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35 Cards in this Set
- Front
- Back
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Mechanism of action of local anesthetics |
Stop conduction by blocking voltage-gated sodium channels |
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Structure and activity of local anesthetics Lipophilic group |
lipophilic group affects drug's affinity for sodium channels, potency and duration of actions Also affects drug's therapeutic index (lipophilicty increases risk for systemic toxicity (may cross blood brain barrier if given at too high of dose) ) |
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Structure and activity of local anesthetics Hydrophilic group |
Hydrophilic group affects drug's degree of ionization at given pH, and onset time of drug (only unionized form can cross cell membrane) Also affects how readily will bind to sodium channel (only ionized form blocks the channel) |
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Which nerve fibres are more susceptible to anesthetic action? |
Smaller nerve fibres more susceptible than larger |
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Why does structure of peripheral nerve matter? |
Order of blockade also depends on structure of peripheral nerve because in mixed nerves, motor fibres are usually located in outer portion of nerve bundle, so they are blocked first |
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Order of blockade of local anesthetics |
Pain -> Cold -> Warm -> Touch -> Pressure -> Motor |
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pH effect on local blocks |
Locals are relatively insoluble molecules, so produced as water-soluble salts (HCl) - solutions are acidic (pH ~5-6), so sting when injected When pKa of drug is close to pH of tissues, more of the drug will be unionized and is able to cross the cell membrane - leads to faster onset Lidocaine faster onset than Mepivacaine which is faster than bupivacaine |
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Protein binding effect on local blocks |
Locals are highly bound to plasma and tissue proteins - binding decreases as pH of tissue decreases - important in patients with acidosis (e.g. cardiovascular collapse) Fraction that is bound to proteins correlations with duration of local anesthetic activity - Highly protein bound = longer duration! |
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Why is there a risk of systemic toxicity with local blocks? |
After you inject, they are absorbed into systemic circulation Lidocaine and bupivacaine induce local vasodilation - can increase their own uptake - If they have epinephrine mixed in then decrease vasodilation and prevent their own uptake **even though injected locally they are circulated to entire body** |
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Systemic Toxicity from local blocks |
Effects can be wide-ranging since potential to affect any excitable tissues in body Most commonly affect CNS and Heart |
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Signs seen from systemic toxicity from local blocks |
1) Muscle twitching (systemic) 2) Unconsciousness 3) Convulsions 4) Coma 5) Respiratory arrest 6) CVS depression |
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Which will be first signs seen from systemic toxicity due to Lidocaine? |
CNS signs = result of depression of CNS tissues - Sedation (only seen if patient is awake) - Excitation (due to differential blockade) - Coma - Death |
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Treatment of systemic toxicity due to local block |
anticonvulsants - benzodiazepines - barbiturates Supportive care - oxygen - ventilation **Typically quick half life so signs often disappear quickly** |
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Cardiac effects from systemic toxicity due to Bupivacaine |
Cardiac signs occur before CNS effects and last long time Blocks Na⁺ channels in pacemaker and myocardial cells Get decreased electrical activity in heart - slowing of heart rate, decreases in contractility - vasodilation - cardiac arrest |
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Treatment of systemic toxicity due to Bupivacaine |
Inotropes Supportive Care Fluids CPB (people) Intralipid |
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When are toxicities additive? |
When more than one drug is administered Consider: - expected rate of absorption from site - Additives (e.g. vasoconstrictors) - Drug characteristics ( vasoconstriction vs vasodilation) - Patient (cardiac output etc) |
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How are amides eliminated? |
Amides are metabolized by the liver
- commonly used local anesthetics considered to be high extraction drugs (clearance dependent on liver blood flow, not enzyme function) - can see decreased extraction when cardiac output is low |
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How are water-soluble metabolites eliminated? |
In urine and bile |
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3 sites of action of muscle relaxants |
1) Peripherally-acting = Neuromuscular blockers - anti-nicotinic at neuromuscular junction 2) Centrally-acting - at spinal cord 3) Direct-acting - stops calcium |
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Activity of ACh in neuron: |
ACh stored in vesicles of neuron - released into neuromuscular junction when AP comes down, to stimulate post-synaptic nicotinic receptors Need 2 ACh molecules to bind to receptor to open ion channels Muscle cell membrane depolarizes and AP is generated Ca²⁺ is released into sarcoplasmic reticulum, and muscle contraction occurs ACh stays bound to receptor for ~2msec then detaches and is metabolized by acetylcholinesterase in the cleft |
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How do neuromuscular blocking agents work? What are the 2 classificiations? |
Depolarizing and non-depolarizing agents Used mainly for anesthesia *Induce skeletal muscle relaxation but NOT anesthesia or analgesia* - potential for patient to be aware but completely paralyzed during anesthesia and surgery |
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What is succinylcholine? |
"Depolarizing" agent - generates action potential when binds to receptor (e.g. depolarizes neuron) - made of 2 ACh molecules Metabolized by "pseudocholinesterase" in plasma - not metabolized by acetylcholinesterase so stays bound to receptors longer than ACh, which prevents another AP from firing - prevents breathing, so animals can suffocate to death - remains bound until blood levels decrease enough that it diffuses away from NMJ **DO NOT USE ANYMORE!** |
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What do you see when you use succinylcholine? |
INitial stimulation seen as muscle fasciculations - then, muscles become flaccid May cause release of potassium from cells (causing hyperkalemia) - arrhythmias, hypertension, increases in intraocular pressure, muscle discomfort in recovery Potent inducer of "malignant hyperthermia" NO antagonist (no reversal) - just have to wait |
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What are non-depolarizing agents? |
Competitive antagonists at the receptor - so ACh cannot bind |
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How do non-depolarizing agents work? |
Bind to receptor and take away a spot for ACh to bind Do not open ion channels so no AP is generated No initial muscle fasciculations are seen ( no risk of pain or hyperkalemia either) ** Only one ACH binding site on receptor needs to be blocked for these drugs to be effective** |
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Patient monitoring and support while using NMBAs |
They paralyze all skeletal muscles in body therefore:
need to monitor ventilation - be able to ventilate patient! Use peripheral nerve stimulator to monitor activity of nerves at NMJ - monitors "depth" of neuromuscular block to assist with dosing and for planning recovery |
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Reversal of NMBAs |
Can use anticholinesterase inhibitor drugs to "reverse" blockade - usually not necessary as they have short half life ACh accumulates at junction and competitively displaces the NMBA from the receptor - normal NMJ function is restored |
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Two examples of drugs that reverse NMBAs |
Neostigmine (slow onset, long duration) Edrophonium (fast onset, shorter duration) |
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Problems with reversal drugs of NMBAs |
ACH builds up at all nicotinic NMJ receptors and other sites as well - post-ganglionic muscarinic receptors = may produce other effects that we do not want (slowing of heart rate, bronchoconstriction, salivation) Therefore we usually administer anticholinesterase inhibitors concurrently with anticholinergic agents such as atropine or glycopyrrolate to minimize "side effects" of NMBA reversal |
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What is Guaifenesin? |
Central acting skeletal muscle relaxant and mild sedative |
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How does Guaifenesin work? |
Selectively depresses transmission of nerve impulses in spinal cord, brainstem, subocritical regions of brain Used combined with other drugs for induction of anesthesia Wide margin of safety |
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What is Methocarbamol? |
Centrally acting muscle relaxant |
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How does methocarboamol work? What do we use it for? |
Derivative of guaifenesin molecule - thought to act centrally to block nerve impulses in brainstem, spinal cord, subcortical levels of brain Occasionally used to treat muscle fasciculations, tremors, seizures associated with toxic agents (small animals) and muscle injuries and diseases (horses) |
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What is dantrolene? How does it work? |
Muscle relaxant that acts by stopping excitation-contraction coupling inside muscle cells - interfere with release of Ca²⁺ from sarcoplasmic reticulum by blocking Ryanodine receptors **Only known treatment for Malignant Hyperthermia** |
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What is malignant hyperthermia? |
Results from a Ryanodine receptor mutation and can be induced by succinylcholine and inhalant anesthetics |
