Pharmacology of Local Anaesthetics

Discuss the pharmacology of local anaesthetic agents including: • Mechanisms of action • Comparative pharmacology of different agents • T oxicity • Use of adjuvant agents to enhance the quality or extend duration of block • Pharmacokinetics of drugs administered in the epidural and subarachnoid space

Structure-Activity Relationships

• All local anaesthetics have a lipophilic and a hydrophilic portion separated by a connecting hydrocarbon chain

• The hydrophilic group is usually a tertiary amine
• The lipophilic portion is usually an unsaturated aromatic ring

• Lipophilic portion gives the anaesthetic activity while hydrophilic portion and formulation as an HCl salt gives water solubility
• 2 portions linked by either an ester -CO- (aminoesther local anaesthetics) or an amide -NHC- (aminoamide local anaesthetics) bond

• Type of linking bond determines site of metabolism and potential to produce allergic reactions

Mechanism of Action

• Inhibit sodium influx through voltage-gated sodium channels on the inner surface of neuronal cell membranes
• When sodium cannot enter the cell, an action potential cannot be generated and conduction is inhibited
• Are weak bases, formulated as a hydrochloride salt to make them water soluble
• Bind more readily to sodium channels in an activated state, thus onset of neuronal blockade is faster in neurons that are rapidly firing - state or frequency dependent blockade
• Also have some activity on voltage gated potassium channels, although much less

Pharmakokinetics

• At pH = pKa, protonated (ionized) and unprotonated (non-ionized) forms exist in equilibrium
• Most local anaesthetics have a higher pKa and therefore exist in a mainly non-ionized form
• Only the non-ionized unprotonated form crosses into the cell

• Once inside the cell, the non-ionized form reaches equilibrium with the ionized form, which cannot leave the inside of the neuron - ion-trapping
• The ionized form acts on the receptor
• Acidosis (eg. inflamed local environment) leads to increased ionization of local anaesthetic and therefore poor quality of anaesthesia
• Local anaesthetics with pKa's nearest to physiological pH have the most rapid onset of action due to optimized ratio of ionized and non-ionized drug fraction
• Intrinsic vasodilator activity also increase potency and duration of local anaesthetics

Absorption and Distribution in Systemic Circulation

• Influenced by site of injection/dosage, use of epinephrine and pharmacologic characteristics of the drug - eg. rate of tissue distribution (influenced by lipid solubility) and rate of clearance
• LA's in systemic circulation firstly pass through the pulmonary circulation where extraction occurs, then rapidly distributed into highly perfused tissues - brain/heart/kidneys, and then into less well perfused tissues
• Following this, eliminated from plasma by metabolism and excretion
• Age, cardiovascular status, hepatic function all influence absorption and plasma concentrations of LA's
• Amide LA's have wider absorption than ester LA's

Placental Transfer

• Can be clinically significant transplacental transfer of local anaesthetics between mother and fetus
• Highly protein bound LA's like bupivacaine have an umbilical vein-marternal arterial concentration ratio much lower than less protein bound lidocaine
• Ester LA's don't reach the placenta due to their rapid hydrolysis
• Fetal acidosis can cause accumulation of LA molecules in the fetus via ion trapping

Clearance

• Clearance of amide LA's reflects hepatic metabolism (renal excretion is minimal due to poor water solubility)
• Ester LA's are rapidly hydrolysed by cholinesterase enzyme in plasma/liver therefore their pharmakokinetics are less relevant

Amide Metabolism

• Metabolism is by microsomal enzymes in the liver
• Initial step is conversion of the amide base to aminocarboxylic acid and a cyclic aniline derivative, followed by other steps
• More complex and slow than ester LA metabolism, therefore high plasma concentrations and toxicity are more likely

Lidocaine

• Lidocaine is an amide local anaesthetic that is also used to control ventricular tachyarrhythmias. It has Class Ib anti-arrhythmic actions.
• Preparation: Lignocaine is formulated as the hydrochloride and is presented as a colourless solution (0.52%) with or without adrenaline (1:200000); a 2% gel; a 5% ointment; a spray delivering 10 mg/dose and a 4% solution for topical use on mucous membranes. It is also combined in suppository form with steroid for use in haemorrhoids.
• pKa of 7.9, therefore 25% unionized at pH 7.4 resulting in fast onset of action
• Hexanol:buffer coeff 2.9 - 10x less soluble than bupivacaine therefore decreased toxicity & potency at a given dose
• Kinetics: Lignocaine is 70% protein-bound to a1-acid glycoprotein. It is extensively metabolized in the liver by dealkylation to monoethylglycine-xylidide and acetaldehyde. The former is further hydrolysed while the latter is hydroxylated to 4-hydroxy2,6-xylidine forming the main metabolite, which is excreted in the urine. Some of the metabolic products of lignocaine have anti-arrhythmic properties while others may potentiate lignocaine-induced seizures.
• Vasodilation at low doses, vasoconstriction at high doses.
• Clearance is reduced in the presence of hepatic or cardiac failure.
• Half life 96 mins
• Maximum dose 3mg/kg without adrenaline, 7mg/kg with adrenaline

Bupivacaine

• Bupivacaine is an amide local anaesthetic with a butyl side chain
• Preparation: colourless solution, 0.25, 0.5 (with or without 1:200000 adrenaline) and 0.75% solution. A 0.5% preparation containing 80 mg/ml glucose (specific gravity 1.026) is available for subarachnoid block
• pKa of 8.1, therefore 15% unionized at pH 7.4 resulting in a medium onset of action
• Hexanol:buffer coeff 28, 10 times more soluble than lignocaine therefore increased speed of uptake, increased potency and increased toxicity
• While it has been the mainstay of epidural infusions in labour and post-operatively, concerns regarding its cardiac toxicity and the availability of ropivacaine may lead to reduced use.
• Kinetics: It is the most highly protein-bound amide local anaesthetic (binds to α1 acid glycoprotein) and therefore an intermediate/slow onset and duration of action as it forms protein conplexes at the target site - significantly slower onset than lignocaine. Metabolized in the liver by dealkylation to pipecolic acid and pipecolylxylidine
• More vasodilation than ropivacaine, less than lignocaine
• Isomerism: A racemic mixture - 1:1 ratio of S to R enantiomers. R is more lipid soluble and therefore associated with more toxic side effects - cardiac toxicity.
• Half life 210 mins
• Maximum dose 2mg/kg
• Reasons why more toxic than ropivacaine: more lipid soluble so more uptake, more vasodilation so more uptake, longer half life

Ropivacaine

• Ropivacaine is an amide local anaesthetic with a propyl side chain
• Preparation: colourless solution, 0.2%, 0.75% and 1% concentrations, in two volumes (10 and 100 ml) and as the pure S-enantiomer. It is not prepared in combination with a vasoconstrictor as this does not alter its duration of action or uptake from tissues.
• pKa of 8.1, therefore 15% unionized at pH 7.4
• Main differences from bupivacaine lie in its pure enantiomeric formulation, improved toxic profile and lower lipid solubility (more than lignocaine, less than bupivacaine).
• Less motor block due to reduced penetration of large myelinated Aa motor fibres cf bupivacaine.
• Kinetics: Hepatic metabolism - hydroxylation via cyt P-450 system
• Intrinsic vasoconstrictor, therefore not given with adrenaline
• Half life 108 mins
• Maximum dose 3mg/kg

Prilocaine

• Prilocaine is a 0.5- 2.0% solution.
• Similar indications to lignocaine but is most frequently used for intravenous regional anaesthesia.
• Kinetics: The most rapidly metabolized amide local anaesthetic, metabolism occurring not only in the liver, but also the kidney and lung. When given in large doses one of its metabolites, o-toluidine, may precipitate methaemoglobinaemia.
• 55% protein bound
• Used in EMLA cream and for regional IV anaesthesia due to low cardiac toxicity and rapid metabolism
• Maximum dose 8mg/kg

Cocaine

• Used in >50% of rhinolaryngologic procedures in the USA
• Topical solution - 4-10%, max dose 150mg
• Unique ability to produce localized vasoconstriction, decreasing blood loss and improving surgical visualisation
• Blocks presynaptic uptake of norepinephrine and dopamine, producing the "high"
• Chronic exposure thought to affect dopaminergic function in the brain by dopamine depletion
• Side Effects:

• Causes coronary vasospasm, myocardial ischaemia/infarction and dysrhythmias eg. VF, cerebrovascular accidents

• GTN can be used to treat cocaine-induced myocardial ischaemia

Side Effects

• Allergic Reactions:

• Rare, cross sensitivity between LA's mediated by metabolite paraaminobenzoic acid
• No cross sensitivity between amide and ester LA's

• Systemic toxicity:

• Due to excess plasma concentrations of a drug
• Accidental intravascular injection is the most common mechanism
• Excess concentration caused by:

• Dose
• Injection site vascularity - intercostal > epidural > brachial plexus
• Presence of epinephrine in solution - decreases systemic absorption of LA's by 1/3
• Physicochemical properties - pKa, lipid solubility

Central Nervous System Toxicity

• Low plasma concentrations of LA's cause numbness of the tongue and circumoral tissues due to the high vascularity of these areas:::* At higher concentrations, cross blood-brain barrier to produce restlessness, vertigo, tinnitus and difficulty focusing
• At high concentrations, slurred speech and skeletal muscle twitching, then seizures
• Seizures are classically followed by CNS depression. accompanied by hypotension and apnea
• Serotonin accumulation, increased CO₂ and hypokalaemia decrease local anaesthetic toxicity
• Treatment:

• Ventilation with oxygen (to treat arterial hypoxaemia and metabolic acidosis)
• IV administration of benzodiazepine to suppress seizures

Neurotoxicity

• Toxicity in peripheral nervous system from LA's in epidural/subarachnoid space
• Lidocaine (and probably other LA's) are directly toxic to sensory neurons, probably by increasing intracellular calcium ion concentration
• Transient Neurologic Symptoms:

• Moderate to severe pain in lower back, buttocks and posterior thoughs
• Appears 6-36 hours post complete recovery from single shot spinal
• Mechanism not known, usually resolves within 1-7 days
• Greatest incidence is after intrathecal lidocaine injection - up to 30%, much less with others

• Cauda Equina Syndrome:

• Diffuse lumbosacral plexus injury causes 1) Sensory anaesthesia 2) Bowel and bladder sphincter dysfunction and 3) Paraplegia
• Associated with high dose or continuous intrathecal lidocaine infusion & contributed by positioning eg. lithotomy

• Anterior Spinal Artery Syndrome:

• Lower-extremity paresis with variable sensory deficit
•  ? If caused by anterior spinal artery spasm or thrombosis

Cardiovascular Toxicity

• Requires greater concentrations of local anaesthetics than CNS
• At very high concentrations, produces profound hypotension due to:

• Relaxation of arteriolar vascular smooth muscle
• Direct myocardial depression

• LA's block cardiac sodium channels

• At lower concentrations, has an antidysrhythmic effect
• At higher concentrations, causes depression in conduction and automaticity
• Seen on ECG as P-R and QRS prolongation

• Selective Cardiac Toxicity can occur due to accidental IV injection of bupivacaine

• Protein binding sites become quickly saturated leaving a large amount of unbound drug for diffusion into conducting tissue
• Causes Precipitous hypotension. cardiac dysrhythmias and atrioventricular heart block
• Enhanced by pregnancy, anti-arrhythmic drugs, epinephrine/phenylephrine and hypoxia/hypercarbia/acidosis
• Bupivacaine R enantimoer is more toxic than the S enantiomer, ropivacaine is a pure S enantiomer therefore less cardiotoxic

Other Side Effects

• Methaemoglobinaemia: Lidocaine/prilocaine/benzocaine can oxidise haemoglobin to methaemoglobin more rapidly than vise versa

• Methaemoglobin cannot bind O₂ or CO₂ resulting in loss of the haemoglobin molecule's transport function
• Methylene blue given to reverse oxidation

• Lidocaine depresses ventilatory response to hypoxia

Specialised uses of Local Anaesthetics

• Eutectic Mixtures of Local Anaesthetics (EMLA):

• Combination of 2.5% lidocaine and 2.5% prilocaine - both solid at room temperature, but form an oil when combined with a melting point of 19 degrees
• Considered eutectic as the melting point of the combined drugs is lower than lidocaine or prilocaine alone
• Allow high concentration of anaesthetic bases to be applied without local irritation or worries about systemic toxicity
• Useful in cannulation/venepuncture/superficial surgery eg. circumcision and warts
• Takes ~45 mins for good effect, but get some effect after 5 mins
• Prilocaine can cause methaemoglobinaemia in neonates or those who have genetic susceptibility to methaemoglobinaemia

• Regional IV anaesthesia - not recommended to use ropivacaine/bupivacaine due to toxicity. Lidocaine/prilocaine most often used.
• Epidural Anaesthesia:

• Works by diffusion into dura to act on nerve roots and spinal cord, as well as by diffusing into paravertebral area through intervertebral foramina
• Lidocaine, bupivacaine and ropivacaine all used, however ropivacaine being used more than bupivacaine due to its reduced toxicity as well as decreased motor block vs lidocaine

Adjuvants

• Adjuvants are drugs that increase the efficacy or potency of other drugs when given concurrently
• Sodium bicarbonate - given with lidocaine. Increases pH of local area to increase the fraction of unionized lidocaine, which means more diffuses across the neural membrane.

• This speeds up the time of onset and increases the spread of the block

• Adrenaline - causes vasoconstriction of local vessels which reduces vascular absorption resulting in improved quality and prolonged duration of block

• Also allows larger doses to be given as lower peak plasma levels mean reduced toxicity for the same dose of local anaesthetic - eg. lidocaine goes from 4mg/kg - 7mg/kg with 1:200000 adrenaline
• Less effective with bupivacane, and not useful with ropivacaine as this causes its own vasoconstrictive properties

• Clonidine - used intrathecally, 30-60 mcg can increase duration of block by 30%

• Can cause bradycardia, hypotension and sedation

• Opioids - used in neuraxial blocks. Improve the quality of intraoperative analgesia, delay regression of sensory blockade and prolong postoperative analgesia.