2.1 Local Anaesthetics Flashcards
Local anaesthetics (LAs) work by
used
`
Reversible Na+ channel blockers
used clinically to produce neuraxial anaesthesia
What was the first LA
used by who
Who isolated this
What was its first clinical use
What was the first synthetic LA
invented when
The use of leaves of coca plant
(Erythroxylon coca) for topical anaesthesia
was known to Incas.
In 1859, Albert Niemann isolated the
chief alkaloid of coca,
which he named ‘cocaine’.
In 1884, Carl Koller became the first
to use cocaine for ophthalmic anaesthesia.
The first synthetic LA was benzocaine (1900).
Describe the structure
How are they classified
LA molecule consists of a
- hydrophobic aromatic ring
- hydrophilic tertiary amine group
held by a hydrocarbon chain
(with an ester or amide linkage),
hence classified as esters or amides.
https://www.bjaed.org/article/S2058-5349(19)30152-0/fulltext
Are LA acids or bases
Because the tertiary amine group
can bind a proton to become a
positively charged quaternary amine,
all LAs exist as a
weak acid– base pair in solution.
How does their structure affect its mechanism
This is most vital for LA action,
as it is the cationic species that binds
to the Na+ channel from inside the cell.
Which LA is different in structure
An exception to this is benzocaine, which lacks the tertiary amine
Name some other
chemicals / drugs / substances
that inhibit Na channels
Many chemicals inhibit Na+ channels including
adrenergic agonists tricyclic antidepressants general anaesthetics substance P inhibitors menthol and nerve toxins (saxitoxin, scorpion toxin and tetrodotoxin).
How do the nerve toxins differ from LA
The nerve toxins block the Na+ channel from the extracellular side
Properties of Esters
Bond Metabolism Potency Synthesis Allergic reaction Duration Toxicity Examples
Bond
Ester
Metabolism
Plasm esterases
Potency Generally less ( - tetracaine)
Synthesis
Manufactured first
Allergic reaction
Commoner cause of PABA
(para aminobenzoic acid)
Duration
Shorter
Toxicity Generally less ( - tetracaine / cocaine)
Examples Benzocaine Procaine Tetracaine 2-Chlorprocaine
Properties of Amides
Bond Metabolism Potency Synthesis Allergic reaction Duration Toxicity Examples
Bond:
Amide
Metabolism
Hepatic enzyme N-Dealkylation + Hydroxylation
Potency
More
Synthesis
Later
Allergic reaction
Rare
Duration
Longer
Toxicity
More
Examples Lignocaine Mepivacaine Prilocaine Bupivacaine Ropivacaine Levobupivacaine
What is a steroIsomer
Stereoisomerism describes those compounds which have the same molecular formula and chemical structure,
but a different three dimensional configuration.
Stereoisomers may be geometric or optical (enantiomers).
What is Geometric isomerism
Geometric isomerism
(or cis–trans isomerism)
describes the orientation of functional groups
within the molecule.
Such isomers typically contain double bonds
or ring structures,
where the rotation of bonds is greatly restricted.
Optical isomers have
Optical isomers have chiral centres,
eg - quaternary nitrogen
- carbon atom surrounded by diff chemical groups.
Chiral molecule,
- lacks an internal plane of symmetry.
These molecules have
non-superimposable mirror images,
imparting a particular type of stereoisomerism
called enantiomerism.
Non-superimposable mirror images
depending on the configuration exist
as R (rectus) and S (sinistra) isomers.
Chiral examples
Many substances in anaesthesia are chiral volatile anaesthetics, ketamine, thiopental local anaesthetics
Achiral examples 4
few anaesthetic substance are Achiral
sevoflurane,
lignocaine,
procaine,
tetracaine
What is Optical rotation
What are the types
Optical rotation (optical activity)
ability to turn the plane of linearly polarised light
about the direction of motion as the light
travels through a substance.
Pure enantiomers may be dextrorotatory (d), (+) or levorotatory (l), (–).
How can isomers be classified based on properties
Based on the above two properties isomers
can be referred to as
R(+) and R(–) or S(+) and S(–) isomers.
Non-superimposable mirror images
depending on the configuration exist
Non-superimposable mirror images
depending on the configuration exist
as R (rectus) and S (sinistra) isomers.
Racemic mixtures consist of
How do they effect light
Racemic mixtures consist of
equal amount of both enantiomers,
and
therefore do not rotate polarised light
in either direction.
Pure enantiomers may have differences
in absorption, distribution, potency, therapeutic
action and most importantly toxicity profiles (ropivacaine and levobupivacaine).
Non-racemic mixtures have
Non-racemic mixtures have
unequal amounts
of two enantiomers.
Pure enantiomers may have differences in
Pure enantiomers may have differences in
absorption,
distribution,
potency,
therapeutic action and
most importantly toxicity profiles
(ropivacaine and levobupivacaine).
The important physicochemical properties of LA x5
molecular weight (MW),
pKa (ionisation),
aqueous solubility,
lipid solubility
protein binding.
MW:
MW:
Addition of a butyl group to mepivacaine (MW 246) results in
formation of bupivacaine (MW 288).
This increase in molecular weight
results in
higher lipid solubility, i.e. partition coefficient (pKa), higher protein binding and higher potency.
pKa is
pKa:
is the pH at which half the LA molecules are in the base form and half in the acid form.
Most LAs have a pKa between 7.5 and 9.0
(weak bases).
How are LA supplied
what happens when they are injected into tissue
Because the LAs are supplied as unbuffered acidic solutions (salts of HCl) with pH of 3.5–5.0, the ionised form predominate.
On injection into tissues (pH 7.4),
the unionised form predominates and
enters the cell to produce Na+ blockade.
How does pKa affect speed of onset
The closer the pKa to the extracellular pH (7.4),
the higher the number of
unionised forms available
and the faster the onset of action.
Hence lignocaine with (pKa 7.7)
has faster onset
than bupivacaine (pKa 8.1).
Aqueous solubility
relies on
related to
Aqueous solubility:
It is the presence of the
tertiary amine group
that provides for ionisation
and hence aqueous solubility.
It is related directly to the extent of
ionisation and inversely to its lipid solubility.
What property of Benzocaine differentiates it
Benzocaine lacks an
ionisable amino group,
and
therefore has poor aqueous solubility,
restricting it to only topical use.
Lipid solubility
depends on
proportional to
Lipid solubility:
(sometimes wrongly called hydrophobicity)
dependent on the size of the
alkyl group on tertiary amine increasing with its size.
It is directly proportional to
- LA potency,
- duration of action
- and toxicity.
The distribution coefficient of LA is
The distribution coefficient of LA is
the ratio of concentration of LA in a mix of an aqueous buffer and a hydrophobic lipid (octanol) after separation.
The partition coefficient
The partition coefficient is the
distribution coefficient at pH of 7.4
(octanol : buffer 7.4).
Protein binding
proportional to
binds to which proteins
decreases with
In general,
lipophilicity is proportional to protein binding.
LA binds to both α1-acid glycoprotein \+ albumin, and this is pH-dependent,
decreasing with acidosis
increasing the amount of
free drug in acidic environment.
This lowers safety of LA in hypoproteinemic
conditions:
malnutrition,
nephrotic syndrome
cirrhosis.
6 Common features of local anaesthetics
Common features of local anaesthetics
Property Implication
1
Weak bases with pKa > 7.4
Free base has poor aqueous solubility
2
Available as acidic solutions (HCl salts)
Results in improved aqueous solubility
3
Exist in equilibrium of free base (unionised, lipid-soluble) and cationic (ionised, water-soluble)
This equilibrium can be shifted to either side by altering the pH of solution (hence adding HCO3 to LA increases the availability of free base)
4
Body buffers raise pH
This raises the amount of free base present; the closer the pKa to the extracellular pH (7.4), the faster the onset of action
5 Free base (lipid-soluble) crosses neural memranes Passes intracellularly to be ionised
6 Cationic moiety (water-soluble) is the active part It blocks the Na+ channel from the inside
Weak bases with pKa > 7.4
1
Weak bases with pKa > 7.4
=
Free base has poor aqueous solubility
Available as acidic solutions (HCl salts)
2
Available as acidic solutions (HCl salts)
=
Results in improved aqueous solubility
Exist in equilibrium of free base
and cationic
3
Exist in equilibrium of free base
(unionised, lipid-soluble) and
cationic (ionised, water-soluble)
=
This equilibrium can be shifted
to either side by
altering the pH of solution
(hence adding HCO3 to LA increases
the availability of free base
Body buffers raise pH
4
Body buffers raise pH
=
This raises the amount of free base present;
the closer the pKa to the extracellular pH (7.4),
the faster the onset of action
Free base (lipid-soluble) crosses neural memranes
Free base (lipid-soluble) crosses neural memranes
=
Passes intracellularly to be ionised
Cationic moiety (water-soluble) is the active part
Cationic moiety (water-soluble) is the active part
=
It blocks the Na+ channel from the inside
2-Chlorprocaine
type
potency
onse
duration
what use
2-Chlorprocaine is a congener of
procaine and thus an ester.
It has low potency,
a fast onset and
short duration of action.
It has been recently used for ambulatory surgeries under spinal anaesthesia.
Are most LAs chiral or achiral
are there exceptions 3
Most LAs are chiral, except lignocaine, procaine and tetracaine.
How do Ropivacaine and Bupivacaine differ
How does this affect their properties
Ropivacaine has a propyl group
in its tertiary amine,
while bupivacaine has a butyl group.
This probably explains
its lower potency,
lower lipid solubility
and lower toxicity than bupivacaine.
Are LA vasoconstrictors or dilators
is there any exceptions
All LAs are vasodilators
(at high concentration),
except
cocaine and ropivacaine,
which are vasoconstrictors
basis of their anaesthetic profile, LAs are classified as
Potency & Duration
Low potency and short duration
(procaine and 2-chlorprocaine)
intermediate potency and duration
(prilocaine, lignocaine and mepivacaine)
high potency and long duration of action
(tetracaine, etidocaine, bupivacaine and ropivacaine).
duration of LA action depends on
duration of LA action depends on the
dose and
the route of injection;
ideally, the recommended doses
should be block-specific.
Issues with cocaine & Uuse
Cocaine is toxic and used topically in ophthalmic anaesthesia.
What can cause methaemoglobinaemia
Benzocaine and prilocaine may cause methaemoglobinaemia.
How do Ropiv and Bupiv differ
how does this affect them
Ropivacaine has a propyl group in its tertiary amine, while bupivacaine has a butyl group.
It is less soluble,
less potent
and less toxic
than bupivacaine.
It produces less motor block as well.
who share a pipechol ring
(2’,6’-pipecoloxylidide).
4
Mepivacaine,
bupivacaine,
ropivacaine
and levobupivacaine
share a pipechol ring (2’,6’-pipecoloxylidide).
What must be crossd before reaches nerve
Multiple neuronal barriers
(epineurium,
perineurium and
endoneurium)
must be crossed before LA can reach the nerve.
What decreases onset
What is most important factor for speed of onset
technique
The vasularity of the surrounding tissue,
fascial layers
and LA absorption by fat
all have a detrimental effect
on the delivery of LA to the nerve,
and result in a decrease in onset.
Hence, the proximity of
injection to the nerve is
the most important factor determining the
onset of LA action.
Addition of what can speed up onset
Importantly, it has been noted that the
addition of vasoconstrictors
and hyaluronidase
may hasten the onset times.
Is it volume concentration or dose that affects onset time
LA dose rather than the
volume or concentration
has been observed to
affect the onset times.
How does lipophilicity affect speed onset
why
whats an example of this
Lipophilic LAs are more
likely to partition away from
the hydrophilic extracellular fluid compartment
into surrounding tissues
and may bind to connective tissues
rather than the nerve,
and hence they have a slower onset.
Clinically, bupivacaine (higher lipid solubility)
has a slower onset than
lignocaine (less lipid-soluble).
Block duration is largely dependent on the
Block duration is largely dependent on the drug clearance rate.
How does dose affect duration
The larger the dose given,
and the slower the metabolism
and clearance,
the greater the duration will be
How does lipid solubility affect duration
More lipid-soluble LAs have
longer duration of action
because of slower clearance.
Higher protein binding increases duration of action by virtue of
lowering the free drug available for metabolism
How does vaso constriction / dilation affect duration
At higher doses,
LAs produce vasodilatation,
enhancing their own clearance.
Addition of vasoconstrictors
may reduce clearance and enhance duration.
How does protein binding affect duration
Higher protein binding increases duration of action by virtue of lowering the free drug available for metabolism.
How does the addition of adrenaline affect
systemic absorption
How does this affect onset time
degree of block
duration
The addition of vasoconstrictors such as adrenaline to LA acts by decreasing systemic absorption of the LA.
This means more LA is
available to act locally
(on the peripheral nerve) :
decreasing onset time,
but improving the
degree of sensory
and motor block,
duration of the block
and the area (extent) covered.
How is the toxicity of LA affected by vasoconstrictors
What group may this not work on
The toxicity of LA may be reduced
by lowering the peak plasma concentration,
allowing administration of a greater dose.
However, the effect of longer-acting
LAs like bupivacaine
may not be much affected.
What produces pharmacological & clinical effects of LA
The pharmacological effects
(neural blockade)
and clinical effects
(analgesia and anaesthesia)
of LAs are the result of the drug
absorption and its disposition.
What is disposition
Disposition refers collectively to the
process of drug distribution
(into and out of the tissues)
and drug elimination
(by metabolism and excretion).
An injection of LA undergoes
local disposition,
systemic absorption
and systemic disposition.
Local disposition of an injection drug pool near the nerve undergoes
Local disposition of an injection drug pool
near the nerve undergoes:
neural tissue uptake, non-neural tissue uptake, uptake by fat, and redistribution to cerebrospinal fluid (if neuraxial).
This involves both
bulk flow and diffusion.
It is the neural tissue uptake
that results in
neural blockade (clinical effect).
What is chiefly responsible for systemic toxicity
How is this inferred
Systemic absorption of LA is
chiefly responsible for its systemic toxicity
(side effect).
This is inferred from
peak plasma concentration (Cmax)
and the time of its occurrence (Tmax).
This is not absolute, as the peak plasma
concentration reflects the net result of systemic absorption and disposition.
Systemic disposition
Lipophilicity
Lipophilicity
Systemic absorption of longer-acting,
more lipophilic agents is slower
Lignocaine absorption is faster,
but bupivacaine is absorbed slowly
into the circulation
Systemic disposition
Site of administration
What is absoption by site in descending order
Site of administration
Anatomical features such as vasularity and presence of tissues and fat that can bind LA influences disposition
Intravascular > intrapleural > intercostal > caudal > epidural > brachial plexus > femoro-sciatic > subcutaneous > intraarticular> spinal
Systemic disposition
Dosage
Dosage
All other factors being constant, dose is the primary determinant of peak plasma concentrations after any route of injection
Cmax ∝ dose given;
therefore, increased Cmax
Systemic disposition
Speed of injection
Speed of injection
Accidental intravenous administration
of LA may result
in higher peak (Cmax)
with higher speed of injection
Dose fractionation may allow early
detection of systemic toxicity
Systemic disposition
Vasocontrictor
Vasocontrictor
Decrease rate of systemic absorption
by reducing uptake
Decreased Cmax
Systemic disposition
Depot formulations
Depot formulations
Slow the release of local anaesthetic
and hence its absorption
Decreased Cmax
The systemic disposition of LA involves
2 processes and their constituents
The systemic disposition of LA involves both its distribution (uptake by lung, plasma proteins and tissues)
and its elimination
(metabolism
and excretion).
What is the first capillary bed reached by LA when exposed to systemic circulation
How does this affect its toxicity profile
Lung is the first capillary bed to be exposed to LA once
it has entered the systemic circulation. This delays and reduces the
exposure of brain and heart to LA
Is protein binding in blood saturable / non
What happens to drug fraction with increasing dose
Protein binding of LA in blood
is a saturable process.
This implies that as the dose increases,
the fraction of drug
bound to plasma proteins falls
(after saturation of all binding sites).
Describe the two types of plasma binding
Binding is of two types:
high affinity and low capacity
(α1-acid glycoprotein)
and
low affinity and high capacity (albumin).
What conditions affect the amount of a1-acid glycoprotein
How do these affect binding
In elevation of the amount of
α1-acid glycoprotein
cancer, inflammatory states, chronic pain, trauma, uraemia, post-operatively)
binding capacity increases.
What conditions decrease a1-acid glycoprotein
However, with a decline in its level
(pregnancy and neonates),
this binding may be limited,
resulting in a higher free fraction of LA
How are Ester LAs metabolised
How is this affected in hepatic and renal disease
Ester LAs are rapidly cleared
by plasma pseudocholinesterase.
In hepatic and renal disease,
a decreased synthesis of
pseudocholinesterase
may be responsible for
its prolonged half-life.
The erythrocyte esterase activity is preserved.
How are the Amides metabolised *
The amides are metabolised in liver by N-dealkylation and hydroxylation.
How is Etidocaine cleared
compared to that of
Ropiv + Bupiv
How is Lignocaine cleared
Etidocaine clearance is dependent
mostly on liver blood flow,
whereas that of ropivacaine and bupivacaine
is dependent on
hepatic enzymatic activity.
The clearance of lignocaine is dependent
on both hepatic blood flow and enzyme activity.
Amide LAs structurally
How are they metaboilised
Amide LAs structurally have an
alkyl chain,
an aromatic ring and
an amide bond between the two.
They undergo N-dealkylation, aromatic
hydroxylation and amide hydrolysis in liver.
What enzyme metabolises Lignocaine
Lignocaine undergoes N-dealkylation by CYP3A4.
How are Bupivicaine + Ropiv metabolised
what enzymes
Both bupivacaine and ropivacaine
undergo N-dealkylation (CYP3A4)
and hydroxylation (CYP1A2).
What substance can affect Metab of:
Bupiv
Ropiv
Inhibitors of CYP3A4
(Itraconazole) reduce bupivacaine elimination
while those of CYP1A2 (Fluvoxamine)
reduced ropivacaine clearance.
What can affect metabolise of all amides
Inhibitors of CYP2D6
(beta blockers and H2 antagonists)
reduce hepatic blood flow
and reduce metabolism of amide LA.
Effects of patient variables
on disposition of amide local anaesthetics
Foetus/age
< 6 months
Reduced metabolism
Deficiency of CYP3A4
Use lower doses
Effects of patient variables on disposition of amide local anaesthetics
Elderly
Clearance of LA decreases
with increasing age
Reduced hepatic mass
in elderly
Use lower doses
Effects of patient variables on disposition of amide local anaesthetics
Obese
Terminal eliminationhalf-life of
lignocaine is prolonged
Increased volume of distribution
rather than a
decreased clearance
Dose according to
total body weight
Effects of patient variables on disposition of amide local anaesthetics
Cardiovascular disease
High Cmax due to
low volume of distribution
and clearance
Reduced hepatic blood flow
and hepatocellular dysfunction
Use lower doses
Effects of patient variables on disposition of amide local anaesthetics
Hepatic disease
Prolonged half-life
Reduced hepatic blood flow
and hepatocellular dysfunction
Use lower doses
Effects of patient variables on disposition of amide local anaesthetics
Renal disease
Disposition kinetics are unaffected
Amides are metabolised by liver
In severe renal insufficiency,
clearance is halved and
metabolites accumulate
How are ester LA affected by
hepatic disease,
renal disease or
pregnancy
ester LAs are
largely unaffected
by hepatic disease, renal disease or pregnancy
How are Pseudocholinesterase levels affected in pregnancy
How does this effect ester LA metabolism
In pregnancy,
though pseudocholinesterase levels
may be decreased,
the metabolism of ester LA is
relatively preserved.
Hence they have better toxicity profiles.
How is lignocaine metabolism affected in pregnancy
How does this occur
Lignocaine is more dependent on hepatic blood
flow, which is increased in pregnancy.
This increases its clearance.
How does pregnancy affect Neural Sensitivity to LA
Why
Does this affect myocardial sensitivity to Ropiv
Pregnancy also increases neural sensitivity to LA.
This has been attributed to progesterone.
However, progesterone has
little effect on myocardial sensitivity
to ropivacaine,
as shown by in vitro studies
How is Bupivacaine metabolism affected by pregnancy
Bupivacaine is more dependent
on hepatic enzymatic activity,
which is reduced in pregnancy,
reducing its clearance.
