C H A P T E R 3 2
Cholinergic agonists
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Neostigmine is a synthetic drug that has a strong
influence at the neuromuscular junction. Neostigmine
has a duration of action of 2 to 4 hours and therefore
must be given every few hours, based on individual
response, to maintain a therapeutic level.
Pyridostigmine has a longer duration of action than
neostigmine (3 to 6 hours) and is preferred in some cases
for the management of myasthenia gravis because it
does not need to be taken as frequently.
Edrophonium is administered intravenously and has
a very short duration of action (10 to 20 minutes). It is
an orphan drug currently not approved by TGA and
remains an unapproved medicine in New Zealand.
The drugs used to treat Alzheimer’s disease are well
absorbed and distributed through the body. They are
metabolised in the liver by the cytochrome P450 system,
so caution must be used for individuals with hepatic
impairment and for cases in which many interacting
drugs are used. The drugs used to treat Alzheimer’s
disease are excreted in the urine.
Galantamine is available in tablet and oral solution
form. It has a half-life of 7 hours and is taken twice a
day. An extended release form, recently available, can
be taken just once a day. Rivastigmine is available in
capsule and solution forms to help with people who have
swallowing difficulties, as well as a transdermal patch
that is applied once a day. The duration of effects for
rivastigmine is 12 hours. Donepezil, with a 70-hour
half-life, is available in oral form, as tablets, as an oral
solution and as a rapidly dissolving tablet. It can be
given in once-a-day dosing, which is advantageous with
a disease that affects memory and the person’s ability to
remember to take pills throughout the day.
Contraindications and cautions
Anticholinesterase inhibitors are contraindicated in the
presence of allergy to any of these drugs
to avoid hyper-
sensitivity reactions
; with bradycardia or intestinal or
urinary tract obstruction,
which could be exacerbated
by the stimulation of cholinergic receptors
; in pregnancy
because the uterus could be stimulated and labour
induced
; and during breastfeeding
because of the poten-
tial effects on the baby.
Caution should be used with
any condition that
could be exacerbated by cholinergic stimulation.
Although the effects of these drugs are generally more
localised to the cortex and the neuromuscular junction,
the possibility of parasympathetic effects must be con-
sidered carefully in individuals with asthma, coronary
disease, peptic ulcer, arrhythmias, epilepsy or par-
kinsonism,
which could be exacerbated by the effects
of parasympathetic stimulation.
Drugs used to treat
Alzheimer’s disease are metabolised in the liver and
excreted in the urine, so caution should be used in the
presence of hepatic or renal dysfunction,
which could
interfere with the metabolism and excretion of the
drugs.
Adverse effects
The adverse effects associated with agents for treating
myasthenia gravis or Alzheimer’s disease are related to the
stimulation of the parasympathetic nervous system. GI
effects can include nausea, vomiting, cramps, diarrhoea,
increased salivation and involuntary defecation related
to the increase in GI secretions and activity due to para-
sympathetic nervous system stimulation. Cardiovascular
effects can include bradycardia, heart block, hypotension
and even cardiac arrest, related to the cardiac-suppressing
effects of the parasympathetic nervous system. Urinary
tract effects can include a sense of urgency related to
stimulation of the bladder muscles and sphincter relaxa-
tion. Miosis and blurred vision, headaches, dizziness and
drowsiness can occur related to CNS cholinergic effects.
Other effects may include flushing and increased sweating
secondary to stimulation of the cholinergic receptors in
the sympathetic nervous system.
Clinically important drug–drug interactions
There may be an increased risk of GI bleeding if these
drugs are used with non-steroidal anti-inflammatory
drugs (NSAIDs) because of the combination of increased
GI secretions and the GI mucosal erosion associated with
the use of NSAIDs. If this combination is used, the person
should be monitored closely for any sign of GI bleeding.
The effect of anticholinesterase drugs is decreased if they
are taken in combination with any cholinergic drugs
because these work in opposition to each other.
Prototype summary: Pyridostigmine
Indications:
Treatment of myasthenia gravis, antidote
for non-depolarising neuromuscular junction
blockers, increased survival after exposure to
nerve gas.
Actions:
Reversible cholinesterase inhibitor that
increases the levels of ACh, facilitating transmission
at the neuromuscular junction.
Pharmacokinetics:
Route
Onset
Duration
Oral
35–45 mins
3–6 hours
IM
15 mins
3–6 hours
T
1/2
:
1.9 to 3.7 hours; metabolism is in the liver and
tissue, and excretion is in the urine.
Adverse effects:
Bradycardia, cardiac arrest, tearing,
miosis, salivation, dysphagia, nausea, vomiting,
increased bronchial secretions, urinary frequency,
and incontinence.
