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Anaesthesiology
Local Anesthetics
Built from Barash Clinical Anesthesia, 9th Edition
What’s inside
16 sections · 199 slides
Overview
- What local anesthetics do
- Scope of this presentation
- Key points from this topic
Anatomy of Nerves
- Organisation of a peripheral nerve
- Connective tissue layers of a nerve
- Layers of a peripheral nerve in cross-section
- Myelination of nerve fibers
- Node of Ranvier
- Saltatory conduction in myelinated fibers
- Schwann cell relationships with axons
- Classification of nerve fibers
- Classification of nerve fibers
Neural Conduction and Sodium Channels
- Resting membrane potential
- Generation of an action potential
- Propagation of the nerve impulse
- Sodium channel states during an action potential
- Structure of the voltage-gated sodium channel
- Three functional states of the sodium channel
- Gating of the sodium channel
- Fast versus slow inactivation
- Sodium channel isoforms
- Sodium channelopathies and pain
- Voltage-gated sodium channels
Molecular Mechanism of Action
- Primary molecular target
- Intracellular site of local anesthetic binding
- Structure of the binding pocket
- Local anesthetic access to the sodium channel
- Hydrophobic binding pocket within the sodium channel pore
- Tonic and use-dependent blockade
- Modulated-receptor and guarded-receptor theories
Mechanism of Nerve Blockade
- Diffusion of drug to the nerve membrane
- Time course of functional block
- Concentration requirements for nerve blockade
- Volume and the critical length of nerve
- Decremental conduction block
- Differential blockade
- Order of modality loss during a block
- Limitations of the size principle
- Channel expression and differential blockade
Chemical Properties, Activity and Potency
- General structure of local anesthetic molecules
- Aminoesters versus aminoamides
- Metabolic routes by chemical linkage
- Weak base behaviour and pKa
- Roles of the neutral and charged forms
- Journey of the drug into the nerve
- Lipid solubility and potency
- Two levels at which lipophilicity acts
- Physicochemical properties of clinically used local anesthetics
- Divergence of laboratory and clinical potency
- Relative potency of local anesthetics by clinical application
- Stereochemistry and cardiotoxicity
Additives to Increase Local Anesthetic Activity
- Epinephrine as an adjuvant
- Cautions with epinephrine
- Effects of adding epinephrine to local anesthetics
- Effects of adding epinephrine to local anesthetics (continued)
- Rationale for alkalinisation
- Limitations of alkalinisation
- Opioids as neuraxial adjuvants
- Opioids in peripheral nerve blockade
- Alpha-2 adrenergic agonists
- Dexamethasone as a perineural adjuvant
- Dose-response of perineural dexamethasone
- Dexamethasone and interscalene block duration
- Perineural versus systemic steroid effect
- Conflicting evidence on dexamethasone
- Inflammation hypothesis for the steroid effect
- Liposomal bupivacaine: the concept
- Trial evidence for liposomal bupivacaine
- Choice of comparator in liposomal bupivacaine trials
- Liposomal bupivacaine versus bupivacaine with dexamethasone
- Safety profile of liposomal bupivacaine
Pharmacokinetics
- Determinants of plasma concentration
- Factors governing systemic absorption
- Ranking of injection sites by absorption rate
- Clinical implication of site-dependent absorption
- Typical peak plasma concentrations after regional anesthesia
- Dose and peak plasma level
- Drug-specific differences in absorption
- Systemic absorption from epidural injection
- Distribution of local anesthetics
- Elimination pathways
- Pharmacokinetic parameters of clinically used local anesthetics
- Reading the pharmacokinetic table
Clinical Pharmacokinetics
- Predicting peak plasma concentration
- Effect of age, weight, sex and pregnancy
- Weight and peak plasma concentration
- Disease states and lidocaine pharmacokinetics
- Effects of cardiac, hepatic and renal disease on lidocaine pharmacokinetics
- Relative potency for nervous system toxicity and the CVS to CNS ratio
- Relative potency for nervous system toxicity and the CVS to CNS ratio (continued)
- Interpreting the CVS to CNS toxicity ratio
Clinical Use of Local Anesthetics
- Topical and mucosal applications
- Intravenous lidocaine
- Infiltration and regional techniques
- Neuraxial and plexus placement
- Routes of local anesthetic administration
- Clinical profile of local anesthetics
Local Anesthetic Systemic Toxicity
- Definition and mechanism of systemic toxicity
- Target systems in systemic toxicity
- Central nervous system toxicity
- Progression of central nervous system toxicity
- Dose-dependent systemic effects of lidocaine
- Modifiers of central nervous system toxicity risk
- Cardiovascular toxicity
- Resuscitation after cardiovascular collapse
- Comparative cardiotoxicity of the long-acting agents
- Toxic thresholds in sheep for bupivacaine, levobupivacaine and ropivacaine
- QRS prolongation and cardiac output change after intravenous local anesthetic
- Indirect cardiovascular mechanisms
- Vascular effects of local anesthetics
- Direct effects on cardiac conduction
- Basis of bupivacaine cardiotoxicity
- Sodium channel binding and release across the cardiac cycle
- Accumulation of channel block with bupivacaine
- Heart rate dependence of conduction slowing
- Plasma concentrations producing myocardial depression in dogs
- Molecular basis of cardiac toxicity
Clinical Presentation and Incidence
- Neurological presentation of systemic toxicity
- Frequency of reported central nervous system signs
- Cardiovascular presentation of systemic toxicity
- Frequency of reported cardiovascular signs
- Timing of onset
- Incidence of local anesthetic systemic toxicity
- Distribution by block type and patient group
Prevention and Treatment
- Prevention through pharmacokinetic awareness
- High-risk populations
- Risk factors for local anesthetic systemic toxicity
- Technical measures to reduce risk
- Immediate response to suspected systemic toxicity
- Seizure management
- Neuromuscular blockade for prolonged seizures
- Haemodynamic management
- Drugs to use and drugs to avoid
- Lipid emulsion therapy
- Practice advisory on treatment of local anesthetic systemic toxicity
- Sequence of management
- Postulated mechanisms of lipid rescue
Neural, Muscle and Allergic Toxicity
- Histopathology of nerve injury
- Determinants of neural injury severity
- Depth of injection and injury
- Clinical incidence of neurological injury
- Recognised scenarios of nerve injury
- Transient neurologic symptoms after spinal anesthesia
- Incidence of transient neurologic symptoms by local anesthetic and surgery
- Incidence of transient neurologic symptoms by local anesthetic and surgery (continued)
- Evidence against a neurotoxic cause
- Alternative explanations for transient neurologic symptoms
- Myotoxicity of local anesthetics
- Muscle changes after continuous local anesthetic exposure
- Subcellular mechanisms of myotoxicity
- Allergic reactions to local anesthetics
- Causative agents and evaluation of allergy
Future Therapeutics and Modalities
- Properties of an ideal local anesthetic
- Site 1 sodium channel blockers
- Clinical findings with neosaxitoxin
- TRP channel-mediated entry of charged blockers
- Selective sensory block strategy
- Animal findings with capsaicin and QX-314
- Duration of nociceptive versus motor block
Summary and References
- Mechanism: key takeaways
- Pharmacology: key takeaways
- Toxicity: key takeaways
- References
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- Barash, Cullen, and Stoelting's Clinical Anesthesia, 9th Edition