LOCAL ANAESTHETIC AGENT
By Dr Nur Hafizah binti Ibrahim
Moderator: Dr Najwa binti Mansor
OUTLINE OF PRESENTATION
•
•
•
•
•
•
•
•
Definition
History
Commercial Preparations
Structure-activity Relationships
Mechanism of Action
Minimum Concentration
Pharmacokinetics
Toxicity
DEFINITION
• A drug that produce reversible conduction blockade of
impulses along central and peripheral nerve pathways
after regional anesthesia, producing autonomic
nervous system blockade, sensory anesthesia and
skeletal muscle paralysis in the area innervated.
• Interruption of transmission of autonomic, somatic
sensory and somatic motor impulses.
• Removal of the local anesthetic is followed by
spontaneous and complete return of nerve conduction,
with no evidence of structural damage to nerve fibers
as a result of the drug’s effects.
HISTORY
• Cocaine
– 1st local anesthetic introduced by Kollar in 1884, for
use in opthalmology.
– It is a naturally occurring compound extracted from
leaves of Erythroxylon coca, a plant growing in the
Andes Mountains.
– Halsted recognized the ability of injected cocaine
to interrupt nerve impulse conduction, leading to
the introduction of peripheral nerve block
anesthesia and spinal anesthesia.
– Another unique feature of this drug is the ability to
produced localized vasoconstriction.
• 1st synthetic local anesthetic was the ester
derivative procaine, introduced by Einhorn in
1905.
• Lidocaine was synthesized as an amide local
anesthetic by Lofgren in 1943.
– It produces more rapid, intense and longer-lasting
effect that procaine.
– It is also effective topically and a highly efficacious
cardiac antidysarhythmic drug.
COMMERCIAL PREPARATIONS
• Poorly soluble in water – marketed most often
as water-soluble hydrochloride salt.
• These HCl salts are acidic (pH 6) – contributing
to the stability of LA.
• An acidic pH also important if epinephrine is
present in LA solution, because this
cathecolamine is unstable at alkaline pH.
• Sodium bisulphite (strongly acidic), may be
added to LA-ephephrine solutions to prevent
oxidative decomposition of epinephrine.
STRUCTURE-ACTIVITY RELATIONSHIPS
• Consist of a lipophilic and a hydrophilic portion
separated by connection hydrocarbon chain.
• Lipophilic group:
– usually unsaturated aromatic ring such as
paraaminobenzoic acid.
– Essential for anesthetic activity
• Hydrophilic group:
– Usually a tertiary amine (diethylamine).
• A hydrocarbon chain (consist of ester or amide)
links both portion to produce delicate balance
between lipid solubility and water solubility
Basic structure
Classifications of LA
ESTER
• Procaine
• Tetracaine
• Amethocaine
• Cocaine
AMIDE
• Lidocaine
• Prilocaine
• Bupivacaine
• Articaine
• Mepivacaine
***If the local anesthetic has
two ‘i’s in its name, it’s an
amide
Properties of LA Agents
PROPERTIES
ESTERS
AMIDES
Metabolism
Rapid – plasma
cholinesterase
Less likely
Slow – hepatic
Allergic reaction
Possible – PABA
derivatives
Very rare
Stability in
solution
Breaks down in
ampules (heat, sun)
Very stable
chemically
Onset of action
Slow as a general rule
Moderate to fast
pKa’s
Higher than pH = 7.4
(8.5-8.9)
Close to pH = 7.4
(7.6-8.1)
Systemic toxicity
More likely
Physicochemical properties
• The chemical structure and physicochemical
characteristics of LA affect their clinical properties.
• Modification of the chemical structure (lengthening of
the hydrocarbon chain within critical length or
increasing the number of carbon atoms in the aromatic
ring or tertiary amine) may alter lipid solubility,
potency, rate of metabolism & duration of action
• In particular, these are modified by:
– Lipid solubility
– Protein binding
– Dissociation constant (pKa value)
• Lipid solubility
– Lipid solubility of diff anesthetics governs their ability
to penetrate perineuronal tissues and neural
membrane, and reaches their site of action in
neuroplasm
– More lipid soluble  penetrates membrane more
easily, less molecule requires for nerve conduction
blockade i.e. more potent
– E.g. Bupivacaine, levobupivacaine and ropivacaine are
app 3-4x as potent as lidocaine or prilocaine due to
differences in their lipid-solubility
• Protein binding:
– Tissue protein binding primarily affect the duration of
action of LA
• plasma protein binding > longer duration of action
– Plasma protein binding acts as depot
– Tissue receptor binding – removed at a slower rate
– Examples:
• Procaine is not extensively bound to tissue protein, has short
duration of action
• Bupivacaine, levobupivacaine & ropivacaine are extensively
bound to plasma and tissue protein --- prolonged effect
• Dissociation constant (pKa value)
– pKa is equal to pH at which the concentration of
ionized base and non-ionized base are equal.
– It can be used to calculate the proportion of 2
forms that are present in solution at diff pH values
pH = pKa + log 10 (BH+) / (B)
– For weak base,
(unionised ) / (ionised) = 10 (pH- pKa)
•
•
•
Is the most important factor affecting rapidity of
onset of action.
pKa value governs the proportions of LA that is
present in non-ionized form at physiological pH
values and therefore available to diffuse across
tissue barrier to its site of action.
LA with a pKa near physiological pH will have a
greater degree of unionized molecules → More
LA diffused across membrane → rapid onset of
action
MECHANISM OF ACTION
• Modulated-receptor theory
• Frequency-dependent blockade
• Guarded-receptor theory
• Membrane Expansion theory
• Surface-charge theory
Modulated-receptor Theory
• Bindings of LA is stereospecific and dependent
on the conformation state of the Na channel.
• 3 functional states:
– Activated, open
– Inactivated/refractory, closed
– Resting, closed
• LA has high affinity for the open and
inactivated closed state and low affinity for
the rested closed state.
• LA prevents transmission of nerve impulses
(conduction blockade) by inhibiting passage of Na ions
through ion-selective Na channels in nerve membrane.
• Na channel itself is a specific receptor for LA molecules.
• So, occlusion of open Na channel by LA molecules
contributes little to overall inhibition of Na
permeability.
• Failure of Na ion channel permeability to increase will
slows the rate of depolarization such that threshold
potential is not reached and thus an action potential is
not propagated
Frequency-dependent blockade
• Defines a situation where the more frequent
the channel are activated, the greater the
degree of block produced.
• During action potential, LA exhibit higher
affinity to receptor at Na channel.
• But when action potential is over, affinity is
less and some unbind.
• If another action potential (frequency) arrives
before all drugs unbound, and additional
increment of blocking will occur.
Guarded-receptor Theory
• The affinity towards receptor is constantly high
in contrast to first theory which depend on
conformational state of Na channel.
• However the access of LA to the receptor is
limited by channel.
Membrane expansion theory
• Lipophilic LA incorporated into lipid bilayer
causing a volume expansion & distortion to
the conformation of axonal membrane and
hence the Na channel resulting in its
inactivation.
• This is mediated by unionized forms.
Surface charge theory
• The protonated form of LA neutralized the
negative charge of membrane of the nerve
which resulting in hyperpolarizing the nerve.
MINIMUM CONCENTRATION
• Minimum concentration (Cm) of LA necessary to
produce conduction blockade of nerve impulses.
• It is analogous to the MAC for inhaled anesthetic.
• Influenced by:
–
–
–
–
nerve diameter (↑D ↑Cm),
Myelinated nerve ↑Cm
Frequency of nerve stimulation (↑F ↓Cm)
Tissue pH (↑pH ↓Cm)
• Differential Conduction Blockade:
– Is illustrated by selective blockade of preganglionic
sympathetic nervous system B fibers using low
concentration of LA.
– Slightly higher concentration of LA interrupt
conduction in small C fibers and small-and-medium
sized A fibers, with loss of sensation for pain and
temperature.
– However touch, proprioception and motor function
still intact.
– Sometimes misinterpreted as failure of LA in an
anxious patient.
PHARMACOKINETICS
•
•
•
•
Absorption
Distribution
Metabolism
Excretion
Absorption
• Influenced by :
– Site of administration
– Dosage
– Vasoconstrictor effect
– Pharmacologic characteristic of the drugs
– Patient’s factor  age, cardiovascular status and
hepatic function.
• Site of administration:
– Intravenous
– Mucuos membrane/trachea
– Intercostal block
– Caudal block
– Epidural block
– Brachial plexus block
– Peripheral nerve block
– Subcutaneous infiltration
fastest
slowest
• Dosage
– Blood level of LA is related to total dose of drug rather
than specific volume or conc of solution
– Linear relationship between total dose & peak blood
concentration achieved
• Patient’s factor
– In pregnancy ↑ LA effect d/t ↓ protein binding
– In abscess ↓ LA effect d/t more ionized fraction in acidic
pH
– In hyperkalemic state ↑ LA effect d/t more inactive
channel
• Vasoconstrictor effect:
– Vasoconstriction at site of injection
– ↓ rate of absorption, ↓ Systemic toxicity, ↑ duration
of action
– By addition of adrenaline 5μg/ml (1:200 000)
– Higher Dosage offers no additional benefits but
increases symphatomimetic activites
– Ropivacaine & Cocaine has intrinsic vasoconstrictor
activities
– Lignocaine, mepivacaine, bupivacaine, etidocaine
exhibit vasodilator effects
• all local anesthetics possess some degree of
vasoactivity; most producing some level of
vasodilation
• ester local anesthetics are potent vasodilating
drugs
• Procaine (Novocaine) possesses tremendous
vasodilating abilities which are employed to
halt arteriospasm (accidental IA injection)
Specific properties of the drugs
↑ Lipid solubility
reduce rate of
absortion
Degree of
ionization
reduced protein
binding
↓ pKa
↓ molecular
weight
Distribution
• Depends on organ uptake, which determined
by:
– Tissue perfusion
– Tissue/blood partition coefficient
– Tissue mass
– Lung extraction
– Placental transfer
• Tissue perfussion:
– highly diffuse organ (brain, lungs, liver, kidney & heart) are
responsible for initial rapid uptake
– Followed by slower redistribution to moderately perfused
tissue (muscle & gut)
• Tissue/blood partition coefficient
– strong plasma protein binding eg Bupivacaine, tends to
retain LA in the blood
– Influence by changes in concentration of alpha1 acid
glycoprotein (eg; pregnancy, old age, concurrent liver
disease)
– high lipid solubility; facilitates tissue uptake
• Tissue mass:
– muscle provides greatest reservoir for LA agents
d/t its large mass
• Lung extraction:
– First pass pulmonary extraction esp lidocaine,
bupivacaine & prilocaine.
– Limit the concentration of drug that reaches
systemic circulation for distribution to the
coronary and cerebral circulation.
• Placental transfer:
– Highly plasma protein binding LA limits diffusion
across placenta
– Esters undergo rapid hydrolysis hence not available for
transfer across placenta
– Acidosis in fetus, which may occur during prolonged
labour, can result in accumulation of LA molecules in
the fetus (ion trapping)
– This results in an accumulated concentration of drug
in the fetus for two reasons.
• once the drug becomes ionized it cannot readily diffuse back
across the placenta. This is known as ion trapping.
• a concentration gradient of nonionized drug is maintained
between the mother and the fetus.
Ion trapping
• Fetal blood is slightly more acidic than
maternal blood, with a pH about 0.1 unit less
than maternal blood pH.
• The lower pH of fetal blood facilitates the fetal
uptake of drugs that are basic.
• Weakly basic drugs, such as local anesthetics
and opioids, that cross the placenta in the
nonionized state become ionized in the fetal
circulation
Metabolism
Metabolism of ESTER
• Undergo hydrolysis by cholinesterase enzyme, in
the plasma and liver
• Rate of hydrolysis varies, and resulting
metabolites are pharmacologically inactive
• PABA may be associated with allergic reaction
• Systemic toxicity is inversely propotional to the
rate of hydrolysis
• In SAB, in view of lack of cholinesterase enzyme
in cerebrospinal fluid, so the termination of
action of intrathecal LA depends on absorption
into the blood stream.
• Prolonged in neonates, liver dysfunction,
↑BUN, parturient and atypical plasma
cholinesterase homozygotes activity only
~50% in the newborn and doesn’t reach adult
values until about 1 yr
Metabolism of AMIDE
• Metabolized by microsomal enzyme located
primarily in the liver.
amide base
aminocarboxilic acid + cyclic aniline derivative
↓
↓
N-dealkylation
hydroxylation
• The rate of metabolism are more slower and
complex as compared to ester
• Systemic toxicity are more likely.
• initial reaction N-alkylation subsequently
hydrolysis
– exception to Prilocaine
– hydrolysis take place first forming o-toluidine
– further metabolized to 4 and 6-hydroxytoluidine
– o-toluidine responsible in metHb in high doses
• Benzocaine also can cause metHb
• Rx: methylene blue ( Fe3+ Fe2+ )
COCAINE
• an alkaloid derived from leaves of
Erythroxylon coca
• at low dose :
– produces a feeling of well-being and euphoria
– BRADYCARDIA d/t central vagal stimulation
– block uptake of noradrenaline results
vasoconstriction and mydriasis
• At higher dose:
– stimulates vomiting center
– central and peripheral sympath stimulation
• tachycardia
• ↑ capacity muscular work
– eventually causes
•
•
•
•
•
•
Convulsion
coma
myocardial depression
medullary depression
respiratory depression
VF and DEATH
• cocaine blocks conduction when applied directly to
nerve tissue & may therefore be used in surface
anesthesia
• cocaine was used in the past for ophthalmological
procedures, however has now been abandoned
• due to sloughing of the corneal epithelium & increased
intraocular pressure
• the only use today is as a topical local anaesthetic in
ENT (5%)
• cocaine itself constricts blood vessels and the use of
adrenaline is contraindicated as it sensitizes the
myocardium
Chloroprocaine
• Chloroprocaine is halogenated Procaine with additional
chlorine atom
• short duration of action d/t ↑ 3-4 x rate of metabolism
• low toxicity
• less allergenic compare to procaine
• rapid onset
• is a halogenated derivative of procaine and has
similar pharmacological properties
• the rapid plasma hydrolysis results in a short
duration of action and low toxicity (potency = 1.0)
• onset of action is ~ 6-12 mins and the duration ~
60 mins, depending upon the administered dose
• maximal recommended doses are 1000 & 800
mg, with and without adrenaline
• it is ineffective for topical anaesthesia but
suitable for infiltration, or peripheral nerve block
in a 1.0% solution
• the low toxicity, short duration, rapid metabolism
and low foetal:maternal blood partitioning make
it a suitable choice in obstetrics
• suspected neural toxicity with epidural/spinal
administration actually related to the addition of
sodium bisulphite to the adrenaline containing
solutions
• this was enhanced by the low pH of the solution
and the limited buffering in the subarachnoid
space
Tetracaine
• this is also an ester of PABA but is a potent, long acting
agent which is hydrolysed at a much slower rate
• its actions are similar to those in this group
• suitable for spinal anaesthesia, hypo & hyperbaric, in a
1.0% solution when the dose ranges from 5.0 to 20 mg
• onset of action is ~ 10 mins and the duration of action
60 to 90 mins
• maximum recommended dose is ~ 100 mg for a 70 kg
male
• NB: this is a useful agent when the amide agents are
contraindicated
Lignocaine
• Etidocaine derived from Lignocaine
subtitution of ethyl group make it 50x more
lipid soluble ↑2-3x duration of action (more
longer than Bupi)
• Structure – Amide LA; derivative of
diethylaminoacetic acid
• Presentation – Clear aq solution lidocaine
hydrochloride
– Plain 0.5% (local infiltration) 1%, 2%(nerve blocks,
extradural anaesthesia)
– with adrenaline 1:200 000
– Gel 2% with or without chlorhexidine
– 4% aq solution for topical application to pharynx,
larynx, trachea
– 10% spray for oral cavity & upper resp tract
• Recommended max dose 3mg/kg (7mg/kg
with adrenaline)
• Acute ventricular dysrhythmia (class 1) –
1mg/kg over 2 min followed by infusion
4mg/min (1st hr), 2mg/min (2nd hr) &
subsequently 1mg/min.
• Reduce stress response – 1-2mg/kg IV 5min
before intubation
• Clinically:
– acts in 2-20min; duration 60-120min depending
on conc, vasoconst
– CVS  therapeutic & toxic effect
– RS  bronchodilation in subtoxic dose
• Pharmacokinetic
MW
pKa
Part coef
234
7.9
2.9
• Absorption – bioavailability by oral route is 24-46%
due to high extraction & 1st pass hepatic metabolism
• Distribution
Prot bind
Vd
70%
0.75-1.5L/kg
• Metabolism – 70% metabolised in liver by Ndealkylation to MEGX, GX with further
hydrolysis prior to renal excretion
• Excretion - <10% excreted unchanged
• Cl – 6.8-11.6ml/kg/min t½ - 90-110min
Bupivacaine
has butyl (C4H9) group to the
piperidine N2, makes it more potent 35 times
and longer action 3-4 times compare to
Mepivacaine (methyl – CH3)
•
Structure – amide LA, pipecoloxylidide group,
racemic
• Presentation – clear colourless, aq solution
(bupivacaine hydrochloride )
– Plain (0.25%, 0.5%, 0.75%)
– With 1:200 000 (5µg/ml ) adrenaline
– Heavy 0.5% with 80mg/ml dextrose (SG 1.026)
• Recommended max dose 2mg/kg (150mg plus
up to 50mg 2 hourly subsequently)
• Clinical - acts within 10-20min and almost
immediate with intrathecal admin, duration of
action 4-8hrs. 4X as potent as lignocaine
•
•
•
•
•
•
Pharmacokinetics
MW
pKa
Part coef
288
8.1
27.5
Absorption addition of adrenaline does not influence rate
of systemic absorption
Distribution :
Prot bind
Vd
95%
1L/kg(41-103L)
Metabolism  liver microsomal enzymes P450 to 2,6Pipecoloxylidine (N-deakylation), N-desbutyl bupivacaine &
4OH bupivacaine also formed
Excretion  5% excreted as PPX, 16% excreted unchanged in
urine
Cl : 0.47L/m
t½ : 0.31-0.61Hr (after IV admin)
• postoperative analgesia can be maintained for
3-4 hours with epidural blockade
• peak plasma levels following caudal or epidural
administration are reached within 30-45
minutes, followed by decline over 3-6 hours
• although more toxic, a lower foetal/maternal ratio has been
observed cf. other agents
• thus, bupivacaine is the recommended for obstetric
analgesia/anaesthesia, with the exception of paracervical
block
• however, caution should be used with repeated doses
• similarly, renal disease is unlikely to affect bupivacaine
clearance in the short term (~ 24 hrs),
• however, toxicity may result with prolonged or repeated
administration
Levobupivacaine
•
•
•
•
Levobupivacaine is S enantiomer of Bupivacaine
Less cardio and CNS toxicity
Less vasodilation
13% Less potent than bupivacaine
• less prolonged motor blockade but longer sensory
blockade after epidural administration
Ropivacaine
ropivacaine is single-enantiomer structurally
resemble of Bupi/Mepivacaine with propyl (C3H7)
group to the piperidine N2 atom
• Ropivacaine is pure S-enantiomer of Bupivacaine
• It’s potency, onset time and duration of action
almost identical to bupivacaine
• less motor block
• larger therapeutic index
• 70% less cardiotoxic contribute fr its lower LIPID
SOLUBLE and its availability as S-isomer.
• Structure – Amide LA, pipecoloxylidide group,
pure S-enantiomer
• Presentation – Clear colourless solution
containing 0.2/ 0.75/ 1.0% ropivacaine
hydrochloride
• Recommended dose – 3.5mg/kg, 250mg
(150mg for C-section under epidural),
Cummulative dose 675mg over 24h according to
data so far; not currently intended for
intrathecal admin and in children < 12 years
• Clinical – sensory blockade similar in time
course to that produced by bupivacaine; motor
blockade is slower in onset & shorter in
duration than after an equivalent dose of
bupivacaine; less cardiotoxic than bupivacaine;
Intrinsic vasoconstrictor, mild CNS Sx
• Pharmacokinetics
MW
274
• Distribution :
Prot bind
94%
pKa
8.1
Part coef
6.1
Vd
0.8L/kg (52-66L)
• Metabolism  occurs in liver to 2,6 pipecoloxylidine (Ndeakylation), Aromatic hydroxylation to 3 & 4OH ropivacaine
• Excretion  86% (mostly conjugated) excreted in the urine,
1% unchanged
Cl – 0.82L/m
t½ - 59-172min
Prilocaine
• Prilocaine (CITANEST)
• equipotent to lignocaine with a longer
duration of action and lower toxicity
• rapid plasma hydrolysis makes it the agent of
choice for regional IV blockade
• causes methaemoglobinaemia in high doses
but this is rarely clinically significant
• used in all types of anaesthesia in similar
concentrations to lignocaine
Mepivacaine
• used for infiltration, nerve block, caudal &
epidural anaesthesia but is ineffective topically
• similar potency and onset to lignocaine but
slightly longer duration of action
• used in similar concentrations to lignocaine
• not recommended for obstetric use due to high
foetal:maternal ratio
Etidocaine
• is a long acting derivative of lignocaine, with much
higher lipid solubility and protein binding
• it is ~ 2-3 times more potent than lignocaine but less
toxic than bupivacaine
• effective in infiltration, nerve block, epidural &
caudal anaesthesia
• results in a high degree of motor blockade when
administered into the epidural space
EMLA
• eutectic mixture of local anaesthetics is a 5%
mixture of lignocaine (25 mg/g) &prilocaine
base (25 mg/g)
• CONTACT TIME AT LEAST 1 HOUR
• Duration of action 1-2 hr
• Typically 1-2g applied to 10cm² area of skin
maximum 2000cm² in adult and 100cm² for
child <10kg
TOXICITY
• Occur due to excessive plasma and tissue
concentrations of the LA.
• Common cause include accidental
intravascular injection and overdose.
The relationship between lignocaine and plasma
concentration and pharmacological effects
Signs of toxicity
BEGIN with numbness of the tongue/circumoral tissue
restless,vertigo,tinnitus,dizziness
slurred speech,
skeletal ms twitching (face &
extrimities)
seizure-tonic-clonic
drowsiness
hypotension & apnea
ASYSTOLE
CNS toxicity
• A relatively small dose (5 to 10ml lignocaine
1%) may cause ringing in the ears, a metallic
taste in the mouth, numbness of the tongue,
blurring of vision, drowsiness with decreased
awareness, muscular twitching, restlessness
and apprehension.
• With a larger dose, delirium may ensue and
progress to grand mal convulsions.
• Asphyxia may develop if the convulsions are
not treated rapidly and adequately.
Cardiovascular toxicity
• In general LA depress myocardial automaticity
• LA also ↓ duration of refractory period
• At higher dose LA depress contractility and
conduction velocity
• Prolongation PR and QRS interval on ECG
• Myocardial depressant and vasodilatation lead to
HYPOTENSION
• Cardiac dysrhythmia or circulatory collapse is
often the presenting sign of LA overdose during
GA
• Lignocaine is a less potent LA as compared to
bupivacaine or ropivacaine and a higher dose is
required to cause cardiovascular and CNS toxicity. The
ratio of the dosage required for irreversible
cardiovascular collapse (CVS) and the dosage that will
produce CNS toxicity (convulsions), i.e. the CVS/CNS
ratio, is lower for bupivacaine than for lignocaine.
• CVS/CNS dose ratio:
– lignocaine 7.1
– bupivacaine 3.7
• This indicates that 7 times as much lignocaine is
required to induce irreversible CVS collapse as is
needed to produce convulsions
Treatment of LA toxicity
• Depends on severity, minor reaction - resolve
spontaneously
• If seizures – protect airways, abort the seizures
by midazolam, thiopentone, propofol
• If cardiac arrest - follow ACLS
• IF NOT RESPONSIVE, intravenous lipid or
cardiopulonary bypass may be considered
Management of severe LA toxicity
by the Australian and New Zealand College of Anaesthetists (AN ZCA )
Intravenous 20% lipid emulsion
• Was invented by Dr Weinberg, 1998
• Rosenblatt 2006, first published rescue
• Officially promoted as a treatment in Irelend
and British
• The mechanism is not clear yet
• it serve as lipid sink which capture the LA
molecules making then unavailable to tissue
• Changes during pregnancy:
– Increased sensitivity (more rapid onset of conduction
blockade) may be present during pregnancy.
– Alteration in protein-binding characteristics of
bupivacaine may result in increased concentration of
pharmacologically active unbound drug in the
parturient’s plasma.
– Nevertheless, progesterone, which binds to the same
alpha1-acid glycoprotein as bupivacaine, does not
influenced protein binding of this LA.
– This evidence suggest that bupivacaine and
progesterone bind to discrete but separate sites on
protein molecules.