Local Anesthetics

Question 1

Describe the general structure of local anesthetics, and key chemical properties of the structures.

Answer 1

Structure: tripartite structure with

1) . Lipophilic aromatic portion: allows the local anesthetic to travel through the plasma membrane.
2) . Intermediate alkyl chain ==> ester or amide moiety (determines side effects & metabolism)
3) . Hydrophilic amine portion: area that can become a cation and therefore bind to the Na channel.

Question 2

Describe the structural and chemical differences between amide and ester local anesthetics.

Answer 2

Amide anesthetics are significantly bound by the plasma protein α1-acid glycoprotein
•these have a LONGER duration of action than do ester local anesthetics.
•Amides can only be metabolized by the liver- Do not use these kind in liver-failure pts.! Also, can be more toxic because lots of things are broken down by the liver

Esters are primarily hydrolyzed by an esterase (cholinesterase).

Question 3

Describe the role of pH in determining the effectiveness of local anesthetics.

Answer 3

Local anesthetics are weak bases with pKa values of 7.7 to 9.0 that are partially ionized at pH 7.4:

•Rapid protonation/deprotonation reaction at the N of the amino group so that local anesthetic molecules rapidly interconvert between positively charged and neutral.
•At pH 7.4: more drug molecules are in the charged form than neutral one
Charged form = binds to the local anesthetic binding site
Neutral form = can cross the plasma membrane to reach its site of action
•Tissue acidity decreases the amount of neutral local anesthetic present and requires applied dose to be increased.

Question 4

Describe the molecular target and structure-based mechanism of action of local anesthetics.

Answer 4

Binding Site for local anesthetic: in a wide region of the water-filled pore of the Na+ channel.

• Ion conduction pathway of the channel is too narrow for the drug to reach its binding site via the extracellular entrance to the channel.
• Main route: when the channel is open and Na ions are rushing in (fast).
• Alternative route: partition into the plasma membrane and cross over to the intracellular compartment due to membrane solubility (slow).

Form that binds: the cationic form

Question 5

Describe physicochemical properties of local anesthetics that determine potency, onset and of drug action.

Answer 5

• Low potency: procaine
• Medium potency: lidocaine
• High potency: bupivacaine, etidocaine

Potency determined by lipid solubility. Larger the percentage of anesthetic bound to protein, the longer the duration of action. Lower pKa = more rapid onset time

Question 6

Describe methods of local anesthetic application.

Answer 6

Topical 
Infiltration (injection)
 Nerve block
Intravenous regional (Bier's block)
Spinal anesthesia
Epidural

Question 7

Describe the rationale for use of a vasoconstrictor with a local anesthetic

Answer 7

Co-utilization of a vasoconstrictor: the vasoconstrictor prolongs the duration of conduction blockade by reducing blood flow in the vicinity of the injection to retard systemic absorption of the anesthetic.

• Epinephrine is usually used.
• Prevents plasma anesthetic levels from rising to potentially toxic levels.
• Cocaine is the only anesthetic that you do not need a vasoconstrictor with.

Question 8

Describe side effects of local anesthetics (overdose)

Answer 8

• Convulsions via action on inhibitory interneurons of the CNS (they cross blood-brain barrier).
• Interfere with autonomic nervous system function (why use epinephrine).
• Act on the heart in a pro-arrhythmic method – especially bupivacaine.
• Vascular smooth muscle actions – significant arteriolar dilation
• Fetal damage
• Inhibit neuromuscular transmission – block nicotinic Ach receptors.
• Allergy

Question 9

Describe how local anesthetics differ in action from tetrodotoxin and saxitoxin.

Answer 9

Two most potents toxins known: tetrodoxin + saxitoxin

• Both act to bind and block the extracellular entrance of voltage-gated Na+ channels.
• Na channels in nerve and muscle have nanomolar affinity for these 2 toxins
• people die from paralyzed respiratory muscles, not heart.
• Cardiac Na channels exhibit micromolar affinity