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

BIOLOGICAL TOXINS: TETRODOTOXIN
AND SAXITOXIN
These two biological toxins also block the pore of the Na + channel.
Tetrodotoxin is found in the gonads and other visceral tissues of
some fish of the order Tetraodontiformes (to which the Japanese
fugu, or puffer fish, belongs); it also occurs in the skin of some newts
of the family Salamandridae and of the Costa Rican frog Atelopus.
Saxitoxin is elaborated by the dinoflagellates Gonyaulax catenella
and G. tamarensis and retained in the tissues of clams and other
shellfish that eat these organisms. Given the right conditions of temperature
and light, the Gonyaulax may multiply so rapidly as to discolor
the ocean, causing the condition known as red tide. Shellfish
feeding on Gonyaulax at this time become extremely toxic to
humans and are responsible for periodic outbreaks of paralytic shellfish
poisoning (Stommel and Watters, 2004). Although the toxins
are chemically different from each other, their mechanisms of action
are similar (Ritchie, 1980). Both toxins, in nanomolar concentrations,
specifically block the outer mouth of the pore of Na + channels
in the membranes of excitable cells. As a result, the action potential
is blocked. The receptor site for these toxins is formed by amino
acid residues in the P loop of the Na + channel α subunit (Figure
20–2) in all four domains (Catterall, 2000; Terlau et al., 1991). Not
all Na + channels are equally sensitive to tetrodotoxin; some Na +
channels in cardiac myocytes and dorsal root ganglion neurons are
resistant, and a tetrodotoxin-resistant Na + channel is expressed when
skeletal muscle is denervated. Tetrodotoxin and saxitoxin are two of
the most potent poisons known; the minimal lethal dose of each in
the mouse is ~ 8 μg/kg. Both toxins have caused fatal poisoning in
humans due to paralysis of the respiratory muscles; therefore the
treatment of severe cases of poisoning requires support of respiration.
Blockade of vasomotor nerves, together with a relaxation of
vascular smooth muscle, seems to be responsible for the hypotension
that is characteristic of tetrodotoxin poisoning. Early gastric
lavage and pressor support also are indicated. If the patient survives
paralytic shellfish poisoning for 24 hours, the prognosis is good.
CLINICAL USES OF LOCAL
ANESTHETICS
Local anesthesia is the loss of sensation in a body part
without the loss of consciousness or the impairment of
central control of vital functions. It offers two major
advantages. First, physiological perturbations associated
with general anesthesia are avoided; second, neurophysiological
responses to pain and stress can be
modified beneficially. As already discussed, local anesthetics
can potentially produce deleterious side effects.
Proper choice of a local anesthetic and care in its use
are the primary determinants in avoiding toxicity. There
is a poor relationship between the amount of local anesthetic
injected and peak plasma levels in adults.
Furthermore, peak plasma levels vary widely depending
on the area of injection. They are highest with interpleural
or intercostal blocks and lowest with subcutaneous
infiltration. Thus, recommended maximum doses serve
only as general guidelines.
This discussion summarizes the pharmacological
and physiological consequences of the use of local
anesthetics categorized by method of administration. A
more comprehensive discussion of their use and administration
is presented in textbooks on regional anesthesia
(e.g., Cousins et al., 2008).
Topical Anesthesia
Anesthesia of mucous membranes of the nose, mouth, throat, tracheobronchial
tree, esophagus, and genitourinary tract can be produced
by direct application of aqueous solutions of salts of many
local anesthetics or by suspension of the poorly soluble local anesthetics.
Tetracaine (2%), lidocaine (2-10%), and cocaine (1-4%) typically
are used. Cocaine is used only in the nose, nasopharynx,
mouth, throat, and ear, where it uniquely produces vasoconstriction
as well as anesthesia. The shrinking of mucous membranes decreases
operative bleeding while improving surgical visualization.
Comparable vasoconstriction can be achieved with other local anesthetics
by the addition of a low concentration of a vasoconstrictor
such as phenylephrine (0.005%). Epinephrine, topically applied, has
no significant local effect and does not prolong the duration of action
of local anesthetics applied to mucous membranes because of poor
penetration. Maximal safe total dosages for topical anesthesia in a
healthy 70-kg adult are 300 mg for lidocaine, 150 mg for cocaine,
and 50 mg for tetracaine.
Peak anesthetic effect following topical application of
cocaine or lidocaine occurs within 2-5 minutes (3-8 minutes with
tetracaine), and anesthesia lasts for 30-45 minutes (30-60 minutes
with tetracaine). Anesthesia is entirely superficial; it does not extend
to submucosal structures. This technique does not alleviate joint pain
or discomfort from subdermal inflammation or injury.
Local anesthetics are absorbed rapidly into the circulation
following topical application to mucous membranes or denuded skin.
Thus, topical anesthesia always carries the risk of systemic toxic
reactions. Systemic toxicity has occurred even following the use of
local anesthetics to control discomfort associated with severe diaper
rash in infants. Absorption is particularly rapid when local anesthetics
are applied to the tracheobronchial tree. Concentrations in blood
after instillation of local anesthetics into the airway are nearly the
same as those following intravenous injection. Surface anesthetics
for the skin and cornea have been described earlier in the chapter.
Use of eutectic mixtures of local anesthetics lidocaine
(2.5%)/prilocaine (2.5%) (EMLA) and lidocaine (7%)/tetracaine
(7%) (PLIAGIS) bridges the gap between topical and infiltration
anesthesia. The efficacy of each of these combinations lies in the
fact that the mixture has a melting point less than that of either
compound alone, existing at room temperature as an oil that can
penetrate intact skin. These creams produce anesthesia to a maximum
depth of 5 mm and are applied as a cream on intact skin under
an occlusive dressing in advance (~30-60 min) of any procedure.
These mixtures are effective for procedures involving skin and
superficial subcutaneous structures (e.g., venipuncture and skin
graft harvesting). The component local anesthetics will be absorbed
into the systemic circulation, potentially producing toxic effects, as
described earlier. Guidelines are available to calculate the maximum
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CHAPTER 20
LOCAL ANESTHETICS