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

Anticholinesterase Agents
Palmer Taylor
The function of acetylcholinesterase (AChE) in terminating
the action of acetylcholine (ACh) at the junctions
of the various cholinergic nerve endings with their
effector organs or postsynaptic sites is considered in
Chapter 8. Drugs that inhibit AChE are called anticholinesterase
(anti- ChE) agents. They cause ACh to
accumulate in the vicinity of cholinergic nerve terminals
and thus are potentially capable of producing
effects equivalent to excessive stimulation of cholinergic
receptors throughout the central and peripheral
nervous systems. In view of the widespread distribution
of cholinergic neurons across animal species, it is
not surprising that the anti- ChE agents have received
extensive application as toxic agents, in the form of
agricultural insecticides, pesticides, and potential chemical
warfare “nerve gases.” Nevertheless, several compounds
of this class are widely used therapeutically;
others that cross the blood- brain barrier have been
approved or are in clinical trials for the treatment of
Alzheimer’s disease.
Prior to World War II, only the “reversible” anti-
ChE agents were generally known, of which
physostigmine is the prototype. Shortly before and
during World War II, a new class of highly toxic
chemicals, the organophosphates, was developed first
as agricultural insecticides and later as potential chemical
warfare agents. The extreme toxicity of these
compounds was found to be due to their “irreversible”
inactivation of AChE, which resulted in prolonged
enzyme inhibition. Since the pharmacological actions
of both the reversible and irreversible anti- ChE agents
are qualitatively similar, they are discussed here as a
group. Interactions of anti- ChE agents with other
drugs acting at peripheral autonomic synapses and the
neuromuscular junction are described in Chapters 9
and 11.
History. Physostigmine, also called eserine, is an alkaloid obtained
from the Calabar or ordeal bean, the dried, ripe seed of Physostigma
venenosum, a perennial plant found in tropical West Africa. The
Calabar bean once was used by native tribes of West Africa as an
“ordeal poison” in trials for witchcraft, in which guilt was judged
by death from the poison, innocence by survival after ingestion of a
bean. A pure alkaloid was isolated by Jobst and Hesse in 1864 and
named physostigmine. The first therapeutic use of the drug was in
1877 by Laqueur, in the treatment of glaucoma, one of its clinical
uses today. Accounts of the history of physostigmine have been presented
by Karczmar (1970) and Holmstedt (2000).
After basic research elucidated the chemical basis of the
activity of physostigmine, scientists began systematic investigations
of a series of substituted aromatic esters of alkyl carbamic acids.
Neostigmine was introduced into therapeutics in 1931 for its stimulant
action on the GI tract and subsequently was reported to be effective
in the symptomatic treatment of myasthenia gravis.
Remarkably, the first account of the synthesis of a highly
potent organophosphorus anti- ChE, tetraethyl pyrophosphate
(TEPP), was published by Clermont in 1854. It is even more remarkable
that the investigator survived to report on the compound’s taste;
a few drops should have been lethal. Modern investigations of the
organophosphorus compounds date from the 1932 publication of
Lange and Krueger on the synthesis of dimethyl and diethyl
phosphorofluoridates.
Upon synthesizing ~2000 compounds, Schrader defined the
structural requirements for insecticidal activity [(and, as learned subsequently,
for anti- ChE) (discussed later) (Gallo and Lawryk, 1991)].
One compound in this early series, parathion (a phosphorothioate),
later became the most widely used insecticide of this class.
Malathion, which currently is used extensively, also contains the
thionophosphorus bond found in parathion. Prior to and during
World War II, the efforts of Schrader’s group were directed toward
the development of chemical warfare agents. The synthesis of several
compounds of much greater toxicity than parathion, such as
sarin, soman, and tabun, was kept secret by the German government.
Investigators in the Allied countries also followed Lange and
Krueger’s lead in the search for potentially toxic compounds; diisopropyl
phosphorofluoridate (diisopropyl fluorophosphate; DFP),
synthesized by McCombie and Saunders, was studied most extensively
by British and American scientists.