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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
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
What are the pKa, class, onset, duration and max doses for Lidocaine, Bupivacaine, Tetracaine, Ropivacaine, Chloroprocaine? Are they Amides or Esters?
