CT - Local Anaesthetics 1

• Local anesthetics disrupt nerve signal transmission by preventing sodium ions from entering through Na+ channels in nerve cell membranes.

Mechanism of Action

• Typically, Na+ channels exist in a resting state, limiting Na+ influx.
• When a neuron is stimulated, Na+ channels open, permitting so sodium ions enter the cell, leading to its depolarization.
• Membrane depolarization triggers conformational changes in channel subunit proteins, inactivating the Na+ channel, preventing further Na+ influx.
• Active transport mechanisms return sodium ions to the extracellular environment, allowing the channel to return to its normal resting state after repolarization.
• Local anesthetics are more effective on sodium channels when they are activated or inactivated than when they are in a resting state.
• Rapid action potential firing rates are more susceptible to local anesthetics.
• Smaller nerve fibers are more susceptible to local anesthetics, because it is easier to disrupt action potential propagation.
• Local anesthetics block nerve conduction in the following order: small myelinated axons (types Aδ and B), non-myelinated axons (type C), and large myelinated axons (types Aα, Aβ, and Aγ).
• Nociceptive and sympathetic transmission are the first to be blocked.
• Small, rapid-firing autonomic and pain fibers are most sensitive, followed by sensory fibers, and lastly, somatic motor nerve fibers.

Progression of Local Anesthesia

• Loss of pain
• Loss of cold sensation
• Loss of warmth sensation
• Loss of touch sensation
• Loss of deep pressure sensation
• Loss of motor function
• Sensory fibers vary in diameter and firing rates, with pain fibers being more sensitive than those carrying pressure and proprioception

Definition of Local Anesthetic

• Local anesthetics are drugs that reversibly prevent nerve impulse transmission in a specific area without affecting consciousness.
• Local anesthetics have a lipophilic group (aromatic ring), a link chain (ester or amide), and an ionizable group (tertiary amine).

Local Anesthetics: Isomers

• Some local anesthetics exist as stereoisomers with the same structural and molecular formula but different spatial orientation around a chiral center, possessing R and S enantiomers with differing efficacy.
• Examples: bupivacaine and prilocaine.
• Some local anesthetics are achiral and don't have isomers, such as lidocaine.

Ester vs. Amide - Clinical Significance

• Ester linkages are more easily broken, making them less stable in solution and not heat-stable, while amide bonds have greater stability.
• Ester metabolism may result in para-aminobenzoate (PABA), associated with allergic reactions.
• Amides very rarely cause allergic reactions.

Characteristics

• Local anesthetics are weak bases used clinically in salt form.

• They exist in the body as uncharged molecules and cations.

• The proportion of ionized (BH+) and un-ionized (B) forms is determined by the anesthetic's pKa and the tissue pH.

• The un-ionized, lipid-soluble form (B) is essential for penetrating the neuronal membrane.

• Once inside the neuron, it becomes ionized (BH+), blocking the sodium channel.

• Higher pKa values result in a greater proportion existing in the quaternary form at physiological pH.

Sodium Channel Blockade

• Local anesthetics stabilize the resting membrane by preventing increases in sodium permeability in response to a stimulus.
• Local anesthetics increase the threshold potential.
• Recovery from drug-induced block is slower with a longer refractory period, decreasing the frequency of impulse conduction.
• Local anesthetics can abolish the ability to generate action potentials, making neurons non-conducting.
• Sodium channel recovery, threshold potential, and refractory period return to normal, making the effect of local anesthetics reversible.

Non-Specific Mode of Action

• Local anesthetics act due to their surface activity.
• Drug molecules dissolve in the phospholipid membrane within neurons
• Causing increased pressure within the membrane
• Leading to small expansion and distortion of the channel protein and blockade of the Na+ channel.