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

Table 10–1
Chemical Classification of Representative Organophosphorus Compounds of Particular Pharmacological or
Toxicological Interest (Continued)
GROUP STRUCTURAL FORMULA COMMON, CHEMICAL, AND OTHER NAMES COMMENTS
C Cl
Chlorpyrifos Insecticide; use
S
Cl O,O-Diethyl O-(3,5,6-trichloro-2-
limited to non-residential
N
H 5 C 2 O P
pyridyl) phosphorothioate
agricultural settings
H 5 C 2 O O
Cl
CH Malathion
Widely employed insecticide
3 O S
P
O,O-Dimethyl S-
of greater safety than
(1,2-dicarbethoxyethyl)
parathion or other agents
CH 3 O S CHCOOC 2 H 5
phosphorodithioate
because of rapid
CH 2 COOC 2 H 5
detoxification by higher
organisms
D C Echothiophate (PHOSPHOLINE 2 H 5 O O Extremely potent choline
I –
P
IODIDE), MI-217
derivative; administered
+
C Diethoxyphosphinylthiocholine
locally in treatment of
2 H 5 O SCH 2 CH 2 N(CH 3 ) 3
iodide
glaucoma; relatively stable
in aqueous solution
Among the quaternary ammonium organophosphorus compounds
(group D in Table 10–1), only echothiophate is useful clinically
and is limited to ophthalmic administration. Being positively
charged, it is not volatile and does not readily penetrate the skin.
Metrifonate is a low- molecular- weight organophosphate that
is spontaneously converted to the active phosphoryl ester, dimethyl
2,2-dichlorovinyl phosphate (DDVP, dichlorvos). Both metrifonate
and DDVP readily cross the blood- brain barrier to inhibit AChE in
the CNS. Metrifonate originally was developed for the treatment of
schistosomiasis (Chapter 51). Its capacity to inhibit AChE in the
CNS and its reported low toxicity led to its clinical trial in treatment
of Alzheimer’s disease (Cummings, 2004); a low incidence of skeletal
muscle paralysis has limited its acceptance.
PHARMACOLOGICAL PROPERTIES
Generally, the pharmacological properties of anti- ChE
agents can be predicted by knowing those loci where
ACh is released physiologically by nerve impulses, the
degree of nerve impulse activity, and the responses of
the corresponding effector organs to ACh (see Chapter 8).
The anti- ChE agents potentially can produce all the following
effects:
• stimulation of muscarinic receptor responses at autonomic
effector organs
• stimulation, followed by depression or paralysis, of
all autonomic ganglia and skeletal muscle (nicotinic
actions)
• stimulation, with occasional subsequent depression,
of cholinergic receptor sites in the CNS.
Following toxic or lethal doses of anti- ChE
agents, most of these effects are evident (discussed
later). However, with smaller doses, particularly those
used therapeutically, several modifying factors are significant.
In general, compounds containing a quaternary
ammonium group do not penetrate cell membranes
readily; hence, anti- ChE agents in this category are
absorbed poorly from the GI tract or across the skin and
are excluded from the CNS by the blood- brain barrier
after moderate doses. On the other hand, such compounds
act preferentially at the neuromuscular junctions
of skeletal muscle, exerting their action both as
anti- ChE agents and as direct agonists. They have comparatively
less effect at autonomic effector sites and
ganglia. In contrast, the more lipid- soluble agents are
well absorbed after oral administration, have ubiquitous
effects at both peripheral and central cholinergic
sites, and may be sequestered in lipids for long periods
of time. Lipid- soluble organophosphorus agents also
are well absorbed through the skin, and the volatile
agents are transferred readily across the alveolar membrane
(Storm et al., 2000).
The actions of anti- ChE agents on autonomic effector
cells and on cortical and subcortical sites in the CNS,
where the receptors are largely of the muscarinic type, are
blocked by atropine. Likewise, atropine blocks some of
the excitatory actions of anti- ChE agents on autonomic
ganglia, since both nicotinic and muscarinic receptors are
involved in ganglionic neurotransmission (Chapter 11).