Local Anesthetics

Question 1

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

Answer 1

Local anesthetics have a tripartite structure, typically consisting of (1) a lipophilic aromatic portion, (2) an intermediate alkyl chain, and (3) a hydrophilic amine portion. The intermediate chain includes either an ester or amide moiety.

Question 2

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

Answer 2

As an aid to memorizing the relationships between
names of compounds and their structures, note that (1) virtually all local anesthetic names end in “-caine” and
that (2) the names of the esters have a single “i” (cocaine) whereas the names of the amides have two “i’s”
(lidocaine)?????????????????????

Question 3

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

Answer 3

At pH 7.4, more drug molecules are in the charged form than are in the neutral form. As described later, both
the cationic form (which binds better to the local anesthetic binding site) and the neutral form (which is able to cross the plasma membrane to reach its site of action) are needed for proper local anesthetic action. Changes in tissue pH, as a result of injury or disease for example, will obviously change the ratio of cationic and neutral drug forms, and thereby alter the effectiveness of local anesthetics.

Question 4

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

Answer 4

The binding site for local anesthetics is in a wide region of the water-filled pore of the Na+ channel. The chief route for local anesthetic access to the binding site is via the intracellular pore entrance. When the Na+ channel is closed or inactivated, the intracellular entrance to the Na+ channel pore is physically obstructed, so that local anesthetics reach their binding site primarily when the channel is open. Since local anesthetic drug molecules spend part of the time in a neutral form and also possess a lipophilic aromatic moiety, local anesthetics are able to partition into the plasma membrane and cross over to the intracellular compartment. The local anesthetic binding site has a much higher affinity for the charged form of the drug, and it is the cationic form of the local anesthetic that binds within the Na+ channel pore. A second, much slower route of local anesthetic entry into and egress from the pore binding site: a hydrophobic pathway directly through the proteinaceous wall of the channel. Via this route, local anesthetic drug molecules can very slowly enter and exit the pore binding site even when the
channel is closed or inactivated. Local anesthetics also increase the stability of the inactivated state
of the channel

Question 5

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

Answer 5

faster onset- lower pKa
More potent- higher lipid solubility
longer-lasting- greater protein binding

The potency of local anesthetics correlates best with
lipid solubility: higher lipid solubility results in higher anesthetic potency. The speed of onset of conduction blockade is primarily determined by pKa, although other factors are also involved. Lower pKa increases lipid solubility and tissue penetrance by increasing the fraction of local anesthetic molecules that are uncharged and hence partition more readily into cell membranes. Generally speaking, a lower pKa and higher lipid solubility are associated with a more rapid onset time. The duration of action of local anesthetics is closely related to protein-binding capacity: the larger the
percentage of local anesthetic bound to plasma protein, the longer the duration of action. Much of the plasma binding of local anesthetic is by α1-acid glycoprotein. However, only the amide local anesthetics are significantly bound by this plasma protein. As a consequence, amide local anesthetics tend to have longer duration action than do ester local anesthetics

Question 6

Describe the Epidural anesthesia method of local anesthetic application

Answer 6

Inject anesthetic right outside dural space. Can use catheter for continuous or multiple bolus injections. Higher plasma levels can lead to toxicity. Lidocaine for short duration, bupivacaine for longer. For delivery, give smaller amount of bupivacaine to avoid cardiotoxic effects, give with fentanyl.

Question 7

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

Answer 7

Slows systemic absorption of anesthetic. Cocaine actually causes vasoconstriction by blocking reuptake of norepi. Most other local anesthetics cause vasodilation by reducing sympathetic nervous system activity.

Question 8

Describe the side effects of local anesthetics

Answer 8

Can cause convulsion due to inhibition of inhibitory neurons in CNS. Interfere with ANS function (can be fixed with co-application of norepinephrine). Can have pro or anti arrhythmic effects on the heart. Can also cause significant vasodilation. Can also inhibit neuromuscular transmission by virtue of their ability to block nicotinic acetylcholine receptors. Allergy/Hypersensitivity- often with Esters due to PABA- a metabolic product that causes local anesthetic hypersensitivity. If allergic to all LAs, can use promethazine in high doses.

Question 9

Describe how local anesthetics differ in action from tetrodotoxin and saxitoxin

Answer 9

tetrodotoxin and saxitoxin block the extracellular entrance of voltage gated Na+ channels. Na+ channels in nerve and muscle have nanomolar affinity for these two toxins, whereas cardiac Na+ channels exhibit micromolar affinity. Tetrodotoxin and saxitoxin therefore cause death by paralyzing respiratory muscles, and not by an action on the heart.

Question 10

Describe the termination of local anesthetic action

Answer 10

Local anesthetics which are esters are hydrolyzed primarily in plasma by an esterase (pseudocholinesterase) the liver also hydrolyzes these local anesthetics. Local anesthetics which are amides are metabolized only in the liver. For individuals with hepatic insufficiency, use of amide-linked local anesthetics may be contraindicated. A significant fraction of the amide local anesthetics is bound to protein in plasma (α1-acid glycoprotein); local anesthetics are bound by other proteins in plasma as well, including albumin. The plasma level of α1-acid glycoprotein is influenced by diverse factors (smoking, contraceptive use, age), so the amount of amide-linked anesthetic delivered to the liver for metabolism is variable from patient to patient.

Question 11

What is the pKa of most local anesthetics?

Answer 11

~7.7-9 weak acid

Question 12

What does the intermediate chain determine?

Answer 12

Amides have faster onset speed, longer duration, and greater potency

Question 13

What part of the molecule gets protonated and why is this important?

Answer 13

The tertiary amine group of the local anesthetic. The neutral form is the one that enter the neuron through the membrane. With a wound, the environment is more acidic, so fewer of the local anesthetic molecules will be in the neutral form- may have to give more.

Question 14

Which fibers are the most sensitive to local anesthetics?

Answer 14

C fibers. Small diameter fibers have a low density of Na channels all along the axon
Large diameter fibers have very high density of Na channels at nodes of ranvier, creating a large safety factor and undergo very little use-dependent block.

Question 15

Discuss termination of local anesthetic action

Answer 15

Ester are mostly hydrolyzed by pseudocholinesterase in the plasma, so don’t last as long. Amides are meabolized in the liver. . A significant fraction of the amide local anesthetics is bound to protein in plasma (α1-acid glycoprotein), the level of which can be affected by diverse factors (smoking, contraceptive use, age).

Question 16

Describe the Topical method of local anesthetic application

Answer 16

Tetracaine, lidocaine and cocaine are typically employed. Anesthesia is always superficial. A disadvantage is that there is considerable absorption of drug into the circulation, which can have toxic affects.
EMLA cream (lidocaine and procaine) exists as an oil at room temperature and can thereby penetrate intact skin, producing anesthesia up to a depth of 5 mm.
Benzocaine has low solubility in water, so it can be directly applied to a wound because it won't have toxic systemic effects.

Question 17

Describe the Infiltration anesthesia method of local anesthetic application

Answer 17

injection of local anesthetic into tissue without consideration of the location of
cutaneous nerves. The advantage is that the function of underlying organs is unaffected; the disadvantage is that large doses are needed and there may be significant absorption into the circulation. Lidocaine, procaine and bupivacaine are typically employed.

Question 18

Describe the Nerve block anesthesia method of local anesthetic application

Answer 18

injection of a high concentration of local anesthetic near a peripheral nerve or nerve plexus. Can anesthetize larger regions. lidocaine most commonly used for procedures requiring up to 2-4 hours of anesthesia, and bupivacaine used for procedures of longer duration.

Question 19

Describe the Intravenous regional anesthesia (Bier’s Block) method of local anesthetic application

Answer 19

blood is squeezed out of limb with tourniquet and local anesthetic is injected. Tourniquet pain and ischemic injury limit the use of this method to a maximum duration of 2 hours. Lidocaine

Question 20

Describe the Spinal anesthesia method of local anesthetic application

Answer 20

injection of a local anesthetic into the cerebrospinal fluid bathing the lumbar section of the
spinal cord. The main advantage of this method is that very large body regions can be anesthetized while
maintaining a low plasma level of drug. Only used for lower abdomen, perineum, and lower extremities. Lidocaine for short duration, bupivacaine for intermediate, and tetracaine for long.