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

N
N
O
C
O
N
H
CH 3
H 3 C
H 5 C 2
H 3 C
N
OH
243
CH 3
CH 3
CH 3
CH 3
PHYSOSTIGMINE
EDROPHONIUM
CH 3
CH 3
N
O C
O
NEOSTIGMINE
N
CH 3
NH 2
CH 3
N
TACRINE
CHAPTER 10
H 3 C
CH
H 3 C
3
O C N
O
N
O
CH
H 3 CO
N
3
H
H 3 CO
PYRIDOSTIGMINE
DONEPEZIL
OH
O
CH 3 CH 3
H 3 CO
O N CH 3
N
N
CH 3
O
CH 3
ANTICHOLINESTERASE AGENTS
RIVASTIGMINE
Figure 10–3. Representative “reversible” anticholinesterase agents employed clinically.
GALANTAMINE
absorption, and penetration into the CNS. After desulfuration, the
insecticides in current use form the dimethoxy or diethoxyphosphoryl
enzyme.
The “nerve gases”—tabun, sarin, and soman— are among the
most potent synthetic toxins known; they are lethal to laboratory animals
in nanogram doses. Insidious employment of these agents has
occurred in warfare and terrorism attacks (Nozaki and Aikawa, 1995).
Because of their low volatility and stability in aqueous solution,
parathion and methylparathion were widely used as insecticides.
Acute and chronic toxicity has limited their use, and potentially less
hazardous compounds have replaced them for home and garden use,
now largely throughout the world. These compounds are inactive in
inhibiting AChE in vitro; paraoxon is the active metabolite. The phosphoryl
oxygen for sulfur substitution is carried out predominantly by
hepatic CYPs. This reaction also occurs in the insect, typically with
more efficiency. Other insecticides possessing the phosphorothioate
structure have been widely employed for home, garden, and agricultural
use. These include diazinon (SPECTRACIDE, others) and chlorpyrifos
(DURSBAN, LORSBAN). Both of these agents have been placed under
restricted use because of evidence of chronic toxicity in the newborn
animal. They have been banned from indoor and outdoor residential
use since 2005.
Malathion (CHEMATHION, MALA-SPRAY) also requires replacement
of a sulfur atom with oxygen in vivo, conferring resistance to
mammalian species. Also, this insecticide can be detoxified by
hydrolysis of the carboxyl ester linkage by plasma carboxylesterases,
and plasma carboxylesterase activity dictates species resistance to
malathion. The detoxification reaction is much more rapid in mammals
and birds than in insects (Costa et al., 2003). In recent years,
malathion has been employed in aerial spraying of relatively populous
areas for control of citrus orchard- destructive Mediterranean fruit
flies and mosquitoes that harbor and transmit viruses harmful to
human beings, such as the West Nile encephalitis virus.
Evidence of acute toxicity from malathion arises only with
suicide attempts or deliberate poisoning. The lethal dose in mammals
is ~1 g/kg. Exposure to the skin results in a small fraction
(<10%) of systemic absorption. Malathion is used topically in the
treatment of pediculosis (lice) infestations.