Local Anesthestics

Question 1

Local anesthetics have greater affinity to Na channels resting or inactive state?

Answer 1

Once inside the cell, it is then the protonated charged cation form which more avidly binds the sodium channel. Sodium channels in the activated or inactivated (meaning it was just active) have greater affinity for local anesthetics than in the resting state (hasn’t been active for a “long” time). This accounts for the observation that more active neurons are blocked to a greater extent than less active neurons.

Question 2

Local anesthetic MoA?

Answer 2

Local anesthetics bind to the alpha subunit of voltage gated sodium channels on the intracellular surface of the cell membrane (not extracellular surface).

By blocking these channels, it prevents action potentials from being propagated.

Question 3

Onset of local anesthetics depends on

Answer 3

onset = pKa!

Crossing the lipid cell membrane occurs quicker when the local anesthetic (a base) is uncharged. The charge of the local anesthetic depends on its pKa (the pH where ½ of the molecules are ionized and ½ are uncharged) and the pH of the local environment.

Therefore, a local anesthetic with a pKa of ~8 (bupivacaine, tetracaine, lidocaine) will have more than half the molecules in the charged form at a pH of 7. In other words, putting a base in a more acidic environment will lead to more than half the molecules picking up an additional H+ and having a positive (cation) charge. Therefore, the more uncharged molecules (the closer the pKa is to pH), the more molecules can quickly cross the membrane.

There are two major complicating situations where the pKa cannot, in itself, be used as perfect guide to determine onset alone (although IT IS a major determinant). First, more lipid soluble local anesthetics can more easily pass through connective tissue and the epineurium to reach the neuron. Secondly, chloroprocaine (for example) is clinically given in such high doses (number of molecules) that its onset is quicker than many other local anesthetics with pKa’s closer to physiological pH’s.

Question 4

Potency of locals depends on ….

Answer 4

potency = lipid solubility

duration of action = protein binding
onset = pKa!

Question 5

Duration of action of locals depends on …

Answer 5

duration of action = protein binding

onset = pKa
potency = lipid solubility

Question 6

The greatest local anesthetics absorption are … (greatest to lowest)

Answer 6

BICEPS:

Blood (IV)
Bronchial (Tracheal)

Intercostal

Cauda
ParaCervical

Epidural

Plexus (Brachial)

Sciatic
SubQ

Question 7

Adding 1:200,00 Epi to lidocaine for peripheral block will …

Answer 7

1) decrease rate of washout/vascular absorption -> linger block by 50% and increases toxic dose.
2) increases density of block by increasing neural uptake (more time the neuron exposed to local).

Question 8

Would adding epinephrine to bupivacaine or topi I ain’t enhance or prolong peripheral block?

Answer 8

No, their duration based on protein binding

Question 9

Would adding Epi to local changes its pH?

Answer 9

No effect

Prepared commercial Epi + loca require lower pH for molecular stability (for long shelf life). But adding Epi just prior to use, dose not affect pH

Question 10

Structures that cases allergic rxn with local use are …

Answer 10

PABA (Esters)

Methylparaben has similar structure to PABA

Question 11

Esters are metabolized by …

Answer 11

Pseudo cholinesterase to PABA product

Except cocaine which is by liver

Question 12

Amides are metabolized by …

Answer 12

Liver

Question 13

Patients with abnormal psudocholensterse enzyme have lower rate of metabolism of …

Answer 13

Succinylcholine
Mivacurium
Ester locals.

Question 14

Locals potentially cause Methemoglobinemia?

Answer 14

Administration of large amounts of benzocaine, prilocaine, and less so lidocaine can lead to methaemoglobinaemia.

With methaemoglobinaemia, the haemoglobin molecules iron ion is oxidized to the ferric (3+) state, leading to a significant left shift in the oxygen- haemoglobin dissociation curve and decreased oxygen release to the tissues (tissue hypoxia). On pulse oximeter, the molecule absorbs both wavelengths of light used (infrared & red) equally, resulting in an (incorrect) saturation level of 85% (classically), see monitors question 21 for more detail on this. Methylene blue reduces the ferric ion back to the ferrous state, therefore normalizing the oxygen- haemoglobin dissociation curve.

Question 15

Local anesthetics has the greatest affinity when voltage gated Na channels are …

Answer 15

Resting – low affinity for local anesthetics

Activated – high affinity for local anesthetics

Inactivated - high affinity for local anesthetics

Local anesthetics bind to alpha subunits (intracellular side), with the greatest affinity for channels in the open or inactivated state.

When the neuron’s membrane reaches threshold (from generated action potentials propagating down the axon, for example), voltage-gated sodium channels are activated and allow the passage (influx) of sodium into the neuron. The voltage-gated channels soon after becomes inactivated (which does not allow sodium to pass through the channel). In both of these states, local anesthetics have a high affinity for the alpha subunit of the channel. Following a brief period time the channel will return to the resting state. In the resting state, local anesthetics have decreased affinity for the channel.

A neuron that is sending more signal will be in the active or inactive states a greater portion of the time as compared to a neuron that is sending less signal (less use). Therefore, this explains the concept of use-dependent block, in that the more active a neuron is, the greater the local anesthetic binding will be.

Question 16

pKa of local and their onset association

Answer 16

The lower pKa -> the more neutral (non-ionized) form -> faster onset.

Question 17

Why you should add the epinephrine with local prior use then using the former mixed bottle?

Answer 17

Block onset will be quicker when the epinephrine is mixed in just prior to use

Epinephrine will degrade quicker in alkaline environments than acidic environments, therefore manufacturers will make their solutions more acidic (around pH 4-5) to ensure such degradation does not occur. Since local anesthetics are bases with high pKa’s, this will increase the proportion of the drug in the ionized (BH, conjugate acid) form that cannot cross the cell membrane (where the binding site of the voltage-gated sodium channel exists for local anesthetics). Therefore by adding in the epinephrine to solutions without epinephrine (pH 6-7), a greater proportion of the drug is in the non-ionized state allowing for transit across the cellular membrane and faster onset. Since the vasopressor activity of epinephrine will be essentially equivalent in premade solution or added just before use, the duration of the two blocks will be about the same.

Question 18

Bupivacaine is known to be highly protein bounded, what is the protein? And why important to know it?

Answer 18

Alpha-1-acid glycoprotein

Protein bound drugs are mostly bound to albumin or alpha-1-acid glycoprotein (AAG).

Albumin carries acidic drugs (like barbiturates) and AAG more often caries basic drugs like local anesthetics.

The unbound drug of any protein-drug pair is the one that is biologically active. Therefore decreased levels of AAG could theoretically increase the side-effects of a drug it normally binds to.

Question 19

Why lidocaine given prior succinylcholine?

Answer 19

For Relaxation of bronchial smooth muscle

Lidocaine and other local anesthetics (other than cocaine) can relax bronchial smooth muscle whereas succinylcholine only blocks skeletal muscle at the nicotinic receptor. Local anesthetics do have variable levels of myotoxicity but do not block nicotinic receptors to produce muscle relaxation. Succinylcholine is not associated with pain on injection and lidocaine’s effects of blunting pain with propofol injection are thought to be (at least partially) independent of its effects on voltage-gated sodium channels.

Question 20

Transit neurologic symptoms caused by

Answer 20

Transient neurologic symptoms (TNS) is a collection of findings including severe buttocks pain, leg burning, various dysethesias that are more likely seen following lidocaine spinals, especially when the patient is in lithotomy position.

Question 21

Cauda equine syndrome caused by which local?

Answer 21

Continuous (or repeated) infusion of high dose lidocaine (as well as tetracaine) through small-bore microcatheters in the intrathecal space has led to neurotoxicity to such a degree than cauda equina syndrome resulted.

Question 22

Sever back pain after epidural caused by which local?

Answer 22

Persistent and severe back pain has been described following chloroprocaine epidurals, and may be due to the preservative EDTA, which was used at the time.

Question 23

How much epi volume should be taken from 1:1,000 to be added to 20 mL of local to get 1:200,000 of epi in 20 ml local?

Answer 23

(1) To get the mcg/ml from epi ratio concentration (eg, 1:200,000) -> divide 1,000,000 by the number to the right of the colon to derive the concentration in mcg/ml. Therefore 1:200,000 would equal: 1,000,000/ 200,000= 5 mcg/ml (also = 1:200,000).
(2) Then multiply the calculated epi mcg needed to be added to local x volume of local (eg, 5 mcg X 20 = 100 mcg). Therefore 100 mcg of epi in 20 cc local to give 5mcg of epi/ ml.
(3) The next step is to figure out how much of the 1:1,000 solution is needed to generate 100 mcg.Therefore since we are starting with a concentration of 1,000 mcg/ ml (also = 1:1,000), we would divide 100 mcg/ 1,000 mcg = 0.1 cc.

Therefore we take 0.1 cc of the epinephrine solution and add it to 20 cc of local.

Question 24

Which local has the most cardio toxicity

Answer 24

Bupivacaine

It is a lipid soluble local anesthetic with a very high degree of protein binging and a long duration of action because of this property. It is in many ways an ideal drug for both peripheral and neuraxial anesthesia. Its one great disadvantage is cardiotoxicity. Solutions of bupivacaine consist of the drug in two enantiomers. The R(+) isomer very avidly binds to cardiac sodium channels (as well as potassium and calcium channels) and does not release from its binding site quickly like lidocaine (for example). Therefore, cardiovascular collapse secondary to bupivacaine is associated with “ACLS-resistant” cardiovascular arrest classically with wide complex bradycardia. The primary treatment for this is supportive (chest compressions) while the bupivacaine is removed from its binding site with intralipid solution.

Levobupivacaine (only the S(-) isomer) and ropivacaine (which only contains the S(-) isomer) have similar efficacy profiles with bupivacaine, but are less cardiotoxic. Mepivacaine and lidocaine are less cardiotoxic than ropivacaine.

Question 25

Liposomal bupivacaine vs plane bupivacaine?

Answer 25

Liposomal bupivacaine has a longer duration of effect and a comparable safety profile

Liposomal bupivacaine is essentially bupivacaine loaded into liposomes. The advantage of this is a longer half-life and therefore extended block. Studies in animals showed a lower peak concentration of bupivacaine in the lisosomal form but some human studies have shown equivalent peak concentrations. The actual dose of bupivacaine used in the liposomal form is higher. Both forms of bupivacaine are cardiotoxic and the liposomal form appears not to be any safer.

Question 26

Prilocaine, benzocaine, and less so lidocaine, are classic for having the potential to cause methaemoglobinaemia. Which metabolites are responsible for each?

Answer 26

Metabolism of prilocaine yields o-toluidine

Lidocaine metabolism likely involves the metabolite 2,6-xylidine to produce methaemoglobin

Benzocaine associated methaemoglobinaemia (possibly independent of metabolism,
is classically after oral topical spray for endoscopy or bronchoscopy.