Local Anesthetics

Question 1

3 structural parts of local anesthetics.

Answer 1

1. lipophilic aromatic ring 2. An intermediate hydrocarbon chain with an ester or amide bond 3. hydrophilic tertiary or quaternary amine. Benzocaine is the only one that has a secondary amine.

Question 2

Which LAs are chiral drugs.

Answer 2

Mepivicaine, bupivicaine, ropivicaine, and levobupivicaine

Question 3

Which two drugs exist as racemic mixtures? What significance do the enantiomers of drugs have clinically?

Answer 3

1. Mepivicaine and bupivicaine. 2. S enantiomers tend to be less neurotoxic and cardiotoxic than racemic mixtures or the R enantiomers of local anesthetics.

Question 4

Which nerve fibers are the largest in diameter and the most heavily myelinated?

Answer 4

A-Alpha fibers

Question 5

Which are the only fibers that are unmyelinated?

Answer 5

C fibers

Question 6

Metabolism of ester LAs

Answer 6

rapid hydrolysis by plasma and tissue cholinesterase

Question 7

Metabolism of amide LAs

Answer 7

CYP enzymes in the liver. Dealkylation and hydroxylation mechanisms.

Question 8

Lung extraction occurs with which LAs? Which drug is known to impair this extraction from the lungs?

Answer 8

lidocaine, bupivacaine, and prilocaine. Propanolol, possibly due to a common receptor site.

Question 9

What is the significance of prolonged labor in a mother who has received LA.

Answer 9

Fetal acidosis can result in accumulation of LA molecules in the fetus (ion trapping).

Question 10

Among the amide LA, which two drugs undergo the slowest metabolism? Which is the fastest?

Answer 10

Bupivacaine and ropivacaine. Prilocaine is the fastest. Lidocaine and mepivacaine are intermediate.

Question 11

MOA of LAs

Answer 11

They work on voltage-gated sodium channels, preventing sodium ion channel permeability. The rate of depolarization is slowed down such that the threshold potential is not reached and thus an action potential is not generated. They do NOT alter the resting transmembrane potential or threshold potential.

Question 12

What 3 states for Na+ channels exist in during an action potential. LA bind to Na+ in what state?

Answer 12

inactivated-closed state, activated-open state, and resting-closed state. LAs bind to Na+ channels in inactivated-closed states, stabilizing these channels in this configuration and preventing their change to activated-open and resting-closed states in response to nerve impulses.

Question 13

Where do LA bind on the Na+ receptor?

Answer 13

On the inner portion of Na+ receptors (internal gate or H gate). They also obstruct Na+ channels near their external opening to maintain channels in the inactivated-closed state.

Question 14

What is minimum effective concentration (Cm)?

Answer 14

The minimum concentration of LA necessary to produce conduction blockade of nerve impulses. It is analogous to MAC for inhaled anesthetics.

Question 15

Susceptibility to block depends on what factors?

Answer 15

1. Length of nerve fiber being exposed to LA 2. Presence of myelin 3. Size of fiber (larger fibers require greater Cm) 4. Position of fiber in nerve bundle 5. The characteristics of the specific LA

Question 16

Increased tissue pH or high-frequency nerve stimulation _____ Cm.

Answer 16

Decreases

Question 17

Which fibers are more readily blocked first?

Answer 17

Preganglionic B fibers, even though they’re myelinated, they are the first to be encountered as they surround the outside of the nerve bundle.

Question 18

Which nerve fibers are most SENSITIVE to LA?

Answer 18

large myelinated > smaller myelinated > unmyelinated

Question 19

Metabolism of lidocaine

Answer 19

oxidative dealkylation in the liver to monoethylglycinexylidide (MEGX) followed by hydrolysis to xylidide

Question 20

MEGX action and SE

Answer 20

Has approx. 80% of the activity of lido in protecting against cardiac dysrhythmias. Has a prolonged half-life, accounting for its efficacy in controlling dysrhythmias after infusion of lido is d/c’d. May be seizuregenic!

Question 21

Which LA is associated with methemoglobinemia? Why does this occur? What is the treatment?

Answer 21

1. Prilocaine 2. It is metabolized to orthotoluidine, which is an oxidizing compound capable of converting Hgb to its oxidized form, methemoglobin. 3. Methylene blue 1-2 mg/kg IV over 5 minutes

Question 22

Why should mepivacaine not be used in obstetrics?

Answer 22

Fetus is unable to metabilize double ring stucture leading to a prolonged half-life and possible toxicity.

Question 23

Compared to lidocaine, what is the duration of action and vasodilatory effects of mepivacaine?

Answer 23

Duration of action is longer than lido and it lacks vasodilator activity so epi is usually not necessary.

Question 24

What is the most important plasma protein binding site for bupivacaine and ropivacaine?

Answer 24

a1-acid glycoprotein. Protein binding 95% and 94% respectively.

Question 25

What is procaine metabolized to?

Answer 25

Paraaminobenzoic acid (PABA)

Question 26

Metabolism of chloroprocaine.

Answer 26

Chloride substitution of the aromatic ring increases the susceptibility of ester ring to hydrolysis. Most rapidly hydrolyzed of the ester LA.

Question 27

What is the longest acting ester LA?

Answer 27

Tetracaine

Question 28

What does the alkalinization of LA solutions do?

Answer 28

It shortens the ONSET of blockade, enhances the depth of sensory and motor blockade, and increases the spread of epidural blockade. It increases the % of LA existing in nonionized form.

Question 29

What is the primary site at which LA exert their action?

Answer 29

nodes of Ranvier. Voltage-gated sodium channels are located in these nonmyelinated segments; action potentials jump from node to node.

Question 30

Peripheral nerves are composed of what 3 layers of connective tissue?

Answer 30

the endoneurium, perineurium, and epineurium.

Question 31

What is the guarded receptor or modulated receptor hypothesis of local anesthetic action?

Answer 31

The concept that local anesthetics preferentially bind to both the open and inactivated states and not to the closed(resting) state.

Question 32

What is use-dependent or phasic block?

Answer 32

The concept that LAs work faster as the Na channels are repetitively depolarized.

Question 33

Which local anesthetic is a secondary amine and thus permanently nonionized or neutral?

Answer 33

Benzocaine

Question 34

Factors that affect the duration of action of LA

Answer 34

Systemic absorption away from the deposition site results in the offset and termination of drug effect. Absorption is affected by vascularity and blood flow of the injection area, lipid and protein binding, and addition of vasoconstrictors.

Question 35

Increased lipid solubility correlates with ____ protein binding, ____ potency, ____ duration of action, and a _____ tendency for severe cardiac toxicity.

Answer 35

increased, increased, longer, and higher

Question 36

LA are weak ___ and bind mainly to what type of protein?

Answer 36

bases. a₁-acid glycoprotein

Question 37

What is the most important factor affecting the onset of action of LA?

Answer 37

Degree of ionization. The more ionized a LA, the slower the onset.

Question 39

What type of block has a greater potential for toxicity?

Answer 39

Intrapleural/intracostal blocks due to higher rates of absorption

Question 40

What is state-dependent blockade?

Answer 40

block depends on the state of the sodium channel receptor: resting vs activated vs inactivated

Question 41

Local anesthetics can only gain access to receptors when sodium channels are in what state?

Answer 41

activated-open

Question 42

Local anesthetics bind more strongly when sodium channels are in what state?

Answer 42

inactivated (hyperpolarized) state

Question 43

Local anesthetics containing methylparaben (a preservative) should never be used in what type of blocks?

Answer 43

Neuraxial blocks

Question 44

pKa of 2-chloroprocaine. What accounts for the rapid onset of action despite its higher pKa?

Answer 44

9.0

The clinical use of high concentrations of the drug attenuates the ionization effect.

Question 45

Max dose of 2-chloroprocaine and duration of action

Answer 45

11 mg/kg or 800 mg total, 30-45 min

with epi: 14 mg/kg or 1000 mg, 30-90 min

Question 46

2% 2-chloroprocaine use

3% 2-chloroprocaine use

Answer 46

2% used for epidural blockade

3% used for peripheral nerve block

Question 47

2-chloroprocaine should not be used in patients with which type of allergy?

Answer 47

sulfa due to the sodium bisulfate preservative

Question 48

Clinical use for:

1% tetracaine

2% tetracaine

Answer 48

1% for spinal anesthesia; reconstituted with D10, CSF, or sterile water

2% for topical anesthetic

Question 49

Max dose of lidocaine and duration of action

Answer 49

4.5 mg/kg or 300 mg without epi; duration 30-120 min

7 mg/kg or 500 mg with epi; duration 120-360 min

Question 50

Max dose of mepivacaine and duration of action

Answer 50

5 mg/kg or 400 mg plain; duration 60-140 min

7 mg/kg or 500 mg w/epi, duration 140-200 min

Question 51

EMLA cream

Answer 51

2.5% prilocaine and 2.5% lidocaine

Question 52

Max dose of bupivacaine and duration of action

Answer 52

2 mg/kg or 175 mg total; 120-240 min

2.5 mg/kg or 225 mg total; 180-420 min

Question 53

Max dosage of Ropivacaine and duration of action

Answer 53

200 mg for minor nerve block with or w/o epi; 2-6 hr

Question 54

Management of LAST

Answer 54

Protect airway, supplemental O2, anticonvulsants for seizures (versed NOT propofol), and 20% lipid emulsion 1-3 mg/kg (bolus may be repeated 2 or 3 times) followed by continuous infusion of 0.25-0.5 mg/kg/hr

Question 55

pKa and protein binding of lidocaine

Answer 55

7.9 and 65%

Question 56

pKa and protein binding of bupivacaine

Answer 56

8.1 and 95%

Question 57

pKa and protein binding of ropivacaine

Answer 57

8.1 and 94%