Pharm U3 local anesthetics.

Question 1

local anesthetic definition

Answer 1

an agent that reversibly prevents transmission of nerve impulse in the region to which it is applied without affecting consciousness accomplished by disruption of afferent nerve conduction by inhibition of nerve impulse generation in the neuron and its propagation

Question 2

describe the typical structure of a local anesthetic

Answer 2

hydrophilic (tertiary amine) and hydrophobic (aromatic) domains separated by an intermediate ester or amide linkage

Question 3

how are local anesthetics stored?

Answer 3

weak bases stored as salts to increase stability

Question 4

how do local anesthetics exist in the body?

Answer 4

2 forms - uncharged base (lipophilic form) and charged cation (hydrophilic form)

Question 5

how are the proportions of the two forms of local anesthetics governed?

Answer 5

by pKa and pH

Question 6

at what pKa will the drug exist as ionized form and NOT be able to penetrate membranes and be slower for onset?

Answer 6

higher difference between pKa and pH of body fluid

Question 7

potency

Answer 7

correlates lipid solubility

Question 8

onset of action

Answer 8

depends on pKa and lipid solubility

Question 9

duration of action

Answer 9

depends on protein binding

Question 10

absorption depends on what?

Answer 10

site of injection, dose, drug intrinsic properties (protein binding - less absorption if highly protein bound), addition of epinephrine (vasoconstriction - less blood flow and uptake)

Question 11

what is the two compartment model of distribution?

Answer 11

initial alpha phase of rapid distribution in blood and highly perfused organs with exponential decline - slow beta phase with distribution into less perfused organs with linear decline

Question 12

metabolism and excretion based on what

Answer 12

differs between amides and esters

Question 13

esters hydrolyzed by what?

Answer 13

hydrolyzed by an enzyme in plasma (pseudocholinesterase or butrylcholinesterase) cases rapid hydrolysis to water soluble metabolites therefore have very short half lives

Question 14

amides transformed by what?

Answer 14

hepatic carboxyl esterases and CYP-450 enzymes (so liver disease such as cirrhosis slows metabolism and may lead to toxicity)

Question 15

local anesthetic mechanism of action

Answer 15

bind reversibly to the intracellular portion of sodium channel and inactivate the channel = threshold for excitation increases, impulse conduction slows, the rate of rise of action potential amplitude decreases and then the ability to generate an action potential is completely abolished

Question 16

what is the critical length to block the sodium current?

Answer 16

in myelinated nerves critical length is 2-3 nodes of Ranvier

Question 17

when is the nerve fiber most easily blocked?

Answer 17

when sodium channel is in the activated state than resting or inactivated state

Question 18

which nerves are blocked first

Answer 18

smaller, myelinated, active fibers blocked first

Question 19

which factors determine toxicity

Answer 19

dose, rate of absorption, site injected, its vascularity, vasoconstrictors, biotransformation and elimination of the drug

Question 20

CNS toxicity - high risk drugs - what makes them high risk?

Answer 20

bupivacaine and ropivacaine - high potency agents

Question 21

CNS toxicity mechanism

Answer 21

anesthetics cause depression of cortical inhibitory pathways allowing unopposed excitatory neuronal pathways (seizure activity) which is followed by generalized CNS depression

Question 22

early signs of CNS toxicity

Answer 22

numbness, dizziness, tinnitus, blurred vision, CNS excitation (restlessness, agitation, seizures)

Question 23

later signs of CNS toxicity

Answer 23

CNS depression - respiratory arrest and unconsciousness

Question 24

factors increasing potential for CNS toxicity

Answer 24

intrinsic: low protein binding (malnourished states, liver disease) and extrinsic: metabolic or respiratory acidosis

Question 25

treatment for CNS toxicity

Answer 25

prevent hypoxemia and acidosis because acidosis worsens the toxicity. rapid intubation and mechanical ventilation

Question 26

cardiovascular toxicity

Answer 26

much higher doses required - cardiac Na channel blocked causing depression of myocardial contractility and reduced refractory period

Question 27

treatment for cardiovascular toxicity

Answer 27

ACLS algorithm, rapid intralipid infusion

Question 28

cauda equina syndrome

Answer 28

due to continuous spinal catheters infusing lidocaine causing severe back pain in the setting of motor deficit, sensory deficit (saddle anesthesia) along with loss of bowel and bladder control

Question 29

what is cauda equina syndrome due to?

Answer 29

NOT sodium channel blockade but a myriad of deleterious effects including conduction failure, membrane damage, cytoskeletal disruption, accumulation of intracellular calcium, disruption of axonal transport and apoptosis

Question 30

transient neurological syndrome (TNS)

Answer 30

lidocaine for spinal anesthesia - pain is very severe. increased risk with certain positions, ambulatory anesthesia, also with procaine and mepivacaine

Question 31

which local anesthesias most likely cause allergic reaction?

Answer 31

esters due to aminiobenzoic acid (PABA) metabolites (known allergen)

Question 32

are amides safe to use if someone is allergic to esters?

Answer 32

yes, no cross reaction between two groups unless methylparaben is used as a preservative (metabolizes to PABA)