Local Anesthetics Flashcards
How do local anesthetics work?
Na channel blockade- depression of excitation in nerve endings or the inhibition of nerve impulse conduction that is reversible and predictable in duration with no impairment of central control of body functions
LA have voltage dependent blockade
Closed channel state has lower affinity for LA’s than activated or inactivated channel states. More LA binding at positive transmembrane potential, so rapidly firing nerves are more sensitive to local anesthetics
Time dependent blockade
Binding of LA’s is greater in rapidly firing axons compared to slower firing fibers. Rapidly cycling fibers have more activates and inactivated channel states.
LA MOA
LA molecule binds to the sodium channel receptor site on the intracellular side
Binding of LA leads to blockade of the sodium channel
Resultant decrease in sodium ion conductance
Unable to reach threshold potential
Failure of action potential development
Nerve impulse conduction blocked
LA binding is reversible and sodium ion channels become unbound restoring action potential generation
Local anesthetics block nerve conduction by
They DO NOT
Decreasing the rate of depolarization in response to excitation, preventing the achievement of an action potential
If the sodium channels are blocked over a critical length of a nerve fiber the propagation of an action potential is blocked
Do not alter the resting trans-membrane potential or alter the threshold potential
ONLY alters the ability to achieve an AP
Differential block
Different nerve fibers have different sensitives to LA block.
Fiber diameter- thinner fibers more sensitive to block than thicker ones
Firing frequency- rapidly/repetitively firing fibers more sensitive to block than slower fibers
Fiber position in nerve bundle- outer fibers more sensitive to block than inner fibers. Mantle bundle is blocked first with core bundle blocked delayed. This accounts for early manifestations of anesthesia in more proximal areas of the extremity than distal areas.
How many nodes of Ranvier must be blocked for LA
Must block 3 nodes to inhibit nerve impulse propagation- which is why a thin nerve fiber is more easily blocked. Internodal distance is proportional to axon diameter
This is also why type C slow pain fibers are the first type of nerve to be blocked, with temperature, touch, deep pressure, and lastly motor nerves follow.
Local anesthetics are composed of
A lipophilic group (aromatic ring)
Intermediate chain (ester or amide)
An ionizable group (tertiary amine)
They are amphipathic*
Local anesthetic drug list-esters
Procaine
Chloroprocaine
Cocaine
Tetracaine
Hydrolyzed by plasma cholinesterases in circulation, short duration of action, allergic reactions are more likely
LA drug list- amides
Lidocaine- problem with allergic reactions
Mepivacaine
Prilocaine
Bupivacaine- longer duration and greater potency than lidocaine.
Ropivacaine
Hydrolyzed by hepatic cytochrome P450 isoenzymes, hepatic disease and decreased hepatic blood flow reduce elimination, longer duration of action than esters
Reports with bupivacaine
Cardiac toxicity with cardiac arrest reported
Ropivacaine special
Formulated as only the S(-) enantiomer
High potency and low toxicity of this enantiomer compared to the racemic mixtures in binding to cardiac sodium channels
Less potent, so more drug is needed for same degree of block
What determines the clinical characteristics of the blockade?
Molecular weight- they are all essentially the same
Ionization- all are weak bases (ph8-9, so most molecules at physiological pH are the charged cationic form) the neutral form is what enters the nerve cell to bind intracellularly, but the charged form binds to the channel once inside. Put with an acidic solution to enhance solubility. Higher pka of LA=less anesthetic that can penetrate the nerve cell (longer onset)
Lipid solubility- high lipid solubility are more potent (tetracaine, bupivacaine, ropivacaine are more lipophilic). Also impacts onset time by enhancing LA penetration of nerve cell membrane.
Protein binding- greater binding is greater duration
Chirality- lidocaine is achiral, all others are racemic stereoisomers mixes (identical physiochemical properties, but different pharmacodynamic, pharmacokinetic, and systemic toxicities.)
Pharmacokinetics of LA
Local anesthetic agents are deposited very near their target site unlike IV or inhalational agents
Determined by- absorption and distribution
Absorption of LA
Total dose- higher dose= greater probability of systemic abs.
Site of injection- more vascular areas with better blood supply will have greater absorption
Drug-tissue binding- greater binding to tissues will reduce absorption
Addition of vasoconstrictor agents to LA
