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PHYSIOLOGY CASES AND PROBLEMS
Case 5
Epidural Anesthesia: Effect of Lidocaine on Nerve
Action Potentials
Sue McKnight, a healthy 27-year-old woman, was pregnant with her first child. The pregnancy
was completely normal. However, as the delivery date approached, Sue became increasingly
fearful of the pain associated with a vaginal delivery. Her mother and five sisters had told her
horror stories about their experiences with labor and delivery. Sue discussed these fears with
her obstetrician, who reassured her that she would be a good candidate for epidural anesthesia. The obstetrician explained that during this procedure, lidocaine, a local anesthetic, is
injected into the epidural space around the lumbar spinal cord. The anesthetic drug prevents
pain by blocking action potentials in the sensory nerve fibers that serve the pelvis and perineum. Sue was comforted by this information and decided to politely excuse herself from further conversations with "helpful" relatives. Sue went into labor on her due date. She received
an epidural anesthetic midway through her 10-hour labor and delivered an 8 lb 10 oz boy with
virtually no pain. She reported to her mother and sisters that epidural anesthesia is "the greatest thing since sliced bread."
QUESTIONS
1. Lidocaine and other local anesthetic agents block action potentials in nerve fibers by binding
to specific ion channels. At low concentration, these drugs decrease the rate of rise of the
upstroke of the action potential. At higher concentrations, they prevent the occurrence of action
potentials altogether. Based on this information and your knowledge of the ionic basis of the
action potential, which ion channel would you conclude is blocked by lidocaine?
2. Lidocaine is a weak base with a pK of 7.9. At physiologic pH, is lidocaine primarily in its charged
or uncharged form?
3. Lidocaine blocks ion channels by binding to receptors from the intracellular side of the channel.
Therefore, to act, lidocaine must cross the nerve cell membrane. Using this information, if the
pH of the epidural space were to decrease from 7.4 to 7.0 (becomes more acidic), would drug
activity increase, decrease, or be unchanged?
4. Based on your knowledge of how nerve action potentials are propagated, how would you expect
lidocaine to alter the conduction of the action potential along a nerve fiber?
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PHYSIOLOGY CASES AND PROBLEMS
ANSWERS AND EXPLANATIONS
1. To determine which ion channel is blocked by lidocaine, it is necessary to review which ion
channels are important in nerve function. At rest (i.e., between action potentials), the conductance to IC' and Cl- is high, mediated respectively, by K' and Cl- channels in the nerve membrane. Thus, the resting membrane potential is driven toward the K + and Cl- equilibrium
potentials. During the upstroke of the nerve action potential, voltage-gated Na + channels are
most important. These channels open in response to depolarization, and this opening leads
to further depolarization toward the Na' equilibrium potential. During repolarization, the
voltage-gated NT' channels close and K+ channels open; as a result, the nerve membrane is repolarized back toward the resting membrane potential.
Lidocaine and other local anesthetic agents block voltage-gated Mr' channels in the nerve
membrane. At low concentrations, this blockade results in a slower rate of rise (dV/dt) of the
upstroke of the action potential. At higher concentrations, the upstroke is prevented altogether,
and no action potentials can occur.
2. According to the Bronsted-Lowry nomenclature for weak acids, the proton donor is called
HA and the proton acceptor is called A-. With weak bases (e.g., lidocaine), the proton donor
has a net positive charge and is called BFI +; the proton acceptor is called B. Because the p1( of
lidocaine (a weak base) is 7.9, the predominant form of lidocaine at physiologic pH (7.4) is
BH., with its net positive charge. This can be confirmed with the Henderson-Hasselbalch
equation, which is used to calculate the relative concentrations of BH* and B at a given pH
as follows:
pH = pK + log B
BH+
Physiologic pH is 7.4, and the pK of lidocaine
is
7.9. Thus:
7.4 = 7.9 + log B
B 1-1 +
—0.5 = log B
BH +
0.316 = B/BH*
or
BH*/B = 3.16
In words, at physiologic pH, the concentration of BH* (with its net positive charge) is approximately three times the concentration of B (uncharged).
3. As discussed in Question 2, the BH + form of lidocaine has a net positive charge, and the B
form of lidocaine is uncharged. You were told that lidocaine must cross the lipid bilayer of
the nerve membrane to act from the intracellular side of the Na + channel. Because the
uncharged (B) form of lidocaine is more lipophilic than the positively charged (BH-) form, it
crosses the nerve cell membrane more readily. Thus, at physiologic pH, although the positively charged (BH*) form is predominant (see Question 2), it is the uncharged form that
enters the nerve fiber.
If the pH of the epidural space decreases to 7.0, the equilibrium shifts toward the BH* form,
again demonstrated by the Henderson-Hasselbalch equation.
pH = pK + log
B
BH'
7.0 = 7.9 + log B+
CELLULAR AND AUTONOMIC PHYSIOLOGY
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-0.9 = log BFI+
0.126 = B/1111+
or
BHVB 7.94
At this more acidic pH, the amount of the charged form of lidocaine is now approximately eight
times that of the uncharged form. When the pH is more acidic, less of the permeant, uncharged
form of the drug is present. Thus, access of the drug to its intracellular site of action is impaired,
and the drug is less effective.
4. Action potentials are propagated (e.g., along sensory nerve axons) by the spread of local currents from active depolarized regions (i.e., regions that are firing action potentials) to adjacent
inactive regions. These local depolarizing currents are caused by the inward Nal- current of the
upstroke of the action potential. When lidocaine blocks voltage-gated Nat channels, the inward
Ma+ current of the upstroke of the action potential does not occur. Thus, propagation of the
action potential, which depends on this depolarizing inward current, is also prevented.
Key topics
Action potential
Henderson-Hasselbalch equation
Lidocaine
Lipid solubility
Local anesthetics
Local currents
Propagation of action potentials
Upstroke of action potential
Weak acids
Weak bases