Local Anesthetics Flashcards

1
Q

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.

A
  1. Autonomic blockade
  2. Somatic sensory blockade
  3. Somatic motor blockade
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2
Q

LAs administered near the site of action.

How are Local Anesthetics used

A
  1. They are infiltrated around the nerve,
  2. applied topically to the skin and mucous membranes, or
  3. injected into blood vessels that are first exsanguinated in order to provide intravenous regional anesthesia
  4. They are also injected into the subarachnoid and epidural spaces for diffusion to desired levels in the spinal column
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3
Q

Myelinated Nerve Fiber:

Unmyelinated Nerve Fiber:

A

A Schwann-cell wraps itself around the axon several times, enveloping the axon in a myelin sheath
A single Schwann cell surrounds several axons

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4
Q

Importance of Myelination.

Myelinated vs Unmyelinated Fibers

A

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

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5
Q

Membrane:

Ion Channels are guarded by a gating mechanism. How does this mechanism operate

A

opens or closes depending on changing physiologic conditions

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6
Q

The membrane forms a barrier across which there is movement of ions along a concentration gradient between the intracellular and extracellular spaces

A

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

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7
Q

Nerve Fibers:

The velocity an impulse travels is proportional to

A

The diameter of the fiber: the larger the diameter, the higher the conduction velocity

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8
Q

How are fibers classified

A

Fibers classified according to diameter, three types: Primary afferent axons
A, B and C fibers

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9
Q

Describe A fibers

A

(myelinated) 1 to 22 microns Subdivided into: α β γ δ in order of decreasing size

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10
Q

Describe B fibers

A

(myelinated) 1 to 3 micrometers

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11
Q

Describe C fibers

A

(unmyelinated fibers) 0.1 to 2.5 micrometers

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12
Q

A-alpha fibers:

MP

A

motor & proprioception

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13
Q

A-beta fibers:

MTP

A

motor, touch, pressure

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14
Q

A- gamma fibers:

M

A

motor/muscle tone (muscle spindle)

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15
Q

A-delta fibers:

PTT

A

fast pain pain, temperature,touch

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16
Q

B-fibers:

A

PREganglionic autonomic

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17
Q

C- fibers:

A

Slow/ dull pain, temperature, touch, POSTganglionic autonomic– NO MYELIN

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18
Q

Nerve Fibers fast and slow pathways.
What is the Slowest of the A fibers?
Slowest nerve fiber?

A

Myelinated A-delta fibers (slowest of the A fibers)

Unmyelinated C fibers (much slower)

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19
Q

Conduction depends on?

A

Large fibers have the highest conduction velocity and the lowest threshold for excitability

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20
Q

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.

A

In motor neuron, due to the space between the nodes are larger you’ll need more anesthetic to cover a larger area.

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21
Q

Difference between clinical observation and research theories

A
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
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22
Q

Difference between clinical observation and research theories

A

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

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23
Q

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.

A

Frequency dependent blockade.

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24
Q

Outer surface of a peripheral nerve is known as the

A

mantle (usually more proximal structures)

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25
Inner surface known as
core (these fibers usually serve more distal structures)
26
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.
27
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
28
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.
29
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
30
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
31
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.
32
Local anesthetics- blocks impulse conduction during which phase of the action potential
depolarization phase so it does not reach threshold there preventing action potential
33
1. What state do Local Anesthetics easily ACCESS nerve cell Na channels In what state LA’s easily bind to the receptor
1. in the “activated-open” | 2. in the “inactivated-closed” state
34
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
35
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.
36
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
37
What happens with the Blockade of three nodes (1cm)
eliminates conduction along a myelinated nerve fiber (A fibers)
38
Differential Nerve Block with bupivacaine
Bupivacaine was the first local anesthetic shown to produce a beneficial differential block: Sensory block with incomplete motor block
39
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
40
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).
41
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
42
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
43
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)
44
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 ```
45
What does Exparel offer
Offer sustained release properties -Prolonged DOA -Theoretical decreased toxicity cannot and should not be mixed with other locals.
46
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
47
Exparel dosing max and dose
Dose: depends on surgical site | Max dose: 266mg or 20 ml
48
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
49
How does epinephrine Impact systemic absorption?
Allows for less systemic absorption as epi causes vasoconstriction
50
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
51
Absorption By Type of Block from high to low based on vascularity
``` Intravenous Tracheal Intercostal Caudal Paracervical Epidural Brachial Plexus Subarachnoid Subcutaneous ```
52
Do ionized or non-ionized drugs cross a lipid membrane?
non ionized
53
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. 1. Unionized form diffuses across the nerve sheath and membrane 2. Once inside the nerve membrane the ionized and non-ionized forms re-equilibrate 3. Ionized form binds a receptor inside the Na channel = blockade
54
The ionized form is favored when:
Acidic drug in relatively basic environment | Basic drug in relatively acidic environment
55
The non-ionized form is favored when:
Acidic drug in relatively acidic environment | Basic drug in a relatively basic environment
56
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
57
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
58
So what would the ideal pKa be?
would be 50/50
59
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
60
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
61
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 membrane ```
62
Explain 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
63
What factors potency
Lipid solubility – most important factor | Highly potent and very lipid soluble = etidocaine, bupivacaine, tetracaine
64
What is Duration of Action for Locals anesthetics
Duration proportional to amount of time LA is in contact with the nerve fiber
65
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
66
Simultaneous use of a vasoconstrictor and a local anesthetic serves three purposes:
1. 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 2. Prolongation of the LA effect 3. Detection of intravascular injection
67
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
68
What determines concentration of LA in the blood?
Concentration of Local Anesthetic Administered- Tissue Blood Flow- vasodilation= more anesthetics aborb
69
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)
70
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
71
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.
72
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
73
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
74
Potency is most influenced by: _______________
Lipid solubility
75
Duration of action is most influenced by: | _____________
Protein binding
76
Onset is most influenced by: _____________
PKa
77
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
78
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..
79
Cocaine toxicity
CNS: Restlessness, tremors, seizures and euphoria CVS: ****Cocaine overdose manifests as massive sympathetic outflow, coronary vasospasm, MI, dysrhythmias including V-fib
80
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
81
Most toxic LA to Cardiovascular System
Bupivacaine most CV toxic – cardiac arrest may occur at lower levels of toxic doses (inadvertent IV injection, etc.)
82
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
83
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
84
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
85
Local Anesthetic Toxicity - CNS | Anterior Spinal Artery Syndrome LE paralysis
with +/- sensory deficit | Unknown cause, vasoconstrictors?, PVD, advanced age increase the risk
86
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! ```
87
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
88
Selection Criteria:How Do I Choose Agents?
``` Type of Surgery “Spreadability” Onset Potency Duration Toxicity Risk Site of Metabolism ```
89
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
90
Specific Local Anesthetics: Highlights Amino Esters
Cocaine Procaine Tetracaine Chloroprocaine
91
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
92
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 ```
93
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
94
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)
95
Specific Local Anesthetics: Highlights | Amino-Amides
``` Amino-Amides Lidocaine Mepivacaine Prilocaine Bupivacaine Ropivacaine Levobupivacaine ```
96
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
97
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
98
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
99
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)
100
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
101
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
102
Levobupivacaine
S(-) enantiomer bupivacaine Less cardiotoxic Serum E1/2t = 2.6hrs More expensive… again reserve for cases where larger local anesthetic doses required