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

increased ACh on the respiratory system; hypoxemia, in turn, can
reinforce both sympathetic tone and ACh- induced discharge of epinephrine
from the adrenal medulla. Hence, it is not surprising that an
increase in heart rate is seen with severe ChE inhibitor poisoning.
Hypoxemia probably is a major factor in the CNS depression that
appears after large doses of anti- ChE agents. The CNS- stimulant
effects are antagonized by larger doses of atropine, although not as
completely as are the muscarinic effects at peripheral autonomic
effector sites.
Absorption, Fate, and Excretion. Physostigmine is
absorbed readily from the GI tract, subcutaneous tissues,
and mucous membranes. The conjunctival instillation
of solutions of the drug may result in systemic
effects if measures (e.g., pressure on the inner canthus)
are not taken to prevent absorption from the nasal
mucosa. Parenterally administered physostigmine is
largely destroyed within 2-3 hours, mainly by
hydrolytic cleavage by plasma esterases; renal excretion
plays only a minor role in its elimination.
Neostigmine and pyridostigmine are absorbed
poorly after oral administration, such that much larger
doses are needed than by the parenteral route.
Whereas the effective parenteral dose of neostigmine
is 0.5-2 mg, the equivalent oral dose may be
15-30 mg or more. Neostigmine and pyridostigmine
are destroyed by plasma esterases, and the quaternary
aromatic alcohols and parent compounds are excreted
in the urine; the half- lives of these drugs are only 1-2 hours
(Cohan et al., 1976).
Organophosphate anti- ChE agents with the highest
risk of toxicity are highly lipid- soluble liquids;
many have high vapor pressures. The less volatile
agents that are commonly used as agricultural insecticides
(e.g., diazinon, malathion) generally are dispersed
as aerosols or as dusts adsorbed to an inert, finely particulate
material. Consequently, the compounds are
absorbed rapidly through the skin and mucous membranes
following contact with moisture, by the lungs
after inhalation, and by the GI tract after ingestion
(Storm et al., 2000).
Following their absorption, most organophosphates
are excreted almost entirely as hydrolysis products
in the urine. Plasma and liver esterases are
responsible for hydrolysis to the corresponding phosphoric
and phosphonic acids. However, the CYPs are
responsible for converting the inactive phosphorothioates
containing a phosphorus- sulfur (thiono) bond to
phosphorates with a phosphorus- oxygen bond, resulting
in their activation. These enzymes also play a role
in the inactivation of certain organophosphorus agents,
and allelic differences are known to affect rates of
metabolism (Furlong, 2007).
The organophosphate anti- ChE agents are hydrolyzed by two
families of enzymes: the carboxylesterases and the paraoxonases
(A- esterases). These enzymes are found in the plasma and liver and
scavenge or hydrolyze a large number of organophosphates by cleaving
the phosphoester, anhydride, PF, or PCN bonds. The paraoxonases
are low- molecular- weight enzymes, requiring Ca 2+ for
catalysis, whose natural substrate may be lactones. Some of the
isozymes are associated with high density lipoproteins, and in addition
to their capacity to hydrolyze organophosphates, they may control
low density lipoprotein oxidation, thereby exerting a protective
effect in atherosclerosis (Harel et al., 2004; Mackness et al., 2004).
Genetic polymorphisms that govern organophosphate substrate
specificity and possible susceptibility to atherosclerosis have been
found (Costa et al., 2003; Mackness et al., 2004). Wide variations in
paraoxonase activity exist among animal species. Young animals are
deficient in carboxylesterases and paraoxonases, which may account
for age- related toxicities seen in newborn animals and suspected to
be a basis for toxicity in human beings (Padilla et al., 2004).
Plasma and hepatic carboxylesterases (aliesterases) and plasma
butyrylcholinesterase are inhibited irreversibly by organophosphates
(Lockridge and Masson, 2000); their scavenging capacity for
organophosphates can afford partial protection against inhibition of
AChE in the nervous system. The carboxylesterases also catalyze
hydrolysis of malathion and other organophosphates that contain
carboxyl- ester linkages, rendering them less active or inactive. Since
carboxylesterases are inhibited by organophosphates, toxicity from
simultaneous exposure to two organophosphorus insecticides can be
synergistic.
TOXICOLOGY
The toxicological aspects of the anti- ChE agents are of
practical importance to clinicians. In addition to cases
of accidental intoxication from the use and manufacture
of organophosphorus compounds as agricultural
insecticides, these agents have been used frequently for
homicidal and suicidal purposes. Organophosphates
account for as many as 80% of pesticide- related hospital
admissions. The World Health Organization documents
pesticide toxicity as a widespread global problem
associated with over 200,000 deaths a year; most poisonings
occur in Southeast Asia (Eddleston et al.,
2008). Occupational exposure occurs most commonly
by the dermal and pulmonary routes, while oral ingestion
is most common in cases of non- occupational
poisoning.
In the U.S., the Environmental Protection Agency (EPA), by
virtue of revised risk assessments and the Food Quality Protection
Act of 1996, has placed several organophosphate insecticides,
including diazinon and chlorpyrifos, on restricted use and phase- out
status in consumer products for home and garden use. A primary
concern relates to children, since the developing nervous system may
be particularly susceptible to certain of these agents (Eaton et al.,
2008). The Office of Pesticide Programs of the EPA provides continuous
reviews of the status of organophosphate pesticides, their
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CHAPTER 10
ANTICHOLINESTERASE AGENTS