Download Local anaesthetics

Local anaesthetics
(dr. P. Sobczynski)
Local anaesthetics (LA) are drugs that produce reversible blockade of conduction of nerve impulses. With
progressive increases in concentrations of local anaesthetics, the transmission of autonomic, somatic sensory, and
somatic motor impulses are interrupted producing specific effects such as:
 sensory blockade
 autonomic nervous system blockade
 skeletal muscle paralysis
Subsequent recovery of nerve conduction occurs spontaneously and there is no evidence of structural damage to
nerve fibres.
Chemistry and structure - activity relationship
Local anaesthetics consist of a lipophilic and hydrophilic portion separated by a hydrocarbon- connecting chain. The
hydrophilic group is usually a tertiary amine. The lipophilic portion is usually an unsaturated aromatic ring (e.g. paminobenzoic acid). To exert clinically useful effect there should be a delicate balance between lipid solubility and
water solubility . In general the increase in lipid solubility produces the block of higher potency and duration of
action. The linkage between hydrocarbon chain to the aromatic ring is an ester or amide bond. The chemical nature
of this bond is the basis for classifying agents as ester local anaesthetics or amide local anaesthetics. The main
differences between those two groups relate to the metabolism - ester LA undergo rapid hydrolysis in plasma while
amide LA are degraded at the slower rate in the liver.
Local anaesthetics are poorly soluble in water and are, therefore marketed as water-soluble highly ionised
hydrochloride salts. These hydrochloride salts are acidic (pH 4.0-6.0) which contributes to their stability. Acidic pH
is also important if epinephrine is added to the solution of LA, as this catecholamine is not stable in alkaline pH.
After injection, the salts are buffered in the tissue to physiologic pH, providing sufficient non-ionised form of local
aesthetic for diffusion through axonal membranes. This uncharged form of LA, being lipid-soluble is very important
for rapid penetration across the nerve cell membrane. Conversely the ionised form of the drug is believed to be the
most active at the receptor site, which is accessible only from the interior of the cell.
Modification of the chemical structure alters the pharmacologic effect of local aesthetic molecule. For example,
increasing the number of carbon atoms on tertiary amine or aromatic ring results in a drug with different lipid
solubility, potency, rate of metabolism and duration of action. Typical example is tetracaine, which is procaine with
the addition of a buthyl group. Compared with procaine, tetracaine is ten times more potent, and has a longer
duration of action corresponding to a four-fold reduction in the rate of metabolism.
Mechanism of action
Local anaesthetics inhibit transmission of nerve impulses (conduction blockade) by preventing increases in
permeability of nerve membranes to sodium ions. Failure of permeability to sodium ions to increase slows the rate of
depolarisation such that threshold potential is not reached and action potential is not propagated.
The exact site of action of a local anaesthetic is voltage-dependent sodium channel in a nerve axon. Sodium channels
exist in activated-open, inactivated-closed, and rested-closed states during various phases of the action potential.
During each action potential, sodium channels cycle from rested-closed to activated-open to inactivated-closed
states. Sodium channels in the rested-closed state have low affinity for LA while the inactivated-closed configuration
has higher affinity. Local anaesthetics preferentially bind to the sodium channels in inactivated-closed states and
stabilise these channels in this configuration. This prevents their change to rested-closed and activated-open states in
response to nerve impulse. Sodium channels in the inactivated-closed state are not permeable to sodium ions and
thus conduction of nerve impulses in the form of action potential cannot occur.
Pharmacokinetics
Absorption
Absorption of LA from its site of injection into the systemic circulation depends on several factors such as:
- site of injection - vascularity of the area affects the rate of absorption
- use of epinephrine - vasoconstriction caused by epinephrine limits the rate of absorption
- pharmacologic characteristics - various drugs differ in their tissue-binding capacity
During regional anaesthesia maximum blood levels of LA decrease according to site of administration:
intercostal (highest) > caudal > epidural > brachial plexus > sciatic nerve (lowest)
Distribution
Amide local anaesthetics are widely distributed in the body. Initial rapid distribution phase is due to the massive
uptake into highly perfused organs such as the brain, kidneys, heart, and liver. This is followed by slower
distribution phase into moderately well perfused organs such as muscle and gut. Sequestration can occur in storage
sites, possibly fat tissue. Moreover the lunge is capable of extracting local anaesthetics, notably lidocaine,
bupivacaine, and prilocaine, from pulmonary circulation. This effect can limit the amount of anaesthetic reaching
coronary and cerebral circulations. However this first-pass pulmonary extraction becomes saturated very rapidly.
Ester local anaesthetics have not been studied with regard to distribution because of rapid breakdown in plasma.
Studies concerning distribution at the nerve fibre level indicate that only very small fraction of LA penetrates the
fibre.
Metabolism and excretion
Amide local anaesthetics undergo varying rates of metabolism by microsomal cytochrome P450 in the liver, in
which amide linkage is hydrolysed. Prilocaine undergoes the most rapid metabolism, lidocaine and mepivacaine are
intermediate, while the rate of breakdown of bupivacaine and etidocaine is the slowest among amide LA.
Ester local anaesthetics are rapidly hydrolysed in plasma by pseudocholinesterse. Compared with ester local
anaesthetics the amide local anaesthetics are metabolised slower and more complex. Hence the toxicity and drug
accumulation are more likely with amide local anaesthetics.
The rate of metabolism can affected by the following factors:
- Liver dysfunction
- Reduction in hepatic blood flow
- The concomitant use a drug that is metabolised by the same p450 isoenzyme.
The metabolites of local anaesthetics are more water-soluble and can then be excreted in the urine. Acidification of
the urine can further augment renal elimination by increasing the ionised, water- soluble fraction of the local
anaesthetic.
Pharmacodynamics
Differential nerve blockade
Local anaesthetics are capable of blocking all nerve fibres. However, different types of nerve fibres differ
significantly in their susceptibility to local anaesthetic blockade. This is mainly due to the size and myelination of
the nerve fibre (table 1).
Differential nerve blockade is illustrated by selective blockade of preganglionic sympathetic B fibres with low
concentrations of LA. Slightly higher concentration of LA interrupts conduction in small C fibres and small- and
medium sized A fibres with loss of sensation for pain and temperature. However touch, proprioception and motor
function can persist in some types of regional blocks such that patient will sense pressure but not pain with surgical
stimulation.
Table 1
Physiologic aspects of differential nerve blockade
Fibre type
Type A
Alpha
Beta
Gamma
Delta
Type B
Type C
Dorsal root
Sympathetic
Function
Proprioception, motor
Myelination
Heavy
Sensitivity to block
+
Touch, pressure
Muscle spindles
Pain temperature
Preganglionic
autonomic
Pain
Heavy
Heavy
Heavy
Light
++
++
+++
++++
None
++++
Postganglionic
None
++++
Systemic toxicity
Systemic toxicity of local anaesthetics is due to an excess plasma concentration of the drugs. Inadvertent
intravascular injection of LA solutions during performance of the block is the most common mechanism responsible.
Systemic toxicity of local anaesthetics involves the central nervous system and cardiovascular system
Central nervous system
Clinical picture is related to blood level of a local anaesthetic. Initially the increasing concentrations of local
anaesthetic in blood will produce excitatory phenomena such as numbness of the tongue and circumoral area,
restlessness, blurred speech, visual disturbances, and muscular twitching which usually signals the onset of seizures.
Signs of CNS depression, such as coma and apnoea, classically follow seizures.
Cocaine in high doses produces tremors, seizures, tachycardia, vasoconstriction, and elevation of body temperature.
This is due to the inhibition of norepinephrine uptake in the peripheral and central nervous systems. The pyrogenic
nature of cocaine probably reflects a direct action on heat-regulating centres in the central nervous system.
Treatment
Immediate treatment involves immediate provision of supplemental oxygen to prevent hypoxia. Diazepam (0.1
mg/kg) is effective in controlling muscle twitching and seizures. Seizures can also be treated with thiopental (1-2
mg/kg). In severe cases seizures have to be terminated with suxamethonium, which allows endotracheal intubation
and hyperventilation of the lungs.
Treatment of cocaine overdose includes administration of alpha- and beta-adrenergic antagonists to relieve
symptoms of excess sympathetic stimulation.
Cardiovascular system
The CVS is more resistant to the toxic effects of LA than CNS. Hypotension is initially due to relaxation arteriolar
smooth muscle and direct myocardial depression (blockade of cardiac sodium channels). Adverse cardiac changes
are especially dangerous after administration of bupivacaine (dissociation of highly lipid soluble bupivacaine from
cardiac sodium channels is very slow). Circulatory collapse is usually the result of direct cardiovascular depression
and acidosis due to the period of apnoea.
Treatment
- massive fluid resuscitation (intravenous fluids)
- vasopressors (dopamine, adrenaline)
- treatment of ventricular arrhythmia (electrical cardioversion, bretylium)
- Cardiopulmonary cerebral resuscitation following cardiac arrest (can be prolonged, massive doses of adrenaline
and atropine usually required).
Best measures to avoid the problem are meticulous attention to detail when performing local block and to follow
recommendations regarding maximum doses in any clinical situations.
Table 2.
Maximum doses of local anaesthetics
Agent
Plain
With adrenaline
mg /kg
Over 24 h
2 – chlorprocaine
800 mg
1000 mg
-
-
Prilocaine
600 mg
600 mg
-
-
Lidocaine
300 mg
500 mg
3 mg/kg
-
Bupivacaine
175 mg
225 mg
2.5 mg/kg
400 mg
Ropivacaine
225 mg
-
-
800 mg
Clinical uses of local anaesthetics
Local anaesthetics are commonly used to produce:
 topical anaesthesia - achieved by placement of local anaesthetic on the mucous membrane of the nose, mouth,
tracheobronchial tree or genitourinary tract.
 local infiltration - achieved by extravascular placement of local anaesthetic in the area to anaesthetise. The
duration of infiltration anaesthesia may be doubled by addition of adrenaline to the solution of local anaesthetic
wit exception of tissues supplied by end-arteries.
 peripheral nerve block anaesthesia - achieved by injection of local anaesthesia in the vicinity of peripheral nerves
or nerve plexuses.
 intravenous block - achieved by intravenous injection of a local anaesthetic into an extremity isolated from the
rest of circulation by a tourniquet.
 epidural block - achieved by injection of a local anaesthetic into epidural space.
 subarachnoid block (intrathecal anaesthesia) - produced by injection of a local anaesthetic into the lumbar
subarachnoid space.
Lidocaine (Lignocaine, Xylokaine)
 Amide-type local anaesthetic
- pKa 7.9
- elimination half-time 96 min
- rapid onset
- duration of action:
plain 1% sol.
1hr
plus epinephrine 2.5hr
 Clinical uses
- local anaesthetic:
0.25-0.5% sol. - infiltration (intradermal, subcutaneous)
4% sol.
- topical (ENT, corneal anaesthesia)
2% jelly
- urethral anaesthesia
5% jelly
- tracheal tubes
1.5 - 2% sol. - peripheral nerve blocks, epidural anaesthesia
5% heavy
- spinal anaesthesia
- antiarrhythmic agent
- anticonvulsive agent (1-2ug/kg), but toxic level >5 ug/ml!
- agent controlling intracranial pressure
- intravenous analgesic (abandoned)
Bupivacaine
(Marcaine, Carbostesin)
 Amide-type local anaesthetic
- pKa 8.1
- elimination half-time 210 min
- slow onset
- duration of action:
0.25-0.5% - 4 - 8 hr (epinephrine does not greatly prolong but reduces toxicity )

Clinical uses
- local anaesthetic:
0.125-0.25%
0.25-0.5%
0.5% heavy
- infiltration (intradermal, subcutaneous )
- peripheral nerve blocks, epidural anaesthesia
- spinal anaesthesia
*Contraindications - intravenous regional anaesthesia (Bier’s
block)
Local anaesthetics suitable for injection
Ester-type
 Procaine (Novocain)
- low potency, short duration
- currently used for infiltration and nerve blocks
 Chloroprocaine (Nasacaine)
- ultra-short duration of action
- epidural anaesthesia
 Tetracaine (Pontocaine)
- more potent and longer duration of action than procaine
- spinal anaesthesia
Amide -type
 Mepivacaine (Carbocaine)
- pharmacological profile similar to lidocaine
- less vasodilatation, anaesthesia lasts longer
 Prilocaine (Citanest)
- less vasodilatation
- increased volume of distribution hence less toxic
- drug of choice for IVRA
- the risk of methemoglobinemia especially with a total dose exceeding 600 mg (Treatment: methylene blue 1-2
mg/kg)
 Etidocaine (Duranest)
- chemically related to lidocaine
- pharmacological profile similar to bupivacaine but:
- better motor block
- faster onset
 Ropivacaine - new investigational drug
- pharmacological profile similar to bupivacaine
- less cardiotoxic than bupivacaine
- onset and duration of sensory block similar to bupivacaine
- motor block slower in onset, shorter in duration and less intense than with bupivacaine
Local anaesthetics largely restricted to ophtalmological use
 Proparacaine (Alcaine, Ophtaine)
 Tetracaine (Pontocaine)
- good tolerance
- no allergic complications
- retarded healing with long-term administration (not for self-administration)
Topical LA (to anaesthetise mucous membranes and skin)


EMLA - eutectic mixture of local anaesthetics (prilocaine and lidocaine) - to anaesthetise the skin before
venipuncture
Benzocaine - low solubility (only to provide anaesthesia of oral and pharyngeal cavities)