DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

the vasoconstriction, leads to hypoxia and local tissue damage. The
use of vasoconstrictors in local anesthetic preparations for anatomical
regions with limited collateral circulation could produce irreversible
hypoxic damage, tissue necrosis, and gangrene, and
therefore is contraindicated.
Undesired Effects of Local Anesthetics. In addition to
blocking conduction in nerve axons in the peripheral
nervous system, local anesthetics interfere with the function
of all organs in which conduction or transmission of
impulses occurs. Thus, they have important effects on
the CNS, the autonomic ganglia, the neuromuscular
junction, and all forms of muscle (for a review, see
Covino, 1987; Garfield and Gugino, 1987; Gintant and
Hoffman, 1987). The danger of such adverse reactions
is proportional to the concentration of local anesthetic
achieved in the circulation. In general, in local anesthetics
with chiral centers, the S-enantiomer is less toxic
than the R-enantiomer (McClure, 1996).
Central Nervous System. Following absorption, local
anesthetics may cause CNS stimulation, producing restlessness
and tremor that may progress to clonic convulsions.
In general, the more potent the anesthetic, the
more readily convulsions may be produced. Alterations
of CNS activity are thus predictable from the local anesthetic
agent in question and the blood concentration
achieved. Central stimulation is followed by depression;
death usually is caused by respiratory failure.
The apparent stimulation and subsequent depression produced
by applying local anesthetics to the CNS presumably is due solely to
depression of neuronal activity; a selective depression of inhibitory
neurons is thought to account for the excitatory phase in vivo. Rapid
systemic administration of local anesthetics may produce death with
no or only transient signs of CNS stimulation. Under these conditions,
the concentration of the drug probably rises so rapidly that all
neurons are depressed simultaneously. Airway control, along with
ventilatory and circulatory support, are essential features of treatment
in the late stage of intoxication. Benzodiazepines or rapidly acting
barbiturates administered intravenously are the drugs of choice for
both the prevention and arrest of convulsions (Chapter 17).
Although drowsiness is the most frequent complaint that
results from the CNS actions of local anesthetics, lidocaine may produce
dysphoria or euphoria and muscle twitching. Moreover, both
lidocaine and procaine may produce a loss of consciousness that is
preceded only by symptoms of sedation (Covino, 1987). Whereas
other local anesthetics also show the effect, cocaine has a particularly
prominent effect on mood and behavior. These effects of cocaine
and its potential for abuse are discussed in Chapter 24.
Cardiovascular System. Following systemic absorption,
local anesthetics act on the cardiovascular system
(Covino, 1987). The primary site of action is the
myocardium, where decreases in electrical excitability,
conduction rate, and force of contraction occur. In
addition, most local anesthetics cause arteriolar dilation.
Untoward cardiovascular effects usually are seen only
after high systemic concentrations are attained and
effects on the CNS are produced. However, on rare
occasions, lower doses of some local anesthetics will
cause cardiovascular collapse and death, probably due to
either an action on the pacemaker or the sudden onset of
ventricular fibrillation. Ventricular tachycardia and fibrillation
are relatively uncommon consequences of local
anesthetics other than bupivacaine. The effects of local
anesthetics such as lidocaine and procainamide, which
also are used as antiarrhythmic drugs, are discussed in
Chapter 29. Finally, it should be stressed that untoward
cardiovascular effects of local anesthetic agents may
result from their inadvertent intravascular administration,
especially if epinephrine also is present.
Smooth Muscle. Local anesthetics depress contractions
in the intact bowel and in strips of isolated intestine
(Zipf and Dittmann, 1971). They also relax vascular
and bronchial smooth muscle, although low concentrations
initially may produce contraction (Covino, 1987).
Spinal and epidural anesthesia, as well as instillation of
local anesthetics into the peritoneal cavity, cause sympathetic
nervous system paralysis, which can result in
increased tone of GI musculature (described under
“Clinical Uses”). Local anesthetics may increase the
resting tone and decrease the contractions of isolated
human uterine muscle; however, uterine contractions
are seldom depressed directly during intrapartum
regional anesthesia.
Neuromuscular Junction and Ganglionic Synapse. Local
anesthetics also affect transmission at the neuromuscular
junction. Procaine, e.g., can block the response of
skeletal muscle to maximal motor-nerve volleys and to
ACh at concentrations at which the muscle responds
normally to direct electrical stimulation. Similar effects
occur at autonomic ganglia. These effects are due to
block of nicotinic ACh receptors by high concentrations
of the local anesthetic (Charnet et al., 1990; Neher and
Steinbach, 1978).
Hypersensitivity to Local Anesthetics. Rare individuals are hypersensitive
to local anesthetics. The reaction may manifest itself as an
allergic dermatitis or a typical asthmatic attack (Covino, 1987). It is
important to distinguish allergic reactions from toxic side effects and
from the effects of co-administered vasoconstrictors. Hypersensitivity
seems to occur more frequently with local anesthetics of the ester
type and frequently extends to chemically related compounds. For
example, individuals sensitive to procaine also may react to structurally
similar compounds (e.g., tetracaine) through reaction to a common
metabolite. Although allergic responses to agents of the amide
type are uncommon, solutions of such agents may contain preservatives
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CHAPTER 20
LOCAL ANESTHETICS