Lecture 3: Local Anaesthetics PDF

Lecture 3: Local Anaesthetics Prof. David Finn Pharmacology and Therapeutics Chemical structure Classification Learning objectives Mechanism of action Characteristics of LA Pharmacokinetic profile Adverse side effects and toxicity Clinical uses Anaesthetics – Introduction A drug that induces anaesth...

Lecture 3: Local Anaesthetics Prof. David Finn Pharmacology and Therapeutics Chemical structure Classification Learning objectives Mechanism of action Characteristics of LA Pharmacokinetic profile Adverse side effects and toxicity Clinical uses Anaesthetics – Introduction A drug that induces anaesthesia – a substance that causes temporary loss of sensation or awareness, dulling pain to permit painful procedures Two broad classes: o Local anaesthetics o General anaesthetics Local anaesthetics Local anaesthetics (LAs): reversibly block conduction along nerve fibers (1st and 2nd order neurons) Can produce anaesthesia w/o loss of consciousness History of LAs In the beginning there was cocaine (1860) o Incas – Coca leaves o Sigmund Freud o Carl Koller Procaine - the first synthetic ester LA (1905) Lidocaine - the first “amide” LA (1943) Structure of LAs Consists of aromatic group (left), ester or amide group (shaded) and amine group (right) Structure of LAs Weak bases pKa values 8 to 9 Consequently, they get ionised at physiological pH Amides are more stable Therefore, have a longer half-life Chemistry of LA Amide vs Esters o o o o o o o o Cocaine Procaine Benzocaine Tetracaine Lidocaine Bupivacaine Mepivacaine Ropivacaine Amides Classification Local anaesthetics *Benzocaine is an unusual LA with very low solubility o No basic amine group o Long-acting o Used as dry powder for dressing painful skin ulcers and also in throat lozenges Neural transmission – at rest +++ +++ +++ +++ +++ +++ +++ +++ ------ ---- ------ ---- ------ ----------- ---+++ +++ +++ +++ +++ +++ +++ +++ Na+ channel is in its resting functional state Neural transmission – Action potential Activation of peripheral nociceptors allows the opening of some Na+ channels Once threshold is reached, all Na+ channels open Depolarisation of membrane Firing of action potential + propagation of nerve signal +++++++++ +++ +++----- ----+++++++++++++++ +++ ++++++ +++ -------------------------------- ------------- ++++++ -----------------------+++++++++ ++++++++++++ ++++++ +++++++++++++++ Opening of K+ channel & inactivation of Na+ channel restores ionic balance and AP is over Mechanism of action of LAs Local Anaesthetics block Na+ Channel ----- ----+++++++++ ++++++++++++ ++++++ +++++++++++++++ ---------------------- ---------------- --------------------++++++ ----- ----+++ +++ ++++++ +++ ++++++ ++++++ +++++++++++++++ Mechanism of Action of LAs Reversible Na+ channel blockade Na+ Hydrophilic domain RESTING ACTIVE INACTIVE Ion channels are composed of several subunits with hydrophilic (water-liking) and hydrophobic (water-hating) domains Activation of the Na+ channel causes a conformational change in the receptor allowing the opening of a central pore Hydrophobic domain Na+ Hydrophilic domain Ion channels have 3 functional states Resting: Activated: Inactivated Mechanism of Action of LAs Hydrophilic pathway LA Main mode of action Na+ LA LA+ Uncharged LAs can permeate the lipid bilayer Once inside the neuron they become polarised (charged) and can then block the channel once it opens LAs have higher affinity for inactive > active > resting state NB – frequency dependent block Mechanism of Action of LAs Hydrophobic pathway LA Na+ Secondary mode of action LA Uncharged LAs can permeate the lipid bilayer and block the Na+ channel from within the membrane Characteristics of LA action Nerves with higher firing frequency and more positive membrane potential are more sensitive to LAs (use/frequency dependent block) LAs prefentially block small nerve fibres In nerve bundles, fibres located circumferentially are affected first by LAs Effectiveness of LAs is pH dependent Characteristics of LA action – (1) Use / Frequency dependent block Nerves with higher firing frequency and more positive membrane potential are more sensitive to LA’s Depth of block increases with action potential frequency o o Charged LAs are more likely to access active Na+ channels LAs have higher affinity for inactivated Na+ channels than resting state Sensory fibres (especially nociceptive fibres) have a high firing rate and a longer action potential than motor fibres – more susceptible to LA block Characteristics of LA action – (1) Use / frequency dependent block Effect of repetitive activity on the block of sodium current produced by a local anesthetic in a myelinated axon. A series of 25 pulses was applied, and the resulting sodium currents (downward deflections) are superimposed. Note that the current produced by the pulses rapidly decreased from the first to the 25th pulse. A long rest period following the train resulted in recovery from block, but the block could be reinstated by a subsequent train. (nA, nanoamperes.) (Modified slightly and reproduced, with permission, from Courtney KR: Mechanism of frequency-dependent inhibition of sodium currents in frog myelinated nerve by the lidocaine derivative GEA. J Pharmacol Exp Ther 1975;195:225) Effect of frequency and lidocaine on neuronal action potentials Characteristics of LA action – (2) LAs preferentially block small nerve fibres Small myelinated axons > non-myelinated axons > large myelinated axons Small myelinated axons => nociceptors: Aδ and C fibres Pain sensation blocked more readily than other sensory modalities o cold, warmth, touch, deep pressure, motor Characteristics of LA action – (3) Circumferential fibres are affected first by LAs In nerve bundles, fibres located circumferentially are affected first by LAs o o o Loss of sensation can spread from proximal (site of application) to distal (further away) part of limb In large nerve trunks, motor nerves are normally located on the outer parts May become affected before sensory fibres (loss of movement before loss of sensation) Characteristics of LA action – (4) Effectiveness of LAs is affected by pH Acidic - Basic - LAs are weak bases with pKa of 8-9 At low pH (acidic environment / inflammation) LAs become highly ionised and cannot permeate the membrane of neurons – anaesthesia suppressed Pharmacokinetics Absorption is affected by: o Dosage o Site of injection o Drug binding o Vasoactive drugs Metabolism Esters – rapidly hydrolyzed by plasma (and liver) by plasma cholinesterases o Procaine metabolised to aminobenzoic acid (PABA) – can cause allergic reactions (relatively rare) Amides - hepatic metabolism, longer half-life o More dangerous for patients with impaired liver function Pharmacokinetics Adrenaline Effect on LAs Most LAs have a direct vasodilator action - increases rate absorbed into systemic circulation: o Increases potential toxicity o Reduces local anaesthetic action Adrenaline can be combined with LAs – causes vasoconstriction o Decrease systemic toxicity (reduce uptake by up to 1/3) o Prolong local anaesthesia (by ~50%) o Decrease local bleeding (improve visualisation of surgical field) o Detect whether an injection was “intravascular” Adverse drug reaction/Toxicity Central nervous system Systemic absorption: main hazard for LAs clinically (and sometimes by-products such as PABA) Mixture of depressant and stimulant effects on CNS o Inhibition of inhibitory neuronal activity  stimulation Restlessness, tremor, confusion, agitation, convulsions o Respiratory failure at high concentrations [High] CNS depression and respiratory depression  respiratory failure o Exception is cocaine: produces euphoria at [low]  blocks monoamine uptake Adverse drug reaction/Toxicity Cardiovascular system Myocardial depression: conduction block o Inhibition of Na+ current in cardiac muscles o [Na+]i  [Ca2+]i stores  reduces force of contraction  partial/complete heart block Vasodilation o Direct effect on vascular smooth muscle-arterioles Myocardial + Vasodilation = decreased blood pressure (lifethreatening) Adverse drug reaction/Toxicity PNS and smooth muscle Temporary paralysis at neuromuscular junctions and ganglionic synapses Suppression of contractions of smooth muscle in the gut, blood vessels, and respiratory system LA toxicity Warning signs Lawsuit Numbness of tongue and mouth Behavioral and sensory disturbances Ringing in ears (tinnitus), metallic taste, tingling sensations Seizures (tonic clonic) Depression / Loss of Consciousness Respiratory Failure Arrhythmias*,hypotension, CV collapse Infiltration – gums, minor surgery Topical Anaesthesia – nose, mouth, cornea, skin Field block – surgery , dental Clinical uses of LAs Nerve block – surgery I.v. regional block – surgery Spinal nerve block – surgery e.g. Bupivacaine, slow onset, long duration Epidural block – surgery / labour Most LAs work for 2-3 h when injected locally Key points  LAs block nerve conduction by blocking Na+ channels ( generation of action potential)  LAs bind to Na+ channel either from the cytoplasm when the channel opens (philic) or through the membrane (phobic)  Preferentially block small diameter fibres (nociceptive)  ADRs/toxicity due to systemic blockade of Na+ channels  CNS & CVS Recommended reading + Rang and Dale’s Pharmacology 10th Ed. Chapter 44 + Kalant, Grant and Mitchell. Principles of Medical Pharmacology. Chapter 21