Pharm: 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 propogation

Question 2

Structure of local anesthetics

Answer 2

• Hydrophilic and hydrophobic domains separated by an intermediate ester or amide linkage

Question 3

Local anesthetics - acids or bases?

Answer 3

Weak bases d/t quaternary amine group

Question 4

What 2 forms do LAs exist in in the body?

Answer 4

Uncharged base and charged cation

Cation is hydrophilic, uncharged form is lipophilic and can cross membranes

Question 5

pKa

Answer 5

The pH at which 50% of the molecule is in ionized form and 50% is in non-ionized form

The higher the difference between pKa and pH of body fluid, the more drug will exist in ionized form and therefore unable to penetrate membranes n shit

Question 6

What does potency of LA depend on

Answer 6

lipid solubility

Question 7

What does onset of action depend on

Answer 7

pKa and lipid solubility

Question 8

What does duration of action depend on

Answer 8

Protein binding

Question 9

What does absorption depend on

Answer 9

• Site of injection (vascularity)
• Dose of LA
• Drug’s intrinsic properties (protein binding - more binding, less absorption)
• Addition of epinephrine (vasoconstriction –> less uptake)

Question 10

Peak blood levels at various sites following injection

Answer 10

IV>tracheal>intercostal>caudal>lumbar epidural>brachial plexus>sciatic>SQ

Question 11

Distribution

Answer 11

• Depends on organ uptake or vascularity of injection site
• Two-compartment model: initial alpha phase of rapid distribution in blood and highly perfused organs, exponential decline followed by slow beta phase reflecting distribution into less perfused organs (linear decline)

Question 12

Metabolism and excretion

Answer 12

Differs between amides and esters

Esters: hydrolyzed by enzyme in plasma, pseudocholinesterase or butrylcholinesterase: rapid hydrolysis to water soluble metabolites –> short 1/2life

Amides: transformed by hepatic carboxyl esterases and CYP450 enzymes, metabolites dependent on renal clearance

Question 13

Mechanism of LAs

Answer 13

• REVERSIBLY BIND to intracellular portion of sodium channel and inactivate it –> threshold for excitation increases, impulse conduction slows, rate of rise of AP amplitude decreases, ability to generate AP is diminished as more and more Na channels blocked
• if Na current blocked over critical length of nerve (2-3 nodes of Ranvier in myelinated nerve), propagation no longer possible
• Effects more marked in ACTIVATED state Na channels than resting state or inactivated state
• Recovery from drug block is 10-1000x slower in inhibited channels in ACTIVE state than inactivated

Question 14

Differential block

Answer 14

The action of local anesthetic is not limited to only sensory nerves, but the nerve fibers differ in their susceptibility to local anesthetics

• Smaller and myelinated nerves get blocked earlier
• Active fibers blocker more than inactive
• Nerve fibers proximal to side of LA injection blocked earlier than distal fibers

Question 15

What determines systemic toxicity?

Answer 15

• Dose of drug administered
• Rate of absorption of drug
• Site injected, its vascularity, use of vasoconstrictors
• Biotransformation and elimination of drug from circulation

Question 16

What type of LA is safest w/ respect to systemic toxicity?

Answer 16

Short-acting esters d/t their clearance by pseudocholinesterase

Question 17

How do LA cause CNS toxicity?

Answer 17

• They readily cross BBB creating dose dependent effects
• High risk for high potency agents like bupivacaine and ropivacaine
• They cause depression of cortical inhibitory pathways, allowing unopposed excitatory neuronal pathways (seizures) followed by generalized CNS depression

Question 18

Early signs of CNS toxicity

Answer 18

Circumoral numbness, dizziness, tinnitus, blurred vision, restlessness/agitation/seizures followed by CNS depression (respiratory arrest, unconsciousness

Question 19

Factors increasing potential for CNS toxicity

Answer 19

Intrinsic factors: low protein binding, decreased clearance such as liver failure or pseudocholinesterase deficiency

Extrinsic factors: Metabolic or respiratory acidosis

Question 20

Wtf do we do if CNS tox occurs?!?!

Answer 20

It’s CRITICAL to prevent hypoxemia and acidosis b/c acidosis worsens the toxicity

We must intubate and mechanically ventilate

Question 21

Cardiovascular toxicity

Answer 21

• Requires much higher doses than for CNS tox, correlates w/ potency
• Cardiac Na channel blockade is the cause –> results in depression of myocardial contractility and reduced refractory period
• All LA (except cocaine and ropivacaine at certain doses) are vasodilators –> cardiovascular collapse

Question 22

Tx of cardiovascular tox

Answer 22

ACLS algorithm, rapid intralipid infusion

Question 23

Cauda Equina Syndrome from LA

Answer 23

Reported w/ continuous spinal catheters infusing lidocaine in order to permit repetitive dosing to facilitate adequate anesthesia and maintenance of block for extended periods

Mechanism not related to Na channel blockade, but rather to myriad of deleterious effects including conduction failure, membrane damage, cytoskeletal disruption, accumulation of intracellular Ca, disruption of axonal transport and apoptosis

Question 24

Transient Neurological Syndrome (TNS) from LA

Answer 24

Transient pain or dysesthesia linked to use of lidocaine for spinal anesthesia

Now a/w neurologic deficits like cauda equina syndrome, but pain can be quite severe

Not related to dose of lidocaine used

• Increased risk w/ certain positions during surgery such as lithotomy
• Increased risk with ambulatory anesthesia
• Also found w/ Procaine and Mepivacaine, but not Bupivacaine or Chlorprocaine

Question 25

Allergic reaction to LA

Answer 25

• High incidence w/ esters d/t PABA metabolites, a known allergen
• Amides have no such metabolites. Methylparaben may be a preservative used in some amide preperations of amide LAs which metabolizes to PABA
• No cross rxn between the two groups
• THEREFORE preservative free amides should be used in patients w/ known hypersensitivity to esters