Local anaesthetics 16 January 2013 Pharmacology Batch17 Year2

Effect of local anaesthetic on action potential

Benchmarks in the development of local anaesthesia in medical practice: 1860 – Niemann isolated cocaine 1884 – introduced to ophthalmic anaesthesia by Koller Cocaine alone as LA for 30 years 1905 – procaine was synthesized by Einhorn 50 years after  1943 – lidocaine was synthesized by Lofgren bupivacaine

Basic molecular structure of local anaesthetics

Classification ( based on structure of intermediate chain of the Local anaesthetic molecule) Amino Esters Cocaine Procaine Chloroprocaine Amethocaine Benzocaine Amino Amides Cinchocaine Lignocaine Mepivacaine Prilocaine Bupivacaine Ropivacaine Etidocaine Articaine

Mechanism of action of local anaesthetics

Local anaesthetics block Nerve conduction by modifying the voltage-gated sodium channel activities Causing progressive decrease in rate and degree of depolarization until it is not sufficient to reach the excitability threshold so that no more full action potential resulting in conduction block. Which nerve? Every nerve (sensory/motor/autonomic)

In other words, Local anaesthetics reversibly block impulse conduction along nerve axons and other excitable membranes that utilize sodium channels the primary means of action potential generation

Pharmacokinetics Absorption Systemic absorption of local anaesthetic from the site of Administration is determined by 1.Dosage ( concentration and volume of LA) 2.Site of injection 3.Drug-tissue binding 4.Local blood flow 5.Vasoconstrictors 6.Physicochemical properties of local anaesthetics

Dosage Maximum safe dose Lignocaine without adrenaline Lignocaine with adrenaline Bupivacaine

Site of injection  Tissue surrounding intercostal nerve  more rapid absorption  higher blood level than poorly perfused tissue like tendon, dermis, subcutaneous fat  Highly vascular area like tracheal mucosa  Regional anaesthesia intercostal > caudal> epidural> brachial plexus> sciatic nerve block

Addition of vasoconstrictor to local anaesthetic solution (adrenaline/epinephrine, phenylephrine)  Reduce systemic absorption by decreasing blood flow To the site of injection  prolong duration of action of intermediate acting local anaesthetics like lignocaine, procaine. Blood level lowered up to 30% prolonging duration of action up to 50% by adding vasoconstrictors But less effect on more lipid soluble and longer acting LAs Like bupivacaine and ropivacaine Cocaine is the only local anaesthetic with vasoconstrictor property

Distribution  Amides type of local anaesthetics are widely distributed after intravenous bolus administration.  Sequestration in fat tissue.  Initial rapid distribution phase ( uptake in highly perfused organs) is followed by slower distribution phase ( uptake into moderately well perfused tissue like muscle, GI tract).

Metabolism and excretion  Amide type of LA are metabolized in liver and converted into water soluble compound which is readily available to excrete through kidney.  Amide link is hydrolysed by liver microsomal P450 isozymes.  Ester type undergoes hydrolysis by circulating (plasma) butyrylcholinesterase ( pseudocholinesterase ) to inactive metabolites.So, procain and chloroprocaine have very short plasma half-life ( <1 minute)

Rate of metabolism is different among amide type of LA. Approximate order : Prilo > ligno > mepi > ropi > bupi and levobupivacaine Toxicity can occur in patients with deranged liver function. e.g., Average elimination half-life of lignocaine Normal – 1.6 hours Severe liver disease -- > 6 hours

Side effect and toxicity of local anaesthetics 1. Extension of pharmacological effect on CVS and CNS CNS – excitation followed by depression Excitation phenomena : tingling around the mouth, lightheadness and dizziness, muscle tremors and twitching, tonic – clonic Convulsions Depression : drowsiness, unconciousness, respiratory depression and arrest.

CVS toxicity  Decreased myocardial contractility and cardiac out put  Peripheral vasodilation  Sinus bradycardia  Conduction defections ( heart block )  Ventricular arrythmias with bupivacaine  Cardiac arrest  Initial hypertension and tachycardia due to CNS stimulation

Prevention and treatment of toxicity  Strict adherence to the maximum safe dose limit  Avoid accidental IV injection during all procedures like repeated aspiration and test dose before final delivery of drug  Closed observation after procedure to catch early signs  Timely management of seizure with a small dose of anti- convulsant followed by ABCD for resuscitation

2. Allergic reaction  Rare with amides  Common with ester types of local anaesthetics due to formation of para amino benzoic acid (PABA) as metabolite 3. Methaemoglobinemia By large doses of prilocaine 4. Bupivacaine is the most cardiotoxic of all

Preparations and routes of administration Drop Spray Jelly Ointment Lozenges injection Mucosa covered structure like eye Mucosa – oral,nasal, tracheal Skin (EMLA) Infiltration Nerve block Plexus block Central neuraxial block intravenous

Surface anatomy for lumber spinal/epidural injection

Spinal injection in adult