Local Anesthetics Flashcards
(44 cards)
The typical quimical structure of a local anesthetic contains a …
tertiary amine attached to a substituted aromatic ring by an intermediate chain that almost always contains either an ester or an amide linkage
Describe the Relative Conduction-Blocking Potency (procaine = 1) and pKa at 36°C of lidocaine and bupivacaine
Lidocaine:
- Relative Conduction-Blocking Potency: 2
- pKa 7.8
Bupivacaine:
- Relative Conduction-Blocking Potency: 8
- pKa 8,1
Describe the caracteristics of the Aα fibers
- Myelin: +
- Diameter: 6-22 μm
- Conduction Velocity : 30-120 m/sec
- Location: Efferent to muscles
- Function: Motor
- Susceptibility to Local Anesthetic Block: ++
Describe the caracteristics of the Aβ fibers
- Myelin: +
- Diameter: 6-22 μm
- Conduction Velocity : 30-120 m/sec
- Location: Afferent from skin and joints
- Function: Tactile, proprioception
- Susceptibility to Local Anesthetic Block: ++
Describe the caracteristics of the Aδ fibers
- Myelin: +
- Diameter: 1-4 μm
- Conduction Velocity : 5-25 m/sec
- Location: Afferent sensory nerves
- Function: Pain, cold temperature, touch
- Susceptibility to Local Anesthetic Block: +++
Describe the caracteristics of the Aγ fibers
- Myelin: +
- Diameter: 3-6 μm
- Conduction Velocity : 15-35 m/sec
- Location: Efferent to muscle spindles
- Function: Muscle tone
- Susceptibility to Local Anesthetic Block: ++++
Describe the caracteristics of the B fibers
- Myelin: +
- Diameter: <3 μm
- Conduction Velocity : 3-15 m/sec
- Location: Preganglionic sympathetic
- Function: Various autonomic functions
- Susceptibility to Local Anesthetic Block: ++
Describe the caracteristics of the sC fibers
- Myelin: -
- Diameter: 0.3-1.3 μm
- Conduction Velocity : 0.7-1.3 m/sec
- Location: Postganglionic sympathetic
- Function: Various autonomic functions
- Susceptibility to Local Anesthetic Block: ++
Describe the caracteristics of the dC fibers
- Myelin: -
- Diameter: 0.4-1.2 μm
- Conduction Velocity : 0.1-2.0 m/sec
- Location: Afferent sensory nerves
- Function: Pain, warm temperature,
touch - Susceptibility to Local Anesthetic Block: +
The local circuit current is so robust that it can skip past … nonexcitable nodes (e.g., blocked by local anesthetic) and successfully stimulate a … node.
two completely
third
Do moderately hydrophobic local anesthetics block faster or slower than hydrophilic or highly hydrophobic ones? Explain
Moderately hydrophobic local anesthetics block faster than either hydrophilic or highly hydrophobic ones, delivered at the same concentration.
Moderately hydrophilic local anesthetic block, such as lidocaine, are less bound to tissues than very hydrophobic drugs are (e.g., tetracaine) but are still more membrane permeant than very hydrophilic ones (e.g., 2-chloroprocaine). The highly hydrophobic local anesthetics, having higher intrinsic potencies, are therefore used in lower concentrations and their diffusion-controlled rate of onset is correspondingly
reduced
Which form of the local anesthetic, charged cation or neutral base, is actually responsible for blockade of impulses?
Direct control of axoplasmic pH (or internal perfusion with permanently charged quaternary amine homologs) shows that the dominant potency derives from the
cationic species acting from the cytoplasmic surface.
The uncharged base also has intrinsic pharmacologic activity
Phasic actions are a manifestation of the selective affinity of local anesthetics for conformations of the Na+ channel that result from depolarization. Both … states of the channel bind local anesthetics more avidly than the … does
“open” and “inactivated”
resting state
Overall binding of a local anesthetic is increased by membrane depolarization for two reasons: …
more binding sites become accessible during activation (the “guarded receptor” model) and drug dissociation from inactivated channels is slower than from resting channels (the modulated receptor model).
Describe the composition of the voltage-gated Na+ channel and the local of biding of local anesthetics
Voltage-gated sodium channels normally consist of an alpha subunit that forms the ion conduction pore and one to two beta subunits that have several functions including modulation of channel gating.
The major functional protein of the Na+ channel (the α-subunit) is composed of four homologous “domains” (D-1 to D-4), each of which contains six helical regions (S1 to S6) that span the core of the membrane. Each domain also has a loop, termed the “P region,” that links the extracellular ends of its S5 and S6 transmembrane segments; the P regions extend inward between the transmembrane regions such that when the α-subunit folds together, each P loop contributes a quarter of the cylindrical ion “selectivity pore,” the narrowest passage of an open channel.
Voltage sensitivity derives from the positive charges located on S4 segments, which slide or swing “outward” in response to membrane depolarization.
By linkages still unknown, this movement of S4 results in a conformational rearrangement of the S6 segments, which form the inner, cytoplasmic entry to the channel.
Local anesthetics bind in the “inner vestibule” of the closed Na+ channel (S6)
Clinically, testing of block efficacy is often performed using methods that target Aδ sensory fibers. Why these tests may not guarantee complete and reliable block of all sensory modalities?
Different fiber types are also differentially sensitive to local anesthetic blockade. In vivo experiments show that small myelinated axons (Aγ motor and Aδ sensory fibers) are the most susceptible to impulse suppression. Next in order of block are the large myelinated (Aα and Aβ) fibers, and the least susceptible are the small, nonmyelinated C fibers.
Clinically, testing of block efficacy that target Aδ sensory fibers, so these findings may not guarantee complete and reliable block of all sensory modalities
Nine different mammalian Na+ channels have been physiologically identified and their genes have been sequenced.
Mutations in … may lead to loss of channel function and, in the most extreme form, congenital insensitivity to pain.
In contrast, activating mutations in the same channel can trigger erythromelalgia or paroxysmal extreme pain disorder
Nav1.7
Local anesthetic molecules enter the nerve’s axon membranes and reside there and in the axoplasm. The speed and extent of these processes depend on …
a particular drug’s pKa and on the lipophilicity of its base and cation species
Commonly used aminoester local anesthetics include …
procaine, chloroprocaine, tetracaine
Commonly used aminoamides include …
lidocaine, mepivacaine, prilocaine, bupivacaine (the racemic form and its levoenantiomer), ropivacaine, and etidocaine
General differences between ester and amide local anesthetics
- Amides are extremely stable, whereas esters are relatively unstable in solution.
- Aminoesters are hydrolyzed in plasma by cholinesterase enzymes, but the amides undergo enzymatic degradation in the liver. Two exceptions to this trend include cocaine, an ester that is metabolized predominantly by hepatic carboxylesterase, and articaine, an amide local anesthetic widely used in dentistry that is inactivated by plasma carboxylesterase-induced cleavage of a methyl ester on the aromatic ring.
- p-Aminobenzoic acid is one of the metabolites of estertype compounds that can induce allergic-type reactions in a small percentage of patients. The aminoamides are not metabolized to p-aminobenzoic acid, and reports of allergic reactions to these agents are extremely rare
The α-2 agonist clonidine prolongs the action of local anesthetics by about … with wide variation between studies, and its conjectured mechanisms of action include actions on α-2 receptors and on hyperpolarization-induced currents.
However, there is a large number of negative studies, and adverse systemic events are of concern, including hypotension, bradycardia, and sedation, such that limiting the clonidine dose to … of … body weight has been proposed
Dexmedetomidine is a much more specific α-2 agonist, and prolongs both motor and sensory block by long-acting local anesthetics by approximately …
Nevertheless, risk of systemic adverse effects remains high, and optimal doses have not been determined
2 hours
0.5 to 1 μg/kg
ideal
4 hours
The partial μ-opiate receptor agonist, buprenorphine, intensifies blockade by two mechanisms, namely blockade of … receptors, and blockade of …
Blockade by long-acting local anesthetics is prolonged by about …, but at the price of a high incidence of …, such that the use of buprenorphine has largely been abandoned
κ- and δ-opioid
voltage-gated sodium channel-blocking properties
6 hours
nausea and vomiting
The most effective adjuvant for prolonging block duration with minimal side effects currently available is … , able to prolong duration of medium-acting local anesthetics by …, and the block of long-acting local anesthetics by up to … on average.
The precise mechanism of action of … is not understood and the potential for neurotoxic side effects has not been adequately studied
dexamethasone
2 to 3 hours
10 hours
