492
P A R T 5
Drugs acting on the autonomic nervous system
A
gents
for myasthenia gravis
Myasthenia gravis
is a chronic muscular disease caused
by a defect in neuromuscular transmission. It is thought
to be an autoimmune disease in which individuals make
antibodies to their ACh receptors. These antibodies
cause gradual destruction of the ACh receptors, resulting
in fewer and fewer receptor sites available for stimu-
lation. ACh is the neurotransmitter that is used at the
nerve–muscle synapse. If the ACh receptors are blocked
and cannot be stimulated, muscle activity is decreased.
The disease is marked by progressive weakness and lack
of muscle control, with periodic acute episodes. Some
people have a very mild clinical presentation, such as
drooping eyelids, and go into remission with no further
signs and symptoms for several years. Other individuals
have a more severe course of the disease, with progres-
sive skeletal muscle weakness that may confine them to a
wheelchair. The disease can further progress to paralysis
of the diaphragm, which interferes with breathing and
would prove fatal without intervention. Often, during
the course of the disease, the person will experience a
very intense phase of the disease, called a myasthenic
crisis. Management of this crisis can be very challenging.
A
gents
for
A
lzheimer
’
s disease
Alzheimer’s disease
is a progressive disorder involving
neural degeneration in the cortex that leads to a marked
loss of memory and of the ability to carry on activities
of daily living. Because of this, Alzheimer’s disease can
have very negative effects on the individual and their
family (Box 32.4). Dementia, of which Alzheimer’s
disease is one of the common causes, is an area identi-
fied by the Australian government as a National Health
Priority Area (AIHW, 2013).
The cause of the disease is not yet known, but it is
known that there is a progressive loss of ACh-producing
neurons and their target neurons in the cortex of the
brain. These neurons seem to be related to memory
and associations between memories that allow connec-
tions between thoughts and stimuli (e.g. seeing a face
and being able to know that it is a face and to name
the person the face belongs to). There are four revers
ible indirect-acting cholinergic agonists available to slow
the progression of this disease. These include donepe-
zil (
Aricept
), galantamine (
Galantyl
,
Reminyl
) and
rivastigmine (
Exelon
) (see Table 32.2). In late 2003, an
N-
methyl-D-aspartate receptor antagonist, memantine
(
Ebixa
), was also approved for use in the treatment of
Recent worldwide events and conflicts have made
the potential use of nerve gas a major news story.
Developed as a weapon, nerve gas is an irreversible
acetylcholinesterase inhibitor. The drug is inhaled
and quickly spreads throughout the body, where it
permanently binds with acetylcholinesterase. This
causes an accumulation of ACh at nerve endings and a
massive cholinergic response. The heart rate slows and
becomes ineffective, pupils and bronchi constrict, the
gastrointestinal tract increases activity and secretions,
and muscles contract and remain that way. The muscle
contraction soon immobilises the diaphragm, causing
breathing to stop. The bodies of people who are killed
by nerve gas have a characteristic rigor of muscle
contraction.
If an attack using nerve gas is expected, individuals
who may be exposed are given intramuscular injections
of atropine (to temporarily block cholinergic activity
and to activate ACh sites in the central nervous system)
and pralidoxime (to free up the acetylcholinesterase to
start breaking down ACh). An autoinjection is provided
to military personnel who may be at risk. The injector
is used to give atropine and then pralidoxime. The
injections are repeated in 15 minutes.
If symptoms of nerve gas exposure exist after an
additional 15 minutes, the injections are repeated.
If symptoms still persist after a third set of injections,
medical help should be sought.
■■
BOX 32.2
Nerve gas: An irreversible indirect-
acting cholinergic agonist
Pralidoxime, the antidote for irreversible
acetylcholinesterase-inhibiting drugs, or nerve gas, is
given intramuscularly or intravenously to reactivate
the acetylcholinesterase that has been blocked by these
drugs. Freeing up the acetylcholinesterase allows it to
break down accumulated ACh that has overstimulated
ACh receptor sites, causing paralysis.
Pralidoxime does not readily cross the blood–brain
barrier, and it is most useful for treating peripheral
drug effects. It reacts within minutes after injection and
should be available for any person receiving indirect-
acting cholinergic agonists to treat myasthenia gravis.
The person and a significant other should understand
when to use the drug and how to administer it.
Pralidoxime is also used with atropine (which
does cross the blood–brain barrier and will block
the effects of accumulated ACh at CNS sites) to treat
organophosphate pesticide poisonings and nerve
gas exposure (see Box 32.2), both of which cause
inactivation of acetylcholinesterase.
Adverse effects associated with the use of pralidoxime
include dizziness, blurred vision, diplopia, headache,
drowsiness, hyperventilation and nausea. These
effects are also seen with exposure to nerve gas and
organophosphate pesticides, so it can be difficult
to differentiate drug effects from the effects of the
poisoning.
■■
BOX 32.3
Pralidoxime: Antidote for irreversible
indirect-acting cholinergic agonists
