Chapter 32: Cholinergic Agonists
DRUG LIST
DIRECT-ACTING CHOLINERGIC AGONISTS
Bethanechol (P) Carbachol
INDIRECT-ACTING CHOLINERGIC AGONISTS
AGENTS FOR MYASTHENIA GRAVIS
Edrophonium Neostigmine
CHOLINERGIC AGONISTS
 responding to acetylcholine
 refers to receptor sites stimulated by
acetylcholine as well as neurons that release
acetylcholine
 act at the same site as the neurotransmitter
acetylcholine (ACh) and increase the activity of
the ACh receptor sites throughout the body
 “parasympathomimetic” drugs
o mimicking the effects of the
parasympathetic nervous system
leading to bradycardia, hypotension,
pupil constriction, increased
gastrointestinal secretions and
activity, increased bladder tone,
relaxation of sphincters, and
bronchoconstriction
 Direct-acting cholinergic agonists occupy
receptor sites for ACh on the membranes of the
effector cells of the postganglionic cholinergic
nerves, causing increased stimulation of the
cholinergic receptor
 indirect-acting cholinergic agonists cause
increased stimulation of the ACh receptor sites
by reacting with the enzyme
acetylcholinesterase and preventing it from
breaking down the ACh that was released from
the nerve
acetylcholinesterase: enzyme responsible for the
immediate breakdown of acetylcholine when released
from the nerve ending; prevents overstimulation of
cholinergic receptor sites
 produce their effects indirectly by producing an
increase in the level of ACh in the synaptic
cleft, leading to increased stimulation of the
cholinergic receptor site
DIRECT-ACTING CHOLINERGIC AGONISTS
Cevimeline Pilocarpine
AGENTS FOR ALZHEIMER DISEASE
Donepezil (P) Galantamine
Rivastigmine
 similar to ACh and react directly with receptor
sites to cause the same reaction as if ACh had
stimulated the receptor sites
 stimulate muscarinic receptors within the
parasympathetic system
 used as systemic agents to increase bladder
tone, urinary excretion, and gastrointestinal (GI)
secretions and as ophthalmic agents to induce
miosis to relieve the increased intraocular
pressure of glaucoma
miosis: constriction of the pupil; relieves intraocular
pressure in some types of glaucoma
Drugs in focus
Therapeutic Actions and Indications
 act at cholinergic receptors in the peripheral
nervous system to mimic the effects of ACh and
parasympathetic stimulation
 slowed heart rate and decreased myocardial
contractility, vasodilation, bronchoconstriction
and increased bronchial mucus secretion,
increased GI activity and secretions, increased
bladder tone, relaxation of GI and bladder
sphincters, and pupil constriction
bethanechol
 has an affinity for the cholinergic receptors in
the urinary bladder
 has an affinity for the cholinergic receptors in
the urinary bladder
 treat nonobstructive postoperative and
postpartum urinary retention and to treat
neurogenic bladder atony
 increases detrusor muscle tone and relaxes the
sphincters to improve bladder emptying
 not destroyed by acetylcholinesterase, the
effects on the receptor site are longer lasting
than with stimulation by ACh.
Carbachol
 available as an ophthalmic agent
 induce miosis, or pupil constriction; to relieve
the increased intraocular pressure of glaucoma;
and to allow surgeons to perform certain
surgical procedures
Cevimeline and pilocarpine Drug–Drug Interactions

 bind to muscarinic receptors throughout the  increased risk of cholinergic effects if these
system drugs are combined or given with
 used to increase secretions in the mouth and acetylcholinesterase inhibitors (neostigmine)
GI tract and relieve the symptoms of dry mouth
that are seen in Sjögren syndrome
 use in adults and are given three times a day,
often with meals

Pharmacokinetics

 well absorbed after oral administration

 relatively short half-lives, ranging from 1 to 6
hours
 metabolism and excretion of these drugs are
not known but are believed to occur at the
synaptic level using normal processes similar to
the way that ACh is handled
 Drugs used topically are not generally absorbed
systemically

Contraindications
Nursing Considerations
 used sparingly (potential undesirable systemic
effects of parasympathetic stimulation)
 hypersensitivity to any component of the drug
 hypersensitivity to any component of the drug
(made worse by the cardiac- and
cardiovascular-suppressing effects of the
parasympathetic system)
 Peptic ulcer, intestinal obstruction, or recent GI
surgery (negatively affected by the GI-
stimulating effects of the parasympathetic
nervous system)
 Asthma (exacerbated by the increased
parasympathetic effect, overriding the
protective sympathetic bronchodilation)
 Bladder obstruction or impaired healing of sites
from recent bladder surgery (aggravated by the
stimulatory effects on the bladder)
INDIRECT-ACTING CHOLINERGIC AGONISTS
 Epilepsy and parkinsonism (affected by the
stimulation of ACh receptors in the brain)
 do not react directly with ACh receptor sites;
Caution instead, they react chemically with
acetylcholinesterase (the enzyme responsible
 pregnancy and lactation for the breakdown of ACh) in the synaptic cleft
to prevent it from breaking down Ach
Adverse Effects  most drugs bind reversibly to
acetylcholinesterase, so their effects pass with
 related to parasympathetic nervous system time when the acetylcholinesterase is released
stimulation and allowed to break down Ach
 CV effects: bradycardia, heart block,  not used therapeutically
hypotension, and even cardiac arrest related to  developed as nerve gas to be used as weapons
the cardiac-suppressing effects of the
parasympathetic nervous system nerve gas: irreversible acetylcholinesterase inhibitor used
 GI effects: nausea, vomiting, cramps, diarrhea, in warfare to cause paralysis and death by prolonged
increased salivation, and involuntary defecation muscle contraction and parasympathetic crisis
related to the increase in GI secretions and
activity  2 main categories:
 Swallowing difficulties leading to aspiration may o agents used to treat myasthenia
occur with cevimeline or oral pilocarpine due to gravis
the increase in salivary secretions o agents used to treat Alzheimer
 Dehydration is possible due to the increase in disease
GI motility and resultant diarrhea
 GU effects: sense of urgency related to the Therapeutic Actions and Indications
stimulation of the bladder muscles and
sphincter relaxation  work by reversibly blocking
 flushing and increased sweating secondary to acetylcholinesterase at the synaptic cleft
stimulation of the cholinergic receptors in the
sympathetic nervous system
  blocking allows the accumulation of ACh  Anticholinesterase inhibitors are
released from the nerve endings and leads to contraindicated in the presence of allergy to
increased and prolonged stimulation of ACh any of these drugs
receptor sites at all of the postsynaptic  bradycardia or intestinal or urinary tract
cholinergic sites obstruction (exacerbated by the stimulation of
cholinergic receptors)
 relieve the signs and symptoms of myasthenia  pregnancy (uterus could be stimulated and
gravis and increase muscle strength by labor induced)
allowing ACh to accumulate in the synaptic cleft  lactation
at neuromuscular junctions
Cautions
Pharmacokinetics
 asthma, coronary disease, peptic ulcer,
 Anticholinesterase inhibitors arrhythmias, epilepsy, or parkinsonism
o well absorbed after oral (exacerbated by the effects of parasympathetic
administration and distributed stimulation)
throughout the body  hepatic or renal dysfunction (interfere with the
o e sites of metabolism and excretion metabolism and excretion of the drugs)
for all of these drugs are not known
o metabolized at the nerve synapse or Adverse Effects
in the tissues
 Neostigmine  GI effects: nausea, vomiting, cramps, diarrhea,
o has a strong influence at the increased salivation, and involuntary defecation
neuromuscular junction related to the increase in GI secretions and
o duration of action of 2 to 4 hours activity due to parasympathetic nervous system
stimulation
 Pyridostigmine
o has a longer duration of action than  CV effects: bradycardia, heart block,
hypotension, and even cardiac arrest related to
neostigmine (3 to 6 hours)
the cardiac-suppressing effects of the
o preferred in some cases for the
parasympathetic nervous system
management of myasthenia gravis
 GU effects: a sense of urgency related to
because it does not need to be taken
stimulation of the bladder muscles and
as frequently
sphincter relaxation
o available in oral and parenteral forms
 CNS effects: Miosis and blurred vision,
o latter can be used if the patient is
headaches, dizziness, and drowsiness
having trouble swallowing
 flushing and increased sweating secondary to
 Edrophonium
stimulation of the cholinergic receptors in the
o administered intravenously
sympathetic nervous system
o short duration of action (10 to 20
minutes) Drug–Drug Interactions
 agents for Alzheimer disease
o well absorbed and distributed  increased risk of GI bleeding if these drugs are
throughout the body used with nonsteroidal anti-inflammatory drugs
o metabolized in the liver by the (NSAIDs) because of the combination of
cytochrome P450 system increased GI secretions and the GI mucosal
o excreted in the urine erosion associated with the use of NSAIDs
 Galantamine  effect of anticholinesterase drugs is decreased
o available in tablet and oral solution if they are taken in combination with any
form cholinergic drugs because these work in
o half-life of 7 hours and is taken twice opposition to each other
a day Nursing considerations
 Rivastigmine
o available in capsule and solution
forms
o help with patients who have
swallowing difficulties, as well as a
transdermal patch that is applied
once a day
o duration of effects for rivastigmine is
12 hours
 Donepezil
o 70-hour half-life
o available in oral form
o advantageous with a disease that
affects memory and the patient’s
ability to remember to take pills
throughout the day

Contraindications
 AGENTS USED TO TREAT ALZHEIMER DISEASE

Myasthenia gravis

 autoimmune disease characterized by

antibodies to cholinergic receptor sites leading
to destruction of the receptor sites and
decreased response at the neuromuscular
junction; it is progressive and debilitating,
leading to paralysis
If the ACh receptors are blocked and cannot be
stimulated, muscle activity is decreased
Some patients have a mild clinical presentation, such as
drooping eyelids, and go into remission with no further
signs and symptoms for several years
Memantine
 approved for use in the treatment of Alzheimer
disease
 block various receptor sites in the brain and
slow the buildup of plaque on the involved
axons, which seems to slow the effects of this
disease, and is the only drug of its class that is
available

Other patients have a more severe course of the disease,

with progressive skeletal muscle weakness that may
confine them to a wheelchair

patient will experience an intense phase of the disease,

called a myasthenic crisis

Drugs in focus

AGENTS FOR ALZHEIMER DISEASE

Alzheimer disease

 degenerative disease of the cortex with loss of

acetylcholine-producing cells and cholinergic
receptors; characterized by progressive
dementia
 progressive loss of ACh-producing neurons and
their target neurons in the cortex of the brain

Drugs in focus