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What determines potency of a local anesthetic?
Lipid solubility.
↑ lipid solubility allows more LA to penetrate tissue and cell membranes causing and ↑potency
DOA for LA determined by
Protein binding
MOA of LA
LAs reversibly inhibit nerve transmission by binding voltage-gated sodium channels (Na) in the nerve plasma membrane
What is the structure of LAs characterized by
having both lipophilic and hydrophilic ends (amphipathic) connected by a hydrocarbon chain
Primary route of metabolism of amide LAs
Ester (-CO) link metabolized by plasma cholinesterase
Amide (-NHC) link metabolized by the liver
Class of LAs that patients are most allergic to
Ester-type local anesthetics
Hydrolysis of ester-type LAs by plasma cholinesterase release PABA
Compound responsible for the majority of allergic reactions to amide class of LAs
Para-aminobenzoic acid (PABA) a metabolite of esters
What preservatives used in both ester and amide LAs have metabolites similar in structure to PABA?
Methylparaben and propylparaben
CNS symptoms associated with toxic blood levels of LA
CNS: agitation, confusion, dizziness, drowsiness, dysphoria, auditory changes, tinnitus, perioral numbness, metallic taste, and dysarthria
**If untreated can progress to seizures
First signs of cardiac toxicity of LAs
Hypotension and bradycardia
Additional signs of cardiac toxicity with LAs
hypertension, dyspnea, pain, wide complex, ST-segment changes, asystole, tachycardia, and ventricular ectopy/tachycardia/fibrillation
Intravascular injection of LAs can immediately lead to
Seizures
Factors that contribute to CNS and cardiotoxicity from LA
inhibit oxidative phosphorylation pathway
bind to and inhibit voltage-gated sodium channels
block the voltage-dependent calcium channels
Heart and brain less tolerant to anaerobic metabolism therefore have the most
LAs bind to and inhibit voltage-gated sodium channels which can cause
conduction disturbances
contractile dysfunction
and ventricular arrhythmias
(T/F) The incidence of cardiac toxicity decreases with bupivacaine, a longer-acting anesthetic
FALSE - It increases with Bupivicaine
Bupivacaine blocks inactive Na+ channels during cardiac action potential at [ ] of 2 mcg/ml.
Fast-in/slow-out fashion: bupivacaine binds quickly to sodium channels during the cardiac action potential, but releases from channels slowly during diastole, resulting in a large amount of medication accumulating at 60 to 150 beats per minute.
Bupivacaine and Fast-in/slow-out fashion
bupivacaine binds quickly to sodium channels during the cardiac action potential, but releases from channels slowly during diastole, resulting in a large amount of medication accumulating at 60 to 150 beats per minute
Lidocaine and fast-in/fast-out principle
Lidocaine releases from sodium channels rapidly during diastole.
Allows for a quicker recovery, and a ↓ incidence of cardiac toxicity when compared to bupivacaine
What is the mechanistic theory about Twik-related acid-sensitive K+ channels (TASK) in relation to LAST
pH-sensitive channels generate neuronal potassium “leak” currents.
LA inhibition causes membrane depolarization and increased neuronal excitability which leads to seizures
(T/F) Local anesthetic agents also block voltage-dependent calcium channels because they closely resembles that of sodium channels
True
______ channels mediate synaptic transmission within cardiac muscle cells and are involved in the coupling of electrical excitability with mechanical contraction
Calcium
(T/F) bupivacaine exerts a greater degree of direct myocardial depression than less potent agents
TRUE
With bupivacaine, slow rate of dissociation prevents a complete recovery of the Na+ channels at end of cardiac cycle, thereby leading to more blocked channels and worsening of the conduction defect
Factors that contribute to LAST when voltage-dependent calcium channels are blocked by LAs
Calcium channels mediate synaptic transmission within cardiac muscle cells therefore causes:
↓intracellular Ca++ release from sarcoplasmic reticulum
↓myocardial contractility
Inactivation of β-adrenergic receptors cause ↓adenylate cyclase and ↓ production of cyclic adenosine monophosphate
Ultimately causes, ↓ATP synthesis which results in ↓myocardial function, tissue hypoxia and metabolic acidosis which augment the cellular effects of LAST and further depresses myocardial contractility
How does hypercarbia increase toxicity to local anesthetics?
Increases CBF which results in greater amounts of LA in brain
The pKa is the pH at which a solution of local anesthetic is in equilibrium with
half in the neutral base (salt) and half in the ionized state (cation).
Most local anesthetics have a pKa (greater/less) than 7.4
greater
Because the neutral base form of the local anesthetic is more (lipophilic/hydrophobic), it can penetrate nerve membranes faster
lipophilic
As the pKa of a local anesthetic (rises/lowers), the percentage in the ionized state increases and the onset of the block is slowed
Rises
LAs with LOW pKa have fast onset of action
LAs with HIGH pKa have slow onset of action
Once the local anesthetic has passed through the cell membrane it favors the (ionized/unionized) state
Ionized state
By favoring the ionized state inside the cell, the local anesthetic remains effective for a longer duration.
The ionized form of the molecule binds the sodium channel and blocks conduction.
What effect does sodium bicarbonate have when mixed with local anesthetics?
Sodium bicarbonate can be added to LA to increase the pH and reduce the burning or stinging sensation.
The increase in pH will enhance onset of action
Which local anesthetic is associated with a low risk of systemic toxicity?
Ropivacaine (pKa 8.2)
Chemically similar to mepivacaine and bupivacaine, but is first LA marketed as a pure levorotatory stereoisomer rather then a racemic mixture
Levorotatory enantiomers of local anesthetics are typically (less/more) toxic than dextrorotatory enantiomers.
Less
(T/F) Ropivacaine is less cardiotoxic than bupivacaine
True
Ropivacaine is the preferred and safest long-acting local anesthetic for peripheral nerve block anesthesia
Ropivacaine during spinal and epidural anesthesia provides what advantage that bupivacaine does not
Motorblock–sparing properties
Ropivacaine is known for its ability to preserve motor function
Rare cardiac side effect with ropivacaine
cardiovascular collapse
Which neuronal membranes are blocked first by local anesthetics
Occurs in stepwise sequence w/autonomic impulses blocked first, then sensory, and finally motor impulses
With LA, are Unmyelinated and smaller myelinated nerve fibers (easier/harder) to block than larger myelinated fibers
easier
Larger myelinated fibers are more difficult to block with LA
Order of blockade during local anesthesia is typically:
C-fibers (pain) → B-fibers (heat/cold) → Aα and Aβ fibers (motor and touch/pressure)
Which class of local anesthetics is more rapidly metabolized esters or amides?
Esters
Esters are rapidly hydrolyzed by pseudocholinesterase into PABA
Amide LAs undergo aromatic hydroxylation, amide hydrolysis and N-dealkylation which is a slower process
Plasma half life of Ester LAs
less than 1 minute (chloroprocaine) to 8 minutes (tetracaine) and is prolonged in the presence of atypical cholinesterase
metabolism of cocaine
unlike other esters, undergoes hepatic hydrolysis followed by renal excretion.
Because amide LA metabolism is slow, it is prone to accumulation in the presence of
hepatic dysfunction or reduced hepatic blood flow
Prilocaine undergoes metabolism in the
lungs
(T/F) Amides have a very low potential for allergic reaction
True
**an observed reaction may be caused by an additive such as the stabilizing agent methylparaben
A patient with liver failure is susceptible to local anesthetic toxicity from which class of agents?
Amides
What effect does protein binding have on DOA of local anesthetics?
DOA is determined by protein binding
(T/F) Local anesthetics with low affinity for protein binding remain bound to nerve membranes longer, resulting in an increased duration of action
FALSE
Local anesthetics with HIGH affinity for protein binding remain bound to nerve membranes longer, resulting in an increased duration of action
What does binding to serum a1-acid glycoproteins and other proteins do to the potential for toxicity?
Decreases availability of free drug in blood and ↓toxicity potential in primary organs
free fraction is the portion of LA that is
not bound to proteins and is available to exert its pharmacological effects.
free fraction LA in the blood is increased in what conditions
acidosis or decreased serum protein, thus heightening the potential for toxicity
free fraction = unbound; not bound to proteins
A patient allergic to PABA should not receive which type of local anesthetics?
Ester local anesthetics = procaine, tetracaine, chloro-procaine
** derivatives of para-aminobenzoic acid (PABA), a substance known to be allergenic
an allergic response to (PABA derivative) Ester LAs is most likely the result of what cross-sensitivity
sulfonamides
Biggest factor influencing onset of action of LAs
Lipid solubility
Greater lipid solubility of a drug not only enhances potency but also enables more rapid diffusion through cell membranes
(T/F) Although bupivacaine and articaine are both highly lipid soluble, the 4% concentration of articaine provides for a much slower onset
FALSE
articaine provides for a much FASTER onset due to its higher concentration
*Injecting higher concentrations that allow a greater number of molecules to reach the membrane can speed up the onset
(T/F) Most important factor that determines onset of anesthesia is the proportion of molecules that exist in a water-soluble state rather than lipid-soluble state
FALSE
Lipid-soluble state is the most important factor for onset
The terminal amine may exist in a tertiary form (3 bonds) that is
lipid soluble
The terminal amine may also exist as a quaternary form (4 bonds) that is (positively/negatively) charged and renders the molecule water soluble
positively
the local anesthetic base to be stable in solution, it is formulated as a
hydrochloride salt
are molecules that exist in a quaternary state able to penetrate the neuron?
No
positively charged quaternary molecules can’t penetrate the neuron
The time for onset of LA is directly related to the proportion of molecules that convert to the (tertiary/quaternary), lipid-soluble structure when exposed to physiologic pH (7.4).
Tertiary
They are lipid soluble unlike quaternary
(T/F) The pKa for all local anesthetics is greater than 7.4 (physiologic pH), and therefore a greater proportion of the molecules exist in the quaternary, water-soluble form when injected into normal tissue.
True
The higher the pKa for a local anesthetic, the _____ molecules are available in their lipid-soluble form
fewer
Acidic environment associated with inflamed tissues lowers their pH well below 7.4 and favors the ______, water-soluble LAs
quaternary
If injecting inflamed or infected tissue with LA, which compound would be more effective: bupivacaine or mepivacaine
Bupivacaine- pKa 8.1 (more water soluble therefore more desireable in this situation)
vs mepivacaine pKa 7.6
(T/F) Once tertiary molecules enter neuron, they re-ionize to quaternary form, which is credited with actual blockade of Na+ channel
True
What are the ester local anesthetics?
Benzocaine
chloroprocaine
cocaine
procaine
proparacaine
tetracaine
amylocaine
oxybuprocaine
What are the amide local anesthetics?
Lidocaine
bupivacaine
ropivacaine
mepivacaine
levobupivacaine
atricaine
How does fetal acidosis affect fetal transfer of local anesthetics?
Since amide-type anesthetics are weak bases, fetal acidosis will increase the maternal/fetal pH gradient and will result in accumulation of free drug in the fetus and possible fetal side effects
How is lidocaine metabolized?
primary in the liver with around 80% of dose excreted as metabolites
A newly discovered local anesthetic has a pKa of 7.4. What percent of the anesthetic will be unionized in the plasma?
50%
How are ester local anesthetics metabolized?
Ester-type local anesthetics are metabolized by plasma pseudocholinesterase and their metabolites are excreted through urine.
Where are the principal sites of effect of spinal local anesthesia?
Spinal anesthesia is injected directly into the cerebrospinal fluid that surrounds the spinal cord and nerve roots
At what lumbar levels should a spinal be administered?
the insertion of the spinal needle for spinal anesthesia is usually at the L3/4 or L4/5 interspace
goal is to deliver appropriately dosed anesthetic into the intrathecal (subarachnoid) space
What structures are crossed when doing a spinal?
structures traversed depend on the approach
The spine comprises how many of each: cervical, thoracic, lumbar, and fused sacral vertebral bones
7 cervical, 12 thoracic, 5 lumbar, and 5 fused sacral vertebral bones
The vertebrae are stacked end-to-end with articulating joints and ligaments with a hollow space called the
spinal canal
*This canal houses the spinal cord
The spinal nerves exit the spinal canal via ____ spaces between pedicles from adjacent vertebrae
lateral
spinal anesthesia is only performed in the mid to low lumbar area, to avoid damage to the spinal cord and also to prevent intrathecally injected medications from affecting
upper thoracic and cervical regions
The caudal end of the spinal cord is the
conus medullaris
and usually is at the lower border of the first or sometimes the second lumbar vertebral body.
*inferior in pediatric patients, generally ending around L3.
In the adult population, the mean conus position is the lower third of
L1 (range: the middle third of T12 down to the upper third of L3).
(T/F) No significant difference in conus position is seen between male and female patients or with increasing age
True
Tough fibrous band that connects the tips of the spinous processes from the 7th cervical vertebra to the sacrum.
supra spinous ligament
*Above C7, this ligament continues as the ligamentum nuchae where it attaches to the base of the skull.
a thin membranous ligament that connects adjacent spinous processes.
intra spinous ligament
*Anteriorly the interspinous ligament fuses with the ligamentum flavum and posteriorly with the supraspinous ligament.
firm dense structure, composed of elastin, which connects the lamina of adjacent vertebra.
ligamentum flavum
*The thickness increases as it moves down the spine, with the thickest region adjacent to lumbar vertebra (3-5mm).
Is an extension of the medulla oblongata and is contained within the dural sac along with the pial and arachnoid linings that surround it
The spinal cord
The linings that surround the spinal cord delineate into three compartments within the vertebral canal:
The epidural, subdural, and subarachnoid spaces.
By adulthood, the cord ends at the lower border of L1 as the
conus medullaris
Is a fibrous extension of the conus medularis, stabilizing the distal spinal cord an attaching to the coccygeal periosteum
The filum terminale
Is continuous with the foramen magnum, extending to the lower border of S2, where it spreads distally to cover the filum terminale
The dural sac
There are __ paired spinal nerves serving motor, sensory and autonomic functions
31:
8 Cervical spinal nerve pairs (C1-C8)
12 Thoracic (T1-T12)
5 Lumbar (L1-L5)
5 Sacral (S1-S5)
1 Coccygeal pair
Is a bundle of nerve roots emerging from the conus medullaris, sitting withing the subarachnoid space. These nerve roots continue inferiorly, below the spinal cord, towards their respective foramina.
Cauda equina
Injection of LA into the epidural space causes fluid to spread as ____ through many small channels.
‘rivulets’ (a very small stream)
- What is Tuffier’s line?
intersects the spine at the L4 spinous process or at the L4-L5 intervertebral space.
Where is the epidural space?
lies between the dura mater and the osteoligamentous structure lining the vertebral canal.
starts at the foramen magnum and terminates at the sacral hiatus at S4 and S5 levels.
It is subdivided into anterior and posterior compartments
(T/F) Spinal provides total pain relief, while epidurals provide partial pain relief.
True
A spinal can be considered an anesthetic while epidural an
analgesic
*No sensation vs no pain.
Is a single dose of anesthesia into the dural sac around the spinal cord
Spinal
Provides continued applications via a catheter
Epidural
Involves inserting a fine needle in the lower back and passing it beyond the epidural space
Spinal anesthesia
Advantages of Spinal block
Stay awake during procedure
Complete pain relief
Fast acting
Single injection
No catheter
No mental changes
Stay conscious during baby delivery and during c-section
Safer than general anesthesia during child birth
Disadvantages of Spinal Block
Only last 2-4 hours
Single injection
Low grade headache more likely
Difficulty urinating, itching, shivering, nausea
Is a catheter fed into the epidural space allowing for continuous administration of anesthetics.
Epidural
Major advantage in first time births, which can last from 12 to 18 hours
Side effects of epidurals
Sore back
Headache
Bleed pressure decrease
Difficult urinating
Tingling or numbness
Leg weakness
Contraindications for spinal/epidural anesthesia
Preexisting neurological diseases
Severe dehydration (risk for hypotension)
Thrombocytopenia or coagulopathy
Severe mitral and aortic stenosis and left ventricular outflow obstruction
patients on oral anticoagulants, antiplatelets, thrombolytic therapy, un-fractioned and low molecular weight heparin.
(T/F) Toxicity of LA may occur at serum concentrations that are lower than expected because LAs accumulate in mitochondria and cardiac tissue at a ratio of about 6:1 relative to plasma
True
High levels of serum LA can block
calcium channels
____ is more lipophilic LA and has a grater affinity for the voltage-gated sodium channels.
Bupivacaine
*These qualities may contribute to its cardiotoxic profile.
Signs/symptoms of LAs toxicity
Begins with prodromal s/s such as perioral numbness, tinnitus, agitation, dysarthria, and confusion.
Followed by more CNS symptoms such as seizures and coma.
hypertension and tachycardia, then bradycardia and hypotension,
with progression to more serious complications, including ventricular arrhythmias and asystole.
The majority of adverse events occur within 1 minute after injection of LA
(T/F) Toxicity can have a delayed onset of greater than 1 hour after injection and can manifest as isolated CV dysfunction or as a combination of CNS and CV signs without the classical progression
True
g. Variables that increase the risk of toxicity include
the type of LA and dose,
site of injection,
the patients comorbidities,
extremes of age,
and small size or limited muscle mass.
(T/F) More lipophilic LAs like mepivacaine have an increased risk of toxicity relative to the less-lipophilic LAs like bupivacaine and lidocaine.
FALSE
More lipophilic LAs like BUPIVACAINE have an increased risk of toxicity relative to the less-lipophilic LAs like MEPIVACAINE and lidocaine.
What accounts for the clinical risk of LAST in smaller patients?
skeletal muscle acts as a depot for LAs, therefore, patients will less muscle mass than normal are at risk for LAST
Nerve blocks and epidural anesthetics that require larger doses are higher risk for patients with
less muscle mass than normal
Absorption of LAs is highest with intercostal nerve blocks, followed by
epidural and brachial plexus injections
*Therefore, highest incidence of LAST occurs with paravertebral nerve blocks, followed by upper extremity
Three pillars of LAST treatment
Seizure management
Advanced cardiac life support (ACLS)
Prompt administration of a 20% lipid emulsion
The mechanism of lipid resuscitation therapy (LRT) is multimodal in action with lipid exerting both a
scavenging effect and a direct cardiotonic effect.
Moderated by the lipid emulsions ability to take up lipophilic moieties and transfer them around the blood to sites of storage and detoxification.
Scavenging
Lipid emulsion increases cardiac output through a combination of volume and direct cardiotonic effects to improve cardiac output once the cardiac concentration of drug drops below ion channel-blocking thresholds.
Cardiotonic effect
What are the common local anesthetics used in spinal anesthesia?
Lidocaine (5%)
Bupivacaine (0.75%)
Lidocaine 5%
Tetracaine 0.5%
Mepivacaine 2%
Ropivacaine 0.75%
Levobupivacaine 0.5%
Chloroprocaine 3% [5]
What are the common local anesthetics used in epidural anesthesia?
Lidocaine
Bupivacaine
Ropivacaine
Chloroprocaine
What are the pKa, class, onset, duration and max doses for Lidocaine, Bupivacaine, Tetracaine, Ropivacaine, Chloroprocaine? Are they Amides or Esters?
