Local Anesthetics Flashcards
Development of Local Anesthetics
1800’s Cocaine isolated & used for variety of ailments leading to it’s use as a local anesthetic in ophthalmology
1905 The first synthetic local anesthetic was the ester derivative procaine
1943 Lidocaine was synthesized as an amide local anesthetic and is the standard to which all other anesthetics are compared.
Local Anesthetics
- are drugs that reversibly block the conduction of electrical impulses along nerve fibers.
- produce a transient and reversible loss of sensation (analgesia) in a circumscribed region of the body without loss of consciousness.
- Their ability to perform this function depends on nerves being blocked and the chemical structure & properties of the local anesthetic.
- consist of a lipophilic & a hydrophilic portion separated by a connecting hydrocarbon chain.
Molecular Structure of Local Anesthetics
The hydrophilic group is usually a tertiary amine, such as diethylamine, whereas the lipophilic portion is usually an unsaturated aromatic ring, such as para-aminobenzoic acid.
The lipophilic portion is essential for anesthetic activity
Lipophilic or hydrophilic
The hydrophilic group is usually a tertiary amine, such as diethylamine
The lipophilic portion is usually an unsaturated benzene ring, such as para-aminobenzoic acid. The lipophilic portion is essential for anesthetic activity (aromatic ring).
The Axon
The axon is the functional unit of peripheral nerves: where the LA works!
Each peripheral nerve axon possesses its own cell membrane—the axolemma.
A cell membrane (axolemma), and intracellular contents (axoplasm): are the major components of the axon.
Schwann cells surround each axon
Nodes of Ranvier
Between Schwann cells are periodic segments of nerve that do not contain myelin: Nodes of Ranvier
Voltage-gated sodium channels are located in these nonmyelinated segments and are the primary site at which local anesthetics exert their action.
Action potentials jump from node to node, and this phenomenon is known as saltatory conduction
Conduction block occurs when the ionized form of the LA binds to the voltage gated sodium channel inside the cell
Structure-Activity Relationship
Modifying the chemical structure of a local anesthetic alters its pharmacologic effects.
Substituting a butyl group for the amine group on the benzene ring of procaine results in tetracaine.
Compared with procaine, tetracaine is more lipid soluble, is 10 times more potent, and has a longer duration of action corresponding to a 4- to 5-fold decrease in the rate of metabolism.
Mechanism of Action
Local anesthetics bind to specific sites in voltage-gated Na+ channels.
Local anesthetics block initiation and propagation of action potential.
They block Na+ current, thereby reducing excitability of neuronal, cardiac or central nervous system tissue.
Local anesthetics prevent transmission of nerve impulses (conduction blockade) by inhibiting passage of sodium ions through ion-selective sodium channels in nerve membranes.
The sodium channel itself is a specific receptor for local anesthetic molecules.
Failure of sodium ion channel permeability to increase slows the rate of depolarization such that threshold potential is not reached and thus an action potential is not propagated
Local anesthetics do not alter the resting transmembrane potential or threshold potential.
(Na+) Sodium Channels
Local anesthetics slow the rate of depolarization of the nerve action potential such that the threshold potential is not reached. As a result, an action potential cannot be propagated in the presence of local anesthetic and conduction blockade results.
Local anesthetics gain access to the inner axonal membrane by
traversing sodium channels while they are more often in an open configuration
passage directly through the plasma membrane
Electrophysiology
- A resting peripheral nerve demonstrates a negative membrane potential of −70 to −90 mV.
- This voltage difference across the neuronal membrane at steady state is called the resting membrane potential
- Sodium-potassium pump (Na+-K+/ATPase) located in the axolemma (energy driven)
Action Potential
The action potential is a wave of depolarization that is propagated along the axon by continuous coupling between excited and nonexcited regions of membrane. Ionic current (the action current) enters the axon in the excited, depolarized region and then flows down the axoplasm and exits through the surrounding membrane, thereby passively depolarizing this adjacent region (seeFig. 36-3). Although this local circuit current spreads away from the excited zone in both directions, the region behind the impulse, having just been depolarized, is absolutely refractory, and propagation of impulses is thus unidirectional.
Sodium, Chloride & Potassium & Local Anesthetic
Outside of Axon / Cell Sodium (Na+) has a + charge Chloride (Clˉ) has a – charge Inside the Axon / Cell Potassium (K+) has a + charge The differences in charge of Na, K & Cl keep the neuron in dynamic equilibrium & ready for an action potential while at rest.
Mechanism of action of LA
*Local anesthetics block sodium channel:
Stops influx of Na by blocking NA channels
in a nerve
*Local anesthestics bind to the alpha subunit of the sodium channel in the active and inactive states
*Sodium channels have three functional states: resting (closed), open, and inactive.
*The resting state exists when the membrane is at its resting potential.
*An inactive state (impermeable to Na) follows the open state (activated).
*The activated state, which prevents initiation of an action potential, lasts until the restoration of the resting membrane potential (-70 to -90 RMP).
Resting Membrane Potential
When a neuron is not sending a signal, it is “at rest.” When a neuron is at rest, the inside of the neuron is negative relative to the outside. Although the concentrations of the different ions attempt to balance out on both sides of the membrane, they cannot because the cell membrane allows only some ions to pass through channels (ion channels). At rest, potassium ions (K+) can cross through the membrane easily. Also at rest, chloride ions (Cl-)and sodium ions (Na+) have a more difficult time crossing.The negatively charged protein molecules (A-) inside the neuron cannot cross the membrane. In addition to these selective ion channels, there is apumpthat uses energy to move three sodium ions out of the neuron for every two potassium ions it puts in. Finally, when all these forces balance out, and the difference in the voltage between the inside and outside of the neuron is measured, you have theresting potential. The resting membrane potential of a neuron is about -70 to -90 mV (mV=millivolt) - this means that the inside of the neuron is 70 to 90 mV less than the outside. At rest, there are relatively more sodium ions outside the neuron and more potassium ions inside that neuron
Pharmacokinetics
Local anesthetics are weak bases that have pK values somewhat above physiologic pH. As a result, <50% of the local anesthetic exists in a lipid-soluble nonionized form at physiologic pH. For example, at pH 7.4, only 5% of tetracaine exists in a nonionized form. Acidosis in the environment into which the local anesthetic is injected (as is present with tissue infection) further increases the ionized fraction of drug. This is consistent with the poor quality of local anesthesia that often results when a local anesthetic is injected into an acidic infected area. Local anesthetics with pKs nearest to physiologic pH have the most rapid onset of action, reflecting the presence of an optimal ratio of ionized to nonionized drug fraction
Important Pearls of Local Anesthetics
For myelinated axons, 2-3 nodes of Ranvier must be blocked to stop the conduction
The greater the frequency of action potentials, the faster the nerve is blocked by the LA. The LA must attache to the NA channel it’s inactivated state; the faster the nerve is firing, the more opportunities the LA will have to catch the sodium channel in the inactivated state.
Both unionized and ionized forms of the LA are required for a conduction block: the unionized form diffused across the lipid bilayer into the axon, the ionized form attaches to the inside of sodium channel and locks it shut in the inactivated state
Voltage gated sodium channels are found only in the nerve’s axon
Afferent & Efferent nerves
Afferent nerve: Carries nerve impulses from sensory receptors or sense organs toward the central nervous system.
Efferent nerve: Nerves that conduct signals from the central nervous system along motor neurons to their target muscles and glands.
AS:ME
Peripheral Nerve Fibers
Peripheral nerve fibers are grouped based on the diameter, signal conduction velocity, and myelination state of the axons. These classifications apply to both sensory and motor fibers. Fibers of the A group have a large diameter, high conduction velocity, and are myelinated.
A alpha Nerve Fibers
Heavy myelinated
Skeletal muscle–Motor
Proprioception
A beta Nerve Fibers
Heavy myelinated
Touch
Pressure
A gamma Nerve Fibers
Medium myelinated
Skeletal muscle–tone
A delta Nerve Fibers
Medium myelinated
Fast pain
Temperature
Touch
B Nerve Fibers
Light myelination
Preganglionic ANS fibers
C Nerve Fibers
Sympathetic:
0 myelination
Postganglionic ANS fibers
Dorsal Root: 0 myelination Slow pain Temperature Touch
Sequence of clinical anesthesia
Sympathetic block (vasodilatation) Loss of pain and temperature sensation Loss of proprioception Loss of touch and pressure sensation Loss of motor function
Adverse Effects of local anesthetics
CNS Ringing in ears Circumoral numbness Excitation – anxiety, agitation, restlessness, twitching Convulsions
Reduced myocardial contractility
Vasodilatation
Cardiovascular collapse
