Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

LOCAL ANESTHETICS
Table 5.4 A comparison of the pharmacology of commonly used local anesthetics
Drug Onset Duration (min) pK a Unionized fraction (%) at pH 7.4 Protein binding (%)
Ester linked
Procaine Intermediate 45–60 8.9 3 6
Amide linked
Lidocaine Rapid 60–120 7.9 25 70
Mepivacaine Rapid 90–180 7.6 39 77
Bupivacaine Slow 240–480 8.1 15 95
Ropivacaine Slow 240–480 8.1 15 94
Local anesthetics that are highly protein bound, e.g.
bupivacaine, tend to have a longer duration of action.
It is presumed that an agent that binds readily to plasma
proteins will likewise have a high affinity for the receptor
protein within the ion channel.
Ester-linked local anesthetics, e.g. procaine and
proxymetacaine, undergo rapid hydrolysis by plasma
cholinesterase enzymes and typically have a short duration.
Most of the commonly used agents, including lidocaine,
bupivacaine, mepivacaine and ropivacaine, are
amide linked and are metabolized by hepatic microsomal
enzymes. The precise metabolic pathway varies
but frequently involves dealkylation followed by hydrolysis.
Impaired hepatic function is likely to extend the
duration of amide-linked drugs and increase the risk of
toxicity.
Adverse effects
Systemic toxicity is associated with high plasma concentrations
of local anesthetic and typically follows administration
of an excessive dose or inadvertent intravascular
injection.
Central nervous system effects
● The CNS is particularly sensitive to the toxic effects
of local anesthetics. Excessive plasma concentrations
initially produce excitatory signs such as restlessness,
agitation and muscle twitching. With increasing concentrations,
seizures develop. These excitatory signs
are believed to result from the selective depression of
cortical inhibitory pathways.
● If plasma concentrations rise further, generalized
CNS depression, with unconsciousness and respiratory
arrest, ensues. Local anesthetic-induced seizures
should be treated with intravenous diazepam. Measures
to protect the airway and support ventilation
may also be required.
Cardiovascular effects
● The cardiovascular system is generally more resistant
to signs of toxicity than the CNS. Local anesthetics
act directly on the heart to depress automaticity,
conduction velocity and myocardial contractility. At
low plasma concentrations the resultant antiarrhythmic
effect may be beneficial but as the concentration
rises cardiac output is reduced. In addition, some
local anesthetics, particularly lidocaine, cause vasodilation
and profound hypotension can develop.
These effects may be compounded by autonomic
nervous system blockade.
● Bupivacaine is more cardiotoxic than either lidocaine
or ropivacaine. Its optical isomers also differ in terms
of cardiotoxicity. The S isomer has fewer adverse
effects and is available separately for use in people.
● Caution must be exercised with local anesthetic–
adrenaline (epinephrine) combinations, as prolonged
vasoconstriction of an extremity can result in ischemic
necrosis. These combinations should therefore
never be used in the penis or near vessels supplying
the digits or tail.
Other effects
● Some adverse effects can be related to the technique
used. For example, epidural administration of local
anesthetic can produce a range of complications
depending on the nature of the nerves affected.
Blockade of the sacral parasympathetic nerves can
cause urinary retention. Sympathetic blockade is
associated with peripheral vasodilation and if widespread,
this will depress blood pressure. Interference
with conduction in motor nerves can cause hindlimb
weakness or paralysis and if the local anesthetic
migrates as far cranially as the cervical spinal segments,
hypoventilation is possible.
● Allergic reactions have been reported but are considered
rare. The ester-linked local anesthetics are considered
more allergenic than the amide-linked drugs.
Methylparaben, a preservative included in some
local anesthetic preparations, is also allergenic.
● High doses of prilocaine have been linked to methemoglobinemia.
A metabolite, o-toluidine, is believed
to be responsible.
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