Exam 2: Local Anesthetics
Spinal Anesthesia: Physiologic Effects
Apnea - occurs with excessive levels - reflects ischemic paralysis of the medullary ventilatory centers due to profound hypotension and decreases in cerebral blood flow - concentrations in CSF too low to cause blockade of the ventilatory centers - phrenic nerve paralysis is rare (C3-C5)
LA Overdose Treatment
ABCD: Airway, Breathing, Circulation, Drugs - ventilate patient with 100% O2 - arterial hypoxemia and metabolic acidosis occur within seconds - hyperventilation will decrease delivery of drug to the brain (hypocarbic - cerebral vasoconstriction) but may inhibit removal as well Administer a benzodiazepine, barbiturate, or propofol to suppress seizures. In the perioperative setting, when we place blocks most of the patients are given a relatively high dose of versed for that block to be placed (generally between 4-8 mg). When patients get this high dose of versed, they have essentially been pretreated for seizures so there is some degree of protection. - it is helpful to have a syringe of propofol available just in case additional medication is needed Supportive measures as required.
Absorption and Distribution
Absorption from site of injection into systemic circulation is how we terminate the action of these agents. This is influenced by: - site of injection - dosage - use of epinephrine (vasoconstrictor) - pharmacologic characteristics of drug The plasma concentration of a drug is determined by the rate of tissue distribution and the rate of clearance. - when we are talking about plasma concentration of LAs, it is different than the dose-response curves after IV injection - there is no alpha and beta phase because there is no intravenous injection - LAs have to absorbed into the central circulation, they are then going to be distributed to the tissues, then back into central circulation and then to liver/kidneys to be excreted from body So if the rate at which the drug is entering into central circulation is greater than the rate at which the liver and kidneys can clear that drug, that's when we're going to start to see concentrations of LA rising and toxic effects of the agents. As long as the drug is being cleared at a rate that is less than or equal to the rate at which it is entering central circulation, you are not going to have accumulation of those agents. - various factors impact this process
Peripheral Nerve Blocks
Achieved by injection of LA around peripheral nerves or nerve plexuses. - the drugs diffuse from the outer mantle towards the core of that plexus along a concentration gradient - if you are injecting around mixed nerve fibers, the fibers in the mantle are anesthetized first and then distributed to more proximal tissues - skeletal muscle paralysis may precede sensory blockade if the motor fibers are peripheral to sensory fibers Cm is highest in motor fibers and therefore take the longest to block (because you require a higher concentration) but this applies when you are injecting directly into the CSF and the LA comes into contact with everything at the same time. Now that we use ultrasound, you will see providers inject in one place, withdraw, inject in another, etc. this way they can bathe all the tissues in the area with LA at the same time.
Common Preparations
All of the LA are weak bases that are poorly soluble in water. Therefore, they need to be marketed as water-soluble hydrochloride salts with an acidic pH (pH 4-6). - the addition of epinephrine to the solution, it will require a lower pH - acidic pH will enhance the stability of the LA and the epinephrine that is added to it These LA are prepared as salt at an acidic pH. This should tell you 2 things: 1. they are bases in an acid environment therefore the majority of the LA is in the ionized form so when they are injecting it, it will have to undergo some degree of change in degree of ionization in order to exert an effect 2. the LA burn significantly when they are administered
Side Effects: Allergic Reactions
Allergic reactions to LAs are rare. - <1% of reactions to LA are due to allergic rxn (IgE) - ester LAs that produce metabolites similar to PABA are more likely to produce allergic reactions - amides are not metabolized to PABA While a patient who is allergic to an ester LA can have an amide LA, it must be preservative free. - substances used as preservatives in ester and amide LA such as methyparaben (similar to PABA) may produce an allergic reaction - any LA injected neuraxially (spinal or epidural) must be preservative free otherwise toxic to the CNS - preservative free considered the "safe" LA Very important to understand what the patients allergy is when they tell you they are allergic to LAs. Documentation of Occurrence - many LA reactions attributed as allergy are in fact due to high plasma concentrations - true allergy: rash, urticaria, laryngeal edema - IV injection: hypotension, tachycardia, syncope - if there is a true allergic reaction, it must be documented clearly because it is important for people to know if they had an anaphylactic reaction to LAs
Metabolism: Amides
Amide Local Anesthetics - undergo varying rates of metabolism by the hepatic microsomal enzymes (cytochrome P450) - prilocaine most rapid metabolism - lidocaine, mepivacaine are intermediate - etidocaine, bupivacaine, ropivacaine are the slowest The initial step is the conversion of the amide base to aminocarboxylic acid and a cyclic aniline derivative. Due to the slower rate of metabolism, systemic toxicity is more likely as compared to the ester local anesthetics (ester anesthetics are rapidly metabolized in the plasma).
Systemic Toxicity: CNS
As we increase the plasma concentration level, with respect to systemic toxicity, our S/S are going to become more profound. At low plasma concentrations (even therapeutic concentrations) it is possible to have numbness of the tongue and circumoral tissues. - these are highly vascular tissues - blood will take a higher amount of LA to these tissues As plasma concentrations begin to rise, LA readily crosses the BBB and produces predictable patterns of change. - first, restlessness, vertigo, tinnitus, difficulty focusing - then, slurred speech and skeletal muscle twitching - then, drowsiness with amides ᐧ one of the most common side effects of lidocaine systemic toxicity = to starts to get sedated ᐧ once you see this, the next thing the patient will do is have a seizure - followed, by seizures, CNS depression, CV collapse
Maximum Dosages of Local Anesthetics
Essentially the same chart but assuming a 70 kg patient. Example: bupivacaine 175 mg is still 2.5 mg/kg
Metabolism: Esters
Benzocaine - unique in that its pKa is 3.5 so it exists almost entirely in the nonionized form at physiologic pH - it is ideal for use as a topical anesthetic of the mucous membranes - rapid onset - 30-60 minute duration of action - methemoglobinemia is a rare complication
Intravenous Regional Anesthesia
Bier Block - injection of LA into an extremity isolated from the rest of the circulation - rapid onset of anesthesia - duration of action is determined by how long the tourniquet is on - mechanism of action is unknown - may be due to action of LA on nerve endings and nerve trunks - this block can only be used for short procedures because you can't leave a tourniquet up for more than 1-2 hours maximum - these patients are awake so a tourniquet for more than 30 minutes becomes very uncomfortable - a double tourniquet is used because, in theory, the skin underneath the distal tourniquet should be anesthetized - the provider can inflate the distal tourniquet and deflate the proximal to buy themselves a little more time once it becomes uncomfortable for the patient - typically used in procedures that last 5-20 minutes ᐧ e.g. carpal tunnel, trigger finger release, etc.
Bier Block Process
Bier block process - can be used for the upper or lower extremities, usually from the elbow/knee down - the patient will have 2 PIVs ᐧ one in the nonoperative hand, and one in the operative hand - the tourniquet is placed on the extremity ᐧ it will have 2 bladders: distal and proximal - the extremity is elevated - an esmark tourniquet is wrapped extremely tightly starting from the fingers and continuing down the entire arm and up above the tourniquet - the proximal (upper) tourniquet is then inflated ᐧ usually to 250 mmHg - then the arm is unwrapped, leaving the arm cadaveric (white because the blood has been exsanguinated from the venous system) - LA is injected into the circulation ᐧ usually 40-50 mLs of 0.5% lidocaine ᐧ can use prilocaine but concerns d/t methemoglobinemia - the patient's arm then goes numb Removal - tourniquet must be let down gradually - tourniquet is briefly let down (seconds), then turned back up, let down again, and turned back up again, etc. - this slowly washes out the LA from the extremity - while doing this you are continuously asking the patient if they are having any ringing in the ears, funny taste in mouth, numb lips, etc. to assess for early signs of LAST
Selective Cardiac Toxicity
Both bupivacaine and lidocaine block cardiac Na+ channels during systole. - conduction is occurring, Na+ channels are in the open phase During diastole, bupivacaine does not readily dissociate from the Na+ channels so there are persistent depressant effects on cardiac action potential (Vmax). Tachycardia enhanced frequency dependent blockage of Na+ channels because there is constant action potential being propagated. - this will increase selective cardiac toxicity
Epidural Anesthesia
Local Anesthetics Used - lidocaine: easily diffuses across tissues - bupivacaine: 0.25-0.5% solutions ᐧ restricted to a maximum concentration of 0.5% in epidural use, most people use 0.25% - ropivacaine/levobupivacaine ᐧ expensive, not often used ᐧ enhanced safety profile The spread of an epidural is dependent upon the total volume given, not necessarily the concentration given because it has to diffuse across the dura and into the paraverterbral space. We need a lot of volume to do that. Usually 1 cc per dermatome, which is often upwards of 15-20 mLs of LA.
Zones of Differential Blockade
Cardiac accelerator fibers emerge from the T1-T4 spinal segments. So in the previous example where the sympathetic blockade ends at the T1/T2 level - you can assume that some of the cardiac accelerator fibers have been anesthetized. With an epidural anesthesia, because we're not going directly into the CSF with out local, the zones of differential blockade do not happen/are much less likely to occur. Large doses are required and there can be significant systemic absorption.
Side Effects
Cardiovascular System - more resistant to toxicity than the CNS - lidocaine <5 mcg/mL has no CV effects - lidocaine plasma concentrations between 5-10 mcg/mL may produce hypotension due to relaxation of the arteriolar vascular smooth muscle and direct myocardial depression - part of cardio toxicity is due to blockade of cardiac Na+ channels - the Na+ channels in the heart are no different than the Na+ channels anywhere else in the body - low [ ] of LA contributes to antidysrhythmic effects - high [ ] of LA are able to block enough channels to completely impair conduction, inhibit automaticity, and cause cardiac arrest
Side Effects
Cauda Equina Syndrome - diffuse injury across the lumbosacral plexus - these patients will have sensory anesthesia, bladder and bowel dysfunction, paraplegia - initial reports associated with use of 5% lidocaine for continuous spinal anesthesia (not used anymore) ᐧ use of micro catheters resulted in patchy distribution of LA with pooling of agent on dependent or stretched nerves ᐧ bathed lumbosacral plexus with very high concentrations of LA
Na+ Channel States
Closed - membrane polarized - back to resting transmembrane potential Inactivated/Open - the membrane has been depolarized
Minimum Concentration*
Cm = minimum concentration of LA required to produce conduction blockade - influenced by nerve fiber diameter ᐧ larger nerve fibers require higher Cm - influenced by the presence of myelin ᐧ myelinated neurons are easier to block than unmyelinated neurons, however diameter takes precedence - increase in tissue pH or high frequency of nerve stimulation decreases Cm ᐧ higher tissue pH with basic drugs -> more in nonionized state ᐧ high frequency makes it easier for LA to get to its site of action Each LA is going to have a different Cm due to differences in potency.
Minimum Concentration
Cm of the motor fibers is 2x that of sensory fibers - motor blockade may not accompany sensory blockade - e.g. laboring woman with an epidural - you don't want motor blockade because they need to be able to push but you still want her to be comfortable - so we are able to adjust our LA concentrations to produce sensory block without motor Cm is unchanged, but less LA is required for spinal anesthesia than for epidural anesthesia because with epidural anesthesia the agent has to diffuse to its site of action via a concentration gradient. A minimal length of myelinated nerve fiber must be exposed to LA for conduction blockade to occur. - in an A fiber (motor) a minimum of 2 nodes, preferably 3 must be exposed - if only 1 node exposed, the impulse can "jump" across the node
Early Local Anesthetics
Cocaine - ester local anesthetic - first LA introduced in 1884 by Kollar for use in ophthalmology - Halsted discovered the ability of injected cocaine to halt nerve conduction -> introduction of peripheral nerve blocks and spinal anesthesia - unique in its ability to produce localized vasoconstriction (used for ENT until 10-15 yrs ago) Procaine - first synthetic ester derivative, introduced in 1905 Lidocaine - first synthetic amide LA, introduced in 1943 - faster onset, longer duration of action, and more intense blockade than procaine - prototype LA: standard by which all LA are compared because it can be used topically, for neuraxial anesthesia, peripheral nerve blocks, and as a cardiac antidysrhythmic
Cocaine Toxicity
Cocaine is administered as a 4% or 10% solution (10% is usually diluted down to 4%). It is predominantly used in ENT and it is used for its unique ability to produce SNS stimulation. It produces SNS stimulation by blocking the presynaptic uptake of NE and dopamine. - increases postsynaptic concentrations - increases dopamine within the brain ᐧ affects adjacent neurons causing the characteristic cocaine high
Epidural Anesthesia
Epidural anesthesia is produced by the diffusion of LA across the dura to act on nerve roots. The LA is also able to diffuse into the paravertebral area through the intervertebral foramina to produce paravertebral nerve blocks. - it gets into the spinal canal, its getting those nerve roots centrally and then it also gets into the paravertebral nerve roots to produce some blockade
Drugs for Major Nerve Blocks
Do not memorize.
Epidural Anesthesia Doses
Do not memorize.
Spinal Anesthesia Doses
Do not memorize.
Continuous Peripheral Nerve Blocks
Do not memorize. With the utilization of exparel, we tend not to see as many continuous nerve blocks being used. A continuous nerve block would require the patient to stay in the hospital for the duration of the block.
Infiltration Anesthesia
Do not need to memorize for this exam.
Spinal Anesthesia
Dosage varies with - height of the patient ᐧ determines the volume of the subarachnoid space ᐧ the greater the volume, the greater the dose we're going to have to give to maintain a certain [ ] - segmental level of anesthesia required ᐧ total knee - don't need to numb patient up to the nipple line - duration of anesthesia required ᐧ long cases will require longer acting drug and you will need to achieve a higher level than you want because the level will recede as the LA wears off Dose more important than [ ] or volume as with epidural anesthesia. Drugs used include lidocaine, ropivacaine, bupivacaine, tetracaine.
Side Effects: Systemic Toxicity
Due to excess plasma concentrations of LA. LAs are administered to stop conduction in nerves. We have action potentials propagated in almost every tissue in the body (CNS, heart, muscle, etc.) so there are risks of S/E when plasma concentrations get too high because they are going to get into other tissues. Accidental intravascular injection is the most common cause. E.g. LA peripheral block without aspirating before injection. The excess plasma concentrations are due to systemic absorption related to: - dose administered - vascularity of the injection site - whether or not epinephrine was used ᐧ less likely with epinephrine use - physiochemical properties of each agent - technique ᐧ single injection block (e.g. interscalene block) less likely to cause toxicity than is a constant infusion (e.g. epidural infusion) - type of block ᐧ greatest risk with intercostal blocks (most rapid absorption), followed by the epidural space (intermediate blood supply), followed by our peripheral nerve blocks (e.g. femoral, interscalene, axillary) In the case of peripheral nerve blocks, unless we have an accidental intravascular injection, there are very rarely any type of systemic toxicity regardless of the type of LA.
Metabolism: Esters
Ester Local Anesthetics - undergo hydrolysis by plasma cholinesterase - chloroprocaine > procaine > tetracaine ᐧ from most to least rapidly metabolized - all of the metabolites of ester LAs are inactive ᐧ para-aminobenzoic acid (PABA) is an antigen responsible for the allergic reactions to esters ᐧ PABA found in skincare products, detergents, etc. ᐧ if someone is allergic to PABA, they are allergic to ester local anesthetics - cocaine is metabolized both by ester hydrolysis and the cytochrome P450 system (principally in the liver) - the systemic toxicity of ester LAs is inversely proportional to the rate of hydrolysis ᐧ the faster it is hydrolyzed, the less toxic the drug is - CSF has no cholinesterase enzyme ᐧ the metabolism of spinal and epidural anesthetics is dependent upon systemic absorption ᐧ ester LAs must be removed from the neuraxial space and be absorbed into the central circulation where they will be metabolized
Comparative Pharmacology of LA
Esters (procaine, chloroprocaine, tetracaine) have pKa between 8.5-8.9. So when you look at the percentage of drug in the nonionized form, it is very low. Amides (lidocaine, bupivacaine, mepivacaine, etc.) have pKa between 7.6-8.1 (slightly lower than the esters). Because mepivicaine has a pKa that is closest to physiologic pH, it has the highest percentage of drug in the nonionized form (39%). When you look at the onset of action of the various different agents, you will see that it is more complicated than just looking at the degree of ionization. - e.g. chloraprocaine has a rapid onset of action despite having a very high pKa. This is because it is given in very high volumes/concentrations (maximum dose 600 mg) so there is just so much more of it around to get to its site of action
EMLA Cream
Eutectic mixture of local anesthetics. - 50:50 mixture of 5% lidocaine and 5% prilocaine - the skin is keratinized and is a barrier to drug diffusion - this mixture allows the use of high concentrations without concern for local irritation, uneven absorption, or systemic toxicity EMLA cream would be placed on the hands, antecubital spaces, and sometimes their ankles. Because there was so much high concentration LA, it would diffuse through the skin and get to the peripheral nerve endings and topicalize the receptors (block). Acts by diffusing through the intact skin to block neuronal transmission from the dermal receptors. Duration of application varies with the type of procedure and site of application. Effective in relieving pain with IV insertion. - must be placed 45 minutes prior to insertion - this duration of time limits its usefulness
Local Infiltration
Extravascular placement of LA in an area to be anesthetized. - lidocaine is the most frequent choice because of its rapid onset of action - you can see lidocaine being combined with bupivacaine, especially in the perioperative setting for the purpose of providing some degree of postoperative anesthesia The duration of anesthesia can be double by the addition of 1:200,000 epinephrine to the solution. Epinephrine containing solutions should not be used in tissues supplied by end arteries. - fingers, ears, nose, penis - if there is no collateral blood flow to the area, you should not be using epinephrine (use plain solution)
Absorption and Distribution
Factors affecting distribution: - just like with any other agent, lipid-solubility is an important determinant of distribution and potency ᐧ a highly lipid-soluble agent is going to get to the receptor and bind with a greater affinity for that receptor ᐧ highly lipid-soluble agents tend to be highly protein bound - protein binding ᐧ parallels the lipid solubility and is inversely proportional to plasma concentration (the greater the protein binding, the lower the plasma concentration) ᐧ the greater the lipid-solubility, the greater the degree of protein binding ᐧ when we talk about protein binding with respect to LA, were talking about protein binding in the tissue because we are not giving these agents intravenously ᐧ it will be the opposite of what happens when we give a drug IV, if it is highly protein bound, that is at its site of administration (which is in the tissues) - tissue blood flow ᐧ because we are giving these drugs into the tissues ᐧ if you give LA into a tissue with high blood flow, it is going to be cleared from that tissue and distributed to the VRG at a faster rate than if the tissue has poor blood supply ᐧ if you administer LA into SQ tissue vs. into muscle - it will be cleared from the muscle much faster due to the blood supply - tissue blood flow
Combinations of LAs
In addition to combining LAs to speed onset/prolong duration, we also do this because if 2 agents have different toxicity profiles we are able to give lower concentrations of each agent making it less likely that we approach toxic doses of either agent.
Structure-Activity Relationships
Local anesthetics contain: Lipophilic portion: lipid-soluble portion - consists of an unsaturated (substituted) aromatic ring - the ring is what makes it lipid-soluble - the ring structure is essential for the anesthetic activity Hydrophilic portion: tertiary amine - at the other end you will see tertiary amine present The hydrophilic and lipophilic group are going to be attached to each other by a hydrocarbon chain. - the hydrocarbon chain is then going to be attached to the aromatic component by either an ester (-CO-) or an amide (-NHC) bond. The ability of these drugs to be either lipophilic or hydrophilic is dependent upon the size of the alkyl substituents on or near the tertiary amine. - the longer, more substitutions, the more water-soluble the LA will be
Onset of Action
In addition to entering the neuron through open receptor channels, the LAs have to diffuse through the axolemma before they can interact with receptors. - dependent upon lipid solubility, degree of ionization, molecular weight, and chemical structure ᐧ the more lipid soluble a drug is, the faster it will get to the site of action Of these, the degree of ionization is the most important because the charged particles cannot diffuse through the membrane. - highly ionized drugs have a slower onset ᐧ e.g. bupivacaine - highly nonionized drugs have a faster onset ᐧ e.g. mepivacaine - the greater the protein binding, the longer the duration of action We tend to mix bupivacaine and mepivacaine together frequently for interscalene blocks because the mepivacaine will start to work more quickly providing some degree of anesthesia so they can start the procedure and then the bupivacaine kicks in and carries you through into the postop period
Duration of Action
Influenced by protein binding and lipid solubility. In general, drugs that have a high affinity for protein and are highly lipid-soluble will attach more firmly to the Na+ channel receptor and will therefore stay in the channel longer, producing a longer duration of action. - the addition of large radicals to the amide or aromatic end results in greater protein binding - there are drugs that do not conform to this
Spinal Anesthesia
Injection of LA directly into the subarachnoid space. Principle site of action is the preganglionic fibers as they enter the spinal cord in the anterior rami. Because the concentration of LA in CSF decreases as a function of the distance from the site of injection, zones of differential blockade develop. For a spinal anesthetic, unlike the epidural anesthetic, the dose we administer is going to determine the height/level of the spinal. For an epidural, it's the volume that we administer that determines the level. - this has to do with the fact that one is given into the CSF where it has the ability to mix so we get a concentration in a defined volume of fluid vs. something that has to diffuse across all these membranes - there is no fluid in the epidural space, you are just giving the LA into the tissue and it has to diffuse Spinal anesthesia = dose determines level Epidural anesthesia = volume determines level
Lipid Rescue Guidelines
Intralipids are now a part of every block cart. FIRST START CPR. - intralipid 20% 1.5 mL/kg bolus over 1 minute - follow immediately with an infusion at a rate of 0.25 mL/kg/min - continue chest compressions (lipid must circulate) - if the patient doesn't recover, repeat bolus q3-5min up to 3 mL/kg total dose until circulation restored - continue infusion until hemodynamic stability is restored. Increase the infusion rate to 0.5 mL/kg/min if BP declines - a maximum total dose of 8 mL/kg is recommended - at this point, the patient will be taken to the OR and put on bypass until the LA wears off and spontaneous circulation is restored
Cocaine Toxicity
It is very important to know about cocaine use in patients, in particular when they last used. If someone has used cocaine in the last couple of weeks, it will change the way we manage that patient from an anesthetic perspective. Treatment - #1 have to be thinking about managing any ischemia ᐧ NTG to treat myocardial ischemia - if the patient is profoundly HTN, you'll want to use direct vasodilators ᐧ alpha blockade (e.g. hydralazine) or nitride for HTN - beta blockade is controversial ᐧ we don't necessarily want a tachycardic patient but controlled tachycardia can precipitate coronary vasospasm in the setting of acute overdose ᐧ beta receptors in the coronaries are responsible for vasodilation so if we administer beta blockers, we can potentially constrict the coronaries - most providers will tolerate some degree of tachycardia in this setting (100-110's) but will intervene if the patient is tachycardic enough to impact coronary perfusion - beta blockade may precipitate CV collapse Benzodiazepines to control seizures, if present.
Lung Extraction of LA
LA are extracted by the lungs at a relatively high rate. - bupivacaine, lidocaine, and prilocaine (amides) - this limits the concentration of LA that reaches the systemic circulation for distribution to the heart and CNS - we tend not to see extensive lung extraction with the esters because they are metabolized in the plasma by the plasma cholinesterases so there is just not a lot around
LA: Mechanism of Action
LA bind reversibly to the H receptors located within or adjacent to the internal opening of the Na+ channel. Internal receptors have a greater affinity for the charged or protonated form of the local anesthetic. Therefore, the local anesthetic needs to be in the lipid-soluble, nonionized form to get to the internal receptor but once it gets to the internal receptor, the degree of ionization is going to change - the ionized form has a higher affinity for the receptor. This doesn't mean the nonionized form doesn't bind to the receptor, but the ionized form has a greater affinity. So a LA must first penetrate the cell membrane before producing its effects (diffusion through a cell membrane). Diffusion through the cell membrane is facilitated if the drug is in the nonionized, lipid soluble, uncharged state. Though not their primary mechanism of action, LAs also have the ability to just get into an open Na+ channel and obstruct the Na+ channel (near its external opening), maintaining the channel in the inactivated-closed state. So the primary MOA is via binding the the H receptors but it can also block the external surface of the channel.
Topical Anesthesia
LA is placed on the mucous membranes of the nose, mouth, tracheobronchial tree, esophagus, and GU tract Most commonly used: - cocaine 4-10% ᐧ produces localized vasoconstriction ᐧ utilized in ENT - tetracaine 1-2% nebulized - lidocaine 2-4% nebulized ᐧ can also be used in gels These are absorbed into the systemic circulation due to the high vascularity of the tissues so you must be cognizant of toxic doses.
Local Anesthetics
LA produce reversible conduction blockade of impulses along central and peripheral nerve pathways. - central vs. peripheral pathway dependent upon where we inject the LA - if we inject it into the skin in the hand for someone having a trigger finger release = peripheral nerves - if we are doing neuraxial anesthesia (spinals and epidurals) = central nerves Removal of LA is associated with complete return of nerve conduction. With progressive increases in concentration of drug, the transmission of autonomic, somatic sensory, and somatic motor impulses are interrupted.
Pharmacokinetics
LAs are weak bases with pKa above physiologic pH - pH 7.6-8.9 - there is one LA that is used topically (cetacaine, used in throat sprays) that has a pKa ~3 which enables it to be used topically (once it hits tissues -> nonionized) - they are prepared as hydrochloride salts (conjugate acids) - because of their pKa, <50% exists in the nonionized (active), lipid-soluble form - acidosis in the environment further favors the ionized form (inactive) which is why injecting LA into necrotic tissue is a setup for failure - LA with pKa values nearest to physiologic pH have the most rapid onset of action because they have more of the molecule present in the nonionized form - the greater the concentration in the nonionized form, the more lipid soluble the agent is
Metabolism: Amides
Lidocaine - primary metabolic pathway is dealkylation in the liver to monoethylglycinexylidide, followed by hydrolysis to xylidide, which is excreted by the kidneys - decreases in hepatic blood flow as occur under anesthesia are going to decrease the rate of metabolism because it will decrease the delivery of lidocaine to the liver - lidocaine produces vasodilation, activity can be prolonged by the concomitant administration of epinephrine ᐧ lidocaine, in and of itself, can actually speed its metabolism by increasing blood flow
Bupivacaine Toxicity Treatment
Lipid Emulsion Therapy - works for any LA, not just bupivacaine - lipids are able to encapsulate the LA and remove it from the circulation - LAs are amphipathic chemicals: because of their structure, they have a hydrophilic and a lipophilic component. Therefore, they have an affinity for both lipid environments and water environments. - this structure allows LAs to cross plasma and intracellular membranes quickly and also to interact with charged targets such as structural or catalytic proteins and signaling systems - intralipids bind the lipophilic component of LAs and prevent them from binding to cellular structures
Liposomal Local Anesthetics
Liposomal LA are a drug delivery system that utilizes liposomes to prolong the duration of action and to limit the toxicity of LAs. - it allows you to give a lot of LA that is going to be released over a long period of time Goal: upload higher concentration of LAs for a consistent release over time (extended release form) - liposomes are hydrophobic-based polymer particles that have small microspheres with internal aqueous chambers within them - LA is put into the aqueous chambers and as those chambers start to break down after injection, the LA is released The #1 liposomal LA on the market right now is Exparel, which is a bupivacaine ER liposome injection indicated for single-dose infiltration in adults to produce post-surgery analgesia and as part of a brachial plexus block. - it is not used in epidural or spinal anesthesia - used for shoulders, knees, hemorrhoids, etc. - bupivacaine released from the liposomes over an extended period of time (up to 96 hours) - associated with decreased narcotic use over the first 72 hours
Na+ Channels: Mechanism of Action
Na+ channels are dynamic transmembrane proteins containing: - a large Na+ conducting pore (α subunit) - a varying # of adjacent β subunits ᐧ β subunits are capable of modulating the ability of the LA to bind to the α subunit There are 9 distinct functional subtypes of Na+ channels that correspond to the 9 genes that are responsible for the formation of the α subunits. They code for the α subunits. Each α subunit is then further divided into 4 domains designated as DI- DIV. There is an H receptor on the α subunit (located inside the cell membrane) that allows for ion conduction and to which the LA will specifically bind. - the receptor is internal so the LA has to get inside the neuron in order for it to block
Frequency Dependent Blockade
Na+ channels recover from LA conduction blockade between action potentials. This means that the LA binds to it but then dissociates from the receptor and the axon is able to propagate another action potential. We have to have a certain concentration of LA inside the neuron in order for the conduction blockade to set. Develop additional conduction blockade each time channels open during an action potential. - LA gain access to internal H receptors only when receptors in activated-open state - also, gain access to H subunit of inactivated-closed after entering the cell and channel transitions from open to closed state - also bind to the channels pore in the inactivated state Therefore the blockade is related to frequency of activity and thus referred to as "frequency dependent". So the more times that you depolarize the membrane, the faster the LA is going to be able to set up its blockade. In other words, with repeated depolarization, a greater number of Na+ channels are present in the active or inactivated state and can be bound to LA. In addition, LA dissociated slower than the rate of transition from inactive to resting state. When we talk about LA cardiotoxicity, the first place that we started seeing this occur was in our OB population. When a woman is in labor, she tends to be hyperdynamic (tachycardic). Because she is tachycardic, her SA node is depolarizing at a very rapid rate so the LA were able to gain access to the Na+ channels inside the heart at a much more rapid rate, thus these women were more likely to develop cardiotoxicity than other populations.
Side Effects
Neurotoxicity - LA have the ability to produce some degree of neurotoxicity - this is due to the placement of LA into the epidural or subarachnoid space - this is a dose-dependent phenomenon ᐧ the higher the dose, the more likely it is - patients experience side effects on a spectrum: ᐧ patchy groin numbness ᐧ persistent myotomal weakness (nerve root) ᐧ full cauda equina syndrome (CES) - most S/S are reversible and typically resolve over time, however CES tends to be permanent Anterior Spinal Artery Syndrome - lower extremity paresis with a variable sensory deficits ᐧ depending on what area of the anterior spinal artery has been affected - the etiology is unknown, may be due to spasm of the artery or due to the addition of vasoconstrictors - resolves with time
Placental Transfer of LA
Not all drugs are capable of crossing the placenta. LA can cross the placenta and the degree to which they cross is determined by: - molecular weight, pKa, lipid-solubility, protein binding Nonionized drugs cross the placenta more readily than ionized drugs (this is determined by the pKa). Because fetal pH is more acidic than maternal blood, so when LA cross the placenta (weak bases) they will ionize in the acidic fetal environment. This will cause them to trap in the fetal tissues (ion trapping). - the ionized drug will be inactive but when the fetus is delivered and the pH goes up, there will be more drug available in the nonionized, active form The ester LA undergo rapid hydrolysis in the plasma and don't cross the placenta in significant amounts.
Cocaine Toxicity
Pharmacokinetics - route of administration determines the rate of onset, intensity of effect, and duration ᐧ addicts use the nose d/t the high vascularity of the mucous membranes - E1/2t = 60-90 minutes - metabolism is principally by plasma esterases but there is some metabolism in the liver - urinary excretion is <1% Adverse Physiological Effects - the cardiac effects of cocaine outlast the high - while using, an individual can experience coronary vasospasm, myocardial ischemia, MI, dysrhythmias (including VF) - because there is going to blockade of the uptake of NE, users will develop HTN, tachycardia, increased myocardial O2 demand all in the face of decreased coronary blood flow (supply) - the effects of cocaine on the vasculature (ischemia and hypotension) can occur for up to 6 weeks after use - cocaine sensitizes the vasculature to catecholamines (including endogenous) so there will be a hyperactive response - can also cause seizures
Metabolism: Amides
Prilocaine - not utilized very frequently, present in EMLA cream - metabolized to orthotoluidine, an oxidizing compound capable of converting Hgb to methemoglobin which puts patients at risk for methemoglobinemia ᐧ methemoglobin does not bind to O2, decreasing O2 carrying capacity and leading to tissue hypoxia - when prilocaine doses >600 mg, there is sufficient methemoglobin to cause cyanosis and decreased O2-carry capacity - S/S: brownish-gray cyanosis, tachypnea, and metabolic acidosis ᐧ under anesthesia, you may only see patients becoming tachycardic and cyanotic - methemoglobinemia is reversed by the IV administration of methylene blue 1-2 mg/kg over 5 min ᐧ this will reverse the formation of methemoglobin There are other amide LA that have the potential to produce methemoglobinemia but not in the concentrations that we typically use. - e.g. cetacaine (can be seen if a patient uses an entire bottle of throat spray)
Local Anesthetics
Remember: these are not intravenous drugs. These drugs are being injected into the tissues, altering the pharmacokinetics of these agents. In order for them to be removed from the body, they must be absorbed into the bloodstream to get to the site of metabolism. Local anesthetics are used to provide analgesia and anesthesia. We can give LA in varying concentrations to achieve different effects. - high doses: sympathetic, sensory, and motor blockade - low doses: confine to sensory blockade When we administer LA by infiltration, we can provide partial analgesia to a patient by infiltrating the skin and the muscle but if there is work done on the deeper tissues, those LA are not necessarily going to infiltrate deep enough to be able to provide analgesia. - these patients will require another analgesic on top of the local anesthetic
Side Effects
Selective Cardiac Toxicity - seen with bupivacaine - after accidental IV injection or high concentrate/high rate infusion where clearance is much less than the increase in plasma [ ], the plasma protein binding sites (alpha 1-acid glycoprotein) for bupivacaine become saturated very quickly - this leaves a significant mass of free (unbound) drug available for diffusion into the conducting tissues of the heart (preferentially goes here) - the threshold for cardiotoxicity is decreased by pregnancy, antidysrhythmics, hypoxemia, acidosis, or hypercarbia
Spinal Anesthesia: Physiologic Effects
Sensory blockade and skeletal muscle relaxation accompanied by sympathetic nervous system blockade - SNS blockade produces systemic effects ᐧ pt will be hypotensive ᐧ 1st sign spinal is working, cycle BP -> hypotension ᐧ treated with pressors ᐧ especially those with cardiac/renal hx - not going to give fluids Risk of cardiac arrest (called total spinal/high spinal) - the arrest is not because the high spinal is at the level of the medulla (respiratory centers) because the concentration is not great enough at that point - the level of the anesthetic gets too high so the symnpathectomy is significant enough that there is no vasculature above the level of the sympathectomy to vasoconstrict and get the pressure back up ᐧ patient hypotensive, bradycardic, not perfusing their head and they become unconscious ᐧ tx: pressors, intubate, wait until spinal wears off Risk factors for high spinal - sensory level >T5, baseline hypotension, prolonged PR interval/any bradyarrhythmia, beta blockade/CCB
EMLA Cream
Skin blood flow, epidermal and dermal thickness, and presence of skin pathology affect onset, efficacy, and duration of anesthesia. Plasma levels of lidocaine and prilocaine are below toxic levels. - methemoglobin concentration increased in children <3 months due to immature reductase pathways - used by some providers in circumcisions Should never be used on mucous membranes due to high plasma concentration.
Alkalinization of Solutions
Some physicians, particularly in plastics where comfort is prioritized, will alkalinize the solution with the addition of NaHCO3 immediately prior to injection. - once NaHCO3 is added, the pH of the solution increases and thus changes the degree of ionization (more drug will be available in the nonionized/active form) - more drug available in the nonionized form shortens the onset of the blockade - it will also enhance the depth of sensory & motor blockade because more of it is available in the nonionized form - it will increase the spread of epidural blockade - decrease pain on injection
Na+ Channels: Mechanism of Action
Stimulation causes reversal of the membrane potential until threshold potential is reached. Once the threshold potential is reached, there is a conformational change in that Na+ channel. The Na+ channel is going to transition from the resting state to the open state where Na+ conduction is going to occur. It is a relatively rapid transition. The transition from the open to the inactivated state occurs more slowly. The inactive state is characterized by return of the Na+ channel to an impermeable state and therefore an action potential cannot be initiated. The inactivated state lasts until the resting transmembrane potential is restored (refractory period). There is a relative refractory period, during which a supramaximal stimulus has the potential to activate the channel.
LA: Mechanism of Action
The LA work by binding to specific sites in voltage-gated Na+ channels. They produce conduction blockade by inhibiting Na+ passage through the Na+ channels located in the cell membrane. - failure of Na+ channel permeability and thus no Na+ conduction, slows the rate of depolarization so that the threshold potential cannot be reached and an action potential cannot be initiated or propagated Na+ channels contain the specific receptor sites that local anesthetics bind to.
Na+ Channels: Mechanism of Action
The Na+ channels exist in 3 conformational (functional) states during phases of the action potential: - open-activated: Na+ channel has been activated - inactivated-closed: absolute refractory period - resting (closed): capable of being activated ᐧ exists when the membrane reestablishes its resting potential The binding affinities of the LA are stereospecific and depend upon the conformational state of the Na+ channel. They are going to preferentially bind to one channel versus another.
Use of Vasoconstrictors
The duration of action of the LAs is proportionate to the time that it is in contact with the nerve fibers. In order for the drug to be removed from the site of action, we have to have blood flow to the tissue in order for it to gain access to the central circulation and be metabolized. If you administer a vasoconstrictor into the tissues along with that LA, its going to vasoconstrict the vessels in the tissue, limiting blood supply to the tissue, keeping the LA in contact with the nerve fibers for a longer period of time. - decreases systemic absorption of the drug - increases the duration of action of the drug It is going to have a greater effect on the shorter acting agents than the longer acting agents because the long-acting agents are already long acting/staying in contact with the nerve fibers for a long period of time. - although adding a vasoconstrictor can still extend the longer-acting agents, it does so to a greater degree with the short-acting. Vasoconstrictors increase neuronal uptake of LA, producing prolonged blockade.
Structure-Activity Relationships
The majority of LA that we utilize in practice today are chiral molecules (center of asymmetry). - mepivacaine, bupivacaine, ropivacaine - asymmetric carbon atom somewhere in the structure - these drugs exist as isomers (mirror images) called enantiomers - they have a left- (S) or right- (R) handed configuration - mepivacaine and bupivacaine are used clinically as racemic mixtures (50:50) Enantiomers of chiral molecules may have different pharmacokinetic, pharmacodynamic, and therefore toxicity profiles. - the various different isomers are stereoselective for receptors or enzymes so some will have a higher affinity for a receptor, some will have a higher affinity for a particular enzyme and this will change the way that isomer works/is metabolized - the S enantiomers of mepivacaine and bupivacaine are less toxic than the R enantiomers (expensive) - ropivacaine and levobupivacaine are pure S enantiomers
Systemic Toxicity: CNS
The onset of seizures with LA is going to reflect selective depression of the inhibitory cortical neurons. - excitatory neurons are initially spared and are thus unopposed - the normal balance isn't there so the patient has a seizure The LAs within the CNS are also able to inhibit GABA release. Remember: GABA is an inhibitory neurotransmitter. This is believed to occur primarily in the temporal lobes or amygdala but at this point is still unclear. The plasma concentrations that produce toxicity are going to be agent specific. The rate of increase in plasma concentration may be more important than the total amount of the drug given. If you accumulate plasma concentrations over time, the patient is able to compensate for some of those increases vs. the individual that gets an intravascular injection that gets it all at once with no time to compensate.
Structure-Activity Relationships
The original LA were modified in various different ways in order to alter the pharmacologic effects. Procaine - halogenated (chlorine added to its aromatic ring) to produce chloroprocaine - this increased its rate of metabolism by 3-4x - metabolized via hydrolysis by plasma cholinesterase - chloroprocaine is a very short acting LA with a very rapid onset of action - used in OB (epidural anesthesia) for a rapid, dense block for a patient undergoing C-section, then other longer-acting anesthetics were added to last the case Lidocaine - substitution of a propyl group for an ethyl group on the amine end of lidocaine and the addition of an ethyl group on the hydrocarbon chain produces etidocaine - it has a significantly increased lipid-soluble which is increases the duration of action by 2-3x
Saltatory Conduction
The presence of myelin makes it easier to propagate an action potential. It is going to be faster because it's going to skip from one node to next as it travels down the axon. It doesn't have to depolarize every single channel - just at the nodes of Ranvier. This is called saltatory conduction. The LAs also only need to block at the nodes of Ranvier. They do not need to go through the myelin sheath and block all of the Na+ channels because those Na+ channels don't do anything anyway due to the presence of the myelin. In order for the LA to block a myelinated neuron, you have to have at least 3 nodes in sequence that are blocked by the LA. In myelinated neurons blockade occurs at the Nodes of Ranvier.
Na+ Channels: Mechanism of Action
The resting membrane channels exist in equilibrium between the resting and inactivated state. It takes a little bit of time for them to transition back from inactivated to the rested state. Remember: as we propagate down a neuron, the channels at the beginning of the neuron are going to reset themselves before the channels at the end of the neuron - which is the equilibrium exists. LA preferentially bind to channels in the open and inactivated states. They actually like to bind to the channels in the inactivated state to a greater extent than the open state. - they believe that when the Na+ channel is in the inactivated or open state, there is an increase in the affinity of the LA for the receptor - they also believe that it may just be physically easier for the LA to get to the H receptor and bind during these states The LA stabilizes the channel and prevents it from transitioning to the rested-closed state or activated-open state in response to nerve impulses. - inactivated receptors cannot transition to the resting state and depolarize in response to an action potential
Spinal Anesthesia
The specific gravity of the LA solution determines the spread of the drug. LAs come in an ampule. If they are mixed with glucose (majority) we create a hyperbaric solution which means the specific gravity is greater than that of the CSF. - hyperbaric solutions will sink - so the positioning of the patient is going to determine where the LA is going to be - e.g. patient is sitting upright, hyperbaric LA solution administered without changing position, you will not get a T4 sensory level because the LA will sink. If you administer the LA and then immediately put the patient in a trendelenburg potision, the LA will travel cephalad because it will "sink" - e.g. if you administer a spinal to a patient and the level isn't high enough, you can move the patient into trendelenburg to help it move up The addition of distilled water lowers the specific gravity below that of the CSF creating a hypobaric solution. - hypobaric solutions will spread rostral (upward) - e.g. patient with a broken hip requiring a spinal. You are able to turn the patient onto their nonoperative side (broken hip up). You can put the spinal in, the LA will travel rostrally and the patient is already positioned There are isobaric solutions but they are utilized much less frequently. There is no cholinesterase in CSF so the duration of action is terminated by systemic absorption.
Peripheral Nerve Blocks
The speed of onset is dependent upon the pKa of the drug and the pH of the surrounding tissues. - pKa determines the amount of LA in the nonionized form - lidocaine onset is 3 minutes - mepivacaine 10 minutes - bupivacaine, levobupivacaine 15 minutes ᐧ less drug in the nonionized form Duration of blockade dependent upon dose, lipid solubility, protein binding, and use of vasoconstrictors.
Systemic Toxicity: CNS
There is an inverse relationship between PaCO2 and seizure threshold due to the effect of CO2 on cerebral blood flow and delivery of drug to the brain. When we have a patient that is seizing, we have to be careful with the way in which we ventilate that patient. While vasoconstriction will limit the addition of more drug into the CNS, it is also going to limit the ability of that drug to get out of the CNS. - so in these situations you want to make sure the patient has a patent airway and ensure that they are normocarbic. Hyperkalemia increases the TMP and facilitates depolarization and markedly increases CNS toxicity - intracellular K+ 140, plasma K+ 3.5-5 - hypokalemia decreases the TMP and thus has the opposite effect
Liposomal Local Anesthetics
These liposomal delivery systems have been developed for other drugs (e.g. lidocaine, etc.) but not yet FDA approved. Exparel can ONLY be mixed with bupivacaine. Mixing liposomal bupivacaine with non-bupivacaine-based LA, including lidocaine, is not recommended. It may cause an immediate release of bupivacaine from the liposomes which may cause toxicity. Despite the use of liposomal bupivacaine in all surgery settings, there is no clear evidence of benefit when compared with plain bupivacaine, which is much cheaper. - a 2017 Cochrane review of 10 RCTs demonstrated reduced postop pain as compared with a placebo, but limited evidence does not demonstrate superiority when compared with plain bupivacaine
Differential Conduction Blockade
This is the result of different fiber diameters and the presence of myelin. In order of increasing required Cm: - preganglionic sympathetic B fibers (blocked 1st) - C fibers and small diameter A fibers - large A motor fibers (blocked last)
Local Anesthetic Uses
Topical Local infiltration Regional anesthesia - neuraxial anesthesia ᐧ spinal ᐧ epidural - peripheral nerve block - intravenous regional anesthesia
Side Effects
Transient Neurological Symptoms - with spinal and epidural anesthetics - when the spinal are placed as they're passing the needle you can get paresthesias (e.g. tweak the nerve) if this happens, you have to put the needle out and redirect to avoid injecting LA into nerve/nerve root - manifests as moderate to severe pain in lower back, buttocks, and posterior thigh - etiology unknown - the neurological symptoms usually appear 6-36 hours after recovery once the epidural/spinal has worn off - complete recovery usually within 1-7 days - incidence is highest after intrathecal lidocaine injection - may be related to irritation of the lumbosacral nerve roots and may be exaggerated when nerves are stretched by prolonged lithotomy position - the addition of epinephrine or phenylephrine may contribute to the symptoms ᐧ decrease nerve blood flow resulting in a decreased systemic uptake
Maximum Dosages of Local Anesthetics
Two tables provided: one with mg/kg and the other with maximum doses. When a table just gives you maximum doses, they are assuming it is a 70 kg patient. If you have a 7'2", 320 lb patient of solid muscle - the toxic plasma concentrations is going to be much higher than that of a typical 70 kg patient. Doses will be given with and without epinephrine. With epinephrine, we are able to administer higher doses of LA because of the localized vasoconstriction that occurs. We know the drug is going to stay in the tissues longer so it will limit the amount that gets into the central circulation, limiting the toxicity of that agent. - maximum dose of lidocaine 4.5 mg/kg goes up to 7 mg/kg with the addition of lidocaine and essentially doubles the duration of action (120 to 240 minutes) - maximum dose of mepivacaine is 5 mg/kg goes up to 7 mg/kg with epi and duration of action increases from 180 to 360 minutes - maximum dose of bupivacaine 2.5 mg/kg (much lower because it is much more lipid soluble, more potent) goes up to 4 mg/kg (4 to 8 hours duration) ᐧ dose doesn't increase much due to bupivacaines systemic toxicity profile (some people have seizures at 1.5 mg/kg) KNOW ALL DRUG DOSAGES EXCEPT etidocaine and prilocaine.
Tumescent Liposuction
Used in plastic surgery. The subcutaneous infiltration of large volumes ( >5 liter) of solution containing highly diluted [ ] of lidocaine (0.05%-0.1%) with epinephrine 1:100,000. It results in sufficient LA for the liposuction with a virtually bloodless field. It also prolongs the postoperative anesthesia. This can be done in offices, surgery centers, etc. with limited additional anesthetic requirements for the patient. Unfortunately, there is a slow and sustained release of lidocaine into the circulation. Usually plasma concentrations are going to be <1 mcg/mL but much higher concentrations have been seen. - peak concentrations occur 12-14 hours after infiltration - remember: the recommended adult dose is 7 mg/kg, with tumescent liposuction you can see doses of 35-55 mg/kg (mega-dose lidocaine). There have been reports of increased mortality associated with the technique. The cause of death is not always known but may include lidocaine toxicity or LA induced depression of cardiac conduction and contractility. Patients undergoing tumescent liposuction really should not be having liposuction done over the entire body. There should be a limit and these patients should never be sent home after this kind of procedure.
Combinations of LAs
We often combine local anesthetics, taking advantage of the different properties of LAs: those that have a rapid onset, those with a longer duration of action, etc. May be combined to produce a rapid onset (chloroprocaine) and prolonged duration of action (bupivacaine). This allows the surgeon to get going while making sure the patient has adequate analgesia in the postop period. LA toxicity is additive not synergistic. Giving 2 LAs together is not going to increase the patients risk of a toxic reaction. - synergism: 2 agents work together to produce similar effects via different mechanisms - all LAs work via the same mechanism Tachyphylaxis can occur and reflects local acidosis due to low pH of the bathing solution. - it is not a true tachyphylaxis - if you keep administering LAs in the tissues, it will change the tissue pH. If you change the tissue pH, you decrease the degree of ionization of the LA that you are administering so now it just won't work
Zones of Differential Blockade
When we inject a spinal anesthetic, we are going to inject at either the L2/3, L3/4, or L4/5 interspace. We are never going to go anywhere else because L2 is where the spinal cord ends in an adult. We are going to inject the LA directly into the intrathecal space. The LA is going to mix directly with the CSF and as it mixes, it is going to diffuse north. As the LA diffuses north, it is going to start to come into contact with the various different nerve roots. At the level at which the LA was injected, there will be immediate binding occur. As it travels north, LA concentrations are going to decrease because some of it is already bound. So as it travels upward the concentration needed for the Cm is going to decrease. At the area of injection, the Cm is high enough to block the motor, sensory, and sympathetics. As it travels north, it will reach a point where the concentration is too low to produce motor blockade but there will be enough for the sensory and sympathetic. As it continues north, it will reach a point where the concentration is too low for the sensory but can still produce sympathetic blockade. These are known as the zones of differential blockade. - motor, sensory, and sympathetic - sensory and sympathetic - sympathetic For spinal anesthesia we check the level via temperature/pin prick. - e.g. at the level of T4: the patient can feel the pin prick above and cannot below, so this is the level of the sensory blockade - the motor blockade ends 2-4 dermatome levels below the sensory blockade (e.g. T6-T8) - the sympathetic blockade ends 2-4 dermatome levels above the sensory blockade (e.g. T1-T2)
Classification of Nerve Fibers
When we look at the various fiber types, they are differentiated from each other in one of three ways: - size - conduction velocity - presence of myelin - the motor fibers (Aα) are your greatest diameter fibers with the greatest conduction velocity. - the Aβ fibers, responsible for proprioception/joint position, are also the largest diameter with the greatest conduction velocity. - although they have myelin (meaning you don't have to block every Na+ channel) the fact that those fibers are so large mean that they are going to be the hardest to block, requiring the highest concentrations of LA. - sensory fibers A𝛅 are much smaller in diameter - C fibers (sensory and autonomic) are much smaller in diameter and unmyelinated - these fibers are incredibly easy to block This should tell you that when you inject LA, more than likely, some fibers are going to see the onset of action of the LA quicker than others based upon the sizes. - the sympathetics are usually blocked first - then the pain fibers - then the motor fibers
Relationship Between pKa, Protein-Binding, & Onset/Duration of Action
pKa - in general, when you see drugs with relatively high pKa (procaine, tetracaine, bupivacaine) you'll that these drugs are taking 7-10 minutes to have an onset of action. - when you look at (lidocaine, prilocaine, etc.) which have pKa closer to physiological pH, you'll see that they have a much shorter onset of action ~1-2 minutes. - this is because it is determining the degree that is present in the nonionized form. Protein Binding - etidocaine, bupivacaine, tetracaine are all highly protein bound, which will be slower in action onset. - etidocaine tends to be faster because its pKa (7.7) is closer to physiological pH so you end up with more of the drug that can get to where it needs to go - the highly protein bound drugs tend to have a longer duration of action because they are bound to the receptors for longer - mepivacaine, lidocaine, prilocaine are intermediate in their degree of protein binding, as well as in their duration of action - procaine (novocaine) is not highly protein bound but it's pKa is so high that there is very little of it available in the nonionized form therefore it has a long onset and very short duration (very narrow window) ᐧ can add epinephrine to extend duration of action
