Page 478 - Basic _ Clinical Pharmacology ( PDFDrive )

464 SECTION V Drugs That Act in the Central Nervous System

case voltage), the initial number denotes the gene, and the number
following the period indicates the particular isoform. Time
3. Channel blockade—Biologic toxins such as batrachotoxin, 25
aconitine, veratridine, and some scorpion venoms bind to recep- 1
tors within the channel and prevent inactivation. This results in Sodium current
prolonged influx of sodium through the channel and depolar- 2
ization of the resting potential. The marine toxins tetrodotoxin 3 1 ms
(TTX) and saxitoxin have clinical effects that largely resemble 3 2 Use
those of local anesthetics (ie, block of conduction without a nA 1
change in the resting potential). However, in contrast to the local
anesthetics, the toxin binding site is located near the extracel-
lular surface. The sensitivity of these channels to TTX varies, FIGURE 26–3 Effect of repetitive activity on the block of
and subclassification based on this pharmacologic sensitivity has sodium current produced by a local anesthetic in a myelinated
axon. A series of 25 pulses was applied, and the resulting sodium
important physiologic and therapeutic implications. Six of the currents (downward deflections) are superimposed. Note that
aforementioned channels are sensitive to nanomolar concentra- the current produced by the pulses rapidly decreased from the
tion of this biotoxin (TTX-S), while three are resistant (TTX-R). first to the 25th pulse. A long rest period after the train resulted
Of the latter, Na 1.8 and Na 1.9 appear to be exclusively expressed in recovery from block, but the block could be reinstated by a
v
v
in dorsal root ganglia nociceptors, which raises the developmental subsequent train. nA, nanoamperes. (Adapted, with permission, from
possibility of targeting these specific neuronal subpopulations. Courtney KR: Mechanism of frequency-dependent inhibition of sodium currents
Such fine-tuned analgesic therapy has the theoretical potential of in frog myelinated nerve by the lidocaine derivative GEA. J Pharmacol Exp Ther
providing effective analgesia, while limiting the significant adverse 1975;195:225.)
effects produced by nonspecific sodium channel blockers.
When progressively increasing concentrations of a local anes-
thetic are applied to a nerve fiber, the threshold for excitation 4. Other effects—Currently used local anesthetics bind to the
increases, impulse conduction slows, the rate of rise of the action sodium channel with low affinity and poor specificity, and there
potential declines, action potential amplitude decreases, and, are multiple other sites for which their affinity is nearly the same
finally, the ability to generate an action potential is completely as that for sodium channel binding. Thus, at clinically relevant
abolished. These progressive effects result from binding of the concentrations, local anesthetics are potentially active at count-
local anesthetic to more and more sodium channels. If the sodium less other channels (eg, potassium and calcium), enzymes (eg,
current is blocked over a critical length of the nerve, propagation adenylyl cyclase, carnitine-acylcarnitine translocase), and recep-
across the blocked area is no longer possible. In myelinated nerves, tors (eg, N-methyl-d-aspartate [NMDA], G protein-coupled,
the critical length appears to be two to three nodes of Ranvier. 5-HT , neurokinin-1 [substance P receptor]). The role that such
3
At the minimum dose required to block propagation, the resting ancillary effects play in achievement of local anesthesia appears
potential is not significantly altered. to be important but is poorly understood. Further, interactions
The blockade of sodium channels by most local anesthetics is with these other sites are likely the basis for numerous differences
both voltage and time dependent: Channels in the rested state, between the local anesthetics with respect to anesthetic effects (eg,
which predominate at more negative membrane potentials, have differential block) and toxicities that do not parallel anesthetic
a much lower affinity for local anesthetics than activated (open potency, and thus are not adequately accounted for solely by
state) and inactivated channels, which predominate at more blockade of the voltage-gated sodium channel.
positive membrane potentials (see Figure 14–10). Therefore, the The actions of circulating local anesthetics at such diverse
effect of a given drug concentration is more marked in rapidly sites exert a multitude of effects, some of which go beyond pain
firing axons than in resting fibers (Figure 26–3). Between suc- control, including some that are also potentially beneficial. For
cessive action potentials, a portion of the sodium channels will example, there is evidence to suggest that the blunting of the stress
recover from the local anesthetic block (see Figure 14–10). The response and improvements in perioperative outcome that may
recovery from drug-induced block is 10–1000 times slower than occur with epidural anesthesia derive in part from an action of the
the recovery of channels from normal inactivation (as shown for anesthetic beyond its sodium channel block. Circulating anesthet-
the cardiac membrane in Figure 14–4). As a result, the refrac- ics also demonstrate antithrombotic effects having an impact on
tory period is lengthened and the nerve conducts fewer action coagulation, platelet aggregation, and the microcirculation, as well
potentials. as modulation of inflammation.
Elevated extracellular calcium partially antagonizes the action
of local anesthetics owing to the calcium-induced increase in the B. Structure-Activity Characteristics of Local Anesthetics
surface potential on the membrane (which favors the low-affinity The smaller and more highly lipophilic local anesthetics have a
rested state). Conversely, increases in extracellular potassium faster rate of interaction with the sodium channel receptor. As
depolarize the membrane potential and favor the inactivated state, previously noted, potency is also positively correlated with lipid
enhancing the effect of local anesthetics. solubility. Lidocaine, procaine, and mepivacaine are more water