local anesthetics

Question 1

Define local anesthesia

Answer 1

loss of sensation in a circumscribed area of the body. There is no loss of consciousness.

Question 2

How does local anesthesia work?

Answer 2

Block VG Na channels: Block of AP initiation or block of AP conduction in nerves

Question 3

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

Answer 3

Consists of an ester or an amide intermediate chain (key determinant for onset speed, duration and potency), an aromatic moiety (lipophilic) and an amino group (hydrophilic)

Question 4

Naming trick for amide vs ester local anesthetics

Answer 4

amides have two i’s in their names, esters have one i. Ie. Cocaine, lidocaine and procaine are esters. Etidocaine and bupivacaine have two I’s, and are amides.

Question 5

Describe the pH of local anesthetics and protonation

Answer 5

local anesthetics are Weak bases, pka 7.7-9. So at body pH (7.4) they are partially ionized (a fraction of the drug molecules are ionized) with more being charged than neutral. There is a rapid protonation /deprotonation reaction at the nitrogen of the amino group (a tertiary amine) so that local anesthetic molecules rapidly interconvert between positively charged and neutral forms.

Question 6

Henderson hasselbach equation for local anesthetic degree of ionization

Answer 6

(neutral form) / (cationic form) = 10 ^(pH – pKa)

Question 7

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

Answer 7

The cationic form binds better to the local anesthetic binding site and the neutral form is able to cross the plasma membrane to reach its site of action. Both are needed for proper action.

Question 8

How does a change in tissue pH affect local anesthetics

Answer 8

Changes in tissue pH, as a result of injury or disease, will change the ratio of cationic and neutral drug forms, and thereby alter the effectiveness of local anesthetics. For example, tissue acidity (perhaps caused by infection) will decrease the amount of neutral local anesthetic present (membrane crossing form), requiring use of an increased dose of local anesthetic to achieve anesthesia.

Question 9

Where do local anesthetics bind

Answer 9

in a wide region of the water-filled pore of the Na+ channel, but the pore is too narrow to be reached extracellularly, thus the cell must access binding site via intracellular pore entrance

Question 10

Describe the fast mechanism of local anesthetic action

Answer 10

1. The neutral, hydrophobic form of the drug crosses the plasma membrane of the cell (the lipid solubulity is important). 2. When the Na channel is open ( not closed or inactivatd), th intracellular entrance to the pore is available. 3. The cationic, hydorphilic form of the drug binds within the Na channel pore

Question 11

Describe the slow mechanism of local anesthetic action

Answer 11

Hydrophobic pathway thorugh 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.Probably it is still the cationic form of the drug that binds to the site. It becomes protonated by hydrogen ions that are able to pass through the narrow extracellular entrance of the channel and reach the drug

Question 12

How does local anesthetic block Aps

Answer 12

The drug physically blocks the Na channel so no Na ions can flow through it. This prevents membrane depolarization, terminates the action potential in the region of blocked Na+ channels, and if the blocked region is long enough, causes axonal conduction failure

Question 13

Molecular basis of use dependent block

Answer 13

Because local anesthetics primarily have access to their binding site when the channel is open, the more the channel is open, the greater the degree of local anesthetic binding and hence block. Aka frequency dependence

Question 14

How is unblocking of the Na channel use dependent?

Answer 14

local anesthetic molecules can be trapped within the inactivated channel when the “gate” at the intracellular end of the pore closes, thus exit of the drug can only be from th open state

Question 15

How do local anesthetics affect the inactivated state of the Na channel

Answer 15

local anesthetics also increase the stability of the inactivated state of the channel.As a consequence, the refractory period of the nerve is prolonged, since Na+ channels are held inactivated for a longer period of time when they are drug-bound

Question 16

Describe the length of passive propagation in small diameter, unmyelinated axons compared to large diameter, myelinated axons and how this relates to conduction block

Answer 16

length over which an action potential can passively propagate is shorter in the small-diameter, unmyelinated axons. coduction block occurs in smaller diameter, myelinated axons at lower doses than large diameter axons b/c the internodal distance is shorter in smaller diameter.

Question 17

Compare use dependent mechanisms in small vs large fibers and how this relates to local anesthetic block

Answer 17

Large-diameter axons exhibit low firing frequencies and short duration action potentials (<5 ms). Essentially, the Na+ channels of small-diameter axons are “used” more than their counterparts in large-diameter axons, and so the fractional block of Na+ channels in small-diameter axons is greater. Thus, conductoin block occurs in smaller fibers before larger fibers, so pain sensation is the first functionality lost.

Question 18

Potency of local anesthetics depends on what?

Answer 18

Lipid solubility: higher lipid solubility results in higher anesthetic potency. Pka contributes as well

Question 19

Speed of onset of local anesthetics depends on what

Answer 19

Pka: 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

Question 20

Duration of action of local anesthetics depends on what

Answer 20

protein-binding capacity: the larger the percentage of local anesthetic bound to plasma protein, the longer the duration of action. Protein binding serves to maintain the free concentration of anesthetic at an effective concentration for a longer period of time. 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 21

Discuss termination of local anesthetic action

Answer 21

Esters are hydrolyzed in plasma by esterase (ie. Pseudocholinesterase) or by liver. Amides are metabolized only in the liver (and are contraindicated in pts with hepatic insufficiency). Amides bind to protein in plasma (a1-acid glycoprotein or albumin), and the plasma level of these proteins are influence by smoking, contraceptives, etc, so the amount of amide-linked anesthetic delivered to the liver for metabolism is variable. Both are excreted by kidney, with only little of the neutral form being excreted

Question 22

topical anesthesia- examples, where it is applied, disadvantage

Answer 22

application of local anesthetics directly onto skin, cornea or mucous membranes of the nose, mouth, throat et cetera. 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.

Question 23

Unique properties of EMLA cream

Answer 23

topical mixture of lidocaine and prilocaine- the melting point of this cream is below that of either local anesthetic alone. EMLA cream exists as an oil at room temperature and can thereby penetrate intact skin, producing anesthesia up to a depth of 5 mm.

Question 24

unique properties of LA lacking terminal amino group

Answer 24

Local anesthetics lacking the terminal amino group have low solubility in water. These local anesthetics, notably benzocaine, can be directly applied to wounds because their slow absorption reduces the risk of toxicity.

Question 25

Infiltration anesthesia- how its used, advantage, disadvantage, examples

Answer 25

injection of local anesthetic into tissue without consideration of the location of cutaneous nerves. The advantage of this often very superficial anesthesia 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 26

Nerve block anesthesia- how its used, advantage, examples

Answer 26

injection of a high concentration of local anesthetic near a peripheral nerve or nerve plexus. The advantage of this technique, is that larger body regions can be anesthetized as compared to infiltration anesthesia. Most of the various local anesthetics can be employed in this method, with lidocaine most commonly used for procedures requiring up to 2-4 hours of anesthesia, and bupivacaine used for procedures of longer duration.

Question 27

IV regional anesthesia (Biers block)- how its used, limitations, examples, contraindications

Answer 27

blood is squeezed out of a limb or part of a limb, and a tourniquet is placed proximally. Local anesthetic is then injected via a catheter, and limb anesthesia develops within 5-10 minutes. Tourniquet pain and ischemic injury limit the use of this method to a maximum duration of 2 hours. Lidocaine is most commonly employed in this technique. Because the local anesthetic is injected into the blood, more cardiotoxic drugs, such as bupivacaine, are contraindicated in this method.

Question 28

spinal anesthesia- how its used, advantage, uses, examples

Answer 28

injection of a local anesthetic into the cerebrospinal fluid bathing the lumbar section of the spinal cord. The main advantage is that very large body regions can be anesthetized while maintaining a low plasma level of drug. The method is, however, only useful for surgical procedures of the lower abdomen, perineum and lower extremities. Lidocaine is employed for relatively short duration procedures, bupivacaine for intermediate duration procedures, and tetracaine (a long-lasting ester-linked drug) for longer duration procedures. In addition, anesthesia with ester-linked local anesthetics, e.g., tetracaine, is prolonged because there is little or no plasma esterase activity in the cerebrospinal fluid

Question 29

epidural anesthesia- how its used, advantage, disadvantage, exmaples

Answer 29

injection of a local anesthetic just outside the dura-enclosed spinal canal, and at the base of the canal. The principal advantage of this method arises from the ability to use catheters, allowing repeated bolus or continuous application of anesthetic. The major disadvantage, in comparison to spinal anesthesia, is that plasma levels of anesthetic are higher, which can lead to toxicity (for example, cardiovascular). Lidocaine is employed in shorter duration procedures involving epidural anesthesia, and bupivacaine in longer duration procedures. In pregnant patients undergoing labor, a lower concentration of bupivacaine is used in order to avoid the cardiotoxic side effects of the drug, and the opioid analgesic fentanyl is often co-administered.

Question 30

The rationale for use of a vasoconstrictor with a local anesthetic. Drug of choice

Answer 30

prolongs the duration of conduction blockade (by a factor of perhaps 2) by reducing blood flow in the vicinity of the injection, thereby retarding systemic absorption of the anesthetic. Also prevents plasma levels from rising to toxic levels. Epinephrine (5 μg/ml) is usually the chosen vasoconstrictor

Question 31

Side effects of local anesthetics

Answer 31

CNS: convulsions by blocking inhibitory interneurons. Interfer with ANS fnction. Cardio: pro-arrythmia (lidocaine, and bupivacaine). Vascular smooth muscle: arteriolar dilation. Enter fetal circulation. Inhibit neuromuscular transmission

Question 32

allergy to local anesthetics

Answer 32

May cause asthma attack or allergic dermatitis, rarely. Plasma pseudocholinesterase hydrolysis of ester-type local anesthetics produces para-aminobenzoic acid (PABA), which is the primary – but not only – culprit in local anesthetic hypersensitivity. hypersensitivity to amide anesthetics is rare. In patients allergic (hypersensitive) to both amide and ester local anesthetics, high doses of promethazine, an antihistamine at lower doses, can be used as a local anesthetic.

Question 33

How do tetrodotoxin and saxitotoxin work? How is this different from local anesthetics

Answer 33

both act by binding to and blocking the extracellular entrance of voltage-gated Na+ channels. As opposed to local anesthetics which block the Na channel pore from the intracellular side