Local Anesthetics

Question 1

Review of RMP/Action Potential

Answer 1

Question 2

Local Anesthetics

Answer 2

Esters and Amides

• Impair nerve signal transmission by blocking VGaNa+C anywhere
• the aromatic ring is lipophilic (hydrophobic)
• the tertiary amine is hydrophilic (lipophobic)
• more hydrophobic compounds are more potent and produce longer blockade than less hydrophobic ones

we want MORE hydrophobic/lipophilic… longer lasting!

Question 3

Esters

Answer 3

• metabolized by P.cholinesterase (except cocaine)
• one I

Question 4

Amides

Answer 4

• liver metabolism (therefore hepatic blood flow and function are important!!)
• Two I’s

Question 5

Review of Ester/Amide Structures

Answer 5

Question 6

Weak Acid Binding

Answer 6

Weak acids bind with positively charged ions like Na+, Mg++, Ca++

• sodium pentathol is a weak acid

Question 7

Weak Base Binding

Answer 7

Weak bases bind with negatively charged ions like Cl- and SO42-

• lidocaine hydrochloride and morphine sulfate are weak bases

Question 8

2 important determinants of LA function:

Answer 8

pH and pKa

Question 9

pKa

Answer 9

pKa is pH at which 50% is ionized and 50% is unionized

• pKa is different for the different LA

Question 10

pKa Lidocaine example

Answer 10

• pKa Lidocaine is 7.7 - 7.9
• Standard human pH is 7.35 - 7.45 (7.4)
• At pH 7.4, lidocaine is more ionized (75% ionized) than at pH 7.7 so less is available to cross membranes
• base (lidocaine) + acid (human fluids) = ionized LA

generally speaking… lower pKa means more LA in nonionized form and faster onset of block

Question 11

Most LA are ____ ____ (pKa 7.5 - 9) in solution but salts are ____ _____.

Answer 11

Most LA are weak bases (pKa 7.5 - 9) in solution but salts are weak acids.

• ketamine, opioids, and benzos are weak bases

Question 12

Weak bases become ____ nonionized as the pH increases.

Answer 12

MORE

increased pH = decreased H+ ions = increased nonionized LA = good (but bad w babies and ion trapping)

LA must be in the basic form to be unionized and capable of penetrating the cell membrane to block the Na+ channel

Question 13

Is LAST worse in basic or acidotic patient?

Answer 13

LAST is worse with acidosis because the LA moves into the Na+ channels and gets trapped.

ie: in the heart blocking Na+ channels

Question 14

How do you increase the ionization of LA?

Answer 14

LA premixed w Epi = more acidic (pH 3.5) which increases the ionization of the LA

*has increased duration but also increased onset time. Inversely, you can mix w bicarb to bring pH up and get more in the unionized form to get a faster onset but shorting acting LA.

Question 15

LA Protein Binding

Answer 15

LA have high protein binding (A1AG preferred to Albumin) but more albumin exists in the human body.

• LA must release from protein to cause Na+ ch block

- protein binding = duration

- high protein binding = long duration of LA

- as pH decreases, % of bound drug decreases

• protein binding is more important than lipid solubility for duration of aciton

Question 16

LA protein binding and duration order

Answer 16

Bupivacaine

etidocaine

ropivacaine

mepivacaine

lidocaine

procaine

2-chloroprocaine

Question 17

Acidosis and the LAST patient

Answer 17

Do not let a suspected LAST pt become acidotic since the proportion of free LA molecules will increase rapidly!

ie: bupivacaine 95% (5% available for action) protein bound normally decreases to 70% w acidosis (30% available for action!) 6x more blockage

Question 18

Oil:Water Partition Coefficient

Answer 18

is equal to lipid solubility = potency

The greater the oil: water PC for an LA, the greater the potency.

Question 19

Blocking the Na+ Channel

Answer 19

• peripheral nerves are mixed (motor/sensory)
• LA placed near nerve diffuses via concentration gradient from outer sheath to core
• fibers in outer/proximal/motor are blocked first

Question 20

Steps of Blocking Na+ Channel

Answer 20

- unionized LA penetrate cell membrane

• become ionized
• bind to Na+ channel
• prevent opening and Na+ inrush
• NO action potential!
• blocking the Na+ ch blocks conduction of nerve impulse to the brain…*

no impulse = no pain

Question 21

Onset of LA Block

Answer 21

Closer to the nerve = faster onset!

• within the sheath is good, but not on the actual nerve
• intraneural and sub-epineural = faster onset dur to proximity of LA to nerve
• small block faster than large
• myelineated block easier than un
• NO DIFFERENCE in motor vs. sensory

Question 22

Factors determining rate of diffusion across nerve sheath:

Answer 22

• concentration of LA (higher concentration diffuses faster)
• degree of ionization (UNionized faster)
• hydrophobicity
• physical characteristics of tissue around nerve (ie: more vascular taken up faster and not get to nerve)

Question 23

Increased lipid solubility… (4 things)

Answer 23

• increases potency
• increases duration
• increases toxicity
• decreases therapeutic index

Question 24

What 3 factors determine ability of LA to stay near the nerve? (and therefore duration)

Answer 24

1) lipid solubility
2) vascularity of tissue
3) presence of vasoconstrictors (which prevent vascular uptake of LA molecules)

Question 25

Order of Loss of Nerve Sensations

Answer 25

1. Autonomics 2. Pain 3. Cold 4. Warmth 5. Touch 6. Pressure 7. Vibration 8. Proprioception 9. Motor function

Question 26

Desireable Properties of LA

Answer 26

1. reversible conduction block 2. compatible w vasoconstrictors 3. rapid onset 4. non-irritating 5. low potential for LAST 6. long duration w short recovery 7. effective in different delivery modalities

Question 27

Cocaine

Answer 27

- ester - blocks nerve impulses - local vasoconstriction d/t inhibition of local NE reuptake - euphoria d/t blockade of dopamine reuptake in CNS - good for LA in nasal passages (because it is a LA that also vasoconstricts)

Question 28

procaine

Answer 28

ester - 1st synthetic LA (synthetics get rid of the SE we don't want) - low potency, slow onset, short duration

Question 29

2-chloroprocaine

Answer 29

ester - chlorinated procaine, most rapidly metabolized by Pcholinesterase

Question 30

tetracaine

Answer 30

longest duration ester! - more potent, slowly metabolized - too toxic for peripheral blocks but OK for long acting spinals - sometimes mixed w lidocaine for peripherals

Question 31

lidocaine

Answer 31

amide - rapid absorption paernteral, GI, and resp - intermediate duration - 1.5-2% for most regional blocks - more dilute concentrations for pain mgmt

Question 32

mepivacaine

Answer 32

amide - intermediate duration - pharm similar to lido - similar onset w slightly longer duration (3-6 hr) - **toxic to neonates - NOT used in OB!**

Question 33

prilocaine

Answer 33

amide - intermediate duration w pharm like lido - lacks vasodilation, increased Vd (limits CNS toxicity) - **causes methmeglobinemia at 8 mg/kg** (tx w methylene blue 1-2mg/kg) - uncommon in peripheral nerve blocks

Question 34

etidocaine

Answer 34

amide - longer duration - onset like lido, duration like bup - alkyl sub on aliphatic group between hydrophilic amine and amide increases lipid solubility - increased lipid solubility = increased potency = increased duration - downlide is motor block that outlasts sensory! - **not useful for peripheral nerve blocks**

Question 35

bupivacaine

Answer 35

amide - long duration (longer w EPI) - slower onset w variable duration (2-3 hours spinal, 12-24 for peripheral) - **cardiotoxic** (direct inj into medulla = v-arrhythmias, difficult to dissociate from Na+ ch) - widely used for peripheral blocks in dilute concentrations of \<0.5% - **careful** use in OB epidurals (\<0.25%)

Question 36

ropivacaine

Answer 36

amide - S-enantionmer of bup = lower toxicity, less potent at \<0.5% - slower uptake thus lower blood levels - extensive hepatic metabolism - \>0.5% dense block w shorter duration than Bup - at 0.75%, onset is fast, CNS and cardiotoxicity are reduced, and motor block is less than Bup - **popular for peripheral nerve blocks**

Question 37

levobupivacaine

Answer 37

- another single enantiomer of bup - less toxic than Bup but works in similar fashion w similar duration

Question 38

LA Percentages

Answer 38

0. 25% = 2.5 mg/mL 0. 5% = 5 mg/mL 1% = 10 mg/mL 2% = 20 mg/mL

Question 39

Plasma concentration of LA is determined by what 4 things? (LAST)

Answer 39

1. DOSE of drug 2. RATE OF ABSORPTION 3. SITE of injection 4. biotransformation and ELIMINATION from circulation * same dose injected in different locations in diff patients = diff peak plasma levels!*

Question 40

Blood flow and LA absorption (I think I can push each bolus Sslowly for safety)

Answer 40

From shortest to fastest: 1. IV 2. Tracheal 3. Intercostal 4. Caudal 5. Paracervical 6. Epidural 7. Brachial Plexus 8. Subarachnoic, sciatic, femoral 9. SubQ

Question 41

LAST

Answer 41