Local Anesthetics Flashcards
Local anesthetics reversibly block afferent nerve transmission to produce analgesia and anesthesia without loss of consciousness. What are the 3 ways in order easiest to hardest.
- Autonomic blockade
- Somatic sensory blockade
- Somatic motor blockade
LAs administered near the site of action.
How are Local Anesthetics used
- They are infiltrated around the nerve,
- applied topically to the skin and mucous membranes, or
- injected into blood vessels that are first exsanguinated in order to provide intravenous regional anesthesia
- They are also injected into the subarachnoid and epidural spaces for diffusion to desired levels in the spinal column
Myelinated Nerve Fiber:
Unmyelinated Nerve Fiber:
A Schwann-cell wraps itself around the axon several times, enveloping the axon in a myelin sheath
A single Schwann cell surrounds several axons
Importance of Myelination.
Myelinated vs Unmyelinated Fibers
Conduction:
Propagation of impulses is similar in both
Unmyelinated fibers: impulses travel along the length of the fiber in a continuous fashion
Myelinated fibers, conduction is “saltatory”so fast (50X) that it appears as if impulses leap from one node of Ranvier (no myelin) to the next
Membrane:
Ion Channels are guarded by a gating mechanism. How does this mechanism operate
opens or closes depending on changing physiologic conditions
The membrane forms a barrier across which there is movement of ions along a concentration gradient between the intracellular and extracellular spaces
The membrane forms a barrier across which there is movement of ions along a concentration gradient between the intracellular and extracellular spaces
EXTRAcellular contains a high concentration of SODIUM and low concentration of potassium; reverse for intracellular
Nerve Fibers:
The velocity an impulse travels is proportional to
The diameter of the fiber: the larger the diameter, the higher the conduction velocity
How are fibers classified
Fibers classified according to diameter, three types: Primary afferent axons
A, B and C fibers
Describe A fibers
(myelinated) 1 to 22 microns Subdivided into: α β γ δ in order of decreasing size
Describe B fibers
(myelinated) 1 to 3 micrometers
Describe C fibers
(unmyelinated fibers) 0.1 to 2.5 micrometers
A-alpha fibers:
MP
motor & proprioception
A-beta fibers:
MTP
motor, touch, pressure
A- gamma fibers:
M
motor/muscle tone (muscle spindle)
A-delta fibers:
PTT
fast pain pain, temperature,touch
B-fibers:
PREganglionic autonomic
C- fibers:
Slow/ dull pain, temperature, touch, POSTganglionic autonomic– NO MYELIN
Nerve Fibers fast and slow pathways.
What is the Slowest of the A fibers?
Slowest nerve fiber?
Myelinated A-delta fibers (slowest of the A fibers)
Unmyelinated C fibers (much slower)
Conduction depends on?
Large fibers have the highest conduction velocity and the lowest threshold for excitability
Clinically…. The sensitivity of a peripheral nerve to LA is inversely related to size. That is why you see autonomic blockade first, sensory second and motor last.
In motor neuron, due to the space between the nodes are larger you’ll need more anesthetic to cover a larger area.
Difference between clinical observation and research theories
anatomic issues (larger nerves found deeper in nerve bundles – harder for the LA to reach) variable activity in different nerves (pain fibers fire at higher frequency)….i.e. frequency dependent blockade variable ion channel mechanisms
Difference between clinical observation and research theories
anatomic issues
(larger nerves found deeper in nerve bundles – harder for the LA to reach)
variable activity in different nerves (pain fibers fire at higher frequency)….i.e. frequency dependent blockade
variable ion channel mechanisms
Autonomic nerves are outside of the bundle of nerve fibers and are readily and easily blocked first
Activity also affects blockade. Autonomic are consistently firing over motor.
Frequency dependent blockade.
Outer surface of a peripheral nerve is known as the
mantle (usually more proximal structures)
Inner surface known as
core (these fibers usually serve more distal structures)
THE SEQUENCE OF ONSET AND RECOVERY FROM A LOCAL ANESTHETIC BLOCK IN A MIXED PERIPHERAL NERVE RELIES HEAVILY ON WHERE IT IS LOCATED
Autonomic block is seen first
Can be helpful in assessment.
Clinical sequence of anesthesia:
1st- Autonomic sympathetic block (vasodilatation, warm skin)
2nd – Loss pain and temperature sensation
3rd – Loss of proprioception
4th - Loss of touch and pressure
5th – Motor blockade
Nerve Blockade is caused by prevention of voltage dependent increase in Na Conductance
Local anesthetic will bind to a local voltage gated Na+ channel in the nerve membrane ultimate promoting action potential propagation.
They bind in the inactivated closed state
(resting, active, inactive- frequency dependent blockade). The more the channel changes states the easier it is to block.
Local anesthetics bind at specific sites on the internal H gate of the channel & physically obstruct the external openings of the channels
Local anesthetics bind at specific sites on the internal H gate of the channel & physically obstruct the external openings of the channels
Where do LAs bind on a channel ?
Local anesthetics bind at specific sites on the internal H gate of the channel & physically obstruct the external openings of the channels
Acting as a pore blocker
What does Local anesthetics prevent?
Local anesthetics prevent passage of sodium ions through these channels by binding and stabilizing them in the inactivated-closed conformational state.
Essentially acting as an inverse agonist holding in the inactivated close state.
Local anesthetics- blocks impulse conduction during which phase of the action potential
depolarization phase so it does not reach threshold there preventing action potential
- What state do Local Anesthetics easily ACCESS nerve cell Na channels
In what state LA’s easily bind to the receptor
- in the “activated-open”
2. in the “inactivated-closed” state
The more frequently the nerve is in this state, (i.e. cycled through an action potential) the more rapidly blockade occurs
Frequency or Use Dependent Blockade
Resting nerve less sensitive to block than a repetitively stimulated nerve. How are resting nerves blocked
Lipid solubility determines (i.e. it has to diffuse through the axonal membrane instead of through the Na channel to reach its target)
PKa is important.
What contributes to differential nerve block
Distance between Nodes of Ranvier in myelinated fibers contributes to differential nerve block
The internodal distance increases with fiber diameter
An impulse can make it through two blocked nodes but not a third
What happens with the Blockade of three nodes (1cm)
eliminates conduction along a myelinated nerve fiber (A fibers)
Differential Nerve Block with bupivacaine
Bupivacaine was the first local anesthetic shown to produce a beneficial differential block: Sensory block with incomplete motor block
Bupivacine promotes Sensory block with incomplete motor block
What fibers are blocked and what fibers are spared
Pain conducting fibers (A delta, C fibers) blocked
A alpha, beta, & gamma fibers not completely blocked
Patients feel pressure but not pain with surgical stimulation
Local anesthetics are classified chemically
As aminoamides or aminoesters
The typical molecule consists of a lipophilic head (an aromatic ring), an intermediate chain containing either an amide (NH) or an ester (COO-) and a hydrophilic tail (a tertiary amine).
How can the name of a LA identify it as an amide?
Amide’s have an i in the drug name before the –caine part
Examples – lidocaine, bupivacaine, etidocaine
Class of intermediate chain affects biotransformation of the molecule
Ester linkage:
Amide linkage:
Ester linkage: readily hydrolyzed by non-specific esterases in the plasma and tissues (mostly liver)
Cocaine exception: block Na+ profound effect on decreases/ inhibit the uptake of norepi.
Amide linkage: metabolized in the liver.. Higher toxicity risk
Ester hydrolyzed are fast less toxic risk succs
Molecular Structure/Clinical Significance:
Lipid soluble=> potency
Intermediate chain => potency
Length of terminal group => potency
Enantiomers of a chiral drug
Highly lipid-soluble anesthetics are more potent and have a longer duration of action than do water-soluble anesthetics
Increase in the length of the intermediate chain (increase number of carbon atoms) increases potency and toxicity and alters metabolism rate and DOA
Potency and toxicity also increased with the length of the terminal groups located on the tertiary amine (tail) and aromatic ring
Enantiomers of a chiral drug may vary in terms of the pharmacokinetics, pharmacodynamics, and toxicity.
Ex. Bupivacaine (racemic) VS L-Bupivacaine(levo enantiomer)
Minimum concentration needed
Minimum Blocking Concentration Nerve fiber diameter influence Motor nerve higher Cm than sensory Tissue pH Frequency of nerve stimulation Potency of particular LA
What does Exparel offer
Offer sustained release properties
-Prolonged DOA
-Theoretical decreased toxicity
cannot and should not be mixed with other locals.
Describe Exparel
Liposomes- honey comb
Exparel: Bupivacaine extended release liposome injection FDA approved
Do not mix or inject any other local anesthetic at the same site
Exparel dosing max and dose
Dose: depends on surgical site
Max dose: 266mg or 20 ml
LA Systemic Absorption governed?
Absorption is governed by physiochemical characteristics and physiologic conditions at site of deposit, volume of solution or vehicle used (Epi?) and concentration of local anesthetic
How does epinephrine Impact systemic absorption?
Allows for less systemic absorption as epi causes vasoconstriction
What are Physiochemical factors and Physiologic conditions:
Physiochemical factors: pKa, pH, and lipid solubility
Physiologic conditions: tissue pH, pC02, and temperature- cold causes vasoconstriction per longing DOA vs Heating causes Vasodialation, patient characteristics- eg old patient, pregnancy- less protein binding
Absorption By Type of Block from high to low based on vascularity
Intravenous Tracheal Intercostal Caudal Paracervical Epidural Brachial Plexus Subarachnoid Subcutaneous
Do ionized or non-ionized drugs cross a lipid membrane?
non ionized
Ionization of Local Anesthetics.
Which form crosses the nerve sheath membrane?
What happens to the drugs once inside the membrane.
All locals are weak bases.
- Unionized form diffuses across the nerve sheath and membrane
- Once inside the nerve membrane the ionized and non-ionized forms re-equilibrate
- Ionized form binds a receptor inside the Na channel = blockade
The ionized form is favored when:
Acidic drug in relatively basic environment
Basic drug in relatively acidic environment
The non-ionized form is favored when:
Acidic drug in relatively acidic environment
Basic drug in a relatively basic environment
All local anesthetics: weak bases with pka values of
7.5-9
They are packaged in acidic formulations to improve solubility and stability in the vial and often to preserve epinephrine – don’t let this fool you they are basic upon injection
Why is it Good to have equal parts of each form of ionized and nonionized?
pKa = pH at which a drug exists
50% ionized form
50% unionized form
Non-ionized penetrates nerve sheath and axon membrane to reach site of action
Ionized form has better affinity for H gate form binds and blocks Na channel
So what would the ideal pKa be?
would be 50/50
LA Onset
Because Non-ionized form crosses the lipid-rich nerve cell membrane
The pH of the local anesthetic solution and the pKa of the drug determine proportion of drug in the non-ionized state
In areas of high/normal pH values, the rate and amount of absorption is higher; conversely, at lower pH, the rate and amount of absorption are lower
How can the anesthetist influence the pH/pKa relationship to speed onset?
Adding Bicarb increases the onset, enhances block depth, and increases the spread of the block
What affects the pH/pKa relationship decrease local anesthetic onset
Infected tissue alterations
Ion trapping in pregnancy
Temperature: decreasing temperature
reduces drug absorption across the
nerve membraneExplain Bupivacaine and protein relationship
highly Protein binding 99% which keeps it away from placenta so it won’t cause Ion trapping. Has decrease placental crossing
What factors potency
Lipid solubility – most important factor
Highly potent and very lipid soluble = etidocaine, bupivacaine, tetracaine
What is Duration of Action for Locals anesthetics
Duration proportional to amount of time LA is in contact with the nerve fiber
What affects the DOA of locals
Tissue Blood Flow- the more blood flow the more oppurtunity of drug molecules to be cared away.
Addition of Vasoconstrictors- epi prolong DOA
Lipid solubility- Dependent on localatiion eg if injected in breast tissue.
Protein Binding- most important. Good and bad. bad for protien of the heart
Intrinsic vasodilator activity- lidocaine
-Lidocaine VS mepivicaine- don’t have a intrinsic vasodilator
Simultaneous use of a vasoconstrictor and a local anesthetic serves three purposes:
- Inhibition of systemic absorption of LA- decrease systemic toxicicity
Mixed with Epi Helps to detect intra-vascular injections-
give 5cc incremental local at a time. Watch EKG for ST changes - Prolongation of the LA effect
- Detection of intravascular injection
Duration of Action Protein binding (most important factor)
More protein bound increased duration of action (not the same as IV drugs… LAs injected at site of action)
Uptake by the lungs- first pass effect. Acts as a buffer
Metabolism
What determines concentration of LA in the blood?
Concentration of Local Anesthetic Administered-
Tissue Blood Flow- vasodilation= more anesthetics aborb
Metabolism of Local Anesthetics - Esters
Fast metabolism
Primarily hydrolyzed by pseudocholinesterase enzymes in plasma (and to lesser extent - the liver) (<5% excreted unchanged in the urine)
What is the metabolite of ester and why is it important to know
Metabolite = para-aminobenzoic acid (PABA)
Cause allergy reaction in esters. OK switch to AMIDES
Exception ester is cocaine. Why?
*Exceptional ester is cocaine which is significantly metabolized in the liver and 10-12% excreted unchanged in the urine…
Polar, ionized, water soluble exit same as how they enter the body.
Metabolism of Local Anesthetics- Amides
Liver
Microsomal Enzymes P450 system
More complex and slower process than metabolism of Esters-
Aromatic hydroxylation, N-dealkylation and amide hydrolysis
What does it mean for the possibility of systemic toxicity and cumulative effects of AMIDES??
It can build up and cause toxicity. Don’t go above max
Potency is most influenced by: _______________
Lipid solubility
Duration of action is most influenced by:
_____________
Protein binding
Onset is most influenced by: _____________
PKa
Local Anesthetic Toxicity - CNS
Circumoral/tongue numbness, tinnitus, vision changes, dizziness, slurred speech, restlessness
Muscle twitching especially in face and then extremities indicates imminent onset of seizures
Seizure followed by CNS depression, apnea, hyPOtension
What do you do if the patient seizes??
Inhibiting the inhibitor causes seizures.
Sedate.. Give 100% O2, Help ventilated to rid CO2, Give benzo, barbs..
Cocaine toxicity
CNS:
Restlessness, tremors, seizures and euphoria
CVS:
**Cocaine overdose manifests as massive sympathetic outflow, coronary vasospasm, MI, dysrhythmias including V-fib
Local Anesthetic Toxicity – Cardiovascular System
CVS more resistant to toxic effects than CNS!
Hypotension (SNS depression), myocardial depression, and AV conduction block
Reduced SVR and C.O, widened PRi and QRS, arrhythmias including ventricular tachycardia, possible CV collapse
Pregnancy, hypoxia, pH abnormalities and CV modulating drugs increase the risk
Most toxic LA to Cardiovascular System
Bupivacaine most CV toxic – cardiac arrest may occur at lower levels of toxic doses (inadvertent IV injection, etc.)
Local Anesthetic Toxicity – Treatment of CV Collapse
Resuscitation often fails….. Prevention ideal
Incremental fractionated dosing
Aspirate before every injection (false negative possible)
Watch ECG for early signs
Basic CPR immediately
See figure 10-12 in text American Society of Regional Anesthesia and Pain Medicine Guidelines
Modified ACLS (limit medications to epinephrine 10-100ug, amiodarone)
Intralipid 20% 1.5 ml/kg rapid bolus immediately; follow with infusion 0.25 ml/kg/min X 10 minutes
CPB
Local Anesthetic Toxicity - CNS
Transient neurologic symptoms (TNS) or Transient radicular irritation
neuro-inflammatory process causes pain in the lower back, buttocks, posterior thighs 6-36 hours after full recovery from Subarachnoid block (SAB) – lasts about a week
Local Anesthetic Toxicity - CNS
Cauda equina syndrome
Most implicated drug in this toxicity
diffuse lumbosacral injury, numbness in LE, loss of bowel and bladder control, paraplegia
Lidocaine 5%, Tetracaine, and Chloroprocaine have been implicated
Local Anesthetic Toxicity - CNS
Anterior Spinal Artery Syndrome LE paralysis
with +/- sensory deficit
Unknown cause, vasoconstrictors?, PVD, advanced age increase the risk
Allergic Reactions with LAs
Incidence <1% High Plasma Concentration vs. Allergy? Esters implicated more than Amides (PABA?) Preservative Reaction? (Methylparaben) Epinephrine? Neither are MH triggers!
Local Anesthetic Drug Interactions
Pseudocholinesterase inhibitors may prolong the duration of ester anesthetics
Cimetidine and propranolol decrease hepatic blood flow => decrease clearance of amide local anesthetics and cocaine
Adding: Analgesia promoted by opioids, clonidine ( prolongs and analgesia and motor blockage), and epinephrine added to LA
Selection Criteria:How Do I Choose Agents?
Type of Surgery “Spreadability” Onset Potency Duration Toxicity Risk Site of Metabolism
Other Uses of Lidocaine
Cough Suppression
Attenuate ICP elevation during laryngoscopy
Attenuate BP elevation during laryngoscopy
Attenuate reflex bronchospasm that may occur with airway instrumentation
Suppression of ventricular dysrhythmias
Specific Local Anesthetics: Highlights Amino Esters
Cocaine
Procaine
Tetracaine
Chloroprocaine
Cocaine
The unique ester
-Blocks norepinephrine & dopamine reuptake
-Unique side effect profile
–CNS: euphoria
–CV: stimulation, sympathomimetic
Different metabolism; liver and plasma esterases
Currently still used in ENT surgery
Procaine
Ester prototype Used in spinal anesthesia prior to development of lidocaine Not currently a favorite Pka 8.9 = 97% ionized slow onset Short DOA Hypersensitivity Higher nausea incidence Higher incidence of CNS side effects Metabolite interferes with efficacy of sulfonamide antibiotics
Tetracaine
Primarily used in spinal and corneal anesthesia
Long DOA for an ester (especially w/epi added can be up to 6hrs!)
Not popular for epidural or PNB
Slow onset
Profound motor block
Toxicity risk w/lg. doses (long DOA)
High incidence of TNS
Chloroprocaine
Popular in OB epidural anesthesia
Ultra Rapid serum hydrolysis greatly reduces toxicity risk to mother and fetus
Epidural and PNB when short duration desired
Spinal being reinvestigated but still considered “off -label” use
Reports of Neurologic injury possibly related to preservative (data inconclusive)
Specific Local Anesthetics: Highlights
Amino-Amides
Amino-Amides Lidocaine Mepivacaine Prilocaine Bupivacaine Ropivacaine Levobupivacaine
Lidocaine
Very popular
Topical (4%), regional IV (0.25-0.5%), PNB (1-2%), spinal (1.5-5%) and epidural use (1.5-2%)
Rapid onset; intermediate duration
2 active metabolites monoethylglycinexylidide – 80% activity & xylidide 10% activity
Spinal use… especially continuous spinal use controversial
Linked to cauda equina syndrome
Mepivacaine
Structurally similar to bupivacaine
Clinically similar to lidocaine
Rapid onset
Less vasodilation = longer DOA (nice to consider when vasoconstrictor contraindicated)
Serum E1/2t ~ 2hrs
Slightly more CNS toxicity compared with lidocaine
Not effective topically
Prilocaine
Rapid metabolism leads to less CNS toxicity than lidocaine
Toxic metabolite ortho-toluidine
Avoid in OB
Doses greater than 600mg = conversion of hgb to methemoglobin
Methemoglobinemia also possible with benzocaine, topical lidocaine preparations
Give methylene blue 1-2 mg/kg IV over 5 minutes
Etidocaine
Used for infiltration/PNB (0.5-1%), and epidural anesthesia (1-1.5%)
Highly lipid soluble, long acting with rapid onset (pka = 7.7)
Bupivacaine
Longer DOA and longer onset compared w/lidocaine
Popular for differential nerve block (sensory>motor)
Great choice post-op pain, labor epidural
Used spinal (0.5-0.75%), epidural ( 0.0625- 0.5%), peripheral nerve block (0.25-0.5%)
Highly protein bound to alpha-1 glycoprotein
Side effect pro: very low incidence of neuro complications with spinal
Side effect con: very cardio toxic (use 0.5% or lower conc. for epidural, PNB) + Serum E1/2t is 3.5 hours
Ropivacaine
S(-) or levo enantiomer of homolog of bupivacaine with a propyl tail on piperidine ring
Also good for differential blockade
Less cardiotoxic
More vasoconstriction
2 active metabolites; shorter serum e1/2t (~ 2hrs) compared with bupivacaine
More expensive… use when larger doses needed
Levobupivacaine
S(-) enantiomer bupivacaine
Less cardiotoxic
Serum E1/2t = 2.6hrs
More expensive… again reserve for cases where larger local anesthetic doses required
