Local Anesthetics

Question 1

What is the definition of a local anesthetic?

Answer 1

Local inhibitors of PNS without loss of consciousness or vital functions, inhibiting sensory transmission to brain and/or motor impulse transmission to muscles

Question 2

Are local anesthetics analgesics?

Answer 2

No, they are not specific inhibitors of the pain pathway (i.e. opioid analgesics). They just nonspecifically inhibit the conduction of aciton potentials

Question 3

What are the three components of the structure of a local anesthetic?

Answer 3

1. Aromatic ring
2. Intermediate linkage (ester or amide)
3. Terminal amine (can gain proton and become stuck in a compartment)

Question 4

What form of the local anesthetic (LA) is active and how does it work? That is, what is the mechanism of action?

Answer 4

Only the protonated form -> binds to the LA binding site on the OPEN sodium channel and stabilizes the inactive state of the channel

Extends refractory period by delaying return to closed / resting conformation (occurs in a progression from increased threshold to total action potential abolishment)

Question 5

What is meant by critical length?

Answer 5

If sodium current is blocked over a “critical length” of the nerve, action potential propagation will no longer be possible, you will have effective anesthesia

Question 6

What lipid solubility profile for a LA is most clinically effective and why?

Answer 6

Moderate hydrophobicity

Too low - hydrophilic molecules cannot cross to interior of membrane

Too high - hydrophobic molecules will get stuck in the membrane and not want to enter the cellular cytoplasm

Question 7

What does the pKa of the given local anesthetic determine? What is their relative pKa range

Answer 7

The time of onset. All are basic overall, with pkas between 8-9

Low pKa = LA is relatively acidic, will exist in deprotonated and uncharged form -> rapid crossing of membrane and rapid onset

High pKa = LA is relatively basic, will exist in protonated form which is charged -> slow crossing of membrane and slower onset

Question 8

What is the general structure of the voltage-gated sodium channel?

Answer 8

Has four transmembrane domains, with an intracellular site for binding local anesthetic

Question 9

What is the primary factor which determines duration of action of local anesthetics?

Answer 9

Protein binding -> how well they bind the receptor

Since receptor binding site is hydrophobic, more lipophilic = higher binding = increased duration of action

Question 10

What are the characteristics of a very rapid-onset, long-lasting LA?

Answer 10

Moderately lipophilic, low pKa

Question 11

How are LAs typically prepared, and what should be done when administering them clinically?

Answer 11

Typically prepared as a low pH salt, which increases their solubility / stability by keeping them charged.

Add sodium bicarbonate with injection -> makes the pH more basic, deprotonating the LA and giving it a quick onset of action

Question 12

When are topical local anesthetics used and are they safe?

Answer 12

Typically for short-term pain relief of mucous membranes

Can be unsafe and cause irregular heartbeats, respiratory depression, and death with prolonged and toxic effects (absorbed into circulation through skin)

Question 13

What is infiltration vs regional anesthesia and which one is most commonly done?

Answer 13

Infiltration - Injection of LA without considering course of nerve, for minor, superficial surgery

Regional anesthesia - injection of LA around specific nerves that provide sensation to area of body being operated

Question 14

What are three examples of regional anesthesia procedures?

Answer 14

1. Spinal anesthesia - injection into lumbar cistern for lower abdominal, pelvic, rectal, or orthopedic surgery
2. Epidural anesthesia - Injection into epidural space -> for childbirth / labor
3. Nerve block - injection around nerve truck for site distal to surgery -> i.e. brachial plexus for hand surgery

Question 15

What are some uses of nerve blocks?

Answer 15

1. Therapeutic - treat pain
2. Diagnostic - to determine source of pain
3. Prognostic - to see if blocking the nerve surgically would provide pain relief
4. Pre-emptive - to prevent pain from a procedure

Question 16

What is a Bier’s block and it’s limitation?

Answer 16

Intravenous regional anesthesia

IV injection of a LA in patient wearing a tourniquet to prevent blood flow. Easy to do. Can be done for any surgical procedure on an extremity

Limitation = discomfort from wearing tourniquet

Question 17

What are the types of A and C fibers and what information do they carry? How do they relate with respect to diameter / myelination?

Answer 17

A = heavily myelinated, in order of descending diameter
A-alpha - unconscious proprioception, motor
A-beta - DC-ML = fine touch, pressure
A-gamma - intrafusal spindle information
A-delta - ALS - acute pain, temperature

C= unmyelinated, small diameter
C - ALS - slow, aching and burning

Question 18

For a local anesthetic, is it easier to block a myelinated or unmyelinated nerve, and a small or large nerve?

Answer 18

Myelinated nerve -> only needs to block 3 consecutive nodes of Ranvier to block saltatory conduction

small diameter nerve -> electrical field travels farther on sections of larger nerve, and the nodes will be much farther apart (need a wider area of anesthetic to cover)

Question 19

What properties of the nerve fiber with respect to firing rate and location in nerve bundle make it more susceptible to LA? What does this explain with respect to motor / sensory

Answer 19

Hiring firing rate = faster block (more sodium channels vulnerable)

More peripheral = faster block. Explains why motor fibers tend to be blocked before sensory fibers within a fascicle

Question 20

What is often done to prevent toxicity of LA? When is this not indicated?

Answer 20

Reduce blood flow to the area of injection and reduction in systemic circulation by injection with epinephrine

Not indicated for areas with limited collateral circulation, like distal extremities and penis -> can cause gangrene and hypoxic tissue damage

Question 21

How are ester LA’s metabolized?

Answer 21

Via pseudocholinesterase enzymes in the plasma, very rapidly, with metabolites excreted in urine

Question 22

When will ester LA metabolism be slowed or inactive?

Answer 22

1. Pseudocholinesterase deficiency
2. Esters administered into CSF -> need vascular absorption before inactivation
3. Pregnancy / parturition decreases activity -> longer recovery

Question 23

How are amide LA’s metabolized

Answer 23

Via CYP450’s in liver

Question 24

When should amide LA dosage be decreased?

Answer 24

Newborns -> immature hepatic enzymes, contraindicated

Elderly -> reduced hepatic blood flow

Question 25

What are the toxic effects of LA in the CNS and what is done prophylactically?

Answer 25

CNS stimulation by depressing cortical inhibition pathways

-> dizziness, tremors, metallic taste, confusion, respiratory depression

Premedicate with benzodiazepines

Question 26

What are the cardiovascular effects of LA’s?

Answer 26

By blocking SANS conduction, they result in decreased cardiac output and arteriolar vasodilation (except cocaine) -> hypotension

Question 27

What class of LA’s is most likely to cause an allergic reaction and why?

Answer 27

Esters -> derivatives of p-aminobenzoic acid (PABA)

Question 28

List the clinically important ester LA’s?

Answer 28

Drugs not containing “i” before the caine

1. Cocaine
2. Procaine
3. Benzocaine
4. Tetracaine

Question 29

List the clinically important amide LA’s?

Answer 29

Drugs containg ‘i’ before the caine

1. Lidocaine
2. Bupivacaine
3. Ropivacaine

Question 30

What is the primary clinical use and adverse effects of cocaine?

Answer 30

Mucous membrane -> topical agent for numbing and vasoconstriction (sympathetomimetic effect). Can be used to decrease post-op bleeding

Adverse effects - hyper-sympathetic effects cardiac + addiction

Question 31

What is the primary clinical use of procaine and its adverse effects?

Answer 31

Used IV for nerve block, infiltration, and dental procedures

Adverse effects - none - but short half-life and derivative of PABA can reduce effectiveness of sulfonamides

Question 32

What is the primary clinical use of benzocaine and its adverse effects?

Answer 32

Only used TOPICALLY -> low pKa gives rapid onset. Used in creams / ointments

Adverse effects - methemoglobinemia possible

Question 33

What is done to treat methemoglobinemia?

Answer 33

Give IV methylene blue

Question 34

What is the primary clinical use of tetracaine and its primary adverse effect?

Answer 34

Used for high potency and long action in spinal anesthesia. Also for topical anesthesia of trachea, larynx, and esophagus

Adverse effect -> slowly metabolized, can cause systemic toxicity

Question 35

What is the relative onset and clinical uses of lidocaine?

Answer 35

Rapid onset (low pKa)

Used topically, or for all clinical procedures.

Also used to treat ventricular arrythmias

Question 36

Why would bupivacaine or ropivacaine be used over lidocaine?

Answer 36

Produce a much longer duration of action

Question 37

What are the clinical uses of ropivacaine?

Answer 37

Long-term, potent blockade needed in epidural, infiltration, nerve block, and spinal

Question 38

What extra activity does ropivacaine have that’s kinda juicy?

Answer 38

Vasoconstriction - does not need to be given with epinephrine

Question 39

Do bupivacaine and ropivacaine preferentially block the motor system or sensory system? Why is this relevant?

Answer 39

Blocks the sensory system first - good for labor (epidural to facilitate birth of da bb)

Question 40

Why is ropivacaine preferred over bupivacaine?

Answer 40

Bupivacaine is cardiotoxic