Local anesthetics

Local Anaesthetics

Overview

• Local Anaesthetics: Drugs that block impulse conduction in nerve fibres.

• Local Anaesthesia: A drug-induced reversible blockade of nerve impulses in a restricted region of the body, primarily used to prevent acute pain (nociception).

Local vs General Anaesthesia

• Local Anaesthesia:

  • Used for minor surgeries.

  • Produces loss of sensation without loss of consciousness.

  • Patient remains awake; protective airway reflexes are intact.

  • Minimal nausea and vomiting.

  • Requires extensive anatomical knowledge for effective and safe application.

Mechanism of Action

• Blocking Mechanism: Local anaesthetics block voltage-sensitive Na+ channels inhibiting the initiation and propagation of action potentials.

• Some sodium channel blockers have roles as Class I antidysrhythmics and anticonvulsants, but not all are clinically useful (e.g., tetrodotoxin).

Chemistry of Local Anaesthetics

Chemical Structure

• Esters:

  • Amethocaine (Tetracaine)

  • Procaine

  • Cocaine: Noted as an illegal drug.

• Amides:

  • Bupivacaine

  • Levobupivacaine

  • Lidocaine (Lignocaine)

  • Mepivacaine

  • Prilocaine

  • Ropivacaine

Chemical Properties

• Lipid Solubility:

  • Influences potency, plasma protein binding, and duration of action.

  • Increased with more carbon substituents on aromatic ring or amino group.

• Ionization Constant (pKa):

  • Determines the balance between ionized and non-ionized forms of the anaesthetic.

  • Local anaesthetics are weak bases; the proportion of ionized form (BH+) increases as pH decreases, causing less penetration into nerve fibers, particularly in inflamed tissue.

Pharmacokinetics

Absorption and Distribution

• Application: Locally at the action site. Administration can vary based on the method used (e.g., intravenous, epidural).

• Vasoconstrictors (e.g., adrenaline) help prolong local effects.

• Systemic Absorption: Correlates positively with the vascularity of the injection site. The order of absorption from highest to lowest is:

  • Intravenous

  • Tracheal

  • Intracostal

  • Paracervical

  • Epidural

  • Brachial plexus

  • Sciatic

  • Subcutaneous

Metabolism and Excretion

• Metabolism:

  • Esters: Metabolized primarily by plasma cholinesterase.

  • Amides: Initially undergo N-dealkylation, followed by hydrolysis in the liver.

• Excretion: Relatively unimportant in terms of local anaesthetics.

Mechanism of Action of Local Anaesthetics

• Exist in charged (ionized) and uncharged (non-ionized) forms.

• Membrane Receptor Hypothesis: The most comprehensive theory explaining how local anaesthetics work.

• Weak bases (pKa 8-9) dissociate in aqueous solutions, leading to the formation of non-ionized (inactive) and ionized (active) forms:

  • B + H+ ⇌ BH+

Sodium Channel Blockade

• Hydrophobic and Hydrophilic Pathways: Local anaesthetics block Na+ channels through both pathways, interacting differently based on their form.

Use-Dependent Block of Na+ Channel

• States of Na+ Channels:

  • Resting (closed)

  • Open

  • Inactivated (activated)

• Local anaesthetics preferentially bind to inactivated channels, thus providing a use-dependent quality, enhancing blockade with increased nerve stimulation.

• Higher blockade correlates with increased channel openings, consequently increasing anesthetic access.

Differential Sensitivity of Nerve Fibers

• Smaller diameter nerve fibers are blocked before larger ones; myelinated fibers are easier to anesthetize than non-myelinated fibers of the same diameter.

• Pain fibers (Aδ and C fibers) disappear first, followed by temperature, touch, and deep pressure sensations.

Unique Factors Allowing Targeting of Pain Sensations

• Highest effect on small diameter fibers.

• High affinity for the inactivated state of Na+ channels.

• Localized application to the targeted site enhances effectiveness.

Systemic Toxicity of Local Anaesthetics

• Caused by systemic absorption of local anesthetics.

• Management:

  • Co-administration of vasoconstrictors like adrenaline, except in extremities where risk of tissue necrosis exists due to intense vasoconstriction.

  • Treated with intravenous injection of lipid emulsion to extract lipophilic local anesthetic molecules from circulation.

Symptoms of Systemic Toxicity

• CNS Effects:

  • Initial excitation leading to convulsions, coma, and respiratory depression.

• Cardiovascular Effects:

  • Vasodilation and myocardial depression can lead to significant hypotension.

• Allergic Reactions:

  • Most commonly observed with procaine and other esters of p-aminobenzoic acid (dermatitis).

Drug-Specific Toxicity

• Bupivacaine: Can cause malignant ventricular arrhythmias and is composed of a 50:50 mixture of two stereoisomers (S(-) and R(+)); levobupivacaine is safer than R(+)-bupivacaine.

• Prilocaine: Its metabolite, O-toluidine, can convert hemoglobin to methaemoglobin, impairing oxygen transport (methaemoglobinaemia).

Summary of Local Anaesthetics and Their Uses