Locals Flashcards
Procaine onset and pKa
Slow
8.9- 3% unionized
Tetracaine onset and pKa
Slow
8.5- 7% unionized
Bupivacaine onset and pKa
Moderate
8.1- 17% unionized
Chloroprocaine onset and pKa
Fast
8.7- 2% unionized (Given in high concentration, thus fast onset)
Lidocaine onset and pKa
Fast
7.9- 24% unionized
Etidocaine onset and pKa
Fast
7.7- 33% unionized
Mepivacaine onset and pKa
Fast
7.6- 39% unionized
Afferent cell bodies are contained in the
Dorsal root ganglia
Efferent cell bodies are contained in the
Ventral root ganglia
In a nerve, a larger diameter results in slower/faster conduction velocity?
Faster
Describe A fibers
Myelinated, 1-22 microns. Alpha, beta, gamma, delta subtypes (Largest to smallest in that order)
Describe B fibers
Myelinated, 1-3 microns
Describe C fibers
Unmyelinated, 0.1-0.25 microns
A-alpha fibers
Motor, proprioception
A-beta fibers
Motor, touch, pressure
A-gamma fibers
Motor/muscle tone (muscle spindles)
A-delta fibers
Pain, temperature, touch (we care about these ones in particular)
B fibers
PREganglionic autonomic
C fibers
Dull pain, temperature, touch, POSTganglionic autonomic.
FIber conduction velocity fastest to slowest
A-a A-b A-g A-d B C
Do large fibers have a high or low threshold for excitability
Low
Do larger fibers tend to get more or less exposure to LA
Less, the bigger fibers are typically inside of the nerve bundle. The smaller, outer fibers tend to get more LA and are thus easier to block.
Differential block- what do we see clinically? How does this differ with lab experiments?
Clinically, sensitivity is inversely related to size, thus we see autonomic block, sensory block, and then motor block.
In the lab, the larger fibers are actually more sensitive when isolated.
May be due to- larger nerves inside of nerve bundle, variations in nerve activity, variable ion channel mechanisms.
What is more important in determining onset sequence and recovery in a mixed peripheral nerve?
Location! Much more important than inherent sensitivity.
Outer surface of a nerve is the _____ and it serves _____
Inner surface of a nerve is the _____ and it serves ______
Mantle, proximal structures
Core, distal structures
Typical sequence of blockade
Sympathetic (vasodilation, warm skin. feel feet to check uneven block.)
Loss of pain and temperature sensation
Loss of proprioception
Loss of touch and pressure
Motor block
RMP is approximately _____ and it largely determined by __
-70 to -90 millivolts
K+
Action potential
Rapid depolarization of the membrane lasting 1-2 milliseconds
Nerve stimuli include
mechanical, thermal, chemical, and pressure stimuli
____ is responsible for depolarization and changes the membrane potential to _____
Na+ influx
+20 to +40 millivolts
How do LAs block nerve conduction
Inhibition of the influx of Na+ ions by blocking sodium channels (more likely when channels are in the inactivated state)
In a completely resting nerve, what determines sensitivity?
Lipid solubility of the LA, as the drug cannot easily access closed sodium channels. More active nerves are more easily blocked (at least in theory)
LAs easily access ______ Na+ channels and
easily bind to _______ Na+ channels
activated-open
inactivated-closed
How are LAs chemically classified
A lipophilic head (aromatic ring) and either:
Amide (NH) chain or
Ester (COO-) chain and
a hydrophilic tail (tertiary amine)
Amides
Two “i’s” in the drug name. LIdocaIne, bupIvacaIne.
Esthers
One “i” in the drug name. Cocaine.
Esther biotransformation
Hydrolyzed by nonspecific esterases in plasma and tissues (mostly liver). Cocaine is an exception.
Amide biotransformation
Metabolized in the liver
The more lipid soluble a LA is the more/less potent it is and the longer/shorter its duration is compared to water soluble LAs
More potent
Longer duration
A longer intermediate chain leads to
Increased potency and toxicity
Longer terminal groups on the tail and aromatic ring lead to
Increased potency and toxicity
T/F
Enantiomers of chiral LAs differ in kinetics, dynamics, and toxicity.
True
The distance between nodes of ranvier contribute to
Differential block
Internodal distance ______ with fiber diameter
Increases
An impulse can still make it through how many blocked nodes
2, blockade of 3 nodes will eliminate conduction
Differential block can be described as
Sensory block with incomplete motor block
A-delta and C fibers blocked, while A-a, b, g, fibers are not completely blocked
In a differential block, pts will still be able to feel what with surgical stimulation
Pressure
First LA to demonstrate a differential block
Bupivacaine
LA systemic absorption is governed by
physiochemistry (pKa, pH, lipid solubility), physiological conditions at site(pH, pCO2, temperature, pt characteristics), volume of solution, additives (epi), and concentration of the drug
Absorption by block type, high to low
IV Trach Intercostal Caudal Paracervical Epidural Brachial plexus Subarachnoid SubQ
Which form of the LA is able to cross the nerve sheath and membrane
Unionized form
As unionized LA diffuses across the nerve membrane what happens to the remain drug
Ionized and unionized re-equilibrate–> more unionized available to cross membrane
Ionized drug forms are favored when
An acidic drug is in a basic environment
A basic drug is in an acidic environment
Unionized drug forms are favored when
An acidic drug is in an acidic environment
A basic drug is in a basic environment
All LAs are basic/acidic drugs?
All are weak bases, though they come packaged in acidic environments
What is pKa
The pH at which 50% of a drug is ionized and 50% is unionized
What would be the ideal pKa for a LA
7.4 (body pH) Nonionized to penetrate nerve, ionized to block sodium channels
What determines the proportion of the LA in the nonionized state
The pH of the LA solution and the pKa of the drug itself
Areas with high pH will allow for faster/slower absorption
Faster (also greater amount)
Why do LAs rarely work in infected tissues?
Infection tends to drive down the local pH and shifting much more drug into the ionized state
Adding bicarb to a LA injection will do what
Increase speed of onset, enhances block depth, and increases the spread of the block
Explain ion trapping in pregnancy
Fetal pH is lower than maternal pH and results in basic drugs (such as LA) becoming more ionized when they reach fetal circulation. This effectively traps them on the fetal side of the circulation since ionized molecules cannot easily cross the placenta. This also maintains a gradient for further diffusion.
Potency main determinant
Lipid solubility
Highly potent LAs
Etidocaine, bupivacaine, tetracaine
What affects LA duration of action
Amount of time the LA is in contact with the nerve fiber
TIssue blood flow
Addition of vasoconstrictors
Lipid solubility
Protein binding (most important, increased PB–> increased DOA)
Intrinsic vasoconstrictor activity (Lido dilates, mepivacaine constricts)
Lung uptake (bupi, lido, prilo)
Metabolism
LA and vasoconstrictors- three purposes
Inhibit system absorption
Prolong LA effect
Detection of intravascular injection
Procaine Lipid sol, PB, DOA
1
5%
Short
Chloroprocaine Lipid sol, PB, DOA
1
7%
Short
Lidocaine Lipid sol, PB, DOA
4
65%
Moderate
Mepivacaine Lipid sol, PB, DOA
1
75%
Moderate
Tetracaine Lipid sol, PB, DOA
80
85%
Long
Etidocaine Lipid sol, PB, DOA
140
95%
Long
Bupivacaine Lipid sol, PB, DOA
30
95%
Long
What determines LA con. in the blood
Concentration of LA administered
Tissue blood flow
Ester metabolism
Primarily by pseudocholinesterases in the plasma (some in the liver)
Metabolite is PABA
Cocaine is the exception, primarily hepatic metabolism
Amide metabolism
Liver microsomal enzymes
Slower, more complex than esters
hydroxylation, dealkylation, hydrolysis
More likely to create toxicity/accumulation effects
Big summary for kinetics. Primary factor for-
Potency
DOA
Onset
Lipid solubility
Protein binding
pKa
Bupi max dose
2.5mg/kg
Ropi max dose
3mg/kg
3.5mg/kg with epi
Etido max dose
4mg/kg
Lido max dose
4mg/kg
7mg/kg with epi
Mepi max dose
4mg/kg
7mg/kg with epi
Chloro max dose
12mg/kg
Cocaine max dose
3mg/kg
Tetra max dose
3mg/kg
LA toxicity
Mouth/tongue numbness, tinnitus, vision changes, dizziness, slurred speech, restlessness
Muscle twitching of face/extremities indicates imminent sz
Sz followed by CNS depression, apnea, hypotension
Treat with benzos
Cocaine will display restlessness, tremors, sz, euphoria (NE reuptake inhibited)
What is transient neurologic symptoms (TNS)
Neuro-inflammatory process causing pain in lower back, butt, post. thighs, 24 hours after full SAB recovery. Lasts about a week.
What is cauda equina syndrome
Diffuse lumbosacral injury, numbness in LE, loss of bladder/bowel control, paraplegia
Which agents have been implicated in TNS and cauda equina syndrome
Lidocaine 5%, tetracaine, chloroprocaine
LA CV toxicity
CV more resistant to LA toxicity than CNS
Hypotension (SNS depression), myocardial depression, AV block (SVR, CO decreased, wide PR/QRS, arrhythmias, CV collapse)
Which agent is most CV toxic
Bupivacaine- at lower toxic doses, IV injection may cause cardiac arrest
How does cocaine overdose affect the CV system
Massive INCREASE in SNS outflow. Coronary vasospasm, MI, dysrhythmias may result.
Treatment of CV collapse in LA toxicity
Resuscitation often fails, prevention is the best medicine:
Small, incremental dosing
ASPIRATE
Watch for early EKG changes and STOP
Basic CPR immediately Modified ACLS (Epi, atropine, vaso only)
Intralipid 20% 1.5ml/kg rapid bolus immediately followed by 0.25mgml/kg/min for 10 minutes
Allergic reactions to LAs
less than 1% incidence
High concentration vs true allergy
Esters more likely to cause (possible PABA link)
Preservatives also implicated (Methylparaben)
Epi?
Are not MH triggers
LA interactions
Pseudocholinesterase inhibitors may prolong the duration of ester LAs
Cimetidine and propranolol decrease hepatic BF–> decreased clearance of amide LAs and cocaine
Clonidine, opioids, epi added to LA increase analgesic effect
DOA from shortest to longest
Chloro 30-60 Pro 45-60 Lido 60-120 Prilo 60-120 Mepi 90-180 Bupi 240-480 Ropi 240-480
What other uses does lidocaine have?
Cough suppression
Attenuate ICP rise, BP rise with DVL
Attenuate bronchospasm that may occur with airway instrumentation
Suppression of ventricular dysrhythmias
Cocaine
Unique ester Blocks NE and dopamine reuptake CNS- euphoria CV- stimulation Hepatic metabolism
Still used in ENT surgery
Procaine
Ester prototype
Used in spinals prior to development of lidocaine
NOT used much
pKa 8.9= 97% ionized, very slow onset Short DOA Hypersensitivity Higher nausea risk Higher incidence of CNS effects
Metabolite interferes with sulfonamide Abx
Tetracaine
Spinal, corneal anesthesia
Long DOA, up to 6 hours with epi
Not popular in epidurals
Slow onset, profound motor block, toxicity risk with large doses
High incidence of TNS
Chloroprocaine
Popular in OB epidurals- ultra rapid serum hydrolysis reduces tox. risk
Epidural, PNB where short duration is desired
Spinal being reinvestigated, but still considered off-label
Neurotoxicity is possibly related to preservative
Lidocaine
Very popular- topical (4%), regional (0.25-0.5%), PNB (1-2%), spinal (1.5-5%), and epidural (1.5-2%)
Rapid onset, intermediate DOA
2 active metabolites- monoethylglycinexylidide (80% activity) and xylidide (10% activity)
Spinal use is still controversial, especially continuous spinal
Mepivacaine
Similar to bupivacaine structurally
Similar to lidocaine clinically
Rapid onset
Less vasodilation= longer DOA (good when unable to use epi)
E 1/2 t about 2 hrs
Slightly more CNS toxicity compared to lidocaine
Not effective as a topical
Prilocaine
Rapid metabolism leads to less CNS toxicity than lidocaine
Toxic metabolite ortho-toluidine
Avoid in OB
Doses over 600mg converts Hgh to methemoglobin
Give methylene blue 1-2mg/kg IV over 5 minutes
Etidocaine
Used for PNB (0.5-1%) and epidurals (1-1.5%)
Highly lipid soluble, long acting with rapid onset (pKa=7.7)
Bupivacaine
Longer DOA and longer onset compared to lido
Popular for differential blocks (sensory>motor)
Good choice for post-op pain, labor epidural
Used for spinal (0.5-0.75%), epidural (0.0625% pain to 0.5% for surgical block), PNB (0.25-0.5%)
Highly bound to alpha-1 glycoprotein
Very low incidence of CNS effects with spinal
Very cardiotoxic, use 0.5% of lower for PBN or epidural. Serum 1/2t is 3.5hrs, so be careful.
Ropivacaine
S or levo enantiomer of bupivacaine with a propyl tail on the piperidine ring
Also good for differential block
Less cardiotoxic
More vasoconstriction
2 active metabolites, shorter e1/2t (2 hrs) compared to bupivacaine
Expensive
Levobupivacaine
Just the S enantiomer of bupivacaine
Less cardiotoxic
E1/2t 2.6hrs
Even more expensive, save for when large doses are required
Main considerations for dosing
Concentration, volume, and total dose given
PNB dosing
Volume dictated by the type of block
Choose concentration based on the limitations of max dose balanced with the density of the block required
Epidural dosing
Volume dictated to what level of block is desired
1.25-1.6ml per segment desired (count 1 direction)
Choose concentration based on density of block desired
Spinal
Just have to know these doses
