Local anesthetics

Question 1

Aromatic ring determines

Answer 1

how lipid soluble a local anesthetic is, which correlates with potency and duration of action; w/ higher affinity for protein binding the LA’s can remain bound to nerve membrane longer, increasing duration of action

Question 2

Intermediate linkage: examples?

Answer 2

ester or amide bond, which determines the two classes of local anesthetics: amino esters and amino amides;

esters metabolized primarily by PLASMA ESTERASES and hydrolysis is rapid (excreted in urine, more likely to cause allergic reactions since they’re derivatives of PABA)

amides: metabolized in liver and metabolites dependent on renal clearance; amino amides unlikely to cause allergic reaction (2 I’s!!!)

Question 3

Terminal amine (hydrophilic portion) is

Answer 3

to deal with onset of action (determined by pKa of local anesthetic and pH of local environ); ionized form is ACTIVE form vs. uncharged being diffusible across lipid membrane but NOT ACTIVE!!!)

Question 4

Regarding pKa, the higher the pKa of the LA

Answer 4

the lower the concentration of unionized form at physiological pH and slower the onset

Question 5

In which environment would quicker onset of action be favored, acidic or basic?

Answer 5

Basic (think abscesses, or acidic, vs. c-section, or basic!!!!)

Question 6

Local anesthetics bind to and block

Answer 6

intracellular portion of inactivated voltage gated Na channels, slowing repol and preventing propagation of further AP’s

Question 7

Onset of bloc depends on:

Answer 7

1. Size of nerve fiber (smaller diameter allows anesthetic to penetrate more quickly)
2. Degree of myelination (myelinated nerve needs only to be blocked at nodes of Ranvier, so is blocked more quickly)
3. Firing frequency (local anesthetics bind to inactive Na channel, so the more often the nerve fires the more inactive channels are available)

Question 8

Nerve fascicles are blocked from; which are most sens to block?

Answer 8

the outside-in (prox to distal progression);

B > C > Adelta > Agamma > Abeta > Aalpha

Question 9

Pharmacokinetics: absorption:

Answer 9

Determined by:

1. site of injection (highly vascular tissue absorbs more local anesthetic than less vascular tissue)
2. Presence of vasoconstrictors: decreases absorption, increases neuronal uptake, prolongs duration of effect, limits toxic SE’s
3. Local anesthetic agent: LA’s highly tissue-bound more slowly absorbed

Question 10

Pharmacokinetics: distribution:

Answer 10

1. Tissue perfusion (highly perfused organs for initial uptake, then slower redistribution phase to moderately perfused tissue)
2. Tissue/blood partition coefficient: strong plasma protein binding will keep local anesthetic in blood, while high lipid solubility facilitates tissue uptake

Question 11

For systemic toxicity, think; treat

Answer 11

1. CNS toxicity (decreased inhibition, sensory disturbances, restlessness, tremor, tinnitus early; lethargy, hypotension, bradycardia, decreased RR late)
2. Cardiovascular toxicity (LA’s can reduce cardiac conductivity, excitability, contractility because of Na/K channel block, especially the potent, highly soluble, highly protein bound LA’s like bupivicaine)
3. ACLS, intralipid; if methemoglobinemia, think methylene blue

Question 12

Local toxicity examples:

Answer 12

1. Transient neuro symptoms
2. Neuronal injury
3. Allergy (claims; think more ester anesthetics because of being PABA derivatives)