Local Anaesthetics

Local Anaesthetics are drugs that produce reversible loss of sensation to pain in a localized area of the body without loss of consciousness. These agents are capable of providing nerve blockade in a wide variety of clinical circumstances.

Brief History
The first LA (Cocaine) was discovered by accident. Cocaine occurs in abundance in the leaves of the coca shrub (Erythroxylum coca). Coca leaves have been chewed for its stimulatory and euphoric effects by the Andean natives (S. America) chewed alkali extract of the leaves. Cocaine was first isolated in 1860 by Albert Niemann. He tasted it and noted that it caused a numbing of the tongue. Sigmund Freud studied cocaine physiological actions. Carl Koller introduced cocaine into clinical practice 1884 (topical anaesthetic for ophthamological surgery). In 1884, he used the first local anesthetic on a patient with glaucoma. Halstead popularized its use in infiltration and conduction block anaesthesia. William Steward Halsted and Richard John Hall developed the inferior dental nerve block techniques for dentistry. Freud, Halsted, and Koller became addicted to the drug through self-experimentation. The search for a better local anaesthetic led to chemical synthesis of a number of other compounds that have more selective local anaesthetic properties and few systemic side effects

Chemical Aspects and SAR (Structure Activity Relationship)
Local Anaesthetic molecules consist of a lipophilic aromatic portion (a benzene ring) linked by an intermediate ester or amide linkage to a hydrophilic amine portion (a basic side chain). The hydrophilic portion is usually a tertiary or secondary amine. The commonly used local anaesthetics can be classified as esters or amides based on the intermediate linkage. All local anesthetics are weak bases so they are not completely ionized at physiological pH. Benzocaine is an typical local anaesthetic with no basic group.

The ester agents include cocaine, procaine, amethocaine and chloroprocaine while the amides include lignocaine, prilocaine, mepivacaine and bupivacaine. There are important practical differences between these two groups of Local Anaesthetics. Esters are relatively unstable in solution and are rapidly hydrolysed in the body by plasma cholinesterase (and other esterases). One of the main breakdown products is para-amino benzoate (PABA) which is associated with allergic phenomena and hypersensitivity reactions. In contrast, amides are relatively stable in solution, are slowly metabolised by hepatic amidases and hypersensitivity reactions to amide local anaesthetics are extremely rare. In current clinical practice esters have largely been superseded by the amides.

Mechanism Of Action
Local anesthetics block the initiation and propagation of action potentials by preventing the voltage dependent increase in Na+ conductance. This elevates the threshold for electrical excitation, reduces the rate of rise of the action potential, slows the propagation of the impulse, and if the drug concentration is sufficiently high, completely blocks conduction. The Local Anaesthetics interfere with the process fundamental to the generation of the action potential, namely, the large, transient voltage-dependent rise in the permeability of the membrane to Na+. Local Anaesthetics can also block K+ channels but at higher concentrations. Local Anaesthetics block conduction in small-diameter nerve fibres more readily than in large fibres (Aδ and C fibres). Lidocaine can be used intravenously to control neuropathic pain.

Pharmacokinetics
Local anaesthetics gain entrance into the bloodstream by absorption from the injection site, direct intravenous injection or absorption across the mucous membranes after topical application. All tissues will be exposed to local anesthetics after absorption but concentrations will vary among the organs. Although the highest concentrations appear to occur in the more highly perfused organs (i.e., brain, kidneys and lungs) factors such as degree of protein binding and lipid solubility also affect drug distribution. Most ester linked local anaesthetics are rapidly hydrolysed by plasma cholinesterase, so their plasma half-life is short. Procaine is hydrolysed to PABA (p-aminobenzoic acid), a folate precursor that interferes with the antibiotic effect of sulfonamides. Amide linked local anaesthetics are metabolized mainly in the liver by N-dealkylation. Benzocaine has a low solubility and produces long-lasting surface anaesthesia.
Most local anaesthetics are vasodilators which increases the rate of absorption into the bloodstream, increasing their potential toxicity and reducing their local anaesthetic action. Vasoconstrictors delays the absorption which slows down the absorption into the bloodstream.Vasoconstrictor used are epinephrine (adrenaline) or felypressin which are often added to local anaesthetic solutions injected locally to cause vasoconstriction. Side effects of epinephrine - Epinephrine circulates the heart, causes the heart beat stronger and faster and makes people feel nervous.

Clinical Uses

• Topical Anaesthesia
• Infiltration
• Regional Block
• Spinal Anaesthesia
• Lumbar Epidural Anaesthesia
• Caudal Anaesthesia
• Intravenous Extremity Block
• Sympathetic block
• Control of Cardiac Arrhythmia: Procainamide and lidocaine are two of the primary drugs for treating cardiac arrhythmias.

Adverse Effects

The central nervous and cardiopulmonary systems are most commonly affected by high plasma levels of local anesthetics. Local anesthetics given in initially high doses produce central nervous system (CNS) stimulation characterized by restlessness, disorientation, tremors, and at times clonic convulsions. Continued exposure to high concentrations results in general CNS depression; death occurs from respiratory failure secondary to medullary depression. Treatment requires assistance of ventilation and drugs to control the seizures. The ultra–short-acting barbiturates and the benzodiazepine derivatives, such as diazepam, are effective in controlling these seizures. Respiratory stimulants are not effective. CNS manifestations generally occur before cardiopulmonary collapse.

Cardiac toxicity is generally the result of drug- induced depression of cardiac conduction (e.g.,atrioventricular block, intraventricular conduction block) and systemic vasodilation. These effects may progress to severe hypotension and cardiac arrest.
Allergic reactions, such as red and itchy eczematoid dermatitis or vesiculation, are a concern with the ester- type local anaesthetics. True allergic manifestations have been reported with procaine. The amides are essentially free of allergic properties