LOCAL ANESTHETIC (LA) AGENTS

A SUMMARY OF KEY POINTS

 LAs block transmission of pain from nerve endings into the CNS.
 Chemically classified into esters & amides (depends on
intermediate chain between lipophilic aromatic ring & hydrophilic
amine group).
 Mode of action- primarily blockade of the fast voltage‐gated Na+
channels. The unionized fraction of the drug crosses the neuron
membrane & blocks the channel intracellularly.
 Duration of action and density of the block depend on both
volume & concentration of the agent used.
 Efficacy is influenced by pH, pKa, lipid solubility, protein binding &
length of the intermediate chain.
 Efficacy can be augmented by use of adjuncts e.g. epinephrine,
opioids, alpha 2‐adrenergic agonists (clonidine) and alkalinization.
 Toxicity is related to site of injection, vascularity & dose injected.
 Use of vasoconstrictors may reduce toxicity due to reduction in
systemic absorption.
 Racemic bupivacaine has highest affinity for Na+ channels & is
the most difficult to manage in case of systemic toxicity.
Basic structure of a neuron
Peripheral nerve  Epineurium- a cylindrical
sheath which forms the
outermost layer of a peripheral
nerve
 Fascicles- bundles of both
afferent and efferent fibers
contained in peripheral nerves.
 Perineurium- a dense layer of
collagenous connective tissue
which surrounds the fascicle
 Endoneurium-a layer of loose
connective tissue which
surrounds individual nerve
fibers within the fascicle
 Endoneurium houses the glial
cells, fibroblasts and blood
vessel capillaries, all integral to
the function of the nerve fiber.
 All these layers serve to
protect the nerve fibers and
also act as barriers to agents
acting on the nerves including
LAs.
  Neuron resting memb. potential −60 to
Propagation of an
action potential
−70 mV.
 Intracellular neuronal environment –ve
charged vs to extracellular.
 On excitation of nerve fibers, electrical
impulse propagates along the axon.
 A result of changes in adjacent
membrane, alternating from –ve to
+ve of around +50 mV due to rapid
influx of Na+ ions.
 At +50 mV, rapid efflux of K+ ions
occurs in an attempt to maintain
electrical neutrality of cell.
 To restore resting memb. potential,
Na+/K+ ATPase pumps Na+ out & K+
into the cell.
 Conduction of impulses occurs as small
brief, localized spikes of depolarization
cell memb. surface.
 Impulses unidirectional; depolarized
axonal memb. remains in refractory
state till resting potential restored by
theNa+/K+ATPase pumps
Chemical structure of LAs

Consist of a hydrophilic amine and a lipophilic aromatic ring

connected by an intermediate chain.
Structural bond in the intermediate chain determines
Classification as ester or an amide.
Pathway of metabolism of the compound; esters metabolized
by plasma pseudocholinesterases, amides metabolized in the
liver by the cytochrome family of enzymes.
Mechanism of action

Neutral
uncharged
molecules
diffuse through
membrane into
IC milieu, they
are re-ionized
by joining with
H+ ions & can
then block the
Na+ channels

 Block transmission of nerve impulses by reversibly blocking fast

voltage‐gated Na+ channels, inducing analgesia and anesthesia.
 LAs are weak bases formulated in an acidic milieu, thus contain
a larger proportion of the drug in the ionized state. The > acidity
= > ionized fraction.
 However, it is the unionized fraction that can cross the lipid
bilayer neuronal membrane & block Na+ channels from the inside
of the axoplasm.
 Blockade renders the Na+ channel inactive, hence, no further
conduction of impulses occurs.
Determinants of physiological activities of local
anesthetics
pKa: pH at which the number of ionized & unionized fractions
of the drug is in equilibrium. The << pKa, the >> the unionized
fraction is present for any given pH, hence faster onset of action.
pH: The << pH (i.e. acidic milieu), the << the potency because
in acidic conditions the ionized fraction predominates, thus <<
drug available to cross lipid bilayer & block Na+ channels.
This explains why LAs have less efficacy in reducing pain in
infected tissues like abscesses, pH of such tissues is <<<
than physiological pH of 7.4.
Lipid solubility: >> lipid soluble = higher potency, faster onset
of action & longer duration of action. More drug molecules able
to cross neuronal lipid bilayer & create a ‘depot’ of the drug
from within the axoplasm
Intermediate chain: Longer intermediate chain means >
potency. Bupivacaine has longer intermediate chain vs.
lidocaine. Bupivacaine x3-X4 >potent than lidocaine.
Protein binding: LAs with higher degrees of protein binding
have longer duration of action
Write short notes on two of the earliest discovered LAs still in
clinical use today

COCAINE & TETRACAINE

Specific local anesthetics
Cocaine
Earliest (1884) esters along with amethocaine (tetracaine) still
of clinical importance
First used in ophthalmic surgery and later in dental surgery.
Currently mainly used topically in ENT surgeries (conc. 4–10%).
Onset of action is fast and lasts 20–30 min.
Relatively contraindicated in hypertension & IHD, due to ability
to sensitize adrenergic receptors.
Concurrent use of adrenaline is contraindicated because
cocaine is a potent vasoconstrictor.
Amethocaine (tetracaine)
Still widely used in ophthalmology & as a cream to locally
anaesthetize venepuncture sites, esp. in the pediatric
population.
Onset of action relatively fast with a long duration of action.
Maximum dose of 1 mg/kg is recommended.
Least metabolized of ester LAs, hence possesses a higher risk
of toxicity..
Which two of the following local anesthetics are you more
likely to use at your local district hospital? Give examples of
procedures where they are commonly applied.
LIDOCAINE
BUPIVACAINE
ARTICAINE
BENZOCAINE
MEPIVACAINE
ROPIVACAINE
Lidocaine
First amide LA (1948).
Remains one of the most widely used anesthetics (can be used
IV, intrathecally, & as a local infiltration).
Class 1b antiarrhythmic drug.
Fast onset of action (pKa of 7.8, closer to physiological pH of
7.4), & is moderately water and lipid soluble.
Moderate duration of action, & least toxic of all amides (? due
to relatively low protein‐binding capacity of 64%).
Addition of adrenaline reduces its toxicity, allowing for higher
doses to be used for local tissue infiltrations.
Recommended doses: 3 mg/kg without adrenaline & 7 mg/kg
with adrenaline.
Concerns over neurotoxicity have made the drug less popular
for intrathecal usage.
Bupivacaine
Exists as levo and dextro enantiomer.
Racemic form (1963), levobupivacaine (1995).
pKa of 8.1 and a protein binding of 96% (latter makes
bupivacaine longest acting & most cardiotoxic if by accident
administered IV)
Wide use, yardstick for all other long‐acting LA.
“Differential sensitivity”.
 At low concentration, bupivacaine has the propensity for
sensory blocks while mildly sparing the motor blocks.
 This property allows for ‘walking epidural’ in labor
analgesia (reduced sensation & pain but without totally
blunting sensation).
Max. recommended dose 2 mg/kg with or without adrenaline
(there is only a modest increase in duration of action when
combined with a vasoconstrictor).
It is x3-x4 more potent than lidocaine, but onset of action
much slower (compare pKa)
Mepivacaine
Intermediate duration of action vs lidocaine and bupivacaine.
pKa of 7.6. Similar pharmacokinetic & dynamic properties with
lidocaine except some concerns of neurotoxicity in neonates.
Attractive properties: low rates of systemic toxicity, rapid onset &
dense motor block. Popular with shoulder surgery.
Ropivacaine
pKa of 8.2.
Chemical structure similar to both mepivacaine and bupivacaine.
A pure enantiomer (available as a pure levorotatory stereoisomer
only) & less cardiotoxic compared with racemic mixtures of other
LAs.
Better safety profile, preferred long‐acting LA for peripheral nerve
block anesthesia.
Also has motor block sparing properties. May provide advantage
over bupivacaine in spinal and epidural analgesia.
Despite safety profile, cardiovascular collapse reported with its
use, thus all standard precautions pertaining to use of Las are
encouraged.
•
Benzocaine
 Topical (alone or in combination with menthol or phenol)
 Gels, creams, ointments, lotions, aerosols, lozenges
 Relieve pain or irritation from sunburn, insect bites,
toothache, teething, cold sores or canker sores , fever
blisters.
 Can easily cross membranes into systemic circulation to
cause systemic toxicities. Not to be applied to abraded skin
 Contraindicated with sulfonamide antibacterial agents
(PABA derivative, as similar allergenic properties to
procaine)
Articaine
 Wide use in dentistry due to quick onset & short DoA (¼ of
lidocaine).
 Potency is approximately 1.5-fold of lidocaine.
 DOC for dental procedures, safer drug for regional
anesthesea vs other short-acting, amino amide–type Las
eg mepivacaine, lidocaine, or prilocaine.
 Local anesthetic toxicity
Observed at local tissue level and systemically.
A. Toxicity at local tissue level
a)Locally induced neurotoxicity
Can occur on neurons and myocytes and is time and dose‐
dependent.
May occur at clinical conc. levels when accidentally injected
intrafascicularly.
LAs packaged in conc. much higher than used clinically must
be diluted to reduce the risk of nerve toxicity.
The perineurium ( ‘blood‐nerve barrier’) protects the nerve
from chemical injury. Correct dilution of LAs will ensure that
drug conc. in the perineural & intraneural milieu is within
therapeutic range, avoiding neural damage
Lignocaine more prone to LA neurotoxicity than bupivacaine
(risk x 6.5 as high as bupivacaine) probably due to the
former's lower pKa, and hence, more unionised drug crosses
into the axoplasm.
Risk factors for locally induced neurotoxicity
1.Anesthetic factors
 Peripheral nerve blocking (Common in surgery on limbs or
face).
 Injection near specific nerve or nerve bundle.
 Site of injection
 Brachial plexus >> other blocks
 Intrafascicular >> extrafascicular injection (former directly
exposes the nerve fiber to high conc. of the drug)
2. Surgical factors: Tourniquets reduce blood loss & provide
favorable operative field but cause nerve compression & tissue
ischemia.
 Synergetic effect as far as LA neurotoxicity is concerned. .
 Compression of vasa nervorum by tourniquet use reduces
washout of LA, prolonging exposure of nerve fiber to the drug.
3. Patient factors
Pre‐existing neuropathies: diabetic peripheral neuropathy, Guillain‐
Barre syndrome, multiple sclerosis.
Peripheral vascular diseases: vasculitis, smoking, hypertension
affect microvasculature, can thus increase risk of ischaemia &
neurotoxicity.
 b) LA-induced muscle toxicity
Muscle damage after IM injection. >> pronounced with potent
& long‐acting LAs like bupivacaine.
Effects on skeletal muscle transient, full recovery within 2
weeks.
Tissue toxicity may result from preservatives used to maintain
stability of drug molecules in solution eg Sodium bisulphite in
chloroprocaine.
B. Systemic toxicity
Depends on plasma conc.(itself related to dose & site of
injection).
Either excessive dose or inadvertent IV injection.
CVS & CNS (more sensitive) are most affected systems.
Blood conc. required to produce toxic signs & symptoms is
lower for CNS than for CVS.
Thus, clinically, signs & symptoms of CNS toxicity appear
before those of the CVS.
Caution. CNS toxicity may be masked in patients having a
conscious sedation or full GA. CVS collapse may be only
manifestation of LA toxicity.
Main risk factors for systemic toxicity
Extremes of age (<4 months or > 79 years)
Pre‐existing heart conduction abnormality
Ischaemic heart disease
Renal dysfunction, Hepatic dysfunction
Pregnant women
Injection at a highly vascular site (e.g. Intercostal block).
• Which amide LA has a faster onset of action than lidocaine and
why?
• What would be the ideal local anesthetic?
• How is efficacy of LAs improved?