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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