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

572 such as methylparaben that may provoke an allergic reaction (Covino,
1987). Local anesthetic preparations containing a vasoconstrictor also
may elicit allergic responses due to the sulfite added as an antioxidant
for the catecholamine/vasoconstrictor.
SECTION II
NEUROPHARMACOLOGY
Metabolism of Local Anesthetics. The metabolic fate
of local anesthetics is of great practical importance,
because their toxicity depends largely on the balance
between their rates of absorption and elimination. As
noted earlier, the rate of absorption of many anesthetics
can be reduced considerably by the incorporation of a
vasoconstrictor agent in the anesthetic solution.
However, the rate of degradation of local anesthetics
varies greatly, and this is a major factor in determining
the safety of a particular agent. Since toxicity is related
to the free concentration of drug, binding of the anesthetic
to proteins in the serum and to tissues reduces the
concentration of free drug in the systemic circulation,
and consequently reduces toxicity. For example, in
intravenous regional anesthesia of an extremity, about
half of the original anesthetic dose still is tissue-bound
30 minutes after the restoration of normal blood flow
(Arthur, 1987).
Some of the common local anesthetics (e.g., tetracaine) are
esters. They are hydrolyzed and inactivated primarily by a plasma
esterase, probably plasma cholinesterase. The liver also participates
in hydrolysis of local anesthetics. Since spinal fluid contains little or
no esterase, anesthesia produced by the intrathecal injection of an
anesthetic agent will persist until the local anesthetic agent has been
absorbed into the circulation.
The amide-linked local anesthetics are, in general, degraded
by the hepatic CYPs the initial reactions involving N-dealkylation
and subsequent hydrolysis (Arthur, 1987). However, with prilocaine,
the initial step is hydrolytic, forming o-toluidine metabolites that can
cause methemoglobinemia. The extensive use of amide-linked local
anesthetics in patients with severe hepatic disease requires caution.
The amide-linked local anesthetics are extensively (55-95%) bound
to plasma proteins, particularly α 1
-acid glycoprotein. Many factors
increase (e.g., cancer, surgery, trauma, myocardial infarction, smoking,
and uremia) or decrease (e.g., oral contraceptives) the level of
this glycoprotein, thereby changing the amount of anesthetic delivered
to the liver for metabolism and thus influencing systemic toxicity.
Age-related changes in protein binding of local anesthetics also
occur. The neonate is relatively deficient in plasma proteins that bind
local anesthetics and thereby is more susceptible to toxicity. Plasma
proteins are not the sole determinant of local anesthetic availability.
Uptake by the lung also may play an important role in the distribution
of amide-linked local anesthetics in the body. Reduced cardiac
output slows delivery of the amide compounds to the liver, reducing
their metabolism and prolonging their plasma half-lives.
COCAINE
Chemistry. Cocaine, an ester of benzoic acid and methylecgonine,
occurs in abundance in the leaves of the coca shrub. Ecgonine is an
amino alcohol base closely related to tropine, the amino alcohol in
atropine. It has the same fundamental structure as the synthetic local
anesthetics (Figure 20–1).
Pharmacological Actions and Preparations. The clinically desired
actions of cocaine are the blockade of nerve impulses, as a consequence
of its local anesthetic properties, and local vasoconstriction,
secondary to inhibition of local NE reuptake. Toxicity and its potential
for abuse have steadily decreased the clinical uses of cocaine.
Its high toxicity is due to reduced catecholamine uptake in both the
central and peripheral nervous systems. Its euphoric properties are
due primarily to inhibition of catecholamine uptake, particularly DA,
in the CNS. Other local anesthetics do not block the uptake of NE
and do not produce the sensitization to catecholamines, vasoconstriction,
or mydriasis characteristic of cocaine. Currently, cocaine is
used primarily for topical anesthesia of the upper respiratory tract,
where its combination of both vasoconstrictor and local anesthetic
properties provide anesthesia and shrinking of the mucosa. Cocaine
hydrochloride is provided as a 1%, 4%, or 10% solution for topical
application. For most applications, the 1% or 4% preparation is preferred
to reduce toxicity. Because of its abuse potential, cocaine is
listed as a schedule II controlled substance by the U.S. Drug
Enforcement Agency.
LIDOCAINE
Lidocaine (XYLOCAINE, others), an aminoethylamide
(Figure 20–1), is the prototypical amide local anesthetic.
Pharmacological Actions. Lidocaine produces faster, more intense,
longer-lasting, and more extensive anesthesia than does an equal
concentration of procaine. Lidocaine is an alternative choice for individuals
sensitive to ester-type local anesthetics.
Absorption, Fate, and Excretion. Lidocaine is absorbed rapidly
after parenteral administration and from the GI and respiratory tracts.
Although it is effective when used without any vasoconstrictor, epinephrine
decreases the rate of absorption, such that the toxicity is
decreased and the duration of action usually is prolonged. In addition
to preparations for injection, lidocaine is formulated for topical,
opthalmic, mucosal, and transdermal use.
A lidocaine transdermal patch (LIDODERM) is used for relief of
pain associated with postherpetic neuralgia. An oral patch (DEN-
TIPATCH) is available for application to accessible mucous membranes
of the mouth prior to superficial dental procedures. The
combination of lidocaine (2.5%) and prilocaine (2.5%) in an
occlusive dressing (EMLA, others) is used as an anesthetic prior to
venipuncture, skin graft harvesting, and infiltration of anesthetics
into genitalia. Lidocaine in combination with tetracaine (PLIAGLIS) in
a formulation that generates a “peel” is approved for topical local
analgesia prior to superficial dermatological procedures such as filler
injections and laser-based treatments. Lidocaine in combination with
tetracaine is marketed in a formulation that generates heat upon
exposure to air (SYNERA), which is used prior to venous access and
superficial dermatological procedures such as excision, electrodessication,
and shave biopsy of skin lesions. The mild warming is
intended to increase skin temperature by up to 5ºC for the purpose
of enhancing delivery of local anesthetic into the skin.