Case 3 - Local Anaesthetic

Question 1

A 25-year-old, 75-kg man presents for open appendectomy. The surgery is performed under general anesthesia, without complications. After the specimen is removed, the attending surgeon leaves the operating room to dictate the operative report, leaving the intern and medical student to close the skin. Upon leaving, the surgeon asks them to “inject some local anesthetic into the wounds.” The intern turns to you and asks which local anesthetic you suggest and how much to inject.

Questions

What are the benefits of local anesthetic infiltration?

What attributes are you looking for in a local anesthetic in this case?

Which agent would you choose and what is the maximum dose?

Answer 1

Summary: A 25-year-old healthy male undergoes uneventful laparoscopic appendectomy. Local anesthetic infiltration of surgical sites is requested.

Benefits of local anesthetic
infiltration:

Decreased pain and narcotic usage

Local anesthetic attributes: Long-acting, inexpensive, with addition of vasoconstrictor to decrease toxicity and in some cases increase duration

Agent of choice: Bupivacaine with epinephrine, with a maximum dose of 225 mg bupivacaine

Question 2

When would we use local anaesthetics?

Answer 2

Modern local anesthetics are used in a wide array of situations for surgery. Local anesthetics can be used as the sole anesthetic agent for abdominal and lower extremity procedures in the form of a neuraxial block technique (spinal anesthesia or epidural anesthesia). These techniques are overwhelmingly more common for obstetric anesthesia, and are also the technique of choice for joint replacement of the lower extremity in many anesthesia practices.

Local anesthetics have long been used as a part of a multimodal approach for postoperative pain control. Instillation of local anesthetic at the surgical site has commonly been used, but more recently, continuous infusions of local anesthetics in the forms of patient-controlled epidural anesthesia (PCEA) for thoracic and abdominal procedures as well as continuous peripheral nerve catheters are increasingly being used for postprocedural pain control and have been shown to decrease postoperative pain, as well as narcotic-associated morbidity.

Question 3

What do we typically base the maximal acceptable dose of local anaesthetics upon? Why is this controversial?

Answer 3

Historically, the maximal acceptable dose of local anesthetics, as well as adjuvants (such as opiates), have been based on a patient’s weight.

This practice is somewhat controversial since these different compounds are absorbed from different sites in the body at different rates. For example, the systemic absorption of local anesthetics is very high in vascular regions of the body such as the intercostal space for intercostals nerve blocks, but very low in the regions in which a sciatic nerve bloc is performed.

Question 4

What is the chemical structure of local anaesthetics?

Answer 4

These agents are amphipathic molecules consisting of three moieties: a lipophilic aromatic region (benzene ring), connected to a hydrophilic tertiary amide group, via an intermediate chain.

Question 5

What is the mechanism of action of local anaesthetics?

Answer 5

Local anesthetics block neural transmission by blocking voltage-gated sodium (Na+) channels. By binding to the Na+ channel, the local anesthetic blocks Na+ influx, thus abolishing membrane depolarization, action potential generation, and neural transmission.

Question 6

Are local anaesthetics acids or bases? How is this clinically relevant?

Answer 6

Local anesthetics are weak bases, with pKa’s ranging from 7.6 to 9.0. Therefore, both the ionic (protonated) and anionic forms are present at physiologic pH. However, only the nonanionic form can cross a cell’s lipid bilayer and gain access to its site of action on the intracellular domain of the sodium channel protein. Because a low pH favors the ionized or ineffective form of the local anesthetic, its injection into an acidotic environment such as an abscess, will prove ineffective since the ion cannot enter the neuronal cells.

Question 7

How does the local anaesthetic’s mechanism of action of binding to open sodium channels lead to clinical relevance?

Answer 7

The anesthetic molecule preferentially binds to the open sodium channel; therefore, local anesthetics preferentially act upon rapidly-firing nerves, so-called “state-dependent blockade.” This property is important when local anesthetics are used as antiarrhythmics to abolish ventricular tachycardia as they preferentially act on the rapidly depolarizing foci.

Question 8

How is nerve diameter and degree of myelination related to local anaesthetics sequence of nerve function blockade?

Answer 8

Smaller, unmyelinated fibers are typically blocked before larger, myelinated ones. These properties explain the predictable sequence of nerve function blockade beginning with sympathetic fibers, progressing to pain and temperature fibers, followed by proprioception, then touch and pressure, before finally, motor transmission impairment. The sequence of block resolution is the same, but regression is in reverse order.

Question 9

What are the two classes of local anaesthetics?

Answer 9

There are two classes of local anesthetics: the esters, and the amides, based on its intermediate chain.

Question 10

What are the ester local anaesthetics?

Answer 10

Procaine, benzocaine, and tetracaine

Question 11

What is a major concern with using ester local anaesthetics (such as procaine, benzocaine, or tetracaine)?

Answer 11

The esters, such as procaine, benzocaine, and tetracaine, are more likely to cause an allergic reaction because of their cross reactivity to para-aminobenzoic acid (PABA).

Question 12

Besides the possibility of an allergic reaction, what is another drawback to using ester local anaesthetics (procaine, benzocaine and tetracaine)?

Answer 12

Metabolized by plasma esterase, ester anesthetics tend to have a shorter duration of action

Question 13

What are the amide local anaesthetics?

Answer 13

The amide local anesthetics, such as lidocaine and bupivacaine

Question 14

How are amide local anaesthetics (lidocaine, bupivacaine) metabolized?

Answer 14

Amides undergo hepatic metabolism in the form of N-dealkylation followed by hydrolysis.

Question 15

How do we interpret local anaesthetic formulations (such as a 1% or 0.5% solution)?

Answer 15

Local anesthetic formulations are reported as percent solutions, or grams of material per 100 mL solution. Thus a 1% solution contains 1 g of material per 100 mL of solution, or 10 mg material per mL solution. Therefore, 0.5% bupivacaine contains 5 mg/mL, and a total of 45 mL would have to be infiltrated to reach the maximum dose of 225 mg.

Question 16

What is a local anaesthetic’s pKA and how does it affect its onset of action?

Answer 16

An agent’s pKa determines the onset of action. The pKa is the pH at which a local anesthetic is present in both charged and uncharged forms in equal amounts. As mentioned earlier, only the anionic form of a local anesthetic can gain access to the binding site on the sodium channel, which is located on the intracellular portion of the protein. Local anesthetics with a pKa closer to 7.4 will have a greater percentage of molecules in the anionic form compared to those with higher pKa’s, and therefore will have a quicker onset of action. The notable exceptions to this rule are procaine and chloroprocaine both of which have a high pKa but very rapid onset of action.

Question 17

How does a local anaesthetic’s lipid solubility affect its use?

Answer 17

Lipid solubility is directly correlated with potency. More lipophilic agents more easily cross the lipid bilayer and become pharmacodynamically active.

Question 18

How does a local anaesthetic’s protein binding affect its use?

Answer 18

The degree of protein binding is a primary determinant of duration of action for local anesthetics. The higher the degree of protein binding, the longer it engages the sodium channel, and longer is its duration of action. Protein binding in the serum is most commonly to α1-acid glycoprotein and albumin, which leads to sequestration of the local anesthetic and prevents it from being metabolized, extending its plasma half-life.

Question 19

How does the dose of a local anaesthetic affect its use?

Answer 19

The higher the dose, the faster the onset of action and the longer the duration of neural blockade.

Question 20

Where are the most common sites of injection for local anaesthetics and what is this based upon?

Answer 20

The more vascular the area of injection, the higher the peak plasma level of local anesthetic, the higher the potential for toxicity, and the shorter the duration of blockade. The peak plasma levels of local anesthetic depending on site of injection are in descending order: intravenous, intercostal, caudal, epidural, upper extremity (brachial plexus), lower extremity (sciatic/femoral).

Question 21

Would you anaesthetic adjustvants to local anaesthetics?

Answer 21

Addition of adjuvant drugs can favorably affect the pharmacokinetics and pharmacodynamics of local anesthetics.

Question 22

How can the addition of help with local anaesthetic preparations?

Answer 22

Most local anesthetic formulations are prepared with a pH of 4 to 6; as a result, most of the molecules are present in the poorly lipid-soluble ionic form. The addition of sodium bicarbonate to local anesthetic preparations raises the pH of the solution and increases the percentage of anionic local anesthetic molecules, and thus speeds the onset of action. There is also data to suggest that by increasing the pH, the addition of sodium bicarbonate decreases the pain of injection.

Question 23

How can the addition of epinephrine help with local anaesthetic preparations?

Answer 23

One of the most useful applications of epinephrine-containing preparations compared to plain solutions is the ability to rapidly detect an intravascular—specifically an intra-arterial—injection. Even relatively small amounts of local anesthetic, if injected directly into the vasculature can lead to toxicity (see Case 15). If a local anesthetic containing epinephrine is injected into a blood vessel, a 10% to 20% increase in heart rate and/or blood pressure will result. Thus it is a common practice to include epinephrine in the small or “test” dose which precedes the injection of any large amount of local anesthetic. If a rise in heart rate and/or blood pressure is observed, the injection should be halted and the needle/catheter repositioned before continuing.

The addition of epinephrine to the test dose lends an increased sensitivity to intravascular injection when compared to aspiration before injection.The addition of epinephrine to local anesthetics also leads to local vasoconstriction, less systemic uptake of the local anesthetic, and a decreased risk of toxicity. The duration of action of long-acting agents such as bupivacaine are not affected by the addition of epinephrine. However, the decreased systemic absorption can extend the clinical effect of shorter acting agents such as lidocaine and chloroprocaine.

Epinephrine can also potentiate the analgesic action of local anesthetics through alpha-2 receptor-mediated action.