaine. The etiology and significance of TNS remain to be established, but differences between factors affecting TNS and experimental animal toxicity argue strongly against a common mechanism mediating these symptoms and persistent or permanent neurologic deficits. Nonetheless, the high incidence of TNS has greatly contributed to dissatisfaction with lidocaine as a spinal anesthetic, leading to its near abandonment for this technique (although it remains a popular and appropriate anesthetic for all other applications, including epidural anesthesia). Chloroprocaine, once considered a more toxic anesthetic, is now being explored for short-duration spinal anesthesia as an alternative to lidocaine, a compound that has been used for well over 50 million spinal anesthetic procedures.


Pharmacology_Katzung

Pharmacology_Katzung. Approved for use in the USA as a dental anesthetic in April 2000, articaine is unique among the amino-amide anesthetics in having a thiophene, rather than a benzene ring, as well as an additional ester group that is subject to metabolism by plasma esterases (Table 26–1). The modification of the ring serves to enhance lipophilicity, and thus improve tissue penetration, while inclusion of the ester leads to a shorter plasma half-life (approximately 20 minutes), potentially imparting a better therapeutic index with respect to systemic toxicity. These characteristics have led to widespread popularity in dental anesthesia, where it is generally considered to be more effective, and possibly safer, than lidocaine, the prior standard. Balanced against these positive attributes are concerns that development of persistent paresthesias, while rare, may be three times more common with articaine. However, prilocaine has been associated with an even higher relative incidence (twice that of


Pharmacology_Katzung

Pharmacology_Katzung. that development of persistent paresthesias, while rare, may be three times more common with articaine. However, prilocaine has been associated with an even higher relative incidence (twice that of articaine). Importantly, these are the only two dental anesthetics that are formulated as 4% solutions; the others are all marketed at lower concentrations (eg, the maximum concentration of lidocaine used for dental anesthesia is 2%), and it is well established that anesthetic neurotoxicity is, to some extent, concentration-dependent. Thus, it is quite possible that enhanced risk derives from the formulation rather than from an intrinsic property of the anesthetic. In a recent survey of US and Canadian dental schools, over half of respondents indicated that 4% articaine is no longer used for mandibular nerve block.


Pharmacology_Katzung

Pharmacology_Katzung. As previously noted, benzocaine’s pronounced lipophilicity has relegated its application to topical anesthesia. However, despite over a century of use for this purpose, its popularity has recently diminished owing to increasing concerns regarding its potential to induce methemoglobinemia. Elevated levels can be due to inborn errors or can occur with exposure to an oxidizing agent, and such is the case with significant exposure to benzocaine (or nitrites, see Chapter 12). Because methemoglobin does not transport oxygen, elevated levels pose serious risk, with severity obviously paralleling blood levels.


Pharmacology_Katzung

Pharmacology_Katzung. Based on concerns for cardiotoxicity, bupivacaine is often avoided for techniques that demand high volumes of concentrated anesthetic, such as epidural or peripheral nerve blocks performed for surgical anesthesia. In contrast, relatively low concentrations (≤ 0.25%) are frequently used to achieve prolonged peripheral anesthesia and analgesia for postoperative pain control, and the drug enjoys similar popularity where anesthetic infiltration is used to control pain from a surgical incision. It is often the agent of choice for epidural infusions used for postoperative pain control and for labor analgesia. Finally, it has a comparatively unblemished record as a spinal anesthetic, with a relatively favorable therapeutic index with respect to neurotoxicity, and little, if any, risk of TNS. However, spinal bupivacaine is not well suited for outpatient or ambulatory surgery, because its relatively long duration of action can delay recovery, resulting in a longer stay prior to discharge to


Pharmacology_Katzung

Pharmacology_Katzung. spinal bupivacaine is not well suited for outpatient or ambulatory surgery, because its relatively long duration of action can delay recovery, resulting in a longer stay prior to discharge to home.


Pharmacology_Katzung

Pharmacology_Katzung. The introduction of chloroprocaine into clinical practice in 1951 represented a reversion to the earlier amino-ester template. Chloroprocaine gained widespread use as an epidural agent in obstetrical anesthesia where its rapid hydrolysis served to minimize risk of systemic toxicity or fetal exposure. The unfortunate reports of neurologic injury associated with apparent intrathecal misplacement of large doses intended for the epidural space led to its near abandonment. However, the frequent occurrence of TNS with lidocaine administered as a spinal anesthetic has created an anesthetic void that chloroprocaine appears well suited to fill. The onset and duration of action of spinal chloroprocaine are even shorter than those of lidocaine, while presenting little, if any, risk of TNS. Although never exonerated with respect to the early neurologic injuries associated with epidural anesthesia, it is now appreciated that high doses of any local anesthetic are capable of inducing neurotoxic


Pharmacology_Katzung

Pharmacology_Katzung. never exonerated with respect to the early neurologic injuries associated with epidural anesthesia, it is now appreciated that high doses of any local anesthetic are capable of inducing neurotoxic injury. A formulation is now marketed in Europe specifically for spinal anesthesia, and there is considerable off-label use of a preservative-free solution in the USA. Nonetheless, documented use as a spinal anesthetic is relatively limited, and additional experience will be required to firmly establish safety. In addition to chloroprocaine’s emerging use for spinal anesthesia, it still finds some current use as an epidural anesthetic, particularly in circumstances where there is an indwelling catheter and the need for quick attainment of surgical anesthesia, such as caesarian section for a laboring parturient with a compromised fetus.


Pharmacology_Katzung

Pharmacology_Katzung. Current clinical use of cocaine is largely restricted to topical anesthesia for ear, nose, and throat procedures, where its intense vasoconstriction can serve to reduce bleeding. Even here, use has diminished in favor of other anesthetics combined with vasoconstrictors because of concerns about systemic toxicity, as well as the inconvenience of dispensing and handling this controlled substance. Introduced along with bupivacaine, etidocaine has had limited application due to its poor block characteristics. It has a tendency to produce an inverse differential block (ie, compared with other anesthetics such as bupivacaine, it produces excessive motor relative to sensory block), which is rarely a favorable attribute.


Pharmacology_Katzung

Pharmacology_Katzung. As previously discussed, this S(–) enantiomer of bupivacaine is somewhat less cardiotoxic than the racemic mixture. It is also less potent and tends to have a longer duration of action, although the magnitude of these effects is too small to have any substantial clinical significance. Interestingly, recent work with lipid resuscitation suggests a potential advantage of levobupivacaine over ropivacaine, as the former is more effectively sequestered into a so-called lipid sink, implying greater ability to reverse toxic effects should they occur. Aside from the issue of a high incidence of TNS with spinal administration, lidocaine has had an excellent record as an intermediate duration anesthetic and remains the reference standard against which most anesthetics are compared.


Pharmacology_Katzung

Pharmacology_Katzung. Although structurally similar to bupivacaine and ropivacaine (Table 26–1), mepivacaine displays clinical properties that are comparable to lidocaine. However, it differs from lidocaine with respect to vasoactivity, as it has a tendency toward vasoconstriction rather than vasodilation. This characteristic likely accounts for its slightly longer duration of action, which has made it a popular choice for major peripheral blocks. Lidocaine has retained its dominance over mepivacaine for epidural anesthesia, where the routine placement of a catheter negates the importance of a longer duration. More importantly, mepivacaine is slowly metabolized by the fetus, making it a poor choice for epidural anesthesia in the parturient. When used for spinal anesthesia, mepivacaine has a slightly lower incidence of TNS than lidocaine.


Pharmacology_Katzung

Pharmacology_Katzung. Prilocaine has the highest clearance of the amino-amide anesthetics, imparting reduced risk of systemic toxicity. Unfortunately, this is somewhat offset by its propensity to induce methemoglobinemia, which results from accumulation of one of its metabolites, ortho-toluidine, an oxidizing agent. As a spinal anesthetic, prilocaine’s duration of action is slightly longer than that of lidocaine, and the limited data suggest it carries a low risk of TNS. It is gaining increasing use for spinal anesthesia in Europe, where it has been marketed specifically for this purpose. No approved formulation exists in the USA, and there is no formulation that would be appropriate to use for spinal anesthesia as an off-label indication.


Pharmacology_Katzung

Pharmacology_Katzung. Ropivacaine is an S(–) enantiomer in a homologous series that includes bupivacaine and mepivacaine, distinguished by its chirality and the propyl group off the piperidine ring (Table 26–1). Its perceived reduced cardiotoxicity has led to widespread use for high-volume peripheral blocks. It is also a popular choice for epidural infusions for control of labor and postoperative pain. Although there is some evidence to suggest that ropivacaine might produce a more favorable differential block than bupivacaine, the lack of equivalent clinical potency adds complexity to such comparisons.


Pharmacology_Katzung

Pharmacology_Katzung. The term eutectic is applied to mixtures in which the combination of elements has a lower melting temperature than its component elements. Lidocaine and prilocaine can combine to form such a mixture, which is marketed as EMLA (Eutectic Mixture of Local Anesthetics). This formulation, containing 2.5% lidocaine and 2.5% prilocaine, permits anesthetic penetration of the keratinized layer of skin, producing localized numbness. It is commonly used in pediatrics to anesthetize the skin prior to venipuncture for intravenous catheter placement.


Pharmacology_Katzung

Pharmacology_Katzung. The provision of prolonged analgesia or anesthesia, as in the case of postoperative pain management, has traditionally been accomplished by placement of a catheter to permit continuous administration of anesthetic. More recently, efforts have focused on drug delivery systems that can slowly release anesthetic, thereby providing extended duration without the drawbacks of a catheter. Sustained-release delivery has the potential added advantage of reducing risk of systemic toxicity. Preliminary work encapsulating local anesthetic into microspheres, liposomes, and other microparticles has established proof of concept, although significant developmental problems, as well as questions regarding potential tissue toxicity, remain to be resolved.


Pharmacology_Katzung

Pharmacology_Katzung. It has been clearly demonstrated that anesthetic neurotoxicity does not result from blockade of the voltage-gated sodium channel. Thus, effect and tissue toxicity are not mediated by a common mechanism, establishing the possibility of developing compounds with considerably better therapeutic indexes. In addition, a neosaxitoxin, a site 1 sodium channel biotoxin, is currently being explored as a method to provide prolonged block, with the goal of obviating the need for catheter placement and continuous anesthetic infusion.


Pharmacology_Katzung

Pharmacology_Katzung. As previously discussed, the identification and subclassification of families of neuronal sodium channels have spurred research aimed at development of more selective sodium channel blockers. The variable neuronal distribution of these isoforms and the unique role that some play in pain signaling suggest that selective blockade of these channels is feasible and may greatly improve the therapeutic index of sodium channel modulators. For example, compounds with specificity for the Nav1.7 and Nav1.8 isoforms have been identified and are currently under clinical development. Parenteral • duration 3–6 h • Toxicity: CNS excitation • Prilocaine, mepivacaine: Like lidocaine (but also risk of methemoglobinemia with prilocaine) • Articaine: • Ropivacaine, levobupivacaine: Like bupivacaine • Procaine: • Tetracaine: • Benzocaine:


Pharmacology_Katzung

Pharmacology_Katzung. ESTERS • ChloroprocaineLike lidocaine Like lidocaine Very short procedures (not generally used topically or intravenously) Parenteral•duration30–60min•60–90minwithepinephrine•Toxicity: Like lidocaine • CocaineSame as above •alsohassympathomimetic effects Same as above Procedures requiring high surface activity and vasoconstriction Topicalorparenteral•duration1–2h•Toxicity: CNS excitation, convulsions, cardiac arrhythmias, hypertension, stroke Bupivacaine Generic, Marcaine, Sensorcaine Chloroprocaine Generic, Nesacaine Dibucaine (topical) Generic, Nupercainal Dyclonine (topical lozenge) Sepacol, Sucrets, Dyclone Levobupivacaine Chirocaine, others Lidocaine Generic, Xylocaine Mepivacaine Generic, Carbocaine Pramoxine (topical) Generic, Tronothane Procaine Generic, Novocain Proparacaine (ophthalmic) Generic, Alcaine, others Ropivacaine Generic, Naropin Tetracaine Generic, Pontocaine


Pharmacology_Katzung

Pharmacology_Katzung. Pramoxine (topical) Generic, Tronothane Procaine Generic, Novocain Proparacaine (ophthalmic) Generic, Alcaine, others Ropivacaine Generic, Naropin Tetracaine Generic, Pontocaine Albright GA: Cardiac arrest following regional anesthesia with etidocaine or bupivacaine. Anesthesiology 1979;51:285. American Society of Regional Anesthesia and Pain Medicine: Checklist for treatment of local anesthetic systemic toxicity. 2012. http://www.asra.com/ checklist-for-local-anesthetic-toxicity-treatment-1-18-12.pdf. Andavan GS, Lemmens-Gruber R: Voltage-gated sodium channels: Mutations, channelopathies and targets. Curr Med Chem 2011;18:377. Auroy Y et al: Serious complications related to regional anesthesia: Results of a prospective survey in France. Anesthesiology 1997;87:479. Butterworth JF 4th, Strichartz GR: Molecular mechanisms of local anesthesia: A review. Anesthesiology 1990;72:711. Catterall WA, Goldin AL, Waxman SG: International Union of Pharmacology.


Pharmacology_Katzung

Pharmacology_Katzung. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol Rev 2005;57:397. Cave G, Harvey M: Intravenous lipid emulsion as antidote beyond local anesthetic toxicity: A systematic review. Acad Emerg Med 2009;16:815. de Jong RH, Ronfeld RA, DeRosa RA: Cardiovascular effects of convulsant and supraconvulsant doses of amide local anesthetics. Anesth Analg 1982;61:3. Di Gregorio G et al: Clinical presentation of local anesthetic systemic toxicity: A review of published cases, 1979 to 2009. Reg Anesth Pain Med 2010;35:181. Drasner K: Local anesthetic systemic toxicity: a historical perspective. Reg Anesth Pain Med 2010;35:162. Drasner K: Chloroprocaine spinal anesthesia: Back to the future? Anesth Analg 2005;100:549. Drasner K: Local anesthetic neurotoxicity: Clinical injury and strategies that may minimize risk. Reg Anesth Pain Med 2002;27:576. Drasner K: Lidocaine spinal anesthesia: A vanishing therapeutic index? Anesthesiology 1997;87:469.


Pharmacology_Katzung

Pharmacology_Katzung. Drasner K et al: Cauda equina syndrome following intended epidural anesthesia. Anesthesiology 1992;77:582. Drasner K et al: Persistent sacral sensory deficit induced by intrathecal local anesthetic infusion in the rat. Anesthesiology 1994;80:847. Flight MH: Analgesics: Specifically attenuating pain. Nat Rev Drug Discov 2007;6:518. Freedman JM et al: Transient neurologic symptoms after spinal anesthesia: An epidemiologic study of 1,863 patients. Anesthesiology 1998;89:633. Goldblum E, Atchabahian A: The use of 2-chloroprocaine for spinal anaesthesia. Acta Anaesthesiol Scand 2013;57:545. Hampl KF et al: Transient neurologic symptoms after spinal anesthesia. Anesth Analg 1995;81:1148. Hille B: Local anesthetics: Hydrophilic and hydrophobic pathways for the drug-receptor interaction. J Gen Physiol 1977;69:497. Holmdahl MH: Xylocain (lidocaine, lignocaine), its discovery and Gordh’s contribution to its clinical use. Acta Anaesthesiol Scand Suppl 1998;113:8.


Pharmacology_Katzung

Pharmacology_Katzung. Holmdahl MH: Xylocain (lidocaine, lignocaine), its discovery and Gordh’s contribution to its clinical use. Acta Anaesthesiol Scand Suppl 1998;113:8. Kouri ME, Kopacz DJ: Spinal 2-chloroprocaine: A comparison with lidocaine in volunteers. Anesth Analg 2004;98(1):75. Kuo I, Akpa BS: Validity of the lipid sink as a mechanism for the reversal of local anesthetic systemic toxicity: A physiologically based pharmacokinetic model study. Anesthesiology 2013;118:1350. Lahaye LA, Butterworth JF: Site-1 sodium channel blockers as local anesthetics: Will neosaxitoxin supplant the need for continuous nerve blocks? Anesthesiology 2015;123:741. Mattison JB: Cocaine poisoning. Med Surg Rep 1891;115:645. Neal JM et al: ASRA practice advisory on local anesthetic systemic toxicity. Reg Anesth Pain Med 2010;35:152. Pollock JE: Transient neurologic symptoms: Etiology, risk factors, and management. Reg Anesth Pain Med 2002;27:581.


Pharmacology_Katzung

Pharmacology_Katzung. Pollock JE: Transient neurologic symptoms: Etiology, risk factors, and management. Reg Anesth Pain Med 2002;27:581. Priest BT: Future potential and status of selective sodium channel blockers for the treatment of pain. Curr Opin Drug Discov Dev 2009;12:682. Rigler ML et al: Cauda equina syndrome after continuous spinal anesthesia. Anesth Analg 1991;72:275. Rose JS, Neal JM, Kopacz DJ: Extended-duration analgesia: Update on micro-spheres and liposomes. Reg Anesth Pain Med 2005;30:275. Ruetsch YA, Boni T, Borgeat A: From cocaine to ropivacaine: The history of local anesthetic drugs. Curr Top Med Chem 2001;1:175. Sakura S et al: Local anesthetic neurotoxicity does not result from blockade of voltage-gated sodium channels. Anesth Analg 1995;81:338. Schneider M et al: Transient neurologic toxicity after hyperbaric subarachnoid anesthesia with 5% lidocaine. Anesth Analg 1993;76:1154.


Pharmacology_Katzung

Pharmacology_Katzung. Schneider M et al: Transient neurologic toxicity after hyperbaric subarachnoid anesthesia with 5% lidocaine. Anesth Analg 1993;76:1154. Sirianni AJ et al: Use of lipid emulsion in the resuscitation of a patient with prolonged cardiovascular collapse after overdose of bupropion and lamotrigine. Ann Emerg Med 2008;51:412. Taniguchi M, Bollen AW, Drasner K: Sodium bisulfite: Scapegoat for chloroprocaine neurotoxicity? Anesthesiology 2004;100:85. Tremont-Lukats IW et al: Systemic administration of local anesthetics to relieve neuropathic pain: A systematic review and meta-analysis. Anesth Analg 2005;101:1738. Weinberg GL: Lipid Emulsion Infusion: Resuscitation for local anesthetic and other drug overdose. Anesthesiology 2012;117:180. Weinberg GL et al: Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats. Anesthesiology 1998;88:1071.


Pharmacology_Katzung

Pharmacology_Katzung. If a spinal anesthetic technique were selected, bupivacaine would be an excellent choice. It has an adequately long duration of action and a relatively unblemished record with respect to neurotoxic injury and transient neurologic symptoms, which are the complications of most concern with spinal anesthetic technique. Although bupivacaine has greater potential for cardiotoxicity, this is not a concern when the drug is used for spinal anesthesia because of the extremely low doses required for intrathecal administra-tion. If an epidural technique were chosen for the surgical procedure, the potential for systemic toxicity would need to be considered, making lidocaine or mepivacaine (generally with epinephrine) preferable to bupivacaine (or even ropi-vacaine or levobupivacaine) because of their better thera-peutic indexes with respect to cardiotoxicity. However, this does not apply to epidural administration for postopera-tive pain control, which involves administration of more dilute


Pharmacology_Katzung

Pharmacology_Katzung. their better thera-peutic indexes with respect to cardiotoxicity. However, this does not apply to epidural administration for postopera-tive pain control, which involves administration of more dilute anesthetic at a slower rate. The most common agents used for this indication are bupivacaine, ropivacaine, and levobupivacaine.


Pharmacology_Katzung

Pharmacology_Katzung. Marieke Kruidering-Hall, PhD, & Lundy Campbell, MD


Pharmacology_Katzung

Pharmacology_Katzung. NEUROMUSCULAR BLOCKING DRUGS A 70-kg, 45-year-old single, unrestrained male driver, is involved in a motor vehicle crash. He is rushed to a nearby level 1 trauma center where he is found to have multiple facial fractures, a severe, unstable cervical spine injury, and significant left eye trauma. Further examination of his left eye reveals rupture of his globe. The ophthalmolo-gist requests emergency surgery to repair and save his eye. Because the patient has suffered a recent trauma, you decide to perform a rapid sequence intubation in preparation for the surgical procedure. What muscle relaxant would you use to facilitate tracheal intubation? What is the proper dose for your chosen muscle relaxant? After intravenous infusion of your chosen muscle relaxant, you are unable to adequately visualize the patient’s larynx and vocal cords and cannot successfully pass an endotracheal tube. You switch to mask ventilation but are barely able to mask ventilate the patient, and you become worried


Pharmacology_Katzung

Pharmacology_Katzung. the patient’s larynx and vocal cords and cannot successfully pass an endotracheal tube. You switch to mask ventilation but are barely able to mask ventilate the patient, and you become worried that you will soon lose the ability to ventilate at all. Is there a medication that you can give to facilitate rapid return of spontaneous ventilation in this situation?


Pharmacology_Katzung

Pharmacology_Katzung. Drugs that affect skeletal muscle function include two different therapeutic groups: those used during surgical procedures and in the intensive care unit (ICU) to produce muscle paralysis (ie, neuromuscular blockers), and those used to reduce spasticity in a variety of painful conditions (ie, spasmolytics and antispasmodics). Neuromuscular blocking drugs interfere with transmission at the neuromuscular end plate and lack central nervous system (CNS) activity. These compounds are used primarily as adjuncts during general anesthesia to optimize surgical conditions and to facilitate endotracheal intubation in order to ensure adequate ventilation. Drugs in the spasmolytic group have traditionally been called “centrally acting” muscle relaxants and are used primarily to treat chronic back pain and painful fibromyalgic conditions. Dantrolene, an agent that has no significant central effects and is used primarily to treat a rare anesthetic-related complication, malignant hyperthermia, is


Pharmacology_Katzung

Pharmacology_Katzung. and painful fibromyalgic conditions. Dantrolene, an agent that has no significant central effects and is used primarily to treat a rare anesthetic-related complication, malignant hyperthermia, is also discussed in this chapter.


Pharmacology_Katzung

Pharmacology_Katzung. During the 16th century, European explorers found that natives in the Amazon Basin of South America were using curare, an arrow poison that produced skeletal muscle paralysis, to kill animals. The active compound, d-tubocurarine, and its modern synthetic analogs have had a major influence on the practice of anesthesia and surgery and have proved useful in understanding the basic mechanisms involved in neuromuscular transmission.


Pharmacology_Katzung

Pharmacology_Katzung. The mechanism of neuromuscular transmission at the motor end plate is similar to that described for preganglionic cholinergic nerves in Chapter 6. The arrival of an action potential at the motor nerve terminal causes an influx of calcium and release of the neurotransmitter acetylcholine. Acetylcholine then diffuses across the synaptic cleft to activate nicotinic receptors located on the motor end plate, present at a density of 10,000/μm2 in some species. As noted in Chapter 7, the adult NM receptor is composed of five peptides: two alpha peptides, one beta, one gamma, and one delta peptide (Figure 27–1). The binding of two acetylcholine molecules to receptors on the α-β and δ-α subunits causes opening of the channel. The subsequent movement of sodium and potassium through the channel is associated with a graded depolarization of the end plate membrane (see Figure 7–4, panel B). This change in voltage is termed the motor end plate potential. The magnitude of the end plate potential is


Pharmacology_Katzung

Pharmacology_Katzung. with a graded depolarization of the end plate membrane (see Figure 7–4, panel B). This change in voltage is termed the motor end plate potential. The magnitude of the end plate potential is directly related to the amount of acetylcholine released. If the potential is small, the permeability and the end plate potential return to normal without an impulse being propagated from the end plate region to the rest of the muscle membrane. However, if the end plate potential is large, the adjacent muscle membrane is depolarized, and an action potential will be propagated along the entire muscle fiber. Muscle contraction is then initiated by excitation-contraction coupling. The released acetylcholine is quickly removed from the end plate region by both diffusion and enzymatic destruction by the local acetylcholinesterase enzyme.


Pharmacology_Katzung

Pharmacology_Katzung. At least two additional types of acetylcholine receptors are found within the neuromuscular apparatus. One type is located on the presynaptic motor axon terminal, and activation of these receptors mobilizes additional transmitter for subsequent release by moving more acetylcholine vesicles toward the synaptic membrane. The second type of receptor is found on extrajunctional cells and is not normally involved in neuromuscular transmission. However, under certain conditions (eg, prolonged immobilization, thermal burns), these receptors may proliferate sufficiently to affect subsequent neuromuscular transmission. This proliferation of extrajunctional acetylcholine receptors may be clinically relevant when using depolarizing or nondepolarizing skeletal muscle relaxant drugs and is described later.


Pharmacology_Katzung

Pharmacology_Katzung. Skeletal muscle relaxation and paralysis can occur from interruption of function at several sites along the pathway from the CNS to myelinated somatic nerves, unmyelinated motor nerve terminals, nicotinic acetylcholine receptors, the motor end plate, the muscle membrane, and the intracellular muscular contractile apparatus itself.


Pharmacology_Katzung

Pharmacology_Katzung. Blockade of end plate function can be accomplished by two basic mechanisms. First, pharmacologic blockade of the physiologic agonist acetylcholine is characteristic of the antagonist neuromuscular blocking drugs (ie, nondepolarizing neuromuscular blocking drugs). These drugs prevent access of the transmitter to its receptor and thereby prevent depolarization. The prototype of this nondepolarizing subgroup is d-tubocurarine. The second mechanism of blockade can be produced by an excess of a depolarizing agonist, such as acetylcholine. This seemingly paradoxical effect of acetylcholine also occurs at the ganglionic nicotinic acetylcholine receptor. The prototypical depolarizing blocking drug is succinylcholine. A similar depolarizing block can be produced by acetylcholine itself when high local concentrations are achieved in the synaptic cleft (eg, by cholinesterase inhibitor intoxication) and by nicotine and other nicotinic agonists. However, the neuromuscular block produced by


Pharmacology_Katzung

Pharmacology_Katzung. high local concentrations are achieved in the synaptic cleft (eg, by cholinesterase inhibitor intoxication) and by nicotine and other nicotinic agonists. However, the neuromuscular block produced by depolarizing drugs other than succinylcholine cannot be precisely controlled and is of no clinical value.


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 27–1 The adult nicotinic acetylcholine receptor (nAChR) is an intrinsic membrane protein with five distinct subunits (α2 βδγ). A: Cartoon of one of five subunits of the AChR in the end plate surface of adult mammalian muscle. Each subunit contains four helical domains labeled M1 to M4. The M2 domains line the channel pore. B: Cartoon of the full nAChR. The N termini of two subunits cooperate to form two distinct binding pockets for acetylcholine (ACh). These pockets occur at the α-β and the δ-α subunit interfaces. Binding of one molecule of ACh enhances the receptor’s affinity for the second molecule, followed by multiple intermediate steps leading to channel opening. These steps are the subject of intense investigation.


Pharmacology_Katzung

Pharmacology_Katzung. All of the available neuromuscular blocking drugs bear a structural resemblance to acetylcholine. For example, succinylcholine is two acetylcholine molecules linked end-to-end (Figure 27–2). In contrast to the linear structure of succinylcholine and other depolarizing drugs, the nondepolarizing agents (eg, pancuronium) conceal the “double-acetylcholine” structure in one of two types of bulky, semi-rigid ring systems (Figure 27–2). Examples of the two FIGURE 27–2 Structural relationship of succinylcholine, a depolarizing agent, and pancuronium, a nondepolarizing agent, to acetylcholine, the neuromuscular transmitter. Succinylcholine, originally called diacetylcholine, is simply two molecules of acetylcholine linked through the acetate methyl groups. Pancuronium may be viewed as two acetylcholine-like fragments (outlined in color) oriented on a steroid nucleus. FIGURE 27–3 Structures of two isoquinoline neuromuscular blocking drugs. These agents are nondepolarizing muscle relaxants.


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 27–3 Structures of two isoquinoline neuromuscular blocking drugs. These agents are nondepolarizing muscle relaxants. major families of nondepolarizing blocking drugs—the isoquinoline and steroid derivatives—are shown in Figures 27–3 and 27–4. Another feature common to all currently used neuromuscular blockers is the presence of one or two quaternary nitrogens, which makes them poorly lipid soluble and limits entry into the CNS. Pharmacokinetics of Neuromuscular Blocking Drugs All of the neuromuscular blocking drugs are highly polar compounds and inactive orally; they must be administered parenterally. A. Nondepolarizing Relaxant Drugs


Pharmacology_Katzung

Pharmacology_Katzung. All of the neuromuscular blocking drugs are highly polar compounds and inactive orally; they must be administered parenterally. A. Nondepolarizing Relaxant Drugs The rate of disappearance of a nondepolarizing neuromuscular blocking drug from the blood is characterized by a rapid initial distribution phase followed by a slower elimination phase. Neuromuscular blocking drugs are highly ionized, do not readily cross cell membranes, and are not strongly bound in peripheral tissues. Therefore, their volume of distribution (80–140 mL/kg) is only slightly larger than the blood volume.


Pharmacology_Katzung

Pharmacology_Katzung. The duration of neuromuscular blockade produced by non-depolarizing relaxants is strongly correlated with the elimination half-life. Drugs that are excreted by the kidney typically have longer half-lives, leading to longer durations of action (>35 minutes). Drugs eliminated by the liver tend to have shorter half-lives and durations of action (Table 27–1). All steroidal muscle relaxants are metabolized to their 3-hydroxy, 17-hydroxy, or 3,17-dihydroxy products in the liver. The 3-hydroxy metabolites are usually 40–80% as potent as the parent drug. Under normal circumstances, metabolites are not formed in sufficient quantities to produce a significant degree of FIGURE 27–4 Structures of steroid neuromuscular blocking drugs (steroid nucleus in color). These agents are all nondepolarizing muscle relaxants.


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 27–4 Structures of steroid neuromuscular blocking drugs (steroid nucleus in color). These agents are all nondepolarizing muscle relaxants. neuromuscular blockade during or after anesthesia. However, if the parent compound is administered for several days in the ICU setting, the 3-hydroxy metabolite may accumulate and cause prolonged paralysis because it has a longer half-life than the parent compound. The remaining metabolites possess minimal neuromuscular blocking properties. The intermediate-acting steroid muscle relaxants (eg, vecuronium and rocuronium) tend to be more dependent on biliary excretion or hepatic metabolism for their elimination. These muscle relaxants are more commonly used clinically than the long-acting steroid-based drugs (eg, pancuronium). The duration of action of these relaxants may be prolonged significantly in patients with impaired liver function.


Pharmacology_Katzung

Pharmacology_Katzung. Atracurium (Figure 27–3) is an intermediate-acting isoquinoline nondepolarizing muscle relaxant that is no longer in widespread clinical use. In addition to hepatic metabolism, atracurium is inactivated by a form of spontaneous breakdown known as Hofmann elimination. The main breakdown products are laudanosine and a related quaternary acid, neither of which possesses neuromuscular blocking properties. Laudanosine is slowly metabolized by the liver and has a longer elimination half-life (ie, 150 minutes). It readily crosses the blood-brain barrier, and high blood concentrations may cause seizures and an increase in the volatile anesthetic requirement. During surgical anesthesia, blood levels of laudanosine typically range from 0.2 to 1 mcg/mL; however, with prolonged infusions of atracurium in the ICU, laudanosine blood levels may exceed 5 mcg/mL.


Pharmacology_Katzung

Pharmacology_Katzung. Atracurium has several stereoisomers, and the potent isomer cisatracurium has become one of the most common muscle relaxants in use today. Although cisatracurium resembles atracurium, it has less dependence on hepatic inactivation, produces less laudanosine, and is much less likely to release histamine. From a clinical perspective, cisatracurium has all the advantages of atracurium with fewer adverse effects. Therefore, cisatracurium has virtually replaced atracurium in clinical practice.


Pharmacology_Katzung

Pharmacology_Katzung. Gantacurium represents a new class of nondepolarizing neuromuscular blockers, called asymmetric mixed-onium chlorofumarates. It is degraded nonenzymatically by adduction of the amino acid cysteine and ester bond hydrolysis. Gantacurium is currently in phase 3 clinical trials and not yet available for widespread clinical use. Preclinical and clinical data indicate gantacurium has a rapid onset of effect and predictable duration of action (very short, similar to succinylcholine) that can be reversed with neostigmine or more quickly (within 1–2 minutes), with administration of l-cysteine. At doses above three times the ED95, cardiovascular adverse effects (eg, hypotension) have occurred, probably due to histamine release. No bronchospasm or pulmonary vasoconstriction has been reported at these higher doses. B. Depolarizing Relaxant Drugs


Pharmacology_Katzung

Pharmacology_Katzung. B. Depolarizing Relaxant Drugs The extremely short duration of action of succinylcholine (5–10 minutes) is due to its rapid hydrolysis by butyrylcholinesterase and pseudocholinesterase in the liver and plasma, respectively. Plasma cholinesterase metabolism is the predominant pathway for succinylcholine elimination. The primary metabolite of succinylcholine, succinylmonocholine, is rapidly broken down to succinic acid and choline. Because plasma cholinesterase has an enormous capacity to hydrolyze succinylcholine, only a small percentage of the original intravenous dose ever reaches the neuromuscular junction. In addition, because there is little if any plasma cholinesterase at the motor end plate, a succinylcholine-induced blockade is terminated by its diffusion away from the end plate into extracellular fluid. Therefore, the circulating levels of plasma TABLE 27–1 Pharmacokinetic and dynamic properties of neuromuscular blocking drugs.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 27–1 Pharmacokinetic and dynamic properties of neuromuscular blocking drugs. 1Nonenzymatic and enzymatic hydrolysis of ester bonds. 2Butyrylcholinesterase (pseudocholinesterase). cholinesterase influence the duration of action of succinylcholine by determining the amount of the drug that reaches the motor end plate.


Pharmacology_Katzung

Pharmacology_Katzung. Neuromuscular blockade produced by succinylcholine can be prolonged in patients with an abnormal genetic variant of plasma cholinesterase. The dibucaine number is a measure of the ability of a patient to metabolize succinylcholine and can be used to identify at-risk patients. Under standardized test conditions, dibucaine inhibits the normal enzyme by 80% and the abnormal enzyme by only 20%. Many genetic variants of plasma cholinesterase have been identified, although the dibucaine-related variants are the most important. Given the rarity of these genetic variants, plasma cholinesterase testing is not a routine clinical procedure but may be indicated for patients with a family history of plasma cholinesterase deficiency. Another reasonable strategy is to avoid the use of succinylcholine where practical in patients with a possible family history of plasma cholinesterase deficiency. Mechanism of Action


Pharmacology_Katzung

Pharmacology_Katzung. Mechanism of Action The interactions of drugs with the acetylcholine receptor-end plate channel have been described at the molecular level. Several modes of action of drugs on the receptor are illustrated in Figure 27–5. A. Nondepolarizing Relaxant Drugs All the neuromuscular blocking drugs in current use in the USA except succinylcholine are classified as nondepolarizing agents. Although it is no longer in widespread clinical use, d-tubocurarine is considered the prototype neuromuscular blocker. When small doses of nondepolarizing muscle relaxants are administered, they act predominantly at the nicotinic receptor site by competing with acetylcholine. The least potent non-depolarizing relaxants (eg, rocuronium) have the fastest onset and the shortest duration of action. In larger doses, nondepolarizing drugs can enter the pore of the ion channel (Figure 27–5)


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 27–5 Schematic diagram of the interactions of drugs with the acetylcholine receptor on the end plate channel (structures are purely symbolic). Top: The action of the normal agonist, acetylcholine (red) in opening the channel. Bottom, left: A nondepolarizing blocker, eg, rocuronium (yellow), is shown as preventing the opening of the channel when it binds to the receptor. Bottom, right: A depolarizing blocker, eg, succinylcholine (blue), both occupying the receptor and blocking the channel. Normal closure of the channel gate is prevented and the blocker may move rapidly in and out of the pore. Depolarizing blockers may desensitize the end plate by occupying the receptor and causing persistent depolarization. An additional effect of drugs on the end plate channel may occur through changes in the lipid environment surrounding the channel (not shown). General anesthetics and alcohols may impair neuromuscular transmission by this mechanism.


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 27–6 Muscle contraction responses to different patterns of nerve stimulation used in monitoring skeletal muscle relaxation. The alterations produced by a nondepolarizing blocker and depolarizing and desensitizing blockade by succinylcholine are shown. In the trainof-four (TOF) pattern, four stimuli are applied at 2 Hz. The TOF ratio (TOF-R) is calculated from the strength of the fourth contraction divided by that of the first. In the double-burst pattern, three stimuli are applied at 50 Hz, followed by a 700 ms rest period and then repeated. In the posttetanic potentiation pattern, several seconds of 50 Hz stimulation are applied, followed by several seconds of rest and then by single stimuli at a slow rate (eg, 0.5 Hz). The number of detectable posttetanic twitches is the posttetanic count (PTC), * first posttetanic contraction.


Pharmacology_Katzung

Pharmacology_Katzung. to produce a more intense motor blockade. This action further below). One consequence of the surmountable nature of the post-weakens neuromuscular transmission and diminishes the ability synaptic blockade produced by nondepolarizing muscle relaxants is of the acetylcholinesterase inhibitors (eg, neostigmine, edropho-the fact that tetanic stimulation (rapid delivery of electrical stimuli nium, pyridostigmine) to antagonize the effect of nondepolar-to a peripheral nerve) releases a large quantity of acetylcholine izing muscle relaxants. and is followed by transient posttetanic facilitation of the twitch


Pharmacology_Katzung

Pharmacology_Katzung. Nondepolarizing relaxants can also block prejunctional sodium strength (ie, relief of blockade). An important clinical consequence channels. As a result of this action, muscle relaxants interfere with of this principle is the reversal of residual blockade by cholinesterase the mobilization of acetylcholine at the nerve ending and cause fade inhibitors. The characteristics of a nondepolarizing neuromuscular of evoked nerve twitch contractions (Figure 27–6, and described blockade are summarized in Table 27–2 and Figure 27–6. TABLE 27–2 Comparison of a typical nondepolarizing muscle relaxant (rocuronium) and a depolarizing muscle relaxant (succinylcholine). 1It is not known whether this interaction is additive or synergistic (superadditive). 2The amplitude is decreased, but the response is sustained. 3The rate depends on the dose and on the completeness of neuromuscular blockade. B. Depolarizing Relaxant Drugs 1.


Pharmacology_Katzung

Pharmacology_Katzung. Phase I block (depolarizing)—Succinylcholine is the only clinically useful depolarizing blocking drug. Its neuromuscular effects are like those of acetylcholine except that succinylcholine produces a longer effect at the myoneural junction. Succinylcholine reacts with the nicotinic receptor to open the channel and cause depolarization of the motor end plate, and this in turn spreads to the adjacent membranes, causing transient contractions of muscle motor units. Data from single-channel recordings indicate that depolarizing blockers can enter the channel to produce a prolonged “flickering” of the ion conductance (Figure 27–7). Because succinylcholine is not metabolized effectively at the synapse, the depolarized membranes remain depolarized and unresponsive to subsequent impulses (ie, a state of depolarizing blockade). Furthermore, because excitation-contraction coupling requires end plate repolarization (“repriming”) and repetitive firing to maintain muscle tension, a flaccid


Pharmacology_Katzung

Pharmacology_Katzung. a state of depolarizing blockade). Furthermore, because excitation-contraction coupling requires end plate repolarization (“repriming”) and repetitive firing to maintain muscle tension, a flaccid paralysis results. In contrast to the nondepolarizing drugs, this so-called phase I (depolarizing) block is augmented, not reversed, by cholinesterase inhibitors.


Pharmacology_Katzung

Pharmacology_Katzung. The characteristics of a depolarizing neuromuscular blockade are summarized in Table 27–2 and Figure 27–6. 2. Phase II block (desensitizing)—With prolonged exposure to succinylcholine, the initial end plate depolarization decreases and the membrane becomes repolarized. Despite this repolarization, the membrane cannot easily be depolarized again because it is desensitized. The mechanism for this desensitizing phase is unclear, but some evidence indicates that channel block may become more important than agonist action at the receptor in phase II of succinylcholine’s neuromuscular blocking action. Regardless of the mechanism, the channels behave as if they are in a prolonged closed state (Figure 27–6). Later in phase II, the characteristics of the blockade are nearly identical to those of a nondepolarizing block (ie, a nonsustained twitch response to a tetanic stimulus) (Figure 27–6), with possible reversal by acetylcholinesterase inhibitors.


Pharmacology_Katzung

Pharmacology_Katzung. Before the introduction of neuromuscular blocking drugs, profound skeletal muscle relaxation for intracavitary operations could be achieved only by producing levels of volatile (inhaled) anesthesia deep enough to produce profound depressant effects on the cardiovascular and respiratory systems. The adjunctive use of neuromuscular blocking drugs makes it possible to achieve adequate muscle relaxation for all types of surgical procedures without the cardiorespiratory depressant effects produced by deep anesthesia. Assessment of Neuromuscular Transmission


Pharmacology_Katzung

Pharmacology_Katzung. Assessment of Neuromuscular Transmission Monitoring the effect of muscle relaxants during surgery (and recovery following the administration of cholinesterase inhibitors) typically involves the use of a device that produces transdermal electrical stimulation of one of the peripheral nerves to the hand or facial muscles and recording of the evoked contractions (ie, twitch responses). The motor responses to different patterns of peripheral nerve stimulation can be recorded in the operating room during the procedure (Figure 27–6). The standard approach for monitoring the clinical effects of muscle relaxants


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 27–7 Action of succinylcholine on single-channel end plate receptor currents in frog muscle. Currents through a single AChR channel were recorded using the patch clamp technique. The upper trace was recorded in the presence of a low concentration of succinylcholine; the downward deflections represent openings of the channel and passage of inward (depolarizing) current. The lower trace was recorded in the presence of a much higher concentration of succinylcholine and shows prolonged “flickering” of the channel as it repetitively opens and closes or is “plugged” by the drug. (Reproduced, with permission, from Marshall CG, Ogden DC, Colquhoun D: The actions of suxamethonium (succinyldicholine) as an agonist and channel blocker at the nicotinic receptor of frog muscle. J Physiol [Lond] 1990;428:155.) during surgery uses peripheral nerve stimulation to elicit motor responses, which are visually observed by the anesthesiologist. The three most commonly used patterns include (1)


Pharmacology_Katzung

Pharmacology_Katzung. 1990;428:155.) during surgery uses peripheral nerve stimulation to elicit motor responses, which are visually observed by the anesthesiologist. The three most commonly used patterns include (1) single-twitch stimulation, (2) train-of-four (TOF) stimulation, and (3) tetanic stimulation. Two other modalities are also available to monitor neuromuscular transmission: double-burst stimulation and posttetanic count.


Pharmacology_Katzung

Pharmacology_Katzung. With single-twitch stimulation, a single supramaximal electrical stimulus is applied to a peripheral nerve at frequencies from 0.1 Hz to 1.0 Hz. The higher frequency is often used during induction and reversal to more accurately determine the peak (maximal) drug effect. TOF stimulation involves four successive supramaximal stimuli given at intervals of 0.5 second (2 Hz). Each stimulus in the TOF causes the muscle to contract, and the relative magnitude of the response of the fourth twitch compared with the first twitch is the TOF ratio. With a depolarizing block, all four twitches are reduced in a dose-related fashion. With a nondepolarizing block, the TOF ratio decreases (“fades”) and is inversely proportional to the degree of blockade. During recovery from nondepolarizing block, the amount of fade decreases and the TOF ratio approaches 1.0. Recovery to a TOF ratio greater than 0.7 is typically necessary for resumption of spontaneous ventilation. However, complete clinical recovery


Pharmacology_Katzung

Pharmacology_Katzung. of fade decreases and the TOF ratio approaches 1.0. Recovery to a TOF ratio greater than 0.7 is typically necessary for resumption of spontaneous ventilation. However, complete clinical recovery from a nondepolarizing block is considered to require a TOF greater than 0.9. Fade in the TOF response after administration of succinylcholine signifies the development of a phase II block.