4. Local Anaesthetics: Actions Flashcards
Definition:
a local anaesthetic agent is defined as a compound which produces
temporary blockade of neuronal transmission when applied to a nerve axon.
Drugs
Numerous drugs share this characteristic with conventional local anaesthetics.
They include anticonvulsants, many antiarrhythmics, including bretylium and
β-adrenoceptor blockers, some phenothiazines and some antihistamines, as well as
drugs such as pethidine and ketamine. None is used as a local anaesthetic but all have
a similar mechanism of action.
lidocaine, bupivacaine, prilocaine and, ropivacaine.
Basic structure:
lipophilic aromatic portion, which is joined via an ester or amide linkage
to a hydrophilic tertiary amine chain
Esters are hydrolyzed by nonspecific plasma cholinesterase,
and amides are metabolized in the liver
Normal action potential
The axon maintains a voltage differential of 60–90
mV across the nerve membrane.
At rest the membrane is relatively impermeable to
the influx of sodium (Na+) ions and is selectively permeable to potassium (K+) ions.
In the resting cell membrane, this selective permeability allows a small net efflux of
K+ ions, which leaves the axoplasm electrically negative (polarized). At rest, Na+ ions
tend to flow into the axon, both because the inside is electrically negative and because
of the concentration gradient.
This resting membrane potential is maintained by the
Na+/K+ pump which continually extrudes Na+ from within the cell in exchange for
K+, using ATP as an energy source.
When specific sodium channels in the axonal
membrane are opened, there is a selective permeability to Na+ ions, and the membrane
depolarizes. Repolarization takes place when voltage-dependent K+ channels
open to permit a large efflux of K+.
As the membrane becomes less negative, more
Na+ channels open, and open more rapidly; more Na+ ions enter the cell, and
depolarization is further accelerated.
Impulse propagation:
the impulse is propagated by the spread of inward current
through the conducting medium of the axoplasm to adjacent inactive regions.
Inward currents from all the active nodes integrate as they spread, ensuring that
impulse propagation will continue.
Local anaesthetic action:
these mainly block the function of the sodium channels, which exist in ‘open’, ‘resting’ and ‘inactivated’ conformational states.
Local anaesthetic affinity is higher when the channel is in the open or inactivated state.
The drugs exert no effect on cellular integrity or metabolism,
but when a sufficient concentration is reached in the perfusing solution,
depolarization does not occur in response to an electrical stimulus.
Na+ influx is blocked, although repolarization associated with K+ efflux is unaffected.
The agents in their cationic ionized form block
the sodium channels on the inside of the axoplasm.
External perfusion has no effect;
the uncharged form must penetrate the cell wall before dissociating.
The nerve blockade is concentration-dependent and ends when the
local anaesthetic concentration falls below a critical minimum level.
Local anaesthetics work by stabilizing the axonal membrane
will stabilize all excitable membranes,
including those of skeletal, smooth and cardiac muscle.
Local anaesthetics also block some potassium ion channels,
broaden the action potential
and enhance binding by maintaining the sodium channel in the open or
inactivated state.
pKa:
Local anaesthetics exist in equilibrium between ionized and non-ionized
forms.
The ratio of the two states is given by the Henderson–Hasselbalch equation
(originally derived to describe the pH changes resulting from the addition of H+ or
OH− ions to any buffer system).
The Ka is the dissociation constant which governs
the position of equilibrium between the charged and uncharged forms.
By analogy to pH, the pKa is the negative logarithm of that constant.
Rearranging the equation
pH = pKa + log [HCO3 −] / [H2CO3] gives:
pKa = pH – log [base] / [conjugate acid].
This is the same as saying [base] / [conjugate acid] = 1.0,
so the dissociation constant, or pKa,
is the pH at which equal amounts of drug are present in the charged and
uncharged state.
Clinical implications
pKa of 7.4 indicates that, at body pH, there are equal
numbers of molecules in the charged and uncharged forms. Most local anaesthetics
have pKa values higher than body pH, and the more distant the dissociation constant
from body pH, the more molecules that exist in the ionized form
pKa of 8.4, it is 1 pH unit (i.e. a tenfold H+
concentration) away from body pH. At 7.4 there is a 10:1 ratio, that is, the drug is
90% ionized and 10% non-ionized. At pKa 9.4 the difference is 100-fold, so at body
pH of 7.4, 99% of the drug will be charged
Eg of drugs
Uncharged base is necessary for tissue
penetration, and so drugs with lower pKa usually have a more rapid onset of action
Thus, lidocaine and prilocaine (pKa 7.7) have a shorter latency than bupivacaine
(pKa 8.1).
This dominance of the non-diffusible cation also explains the reason why
local anaesthetics are much less effective in the presence of inflamed and acidotic
tissue.
Other factors?
Note, however, that pKa is not the only factor involved. Concentration and
intrinsic potency are also important. Drugs also have to penetrate a perineural
membrane of connective tissue, and this property has not been well quantified, thus
chloroprocaine (popular in the USA although not used in the UK) has one of the
fastest onsets of action of all local anaesthetics, despite having a pKa of 9.1
Barriers to drug passage
peripheral nerves contain both afferent and efferent
axons which are enclosed in a fine matrix of connective tissue which embeds the
axons – the endoneurium
The fascicles of axons are enclosed within a squamous
cellular layer, the perineurium, effective semi-permeable barrier to local
anaesthetics
whole structure is surrounded by a sheath of collagen fibres, the
epineurium, which permits easy diffusion of local anaesthetic
myelinated sensory nerve, the local anaesthetic molecule may have to traverse four or
five connective-tissue and lipid-membrane barriers. The most important of these is
the perineurium, and this squamous cell layer, connected by tight junctions, is one of
the main reasons why, under clinical conditions, only about 5% of the injected
anaesthetic dose will actually penetrate the nerve.
Structure–activity relationships of local anaesthetics
The affinity of the drug to the
channel, which determines its duration of action, is related to the length of the
aliphatic (open carbon) chains on the compound
Small structural changes also
influence factors such as lipid solubility and protein binding.
Increase protein binding = increased duration
Duration
Lidocaine
Duration: 100 minutes
Protein binding: 64%
Lipid solubility: ’1’
Bupivacaine
Duration: 175 minutes
Protein binding: 96%
Lipid solubility: ‘20
Ropivacaine
Duration: 150 minutes
Protein binding: 95%
Lipid solubility: ‘7’
Lipid solubility
prime determinant of potency, which is increased by the substitution of longer side chains
bupivacaine has three times the lipid solubility of ropivacaine and
twenty times that of mepivacaine
From least to most lipid-soluble, therefore, the local anaesthetics are ranked
as follows: prilocaine, lidocaine, ropivacaine, bupivacaine and etidocaine
lipid solubility and potency is not linear
Protein binding
affected by structural differences in the molecule.
Longer aliphatic substituents increase affinity for the sodium channel and prolong
the duration of action
Bupivacaine and ropivacaine are both ~96% protein-bound.
Lidocaine and prilocaine are much more weakly protein-bound (65% and 55%,
respectively), with actions lasting for around 100 minutes. High protein binding
decreases toxicity by reducing the proportion of free drug in the plasma
