LOCAL

ANAESTHETIC
AGENTS
By Dr Sinovuyo Ndlela, MBChB(WSU)
CONTENTS
1. Definition
2. Clinical uses of local anaesthetic agents
3. Anatomy and physiology of nerve conduction
4. Applied physiology
5. Pharmacodynamics
6. Pharmacokinetics
7. Individual local anaesthetic agent overview
8. Additives to local anaesthetic agents
9. Local anaesthetic toxicity and management
10. References
Definition
 Local anaesthetic drugs produce transient loss of sensory, motor and autonomic
function when the drugs are injected or applied in proximity to neuronal tissue.
 When applied to specific nerve pathways, they have a range of effects from
analgesia alone (sensory block) to a complete motor block with paralysis.
Clinical uses of local anaesthetic agents

 Spinal anaesthesia by injecting into the subarachnoid space.

 Epidural anaesthesia by injecting into the epidural space.
 Analgesia topically, by infiltration close to nerve endings.
 Regional anaesthesia with LA has been shown to decrease the incidence of chronic
pain in mutilating surgeries: amputations, mastectomies, thoracotomies and inguinal
hernia surgery.
 Treatment of acute and chronic pain.
 Anti inflammatory and antibacterial properties
Anatomy and physiology of nerve conduction
Applied physiology
 Classification of nerve fibres:
Applied physiology
 The sequence of nerve fibre blockade from first effect (easiest to block with low
concentration of drug) to last effect (most difficult to block requiring high
concentration of drug) is:
1. Peripheral vasodilatation and elevation of skin temperature (C & B fibres)
2. Loss of pain and temperature sensation (C & A d fibres)
3. Loss of proprioception (A b fibres)
4. Loss of touch and pressure sensation (A b fibres)
5. Motor paralysis (A a fibres)
Applied physiology
 Generally, thin nerve fibres are easier to block than thick ones.
 However, myelinated fibres are more readily blocked than non-myelinated ones,
because only the sodium channels at the nodes of Ranvier need to be inactivated.
 By choosing an appropriate agent and concentration, it is possible to selectively
block pain and temperature sensation via A d and C fibres, and to avoid significant
motor blockade by leaving the large A a fibres unblocked.
Pharmacodynamics
1. Chemical structure and classification
Pharmacodynamics
ESTERS AMIDES
 Amethocaine  Lignocaine
 Cocaine  Bupivacaine
 Benzocaine  Ropivacaine
 Tetracaine  Levobupivacaine
 Procaine  Prilocaine
Pharmacodynamics
2. Mechanism of action
Pharmacodynamics
3. Factors influencing activity of local anaesthetics:
a) Lipid solubility
b) Intermediate chain
c) Protein binding
d) pKa
e) PH
Pharmacodynamics
4. Preparations
 Local anaesthetics must be water-soluble and stable in solution.
 Commercially available solutions of local anaesthetics have the pH adjusted to the
acidic side to enhance chemical stability.
 So, although they are weak bases, they are formulated as salts of hydrochloric acid
to give stability and prolong shelf life.
 For example: Bupivacaine hydrochloride and Lignocaine hydrochloride. The drug in
the ampoules will be highly ionised until injected into the body.
Pharmacokinetics
1. Absorption
 LA are usually injected at their site of action  Absorption is rapid across mucous
membranes
 Intact skin requires large concentrations of hydrated LA to penetrate and is
impervious to standard formulations.
 EMLA is an eutectic(easily melted) mixture of LA consisting of 5% Lignocaine and
5% prilocaine in an oil-in-water emulsion. It is sufficient for insertion of IV lines,
suturing of minor wounds, split thickness skin grafts and circumcisions.
 Amethocaine (4% Tetracaine) has more rapid onset than EMLA, but can be markedly
irritant to the skin
Pharmacokinetics
 Systemic absorption depends on blood flow, which in turn depends on:

a) Site of injection
 IVI > tracheal > intercostals > caudal > Paracervical > epidural > brachial
plexus > subcutaneous
b) Vasoconstrictors
 Addition of adrenalin causes vasoconstriction at the site of administration
 Decreases absorption, enhances neuron uptake, enhances the quality of
analgesia, prolongs the duration of action and limit toxic side effects
c) Protein binding in the tissue
 Delays absorption, prolongs the block and decreases peak plasma concentrations
Pharmacokinetics
2. Metabolism and excretion
a) ESTERS
 Predominantly metabolized by pseudocholinesterases.
 Ester hydrolysis is very rapid and water soluble metabolites are excreted in the
urine.
 Patients with abnormal pseudocholinesterase are at an increased risk for toxic side
effects as metabolism is slowed.
 Para –amino benzoic acid is a metabolite of ester hydrolysis which can result in
allergic reactions.
 Cocaine is an exception, it is partially metabolized in the liver and partially excreted
unchanged in the urine.
Pharmacokinetics
b) AMIDES
 Metabolized by microsomal P450 enzymes in the liver.
 The rate of metabolism depends on the individual agent.
 Lignocaine > Ropivacaine > Bupivacaine, but overall is much slower than ester
hydrolysis.
 Decreased hepatic function (cirrhosis) of liver blood flow (CCF, vasopressors) will
reduce the metabolic rate and predisposes patients to systemic toxicity.
Individual local anaesthetic agents overview
1. ESTERS
a) Procaine
 Uses:

 Infiltration, dental and spinal anaesthesia

 Original Bier’s block
 Nerve and plexus blocks

 Conjugation with other drugs to form salts to prolong their duration of action e.g. procainepenicillin
 Potency: Low potency – half as potent as lignocaine

 Onset of action: Slow onset of action (15 – 20 min)

 Duration of action: Short duration (30 min without and 60 min with adrenalin)
 Side effects: High incidence of nausea and vomiting and pruritis when used intrathecally. High allergy
potential of the metabolite para amino benzoic acid
Individual local anaesthetic agents overview

b) Cocaine
 Recommended dose: 3mg/kg
 Uses: Used for topical mucosal anaesthesia in ENT surgery and bronchoscopy
 Onset: Short, 2-5 mins
 Duration: 30-40 mins
 Metabolism: Is unique among the ester drugs in that it is metabolized by the liver as
well as by plasma pseudo-cholienesterases
 Limitations:
 Too short acting to be of clinical use in spinal, epidural or plexus block
 Potential for addiction
Individual local anaesthetic agents overview
c) Amethocaine and Tetracaine
 Recommended and maximum dose: 1mg/kg
 Uses: Topical as eye drops or Ametop cream for venupuncture
 Usual concentration: 0,5 - 2%
 Onset: Fast (< 1min)
 Duration: 30 minutes
 High potency and high toxicity
Individual local anaesthetic agents overview
2. AMIDES
a) Lignocaine
 Dosages
 Plain (Without adrenaline) 3 mg/kg
 With adrenaline 7 mg/kg
 Uses:
 Spinal
 Epidural
 Plexus and peripheral nerve blocks
 Local infiltration
 Topical – in a concentration of 4%
 Intravenous regional anaesthesia
 Blunt hemodynamic response to intubation: IVI or laryngeal administration
Individual local anaesthetic agents overview
a) Lignocaine (Cont)
 Half life: 1.5-2 hours
 Infiltration:
 Onset 5 – 10 minutes
 Duration 30-60 min without adrenaline and 120 min with adrenaline
 Spinal:
 Dose 1 – 3 ml of 1 – 2%
 Onset 5 – 10 min
 Duration 30 to 90 min
 Risk of transient neurological syndrome 4X greater than with bupivacaine with an incidence up to 33%
(so nowadays not commonly used.)
Individual local anaesthetic agents overview
a) Lignocaine (Cont)
 Epidural:
 Dose: 15 – 30 ml 1 – 2%
 Onset 5 – 15 min
 Duration 30 – 90 min
 Plexus block
 Dose: 15 – 50 ml 1 – 2%
 Onset 10 – 20 min
 Duration 90 – 120 min without adrenaline and 120 – 240 with adrenaline
Individual local anaesthetic agents overview
2. Bupivacaine
 Dosages with or without adrenaline:
 Neonates & infants 2 mg/kg
 All other patients 3 mg/kg
 Uses:
 Infiltration anaesthesia
 Topical mucous membrane anaesthesia
 Spinal
 Epidural and caudal
 Potency: 4x Lignocaine
 Half life: 2.7 hrs in adults and 8 hrs in neonates
Individual local anaesthetic agents overview
2. Bupivacaine
 Infiltration:
 0.25 – 0.5%
 Duration: with adrenaline 180 – 300 min, and without 120 – 240 min
 Peripheral nerve block
 0.25 – 0.5%
 Onset: 10 – 15 min
 Duration: 180 – 360 mins without adrenaline and 240 – 480 mins with adrenaline
 PLEXUS BLOCKS
 Brachial plexus
 0.25 – 0.5% with a volume of 0.3 – 0.5 ml/kg
 Onset: 20 – 30 min
 Duration: is 6 – 15 hrs without adrenaline and 10 – 20 hrs with adrenaline o
Individual local anaesthetic agents overview
 Lumbar and sacral plexus blocks
 0.25 – 0.5% with a volume of 30 – 60 ml (0.3 – 1ml/kg)
 Onset: 25 – 35 min
 Duration: blocks can last up to 18 – 24 hrs
 Spinal
 2 – 3ml of 0.5%
 Dose: 10 – 15 mg
 Onset 10 – 20 min
 Duration : 100 – 240 min
Individual local anaesthetic agents overview
3. Ropivacaine
 Dose: 3 – 4 mg/kg
 Structurally similar to bupivacaine but lower lipid soluble which may explain the less
motor block at lower concentrations
 30 – 40% less cardiotoxic than bupivacaine
 Ropivacaine has the unique property of vasoconstriction and may provide either an
advantage or disadvantage when used for local infiltration, depending on the
surgical sitez
Individual local anaesthetic agents overview
4. Levobupivacaine
 S isomer of bupivacaine
 Dose: 2 – 3 mg/kg
 Has similar potency than bupivacaine but appears to have approximately 30 – 40%
less systemic toxicity on a mg:mg basis
Additives to local anaesthetic agents
1. Vasoconstrictors
 Addition of a vasoconstrictor adrenaline 1 : 80 000 - 1 : 200 000
 Some preparations come premixed with adrenaline
 Decreases the rate of absorption and therefore enhances the amount of drug available for
neuronal uptake
 Enhances the quality of analgesia
 Prolongs the duration of action: This depends on the specific local anaesthetic agent and
the site of injection e.g. more effective with lignocaine (shorter-acting) than with
bupivacaine (longer-acting) and more effective with subcutaneous infiltration than with
epidurals
 Limits toxic side-effects
 Decreases surgical bleeding
Additives to local anaesthetic agents
2. pH manipulation: Alkalinisation
 Adding bicarbonate increases the tissue pH; therefore, a higher proportion of
unionised drug is available, accelerating diffusion across the neuronal membrane.
 Alkalinisation has an additional benefit of decreasing the burning sensation often
felt when lignocaine is infiltrated.
 1 ml NaHCO3- 8,5 % added to 10 ml lignocaine.
 0,1 ml NaHCO3- 8,5 % added to 10 ml bupivacaine (precipitates if too alkaline)
Additives to local anaesthetic agents
3. Glucose
 With reference to spinal anaesthesia, local anaesthetic solutions are slightly
hypobaric (at body temperature) when compared to central spinal fluid (CSF), and
will tend to move upwards in the CSF away from the gravitational pull.
 Dextrose is added to the solution to make it “heavy” or hyperbaric, which will then
sink in relation to the CSF.
 This allows the anaesthetist to manipulate the distribution of the LA with the
knowledge of spinal curvatures and strategic positioning of the patient.
Additives to local anaesthetic agents
4. Additives with analgesic activity
 Once again with reference to neuraxial anaesthesia (spinals and epidurals); drugs
with analgesic activity can be added to the LA solution.
 These drugs have a synergistic effect improving both the quality and duration of
analgesia.
 Many different classes have been tried, and they work on their respective receptors
in the spinal cord: Opiates, ketamine, clonidine, midazolam, neostigmine and
adrenaline (as previously mentioned).
 Only opiates are used with any regularity in South Africa.
 The other drugs are not available preservative-free in SA, and some have
unacceptable side effects.
Local anaesthetic toxicity and management
 Toxic effects can occur in organs with excitable membranes. The BRAIN and HEART
are most at risk.
 Systemic toxicity is a rare, but catastrophic event; especially if a cardiac arrest is the
end result.
 Toxicity of the central nervous system (CNS) occurs first.
 Cardiovascular system (CVS) toxicity occurs due to the slowed myocardial
conduction and myocardial depression, plus peripheral vasodilatation (due to the
vascular smooth muscle relaxant effects of the LA).
 Cardiac toxicity is usually only evident clinically after 2 - 4 x the plasma
concentration required to cause a convulsion.
 Resistant ventricular fibrillation (VF) may occur with intravenous injection.
Local anaesthetic toxicity and management
Local anaesthetic toxicity and management
MANAGEMENT OF CNS TOXICITY
 STOP injecting the LA
 CALL FOR HELP
 ABCs
 Maintain the airway, and endo-tracheal intubation may be necessary. In the presence of a full stomach, intubation
is needed for airway protection
 Give 100 % oxygen (O2)
 Apnoea and convulsions result in hypoxia, hypercarbia and a metabolic acidosis.
 Confirm or establish venous access (but should have been sited before the block!!) •
 Control the convulsions: If seizure does not terminate spontaneously within 20 seconds, intravenous diazepam
(0,1 mg/kg), midazolam (0,1 mg/kg) or thiopentone (2 mg/kg) can be administered as anticonvulsants. Propofol
(1 - 2 mg/kg) is also effective (beware of haemodynamic instability)
 Assess cardiovascular status throughout.
 Hypotension: Give IV fluids and vasoconstrictors; start with ephedrine or phenylephrine. Use adrenaline if
unresponsive to these measures
Local anaesthetic toxicity and management
Management of a cardiac arrest/CVS toxicity
 Start CPR in line with standard protocols

 Bupivacaine induced ventricular fibrillation may require prolonged CPR due to the drug’s long duration of action
and slow dissociation from Na+ channels. It may respond to hyperventilation with O2 (to cause hypocarbia);
defibrillation (but may not be successful); Mg SO4 and Intralipid
 Intralipid 20 % (LipidRescue)

 IV bolus 1,5 ml/kg (100 ml for 70 kg patient) over 1 min, repeated every 3 - 5 min x 2

 Continue CPR

 Start infusion at 0,25 ml/kg/min, may increase rate to 0,5 ml/kg/min if necessary

 Maximum recommended total dose = 8 ml/kg.

 NB: Propofol (in 10 % Intralipid) is not a suitable substitute for Intralipid 20 %; as it is a CVS depressant;
unwanted in a situation of haemodynamic collapse and cardiac arrest)
 You should know where Intralipid is kept in each theatre complex

 Intralipid may also be used for CNS toxicity if unresponsive to routine measures
Local anaesthetic toxicity and management
 DIRECT NEURONAL TOXICITY
 CAUDA EQUINA SYNDROME
 Persistent neurological injury
 Associated with large concentrations of Lignocaine in spinal anaesthetics
 Probably not Na+ channel mediated, suggested mechanism include glutamate toxicity, O2 free
radicals and mitochondria injury
 TRANSIENT NEUROLOGICAL SYNDROME (TNS)
 Patients usually present within 24 hrs following complete recovery from an uncomplicated spinal
anaesthetic with marked dysasthesia in the buttock, leg or lower back pain
 The aetiology has been attributed to radicular irritation
 Risk factors include: lignocaine, lithotomy position, obesity and outpatient status
 Most will recover within 1 week
Local anaesthetic toxicity and management

MUSCULOSCELETAL TOXICITY
 All LA are myotoxic, but the potent long acting agents e.g. bupivacaine appears
more myotoxic than lignocaine
 Occurs with direct intramuscular injection, e.g. trigger point injection and retro
bulbar blocks
 Progresses from hyper contraction to vacuole formation, oedema and necrosis.
 Regeneration takes 3 – 4 weeks
Local anaesthetic toxicity and management
HEMATOLOGICAL TOXICITY
 Lignocaine reduces coagulation and enhances fibrinolysis
 Prilocaine is metabolized to orthotoline which oxidizes Hb to MetHb.
 When doses of prilocaine exceed 10mg/kg levels of MetHb results in clinical
cyanosis
 Treatment: methylene blue 1 – 2 mg/kg IVI over 5 min
Local anaesthetic toxicity and management
IMMUNOLOGICAL/ANAPHYLAXIS
 Anaphylactic reactions to local anaesthetics are very rare.
 It is the esters that are implicated more frequently than the amides.
 Esters are metabolised by plasma cholinesterase.
 The degradation product of ester metabolism is p-aminobenzoic acid (PABA); a
compound associated with IgE mediated hypersensitivity and anaphylaxis.
Local anaesthetic toxicity and management
PREVENTION OF TOXICITY
 Calculate proper dose and stay within limits
 Use test dose with adrenalin if indicated
 If large volumes are used, use drugs with low toxicity
 Good technique
 Slow injection and incremental dosing while maintaining contact with the patient o
 Always aspirate before injection
 High index of suspicion for toxicity
References
 MorganGE, Michail MS, Murray MJ. Clinical anaesthesiology. Fourth edition
 Dippenaar JM. Local anaesthetic toxicity. SAJAA 2007; 13(3): 23-28
 Butterworth J. Local anaesthetics: Agents, Additives, Mechanism and
misconceptions. ASA 2006; 132:1-4
 Thannikary L. Nerve conduction blocking drugs. FCA refresher notes 2007
 Hammerschlag C. Clinical pharmacology of local anaesthetic agents. Clinical
notes
THANK YOU 