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Local Anesthetics: Mechanism of Action

Local Anesthetics: Mechanism of Action

Local anesthetics (LAs) block sensory and motor impulses by inhibiting the sodium channels on the nerve cell membranes. This induces temporary loss of sensation, relieving pain in a specific body area.
Local anesthetics are amphiphilic molecules consisting of a hydrophobic aromatic part linked to a hydrophilic group by an ester or amide linkage. They are weak bases and are usually available as salts, which increases their solubility and stability. Once administered, LAs exist in the body either...

Local Anesthetics: Differential Sensitivity of Nerve Fibers

Local Anesthetics: Differential Sensitivity of Nerve Fibers

Local anesthetics (LAs) block the sodium channels of nerve trunks, sensory nerve endings, and neuromuscular junctions. Although LAs can block all kinds of nerves, the sensitivity of nerve fibers differs according to nerve types and structures. LAs are known to block myelinated fibers faster than unmyelinated ones. Also, they block pain or sensory neurons at low concentrations without affecting the motor neurons involved in muscle contractions. This helps relieve labor pain without affecting the...

Local Anesthetics: Adverse Effects

Local Anesthetics: Adverse Effects

While local anesthetics are generally safe and well-tolerated, they can occasionally cause adverse effects that vary in severity. Local anesthetics can induce toxicity at two distinct levels. They can either produce local effects through direct contact with the neural elements or be absorbed into the bloodstream from the injection site, leading to systemic effects.
Once absorbed into the systemic circulation, local anesthetics can affect the organs that depend on the functioning of sodium...

Local Anesthetics: Chemistry and Structure-Activity Relationship

Local Anesthetics: Chemistry and Structure-Activity Relationship

Local anesthetics (LAs) are drugs that induce a temporary loss of sensation in a limited body area, preventing pain. Cocaine was the first local anesthetic discovered in the late 19th century. Cocaine is a benzoic acid ester obtained from the leaves of coca shrubs and was often used for its psychotropic effects. Cocaine was first isolated in 1860 by Albert Niemann. Sigmund Freud studied the physiological actions of cocaine. Carl Koller later introduced it into clinical practice in 1884 as a...

Local Anesthetics: Pharmacokinetics

Local Anesthetics: Pharmacokinetics

The potency and duration of action of local anesthetics (LAs) are determined by their pharmacokinetics. Pharmacokinetics describes how LAs are absorbed, distributed, metabolized, and eliminated from the body. When administered to the vascular tissues, LAs are quickly absorbed and enter the systemic circulation, reducing their localized effects. Adding vasoconstrictors such as epinephrine to LAs reduces their absorption into the systemic circulation, making them clinically effective. The...

Local Anesthetics: Common Agents and Their Applications

Local Anesthetics: Common Agents and Their Applications

Local anesthetics (LAs) are commonly used for various applications in medical and dental procedures. Some of the common agents used are cocaine, lidocaine, and bupivacaine.
Cocaine is an ester of benzoic acid and methylecgogine. It is used to anesthetize and vasoconstrict locally. Currently, it is used primarily for topical applications. It is beneficial for surgeries on the upper respiratory tract, providing anesthesia and shrinking the mucosa. Cocaine in the form of cocaine hydrochloride is...

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Membrane Remodeling of Giant Vesicles in Response to Localized Calcium Ion Gradients

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Published on: July 16, 2018

Membrane permeable local anesthetics modulate Na(V)1.5 mechanosensitivity.

Arthur Beyder¹, Peter R Strege, Cheryl Bernard

¹Division of Gastroenterology and Hepatology, Enteric Neuroscience Program, Mayo Clinic, Rochester, MN, USA.

Channels (Austin, Tex.)

|August 10, 2012

Summary

Local anesthetics like lidocaine can alter the mechanosensitivity of the cardiac sodium channel Na(V)1.5. This modulation affects channel activation but is distinct from use-dependent block, suggesting specific interactions with the channel.

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Area of Science:

Cardiovascular Physiology
Molecular Biology
Ion Channel Biophysics

Background:

The voltage-gated sodium channel Na(V)1.5 is crucial in mechanically active organs like the heart and gastrointestinal tract.
Na(V)1.5 exhibits mechanosensitivity, responding to stimuli that affect other mechanosensitive ion channels.
Local anesthetics and antiarrhythmic drugs interact with Na(V)1.5 through various mechanisms.

Purpose of the Study:

To investigate whether local anesthetics modulate the mechanosensitivity of Na(V)1.5.
To elucidate the specific mechanisms by which local anesthetics affect Na(V)1.5 mechanosensitivity.

Main Methods:

Na(V)1.5 channels were expressed in HEK-293 cells.
Mechanosensitivity was assessed using cell-attached and excised inside-out patch configurations.
A novel protocol involving paired voltage ladders and pressure pulses was employed to measure shifts in voltage-dependence.

Main Results:

Negative patch pressure induced a hyperpolarizing shift in Na(V)1.5 activation and inactivation voltage-dependence.
Lidocaine (50 µM) inhibited the pressure-induced shift in activation (V(1/2a)) but not inactivation (V(1/2i)).
Benzocaine and lidocaine also inhibited mechanosensitivity at a mutated local anesthetic binding site (F1760A), while QX-314 did not.

Conclusions:

Lidocaine's inhibition of pressure-induced shifts in Na(V)1.5 activation is mechanistically separate from use-dependent block.
Modulation of Na(V)1.5 mechanosensitivity by permeable local anesthetics likely involves hydrophobic interactions and membrane-protein binding.