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

248 tolerance reassessments, and revisions of risk assessments through
their Web site (www.epa.gov/pesticides/op/).
Acute Intoxication. The effects of acute intoxication by
anti- ChE agents are manifested by muscarinic and nicotinic
signs and symptoms, and, except for compounds
of extremely low lipid solubility, by signs referable to
the CNS (Costa, 2006). Systemic effects appear within
minutes after inhalation of vapors or aerosols. The onset
of symptoms is delayed after GI and percutaneous
absorption. The duration of toxic symptoms is determined
largely by the properties of the compound: its
lipid solubility, whether it must be activated to form the
oxon, the stability of the organophosphate- AChE bond,
and whether “aging” of the phosphorylated enzyme has
occurred.
SECTION II
NEUROPHARMACOLOGY
After local exposure to vapors or aerosols or after their
inhalation, ocular and respiratory effects generally appear first.
Ocular manifestations include marked miosis, ocular pain, conjunctival
congestion, diminished vision, ciliary spasm, and brow ache.
With acute systemic absorption, miosis may not be evident due to
sympathetic discharge in response to hypotension. In addition to rhinorrhea
and hyperemia of the upper respiratory tract, respiratory
responses consist of tightness in the chest and wheezing respiration,
caused by the combination of bronchoconstriction and increased
bronchial secretion. GI symptoms occur earliest after ingestion and
include anorexia, nausea and vomiting, abdominal cramps, and diarrhea.
With percutaneous absorption of liquid, localized sweating and
muscle fasciculations in the immediate vicinity are generally the earliest
symptoms. Severe intoxication is manifested by extreme salivation,
involuntary defecation and urination, sweating, lacrimation,
penile erection, bradycardia, and hypotension.
Nicotinic actions at the neuromuscular junctions of skeletal
muscle usually consist of fatigability and generalized weakness,
involuntary twitchings, scattered fasciculations, and eventually severe
weakness and paralysis. The most serious consequence is paralysis of
the respiratory muscles. Knockout mice lacking the gene encoding
AChE can survive under highly supportive conditions and with a special
diet, but they exhibit continuous tremors and are stunted in
growth (Xie et al., 2000). Mice that selectively lack AChE expression
in skeletal muscle but have normal or near normal expression in
brain and organs innervated by the autonomic nervous system can
reproduce, but have continuous tremors and severe compromise of
skeletal muscle strength. By contrast, mice with selective reductions
of CNS AChE by elimination of the exons encoding alternative
splices or expression of the structural subunits influencing expression
in brain yield no obvious phenotype. This arises from large compensatory
reductions of acetylcholine synthesis and storage and
receptor responses (Camp et al., 2008; Dobbertin et al., 2009). These
studies show that cholinergic systems in the CNS adapt in development
to chronically diminished hydrolytic capacity for AChE.
The broad spectrum of effects of acute AChE inhibition on
the CNS includes confusion, ataxia, slurred speech, loss of reflexes,
Cheyne- Stokes respiration, generalized convulsions, coma, and central
respiratory paralysis. Actions on the vasomotor and other cardiovascular
centers in the medulla oblongata lead to hypotension.
The time of death after a single acute exposure may range
from < 5 minutes to nearly 24 hours, depending on the dose, route,
agent, and other factors. The cause of death primarily is respiratory
failure, usually accompanied by a secondary cardiovascular component.
Peripheral muscarinic and nicotinic as well as central actions
all contribute to respiratory compromise; effects include laryngospasm,
bronchoconstriction, increased tracheobronchial and salivary
secretions, compromised voluntary control of the diaphragm
and intercostal muscles, and central respiratory depression. Blood
pressure may fall to alarmingly low levels and cardiac arrhythmias
intervene. These effects usually result from hypoxemia and often are
reversed by assisted pulmonary ventilation.
Delayed symptoms appearing after 1-4 days and marked by
persistent low blood ChE and severe muscle weakness are termed
the intermediate syndrome (Lotti, 2002). Delayed neurotoxicity also
may be evident after severe intoxication (discussed later).
Diagnosis and Treatment. The diagnosis of severe,
acute anti- ChE intoxication is made readily from the
history of exposure and the characteristic signs and
symptoms. In suspected cases of milder acute or
chronic intoxication, determination of the ChE activities
in erythrocytes and plasma generally will establish
the diagnosis (Storm et al., 2000). Although these
values vary considerably in the normal population, they
usually are depressed well below the normal range
before symptoms are evident.
Atropine in sufficient dosage (described later in the
chapter) effectively antagonizes the actions at muscarinic
receptor sites, including increased tracheobronchial and
salivary secretion, bronchoconstriction, bradycardia, and
to a moderate extent, peripheral ganglionic and central
actions. Larger doses are required to get appreciable concentrations
of atropine into the CNS. Atropine is virtually
without effect against the peripheral neuromuscular
compromise, which can be reversed by pralidoxime
(2-PAM), a cholinesterase reactivator.
In moderate or severe intoxication with an organophosphorus
anti- ChE agent, the recommended adult dose of pralidoxime is 1-2 g,
infused intravenously over not < 5 minutes. If weakness is not
relieved or if it recurs after 20-60 minutes, the dose should be
repeated. Early treatment is very important to assure that the oxime
reaches the phosphorylated AChE while the latter still can be reactivated.
Many of the alkylphosphates are extremely lipid soluble, and
if extensive partitioning into body fat has occurred and desulfuration
is required for inhibition of AChE, toxicity will persist and
symptoms may recur after initial treatment. With severe toxicities
from the lipid- soluble agents, it is necessary to continue treatment
with atropine and pralidoxime for a week or longer.
General supportive measures also are important,
including:
• termination of exposure, by removal of the patient or
application of a gas mask if the atmosphere remains