Page 131 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 7 Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs 117

TABLE 7–4 Therapeutic uses and durations of action The first group, of which edrophonium is the example, consists
of cholinesterase inhibitors. of quaternary alcohols. These agents reversibly bind electrostati-
cally and by hydrogen bonds to the active site, thus preventing
Approximate access of acetylcholine. The enzyme-inhibitor complex does not
Duration of involve a covalent bond and is correspondingly short-lived (on the
Group, Drug Uses Action
order of 2–10 minutes). The second group consists of carbamate
Alcohols esters, eg, neostigmine and physostigmine. These agents undergo
Edrophonium Myasthenia gravis, ileus, 5–15 minutes a two-step hydrolysis sequence analogous to that described for
arrhythmias acetylcholine. However, the covalent bond of the carbamoylated
Carbamates and related agents enzyme is considerably more resistant to the second (hydration)
Neostigmine Myasthenia gravis, ileus 0.5–4 hours process, and this step is correspondingly prolonged (on the order
Pyridostigmine Myasthenia gravis 4–6 hours of 30 minutes to 6 hours). The third group consists of the organo-
phosphates. These agents also undergo initial binding and hydro-
Physostigmine For anticholinergic 0.5–2 hours
poisoning lysis by the enzyme, resulting in a phosphorylated active site. The
covalent phosphorus-enzyme bond is extremely stable and hydro-
Organophosphates
lyzes in water at a very slow rate (hundreds of hours). After the
Echothiophate Glaucoma 100 hours
initial binding-hydrolysis step, the phosphorylated enzyme com-
plex may undergo a process called aging. This process apparently
involves the breaking of one of the oxygen-phosphorus bonds
other organophosphates. When prepared in aqueous solution for of the inhibitor and further strengthens the phosphorus-enzyme
ophthalmic use, it retains activity for weeks. bond. The rate of aging varies with the particular organophos-
The thiophosphate insecticides (parathion, malathion, and phate compound. For example, aging occurs within 10 minutes
related compounds) are quite lipid-soluble and are rapidly with the chemical warfare agent soman, but as much as 48 hours
absorbed by all routes. They must be activated in the body by con- later with the drug VX. If given before aging has occurred, strong
version to the oxygen analogs (Figure 7–7), a process that occurs nucleophiles like pralidoxime are able to break the phosphorus-
rapidly in both insects and vertebrates. Malathion and a few other enzyme bond and can be used as “cholinesterase regenerator” drugs
organophosphate insecticides are also rapidly metabolized by for organophosphate insecticide poisoning (see Chapter 8). Once
other pathways to inactive products in birds and mammals but aging has occurred, the enzyme-inhibitor complex is even more
not in insects; these agents are therefore considered safe enough stable and is more difficult to break, even with oxime regenerator
for sale to the general public. Unfortunately, fish cannot detoxify compounds.
malathion, and significant numbers of fish have died from the The organophosphate inhibitors are sometimes referred to as
heavy use of this agent on and near waterways. Parathion is not “irreversible” cholinesterase inhibitors, and edrophonium and the
detoxified effectively in vertebrates; thus, it is considerably more carbamates are considered “reversible” inhibitors because of the
dangerous than malathion to humans and livestock and is not marked differences in duration of action. However, the molecular
available for general public use in the USA. mechanisms of action of the three groups do not support this
All the organophosphates except echothiophate are distributed simplistic description.
to all parts of the body, including the central nervous system.
Therefore, central nervous system toxicity is an important com-
ponent of poisoning with these agents. B. Organ System Effects
The most prominent pharmacologic effects of cholinesterase
Pharmacodynamics inhibitors are on the cardiovascular and gastrointestinal systems,
the eye, and the skeletal muscle neuromuscular junction (as
A. Mechanism of Action described in the Case Study). Because the primary action is to
Acetylcholinesterase is the primary target of these drugs, but amplify the actions of endogenous acetylcholine, the effects are
butyrylcholinesterase is also inhibited. Acetylcholinesterase is an similar (but not always identical) to the effects of the direct-acting
extremely active enzyme. In the initial catalytic step, acetylcho- cholinomimetic agonists.
line binds to the enzyme’s active site and is hydrolyzed, yield-
ing free choline and the acetylated enzyme. In the second step, 1. Central nervous system—In low concentrations, the lipid-
the covalent acetyl-enzyme bond is split, with the addition of soluble cholinesterase inhibitors cause diffuse activation on the
water (hydration). The entire process occurs in approximately electroencephalogram and a subjective alerting response. In higher
150 microseconds. concentrations, they cause generalized convulsions, which may be
All the cholinesterase inhibitors increase the concentration of followed by coma and respiratory arrest.
endogenous acetylcholine at cholinoceptors by inhibiting acetyl-
cholinesterase. However, the molecular details of their interaction 2. Eye, respiratory tract, gastrointestinal tract, urinary
with the enzyme vary according to the three chemical subgroups tract—The effects of the cholinesterase inhibitors on these organ
mentioned above. systems, all of which are well innervated by the parasympathetic