2.1 Local Anaesthetics Flashcards
Local anaesthetics (LAs) work by
used
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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
