Local Anesthetics Flashcards by Tricia Vantino

List the 3 layers of a nerve from outer to inner layers

Epineurium
Perineurium
Endoneurium

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Axon conduction velocity is faster in what nerves?

Faster in wider diameter and those that are myelinated

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What is the process called where electrical currents skip along the uninsulated/nonmyelinated regions of an axon?

Saltatory Conduction

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Can differential blockade be explained based on diameter and myelination alone?

No. Other variables such as a local’s ability to penetrate, the anatomical position of the axon within the nerve, and the nerve’s intrinsic sensitivity to stimulation.

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Describe the myelination, function, diameter, velocity, and block onset for A-alpha fibers

Heavy Myelination
Fxn: Skeletal muscle-motor and Proprioception
Diameter: Widest (12-20micrometers)
Velocity: Fastest (+++++)
Block Onset: Last (4th) with A beta fibers

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Describe the myelination, function, diameter, velocity, and block onset for A-beta fibers

Heavy Myelination
Fxn: Touch and Pressure
Diameter: 2nd Widest (5-12 micrometers)
Velocity: 2nd Fastest (++++)
Block Onset: Last (4th) with A alpha fibers

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Describe the myelination, function, diameter, velocity, and block onset for A-y(gamma) fibers

Moderate Myelination
Fxn: Skeletal muscle-tone
Diameter: 3rd Widest (3-6 micrometers)
Velocity: 3rd Fastest (+++)
Block Onset: Second to last (3rd, same as A-delta)

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Describe the myelination, function, diameter, velocity, and block onset for A-delta fibers

Moderate Myelination
Fxn: Fast pain, temperature, touch
Diameter: 4th Widest (2-5 micrometers)
Velocity: 3rd Fastest (+++), same as A-gamma
Block Onset: 3rd, same as a-gamma.

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Describe the myelination, function, diameter, velocity, and block onset for B fibers

Light Myelination
Fxn: Preganglionic Sympathetic ANS fibers
Diameter: (~3 micrometers)
Velocity: 2nd slowest
Block Onset: FIRST

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Describe the myelination, function, diameter, velocity, and block onset for C-sympathetic fibers

No Myelination
Fxn: Postganglionic ANS fibers
Diameter: Smallest (0.3-1.3 micrometers)
Velocity: Slowest (+), same as C-dorsal root fibers
Block Onset: 2nd same as C-dorsal root fibers

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Describe the myelination, function, diameter, velocity, and block onset for C-dorsal root fibers

No myelination
Fxn: Slow pain, temperature, touch
Diameter: Smallest, (0.4-1.2)
Velocity: Slowest (+) same as C-sympathetic fibers
Block Onset: 2nd, same as C-sympathetic fibers

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In the clinical setting, local anesthetics inhibit peripheral nerves (speed of onset) in which order by fiber type. What is the order of regression?

Onset:
B fibers > C fibers > Small diameter A fibers (gamma and delta) > Large diameter A fibers (alpha and beta).

Regression of the block occurs in the opposite direction.

Large Alpha, Small Alpha, C fibers, B fibers

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Minimum effective concentration (Cm) is a unit of measure that quantifies?

The concentration of local anesthetic required to block conduction. (Analogous to the ED50 of IV drugs)

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Is Minimum effective concentration (Cm), higher or lower for nerves with wider diameter?

Higher

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Which type of peripheral nerve fiver mediates fast pain?

A delta

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Which peripheral nerve fiber type is not myelinated?

C fibers - sympathetic and dorsal horn

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Local anesthetics reversibly bind to? How does this influence the mechanism of action?

The alpha subunit of the voltage-gated sodium channel. By binding, it plugs the channel and reduces sodium conductance, thereby blocking nerve conduction.

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What are the three states voltage-gated sodium channels can be in? Which states can local anesthetics bind to?

3 States: Resting, Active, Inactive

LA’s bind when the Sodium Voltage-Gated Channel is Active or Inactive.
NOT the resting state.

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Describe the concept of use-dependent or phasic blockade regarding local anesthetics.

The more frequently the nerve is depolarized and the voltage, gated, sodium channels open, the more time available for local anesthetic binding to occur in the faster the nerve will become blocked.

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Do local anesthetics affect resting membrane potential, threshold potential, or neither?

Neither!

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In the peripheral nerve, the resting membrane potential voltage is?

-70mV

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What electrolyte is the primary determinant for resting membrane potential?

potassium

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What electrolyte is primarily responsible for threshold potential?

Calcium

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Decreasing serum potassium makes the resting member potential become more positive or negative.

More negative

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Increasing serum potassium levels makes the resting membrane potential become more positive or negative?

More positive, easier to depolarize

Decreased serum calcium makes the threshold potential become more positive or negative?

Negative - closer to depolrizing

Increase serum calcium makes the threshold potential more positive or negative

Positive - less likely to depolarize

What maintains the resting membrane potential until the nerve is depolarized again?

Na/K ATPase (pump) 3Na out the cell for every 2K into the cell

do local anesthetics bind to the alpha sub unit on the inside or the outside of the sodium channel?

inside

The threshold potential is the voltage change that must occur to?

Initiate depolarization

A cell repolarizes when _____ leaves the cell or_____ enters the cell

Potassium(+) leaves or chloride(-) enters

The cell is resistant to subsequent depolarization during the refractory period because _____ channels are in the closed, inactive state

Sodium

In an acidic solution, are weak bases more ionized or unionized?

Ionized

In a basic solution, are weak bases more ionized or unionized?

unionized (lipid soluble)

At physiologic pH, 7.4, are local anesthetics more ionized or nonionized

Ionized, but the nonionized portions cross the nerve axolemma

Why can we predict that greater than 50% of lidocaine will exist in the ionized state when it enters the bloodstream?

Lidocaine is a weak base. It's PKA value is greater than physiological pH so a greater fraction will exist in the ionized state.

What three paths can a local anesthetic travel after it is injected near a peripheral nerve?

1. In can diffuse into the nerve 2. It can diffuse into the surrounding tissue and bind to neighboring proteins 3. It can diffuse into the systemic circulation

Name the Ester Local Anesthetics

Benzocaine Cocaine Chloroprocaine Procaine Tetracaine

Name the Amide Local Anesthetics

Bupivacaine Dibucaine Lidocaine Mepivacaine Ropivacaine Levobupivacaine Etidocaine

What molecular component of local anesthetics makes a drug an ester or an amide?

Intermediate Chain

What molecular component makes local anesthetics lipophilic?

Benzene Ring

What molecular component of local anesthetics makes a drug hydrophilic?

Tertiary Amine

How are ester local anesthetics metabolized?

Pseudocholinesterase (deficiency could increase the duration of action)

How are amide local anesthetics metabolized?

Hepatic Carboxylesterase/P450

What component in ester local anesthetics makes them more likely for allergies?

Derivative of ParaAminoBenzoic Acid (PABA), which is an immunogenic molecule

Primary and Secondary variables determining Local Anesthetic Onset of Action

Primary: pKa Secondary: Dose and Concentration

Primary and Secondary variables determining Local Anesthetic potency

Primary: Lipid Solubility Secondary: Intrisinic Vasodilating Effect

Primary and secondary variables determining Local Anesthetic Duration of Action

Primary: Protein Binding Secondary: Lipid Solubility, Intrinsic vasodilating effect, the addition of vasoconstrictors

As the pKa of a local anesthetic is closer to the pH, how will this effect the ionization and onset of action?

The closer the pKa is to the pH, the larger the fraction of non-ionized form, allowing for more to cross the membrane and a faster onset of action.

Which would have a faster onset, a local with a pKa that is closer or further away from physiologic pH?

A drug with a pKa closer to physiologic pH

Is it the conjugate acid or the non-ionized base that binds to the alpha subunit of the voltage-gated sodium channels?

Conjugate Acid (ionized)

Which local anesthetic doesn't possess any intrinsic vasodilating activity?

Cocaine - it inhibits NE reuptake and causes vasoconstriction

Do ester or amide local anesthetics have higher pKas as a group

Esters have higher pKa values (8.5-8.9)

The closer the pKa is to the pH of the blood the faster the onset. What is the one exception to this rule, and why?

Chloroprocaine. pKa=8.7, however, it is given in high concentrations, so it has a fast onset. (similar to how N2O is faster than desflurane bc of concentration)

pKa of Bupivacaine, %ionization at 7.4pH, and % protein binding

8.1 83% ionization 96% protein binding

pKa of Ropivacaine, %ionization at 7.4pH, and protein binding %

8.1 83% ionization 94% protein binding

pKa of Lidocaine, %ionization at 7.4pH, and protein binding %

7.9 76% ionization 65% protein binding

pKa of mepivacaine, %ionization at 7.4pH, and protein binding

7.6 61% ionization 78% protein binding

pKa of chloroprocaine, %ionization at 7.4pH, and protein binding

8.7 95% ionization 0% protein binding (remember you can give high concentrations)

What are the local anesthetics that can cause methemoglobinemia?

Benzocaine Prilocaine Cetacaine (contains benzocaine) EMLA (prilocaine + lidocaine)

Vascular uptake (absorption) generally occurs in what order? (most rapid first, to least rapid)

IV (duh), Tracheal, Interpleural, Intercostal, Caudal, Epidural, Brachial Plexus, Femoral, Sciatic, Subcutaneous

Factors that influence vascular uptake and plasma concentration (Cp)

-Site of injection -Tissue blood flow -physiochemical properties of local anesthetic -metabolism -addition of a vasoconstrictor

MAX dose of Exparel

266mg (2 vials)

Exparel is contraindicated for? And not recommended for?

Contraindicated for Paracervical (cervix) block in obstetric patients. Not recommended for epidural, intrathecal, or intraarticular admin or during pregnancy.

After infiltrating lidocaine, how long before you can administer Exparel (Liposomal Bupivacaine)?

At least 20 min

After infiltrating Exparel (Liposomal Bupivacaine), how long before you can give bupivacaine (in any form)?

For at least 96 hours!

Local anesthetics bind to what serum proteins?

Alpha-1-acid glycoprotein (preferred) Albumin

What is the max dose(mg/kg) and max total dose (mg) for Bupivacaine?

2-2.5mg/kg 175mg

What is the max dose(mg/kg) and max total dose (mg) for Ropivacaine?

3mg/kg 200mg

What is the max dose(mg/kg) and max total dose (mg) for Bupivacaine + Epi?

3mg/kg 200mg

What is the max dose(mg/kg) and max total dose (mg) for Lidocaine?

4.5mg/kg 300mg

What is the max dose(mg/kg) and max total dose (mg) for Lidocaine + Epi?

7mg/kg 500mg

What is the max dose(mg/kg) and max total dose (mg) for Mepivacaine?

7mg/kg 300-400mg

What is the max dose(mg/kg) and max total dose (mg) for Chloroprocaine?

11mg/kg 600(stoelting)-800mg(Nagelhout)

What is the max dose(mg/kg) and max total dose (mg) for Chloroprocaine + Epi?

14mg/kg 1,000mg

At what plasma concentration would you expect lidocaine to produce seizures?

10-15mcg/mL

The most common cause of local anesthetic toxic plasma concentrations is?

inadvertent intravascular injection during regional anesthesia

The most frequent symptom of LAST is? What symptom is the exception for Bupivacaine?

Seizure Bupivacaine LAST - cardiac arrest can occur before a seizure

What are the first CNS effects seen with LAST when serum levels are 5-10mcg/mL?

Tinnitus, skeletal muscle twitching, numbness of lips and tongue, restlessness, vertigo, blurred vision

What are the first cardiac effects seen with LAST when serum levels are 5-10mcg/mL?

Hypotension and Myocardial Depression May manifest initially as htn and tachydysrythmias but then progresses towards depression, bradycardia, hypotension

What are the CNS effects with plasma concentrations of local anesthetics are 10-15mcg/mL

seizures and loss of consciousness

What are the CNS and Cardiac effects seen when local anesthetic level plasma concentrations are 15-25mcg/mL?

Coma, Respiratory arrest

What factors can increase the risk for CNS toxicity from local anesthetics?

-Hypercarbia (increases cerebral blood flow, more drug delivery. & decreases protein binding while increasing the free fraction of drug available to enter the brain) -Hyperkalemia (raises RMP, making neurons more likely to fire) -Metabolic Acidosis (decreases convulsion threshold and favors ion trapping inside the brain)

Rank the drugs in order of difficulty of cardiac resuscitation from LAST

Bupivacaine, Levobupivacaine, Ropivacaine, Lidocaine

Treatment steps for LAST

1. Manage airway -100% O2 (hypoxia and acidosis worsen LAST) 2.Breating - adequate ventilation 3. Maintain adequate coronary perfusion. ACLS. 4. Benzos to tx seizures. If ineffective try low dose NMB. (no prop - myocardial depression) 5. 20% lipid emulsion therapy

Dose of lipid emulsion for patient over 70kg

Bolus: 100mL over 2-3min Infusion: 250mL over 15-20min If pt remains unstable, repeat bolus and/or double the infusion

Dose of lipid emulsion for patients under 70kg

Bolus: 1.5mL/kg of lean body weight over 2-3min Infusion: 0.25mL/kg/min If pt remains unstable, repeat bolus and/or double the infusion

How long after the patient regains cardiovascular stability should the lipid emulsion continue?

Minimum of 15min

Max recommended dose of lipid emulsion?

12mL/kg

What ACLS drugs should be avoided in the patient with LAST?

Vasopressin Lidocaine Procainamide Epinephrine (if needed, limit doses of 1mcg/kg)

Max recommended dose for lidocaine during tumescent anesthesia?

35-55mg/kg (some pts have received 70-80mg/kg without incident)

What is the most common cause of death in patients undergoing liposuction?

LAST or Pulmonary Embolism

When is general anesthesia recommended for patients undergoing liposuction?

Recommended if >2-3L of tumescent is injected due to the risk of fluid shifts

Methemoglobin is produced when?

The iron molecule becomes oxidized to its ferric form (Fe3+)

Methemoglobinemia decreases oxygen carrying capacity in what 2 ways?

1. Methgb cant bind oxygen molecules 2.Methgb shifts oxyhgb curve to the left. more difficult to release oxygen at tissue level.

What will likely be your sPo2 reading on a patient with Methgb?

Error reading of ~85%

What is required to diagnose methemoglobinemia?

co-oximeter

Other drugs besides local anesthetics that can cause methemoglobinemia?

Nitroprusside Nitroglycerine Sulfonamides Phenytoin

Signs and Symptoms of Methemoglobinemia

hypoxia cyanosis chocolate colored blood tachycardia tachypnea mental status change coma and death

Tx of methgb. Dose and Max dose.

Methylene blue 1-2mg/kg over 5 minutes with max dose of 7-8mg/kg Methylene blue reacts with methemoglobin and reduces it back to hemoglobin

What 2 patient populations have the highest risk for methemoglobin toxicity?

Neonates - deficient in methemoglobin reductase Glucose-6-phosphate reductase deficiency. Dont possess methemoglobin reductase

What kind of cells support and insulate axons?

Schwann Cells

Where are the voltage-gated sodium channels located on axons?

In the unmyelinated segments. Nodes of Ranvier