Unit 5: Pharmacology 2 (Local Anesthetics) Flashcards
Match each type of peripheral nerve with its function:
C
A alpha
B
A delta
Motor
Fast pain
Preganglionic SNS
Slow pain
A alpha + Motor
A delta + Fast pain
B + Preganglionic SNS
C + Slow pain
In the clinical setting, local anesthetics inhibit peripheral nerves (speed of onset) in the following order:
- B fibers (preganglionic SNS)
- C fibers (slow pain)
- Small diameter A fibers (delta, gamma)
- Large diameter A fibers (alpha, beta)
True or False: Regression of LA blockade occurs in the opposite order of block onset
True
Function of myelin
Insulates the axon, allows electrical current to skip along only the uninsulated regions, known as the nodes of Ranvier (saltatory conduction)
What two factors increase conduction velocity?
Myelination and larger fiber diameter
Function of A alpha fibers
Skeletal muscle - motor
Proprioception
Function of A beta fibers
Touch
Pressure
Function of A gamma fibers
Skeletal muscle - tone
Function of A delta fibers
Fast pain
Temperature
Touch
Function of B fibers
Preganglionic ANS fibers
Function of C fibers
Sympathetic: Postganglionic ANS fibers
Dorsal root: Slow pain, temperature, touch
Minimum Effective Concentration (Cm)
A unit of measure that quantifies the concentration of local anesthetic required to block conduction. Analogous to ED50 for IV drugs and MAC for volatile anesthetics.
Fibers that are more easily blocked have a lower Cm.
Fibers that are more resistant to LA blockade have a higher Cm.
When is Cm typically higher?
In nerves with a wider diameter (more resistant to blockade)
When is Cm reduced?
Higher tissue pH or a high frequency of nerve stimulation
Which nerve fibers are blocked first (in vivo) by local anesthetic?
B fibers
Which nerve fibers are blocked last (in vivo) by local anesthetic?
A alpha and A beta fibers
C fibers originating in the dorsal root transmit which types of signals?
Slow pain
Temperature
Touch
Which peripheral nerve fiber type is NOT myelinated?
C fibers
What type of nerve fibers mediate skeletal muscle tone?
A gamma fibers
Which type of peripheral nerve fiber mediates fast pain?
A delta fibers
Local anesthetics can bind to the voltage-gated sodium channel when it is in the:
A. Resting and active states
B. Resting and inactive states
C. Active and inactive states
D. Active state only
C. Active and inactive states
How do local anesthetics work?
Bind reversibly to alpha subunit of voltage-gated sodium channels when the channel is in either the active or inactive state. Plugging the channel reduces sodium conductance and blocks nerve conduction.
Define use-dependent or phasic block
The more frequently the nerve is depolarized and the voltage-gated sodium channels open, the more time available for local anesthetic binding to occur, and the faster the nerve will become blocked.
When does the voltage-gated sodium channel assume the active state?
When threshold potential is reached (during depolarization -70 to +35 mV)
When does the voltage-gated sodium channel assume the inactive state?
Repolarization (+35 to -70 mV). The channel is closed and refractory during this time, but LAs can bind
Resting membrane potential in peripheral nerves
-70 mV
Threshold potential in peripheral nerves
-55 mV
What is the primary determinant of resting membrane potential?
Serum K+
Decreased serum K+ - RMP becomes more negative
Increased serum K+ - RMP becomes more positive
Primary determinant of threshold potential
Serum Ca+2
Decreased serum Ca+2 - TP becomes more negative
Increased serum Ca+2 - TP becomes more positive
What ion shifts cause repolarization?
K+ leaving the cell or Cl- entering the cell
True or False: Local anesthetics do NOT affect resting membrane potential or threshold potential
True
When a critical number of sodium channels are blocked, there aren’t enough open channels for sodium to enter the cell in sufficient quantity. The cell can’t depolarize, and the action potential can’t be propagated.
How does hypocalcemia affect the threshold potential?
It makes the TP more negative. Since it moves closer to the RMP, the cell is easier to depolarize.
Primary mechanism of action of local anesthetics
The ionized conjugate acid (NOT the uncharged base) binds to the intracellular portion of the sodium channel
True or False: Local anesthetics are weak acids
False. LAs are weak bases
They rapidly dissociate into an uncharged base (LA) and an ionized conjugate acid (LA+)
pKa
The pH where 50% of the drug exists as the uncharged base and 50% exists as the conjugate acid
Local anesthetics are weak bases with pKa values higher than 7.4 - we can predict that >50% of the LA will exist as the ionized conjugate acid
Diffusion of LA into axoplasm
The uncharged base enters the axoplasm by diffusing through the lipid-rich axolemma. Once inside, a new equilibrium is established. Since the ICF is slightly more acidic than the ECF, there is a greater fraction of the ionized conjugate acid inside the cell
The sodium channel remains in the __________________ state until enough local anesthetic diffuses away
Closed, inactivated
What 3 paths can a local anesthetic travel after it is injected near a peripheral nerve?
- Diffuse into the nerve
- Diffuse into the surrounding tissue and bind to neighboring proteins
- Diffuse into the systemic circulation
Three key components of a local anesthetic molecule
Benzene ring
Intermediate side chain (determines LA drug class and how each drug is metabolized)
Tertiary amine (accepts proton, makes molecule a weak base)
Ester metabolism
Pseudocholinesterase
*PChE deficiency could increase duration of action
*Cocaine is also metabolized by the liver
Amide metabolism
Hepatic carboxylesterase/P450
Local anesthetic allergy
More common with esters since they are derivatives of para-aminobenzoic acid (PABA), an immunogenic molecule capable of causing allergic reaction = cross-sensitivity within ester class
*No cross-sensitivity between esters and amides, so would be safe to select an amide (as long as it does not contain methylparaben as a preservative)
Which characteristics correlate BEST with local anesthetic duration of action?
Primary determinant = Plasma protein binding
Secondary determinant = Lipid solubility, addition of vasoconstrictors, intrinsic vasodilating effects
Which characteristics correlate BEST with LA onset of action?
Primary determinant = pKa (ratio of non-ionized to ionized fractions)
Secondary determinant = Dose and concentration
Which characteristics correlate BEST with LA potency?
Primary determinant = Lipid solubility
Secondary determinant = Intrinsic vasodilating effects
pKa as a determinant of onset of action
If the pKa is closer to the pH of the blood, a larger fraction of molecules will exist as the lipid-soluble, uncharged base, and more molecules will diffuse across the axolemma, translating to a faster onset of action
Why does Chloroprocaine have a rapid onset of action despite its high pKa?
Chloroprocaine is not very potent, so we have to give a large dose. Giving more molecules creates a mass effect that results in a rapid onset of action
Lipid solubility as a determinant of potency
A lipid soluble drug has an easier time diffusing through the epineurium, and more drug inside the nerve means more molecules are available to bind to the receptor. Agents that are more lipophilic tend to be more potent and have longer duration of action
Intrinsic vasodilating activity as a determinant of potency
At higher concentrations (what we use clinically), LAs cause vasodilation (some more than others), with the exception of cocaine (inhibits NE reuptake).
Drugs with a greater degree of intrinsic vasodilating effects (lidocaine) undergo a faster rate of vascular uptake, preventing some of the administered dose from accessing the nerve.
Protein binding as a determinant of duration of action
After LA injection, some molecules penetrate the epineurium, some diffuse away into the systemic circulation, and some bind to tissue proteins. The molecules that bind to the plasma proteins serve as a tissue reservoir that extends the duration of action.
Other determinants:
- Lipid solubility (longer duration)
- Intrinsic vasodilating effect (shorter duration)
Bottom line about weak bases
In an acidic solution, weak bases are more ionized and water-soluble
In a basic solution, weak bases are more non-ionized and lipid-soluble
*The opposite is true for weak acids
Which local anesthetic does not undergo protein binding?
Chloroprocaine
pKa of common LAs
Bupivacaine - 8.1
Ropivacaine - 8.1
Lidocaine - 7.9
Mepivacaine - 7.6
Chloroprocaine - 8.7
Tetracaine - 8.5
Rate of vascular uptake based on site of injection
IV > tracheal > interpleural > intercostal > caudal > epidural > brachial plexus > femoral > sciatic > subcutaneous
“I Think Illogical Imposters Can’t Educate, But Fabulous Schools Should”
Ester metabolism
Psuedocholinesterase in the plasma
*Cocaine both PChE and hepatic P450
Amide metabolism
Liver P450 enzymes
Rules for administering lidocaine and Exparel
After infiltrating lidocaine - no liposomal bupivacaine for at least 20 minutes
After infiltrating liposomal bupivacaine - no lidocaine (in any form) for at least 96 hours
Maximum allowable dose in adult
Bupivacaine = 2.5 mg/kg (or 175 mg)
Bupivacaine + epi = 3 mg/kg (or 200 mg)
Ropivacaine = 3 mg/kg (or 200 mg)
Lidocaine = 4.5 mg/kg (or 300 mg)
Lidocaine + epi = 7 mg/kg (or 500 mg)
Mepivacaine = 7 mg/kg (or 400 mg)
Prilocaine = 8 mg/kg
Maximum allowable dose for ester-type LAs
Procaine = 7-10 mg/kg (or 350-600 mg)
Chloroprocaine = 11 mg/kg (or 800 mg)
Chloroprocaine + epi = 14 mg/kg (or 1,000 mg)
True or False: LAST is more common with peripheral nerve blocks than with epidural anesthesia
True
Most common cause of toxic plasma concentrations of LA
Inadvertent intravascular injection during regional anesthesia
