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What is a local anesthetic?
- an agent that interrupts pain impulses in a specific region of the body without a loss of patient consciousness
- the process is completely reversible
- no residual effect on nerve fibers
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What was the first anesthetic?
- Cocaine
- isolated from Coca leaves by Albert Niemann in Germany in the 1860s
- used by Karl Kollar for clinical opthalmology anesthesia in 1884
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What was the first local synthetic anesthetic?
Procaine-made in 1907
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What is the target of all local anesthetics?
Sodium Voltage Gated Channels (NOT PUMPS!)
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What are the 3 distinct stages of a voltage-gated sodium channel?
- CLOSED
- ACTIVATED
- INACTIVATED
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What are the speeds between the three stages of voltage-gated Na+ channels?
- C-O is fast
- O-I is fast
- I-C is a little slower
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How long does a current exist in an action potential?
A few miliseconds or less
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How many segments and domains are there per voltage gated sodium channel?
- 4 domains
- 6 segments/domain
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What is the voltage sensing segment on voltage-gated sodium channels?
Segment 4
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Where does the pore lie in voltage-gated sodium channels?
between 5 and 6 segment
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What is the guarded Receptor Theory of Ion Channels?
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When can a LA reach the anesthetic binding site?
- When the receptor is in an activated state
- or if the drug is sufficiently lipophilic enough, it can reach when the channel is in the inactivated state
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What is the percentage of non-ionized LA in vitro?
- 10%
- Remember 7.5=8.5*log(base/charged) --> base/charged=10-1
- Also remember Le Chatlier's Principle when discussing this
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What form of the drug actually holds the Na+ channel in the inactive state?
the ionized
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LAs with a lower pK or higher pK will have a more rapid onset of action? why?
lower pK --> aka LAs that are more uncharged will have a more rapid diffusion to the cytoplasmic side of the Na+ channel
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What are the 5 mechanisms of action of LAs? What is NOT a mechanism of action of LA?
- Reduce height of AP
- Reduce rate of rise of AP
- Slow axonal conduction
- Ultimately prevent propagation of AP
- Increase activation threshold
- DO NOT alter the resting membrane potential
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Functional Consequence of Na+ Channel Blockade by LAs
Nerves
Vascular Smooth Muscle
Heart
CNS
- Nerves: decrease or abolition of conduction
- Vascular Smooth Muscle: vasodilation
- Heart: decreased excitability (reduced pacemaker activity, prolongation of effective refractory period)
- CNS: increased excitability, followed by generalized depression
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What are the four characteristics of LAs?
- Blockade of sensory transmission to brain from a localized area
- Blockade of voltage-gated Na+ channels
- Use-dependent block
- Administer to site of action
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What is the basic structure of an LA and what is the importance of each?
- Aromatic Ring: Lipophilicity
- Connecting Chain: ?
- Amino Terminus: Amine can become charged
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What are the 2 classifications of LAs? What is the basis of the classification?
- Benzoic Acid Derivatives: Ester connecting chain
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What determines potency and rate of onset of LAs?
- Lipid Solubility (obviously) the more lipophilic a LA is, the more potent the LA is
- LAs are weak bases pKas of 7.5-9.0
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Why are LAs less effective in infected tissues?
several reasons, the most important being that pH is lower/more acidic causing a decrease in lipophilicity of the drug as a whole
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What LAs are esters?
- cocaine
- procaine
- tetracaine
- chloroprocaine
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Which type of LA is more likely to produce an allergic affect and what is the cause of this effect?
- ESTERS
- caused by the metabolism via pseudocholinesterase into paraaminobenzoic acid, which CAN cause allergic reactions
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What LAs are amides?
- lidocaine
- mepivicaine
- prilocaine
- bupivacaine
- etidocaine
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Where are amides metabolized?
in the liver
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What LAs are applied topically?
- Benzocaine
- lidocaine
- tetracaine
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What LAs are administered via infiltration?
- lidocaine
- procaine
- bupivacaine
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What drugs are administered via nerve block?
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What LAs are administered via spinal?
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What LA is commonly given as an epidural?
Bupivacaine
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What LAs are given via caudal administration?
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What are some toxicities of LAs?
- CNS sedation
- restlessness
- nystagmus
- tinnitus
- vertigo
- convulsions
- cardiovascular-cardiac block
- arrhythmias
- vasodilation
- allergic reactions
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What is common effect of LAs on vascular smooth muscle? How do we counter act this effect?
- vasodilatation
- by using a vasoconstrictor which can cause prolongation of anesthetic action, decreased risk of toxicity, and decrease in bleeding from surgical manipulations
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What is a conventional vasoconstrictor used with LAs?
- Adrenaline (used in variuos concentrations expressed in grams/mL, ex. 1g:100,000mL)
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What adrenergic receptor(s) do these vasoconstrictors work on and hence what is the effect produced when administered?
Epinephrine
Norephinephrine
Levonordefrin
- Epinephrine: a, B1, B2 increase HR, increase BP
- Norephinephrine: a, B1 increase BP
- Levonordefrin:
a increase BP
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What is the order of sensory function block of LAs?
- pain
- cold
- warmth
- touch
- deep pressure
- motor
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What factors influence a neuron's susceptibility to blockage by LAs?
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What does AP duration have to do with LA susceptibility?
the longer the AP, the more probability that Na+ channels are open, meaning more LA activity.....so PAIN is longest (3ms), therefore greatest action on pain
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Is myocardium more or less susceptable to LAs? Why?
more susceptible because of extended duration in AP
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What are the 7 classes of nerve fibers and what do they do?
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