Local Anesthetic Pharmacology Flashcards
3 ways that local anesthetics work are
Autonomic blockade
Somatic sensory blockade
Somatic motor blockade
Local ane sites of administration are?
- infiltrated around nerve
- applied to skin and mucous membranes
- Injected into subarachnoid and pleural space
- Injected into blood vessels..(Exsanguinated)
Membrane ion conc
Extracellular…sodium high/K low
Intracellular …potassium high/sodium low.
Ion Channels guarded by a gating mechanism- opens or closes depending on changing physiologic conditions
How is The Velocity an impulse travels proportional to the diameter of fibre
Directly proportional to fiber diameter.
the larger the diameter, the higher the conduction velocity
3 types of fibre are
A, B and C fibers
Explain A fibres
A fibers (myelinated) 1 to 22 microns Subdivided into: α β γ δ in order of decreasing size. alpha fibers are the fastest
Explain B fibres
B fibers (myelinated) 1 to 3 micrometers
Explain C fibres
C fibers (unmyelinated fibers) 0.1 to 2.5 micrometers slowest
PNS fibres comprise of ?
A-alpha fibers: motor & proprioception .
A-beta fibers: motor, touch, pressure
A- gamma fibers: motor/muscle tone (muscle spindle)
A-delta fibers: pain, temperature,touch
B-fibers: PREganglionic autonomic
C- fibers: dull pain, temperature, touch, POSTganglionic autonomic– NO MYELIN
the lower the size,the slower the conduction,the easiest to block
Characteristics of the fibers include
Fast and Slow pathways
Myelinated A-delta fibers (slowest of the A fibers)
Unmyelinated C fibers (much slower)
XXX Large fibers have the highest conduction velocity and the lowest threshold for excitability
How is the sensitivity of a PN to local Anesthesia related to size
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
Fyi
In a laboratory…larger fibers A delta and gamma are actually more sensitive to local anesthetics than the C fibers which are unmyelinated and small
Factors that affect blockade in different nerve s
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
Motor nerves have larger spaces between their nodes
Autonomic more on the outside…
C fibres are on outside …so easier to block
A alpha needs more to get to it.
Faster or more firing may also increase rate of block
Frequency dependent blockade
Outer…mantle..
Check temp in comparative extremities. Like the toes…if one is colder..pls reposition or pull back catheter…remember autonomic blocked first.
How location affects the spread of local anesthetic
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
This factor is much more important than the inherent sensitivity of the nerve fiber to local anesthetics
What is the Clinical sequence of anesthesia:
1st- sympathetic block (vasodilatation, warm skin)
2nd – Loss pain and temperature sensation
3rd – Loss of proprioception
4th - Loss of touch and pressure
5th – Motor blockade
Mode of action nerve blockade
Voltage gated sodium channels in the inactivated-closed state serve as receptors for local anesthetic molecules
Local anesthetics bind at specific sites on the internal H gate of the channel & physically obstruct the external openings of the channels.
Local anesthetics prevent passage of sodium ions through these channels by binding and stabilizing them in the inactivated-closed conformational state
This blocks impulse conduction during the depolarization phase of the action potential.
prevent from reaching threshold.
can be compared to Inverse agonist.
myelination
Myelinated Nerve Fiber:
A Schwann-cell wraps itself around the axon several times, enveloping the axon in a myelin sheath…lipid insulating barrier
Unmyelinated Nerve Fiber:
A single Schwann cell surrounds several axons
Effects of Myelination on a nerve fibre
Decreasing resistance … increasing capacitance Difficult to assess at the myelin… Works at the node. Block 3 nodes to block a nerve Nerve fiber bigger….spaces get far apart.
Compare conduction btwn myelinated fibre and unmyelinated fibre
propagation of impulse is similar.
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
How Does Frequency of cycling affect the rate of blockade
LA s easily access nerve cell Na channels in the “activated-open” state
LA’s easily bind to the receptor 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
since Resting nerve is less sensitive to block than a repetitively stimulated nerve.What will determine the accessibility for block
Lipid solubility determines (i.e. it has to diffuse through the axonal membrane instead of through the Na channel to reach its target)
The higher the lipid solubility,the faster the block
How does the distance between nodes of ranvier and the size of a fibre affect the sensitivity of a fibre to a block.How can this be mitigated
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
Blockade of three nodes (1cm) eliminates conduction along a myelinated nerve fiber (A fibers)
Explain differential block
Bupivacaine was the first local anesthetic shown to produce a beneficial differential block: Sensory block with incomplete motor block
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
Name the 2 main classifications of LA
and how the structure is arranged
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).
BINDS better if it has a charge.
Analyze the difference in metabolism between Aminoamides and Aminoesters
Ester linkage: readily hydrolyzed by non-specific esterases in the plasma and tissues (mostly liver)
Faster hydrolysis
Cocaine exception…decreases norepi reuptake,,more Norepi in the SA node,hence tarchycardia
Cocaine decreases bleeding 2/2 to being great vasoconstrictor…monitor cardiac numbers for MI
Amide linkage: metabolized in the liver…slower …higher risk of toxicity
What is the variability in potency and DOA between Lipid soluble anesthetics and water soluble anesthetics per molecular structure.
Highly Lipid soluble anesthetics are more potent and have a longer duration of action than water soluble anesthetics.
Factors that affect toxicity and potentcy in the molecular structure.
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)
FYI for block guide(CM)
Minimum Blocking Concentration
Nerve fiber diameter influence
Motor nerve higher Cm than sensory
Tissue pH,,acidic(infected tissue not good)
Onset level becomes very high
Frequency of nerve stimulation…faster block
Potency of particular LA…more potent..need less molecules
With LA,what are the drug delivery systems that we have
Offer sustained release properties Prolonged DOA((about 4days) Theoretical decreased toxicity Liposomes Exparel: Bupivacaine extended release liposome injection FDA approved Do not mix or inject any other local anesthetic at the same site Dose: depends on surgical site Max dose: 266mg or 20 ml Cyclodextrins Biopolymers
LA systemic absorption depends on
Physiochemical characteristics
PKA/PH/Lipid solubilty
physiologic conditions at site of deposit:
TissuepH,Pco2,temp,Patient characteristics
volume of solution or vehicle used
concentration of anesthetic
Peripheral…..use lower conc/higher volume
for elderly give lower doses.
Albumin conc is down in preg women so less protein binding..more available so reduce the dose.
watch for systemic absorption risk
The order of absorption by type of block
Intravenous Tracheal Intercostal Caudal Paracervical Epidural Brachial Plexus Subarachnoid Subcutaneous
The more vascular the region, the higher the risk of toxicity( intercostal)
Ionization action of LA
Unionized form diffuses across the nerve sheath and membrane to reach the site of action
Once inside the nerve membrane the ionized and non-ionized forms re-equilibrate
Ionized form binds a receptor inside the Na channel = blockade
pKa = pH at which a drug exists
50% ionized form
50% unionized form
Ionization concepts
The ionized form is favored when:
1.Acidic drug in relatively basic environment
2.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 7.5-9
Why are local anesthetics packaged in acidic formulations
They are packaged in acidic formulations and often to preserve epinephrine and bring down the PH
– don’t let this fool you they are basic upon injection
All local anesthetics: weak bases with pka values 7.5-9
to improve solubility and stability in the vial.
What factors determine the proportion of drug in the non-ionized state
PH of the LA solution
PKA of the drug.
How does the rate and amount of absorption vary with PH
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
What are the ways to influence the ph/pka relationship to speed onset of LA
Adding Bicarb increases the onset, enhances block depth, and increases the spread of the block
Infected tissue alterations..its acidic..block higher up..does not work
Ion trapping in pregnancy…weak base can cause ion traping..bupi is highly protein bound…this keeps it from crossing in great amount
.
Temperature: decreasing temperature decrease or slows down absorption and onset.
reduces drug absorption across the nerve membrane
Potency of LA depends on?
Lipid solubility
Duration of Action depends on?
Protein binding Capacity
The following factors help with longer duration of action
Tissue Blood Flow..higher flow is better will help move LA
Addition of Vasoconstrictors..this will decrease uptake…prolong duration of action…reduce toxicity
Lipid solubility…stays more in local tissue that is more lipid
Protein Binding…higher protein bound increases duration of action
Intrinsic vasodilator activity
Lidocaine VS mepivacaine……
.no lidocaine for gangrenous limb
Lidocaine is a lil vasodilatory
Long uptake also supports longer DOA
also may depend on metabolism
propranolol and fentanyl may have buffer action. since other drugs are uptake by the lungs
Benefits of injecting vasoconstrictor with Local anesthetic
- Inhibition of systemic absorption of LA
- Prolongation of the LA effect
- Detection of intravascular injection with Epi added..
What determines the concentration of Local Anesthetic in the blood.
Tissue blood flow.
Metabolism of Ester
Primarily hydrolyzed by pseudocholinesterase enzymes in plasma (and to lesser extent - the liver) (<5% excreted unchanged in the urine)
Metabolite = para-aminobenzoic acid (PABA)
*Exceptional ester is cocaine which is significantly metabolized in the liver and 10-12% excreted unchanged in the urine
This is a fast process
Metabolism of LA-Amides
Liver
Microsomal Enzymes
More complex and slower process than metabolism of Esters-
Aromatic hydroxylation, N-dealkylation and amide hydrolysis
What does that mean for the possibility of systemic toxicity and cumulative effects??
Process
Higher possibility of Toxicity….
What determines onset of LA
Ph and Pka
Know the Max doses of ANesthesia
pls see max dose
Local Anesthetic toxicity effects on 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??
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 SAB – lasts about a week
Cauda equina syndrome diffuse lumbosacral injury, numbness in LE, loss of bowel and bladder control, paraplegia
Lidocaine 5%, Tetracaine, and Chloroprocaine have been implicated
Anterior Spinal Artery Syndrome LE paralysis with +/- sensory deficit
Unknown cause, vasoconstrictors?, PVD, advanced age increase the risk
cocaine Toxicity
Cocaine -restlessness, tremors, seizures and euphoria
Cocaine overdose manifests as massive sympathetic outflow, coronary vasospasm, MI, dysrhythmias including V-fib
Local anesthetic toxicity cardiovascular effects
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
What physiologic situations increases the risk of toxicity per CV effects
Pregnancy, hypoxia, pH abnormalities and CV modulating drugs increase the risk
What drug is the most Cv toxic drug
Bupivacaine most CV toxic – cardiac arrest may occur at lower levels of toxic doses (inadvertent IV injection, etc.)
LA 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
For Allergic reactions what are the main culprits?
Esters implicated more than Amides (PABA?)
Preservative Reaction? (Methylparaben)
whats the effect of Pseudocholinesterase inhibitors on Esters
Pseudocholinesterase inhibitors may prolong the duration of ester anesthetics
Whats the effect of CImetidine and Propranol on hepatic blood flow
Cimetidine and propranolol decrease hepatic blood flow decrease clearance of amide local anesthetics and cocaine
FYI
Analgesia promoted by opioids, clonidine, and epinephrine added to LA
Selection criteria for choosing LA agents
Type of surgery Spreadability Duration of action potency Onset of action Risk of toxicity Site of metabolism
These drugs can potentiate LA
opioids, clonidine, and epinephrine added to LA
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
Cocaine uses and side effects
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 uses and side effects
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 the efficacy of sulfonamide antibiotics
Tetracaine uses and side effects
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 uses and side effects
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)
Lidocaine uses and side effects
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 uses and side effects
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 uses and side effects
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 uses and side effects
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 uses and side effects
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 uses and side effects
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
Dosing main points
Concentration, Volume, and Total Dose Administered
Peripheral nerve block
Volume dictated by type of block
Choose concentration based on limitations of max dose balanced with density of blockade desired
Epidural
Volume dictated to what level of block desired
1.25-1.6ml/per segment desired
Choose concentration based on density of block desired (i.e. labor VS surgical epidural)
Spinal
These doses you just have to know
