chapter 20

Cholinergic Drugs
Objectives
AFTER STUDYING THIS CHAPTER, THE STUDENT WILL BE ABLE TO:

1. Describe effects and indications for use of
selected cholinergic drugs.
2. Discuss drug therapy of myasthenia gravis.
3. Discuss the use of cholinergic drug therapy for
paralytic ileus and urinary retention.
4. Discuss drug therapy of Alzheimers disease.
5. Describe major nursing care needs of clients
receiving cholinergic drugs.
6. Describe signs, symptoms, and treatment of
overdose with cholinergic drugs.
7. Discuss atropine and pralidoxime as antidotes
for cholinergic drugs.
8. Discuss principles of therapy for using choliner-
gic drugs in special populations.
9. Teach clients about safe, effective use of
cholinergic drugs.

Critical Thinking Scenario

Jamie, a 14-year-old, was diagnosed with myasthenia gravis 3 years ago and has been well managed on
neostigmine (Prostigmin), an anticholinesterase agent. His mother calls the clinic and, clearly upset, reports
the following symptoms that Jamie is experiencing: severe headache, drooling, and one fainting episode.
Jamie states he just doesnt feel right.

Reflect on:
 Review the underlying pathophysiology of myasthenia gravis. Explain how Prostigmin alters neurotrans-
mitters to manage this condition. (Hint: Think first how the parasympathetic nervous system is altered
and how balance could be restored.)
 Contrast the symptoms of cholinergic crisis (too much Prostigmin) with myasthenic crisis (undertreatment).
Which seems to fit with Jamies symptoms?
 What additional data would you collect to help arrive at a diagnosis before treatment?

 Discuss appropriate medical and pharmacologic management of Jamie.

DESCRIPTION cell membranes of muscle cells to cause muscle contraction.

C holinergic drugs, also called parasympathomimetics and
cholinomimetics, stimulate the parasympathetic nervous
system in the same manner as acetylcholine (see Chap. 17).
Some drugs act directly to stimulate cholinergic receptors;
others act indirectly by slowing acetylcholine metabolism
(by the enzyme acetylcholinesterase) at autonomic nerve
synapses and terminals. Selected drugs are discussed here in
relation to their use in myasthenia gravis, Alzheimers dis-
ease, and atony of the smooth muscle of the gastrointestinal
and urinary systems, which results in paralytic ileus and uri-
nary retention, respectively.
In normal neuromuscular function, acetylcholine is re-
leased from nerve endings and binds to nicotinic receptors on
298
Myasthenia gravis is an autoimmune disorder in which auto-
antibodies are thought to destroy nicotinic receptors for acetyl-
choline on skeletal muscle. As a result, acetylcholine is less able
to stimulate muscle contraction and muscle weakness occurs.
In normal brain function, acetylcholine is an essential
neurotransmitter and plays an important role in cognitive func-
tions, including memory storage and retrieval. Alzheimers
disease, the most common type of dementia in adults, is char-
acterized by abnormalities in the cholinergic, serotonergic,
noradrenergic, and glutamatergic neurotransmission systems
(see Chap. 5). In the cholinergic system, there is a substantial
loss of neurons that secrete acetylcholine in the brain and
decreased activity of choline acetyltransferase, the enzyme
required for synthesis of acetylcholine.

Acetylcholine stimulates cholinergic receptors in the gut to
promote normal secretory and motor activity. Cholinergic
stimulation results in increased peristalsis and relaxation of the
smooth muscle in sphincters to facilitate movement of flatus
and feces. The secretory functions of the salivary and gastric
glands are also stimulated.
Acetylcholine stimulates cholinergic receptors in the uri-
nary system to promote normal urination. Cholinergic stim-
ulation results in contraction of the detrusor muscle and
relaxation of the urinary sphincter to facilitate emptying the
urinary bladder.
Mechanisms of Action and Effects
Direct-acting cholinergic drugs are synthetic derivatives of
choline. Most direct-acting cholinergic drugs are quaternary
amines, carry a positive charge, and are lipid insoluble. They
do not readily enter the central nervous system; thus, their
effects occur primarily in the periphery. These drugs can
exert their therapeutic effects because they are highly resis-
tant to metabolism by acetylcholinesterase, the enzyme that
normally metabolizes acetylcholine. Their action is longer
than that of acetylcholine. They have widespread systemic
effects when they combine with muscarinic receptors in car-
diac muscle, smooth muscle, exocrine glands, and the eye
(Fig. 201). Specific effects include:
1. Decreased heart rate, vasodilation, and unpredictable
changes in blood pressure
2. Increased tone and contractility in gastrointestinal (GI)
smooth muscle, relaxation of sphincters, increased sali-
vary gland and GI secretions
Presynaptic vesicles
Nerve ending containing acetylcholine
Acetylcholinesterase
Acetylcholine
Direct-acting
cholinergic drug Cholinergic
receptor
Effector organ
Figure 201 Mechanism of direct cholinergic drug action. Direct-
acting cholinergic drugs interact with postsynaptic cholinergic recep-
tors on target effector organs, activating the organ in a similar fashion
as the neurotransmitter acetylcholine.
CHAPTER 20 CHOLINERGIC DRUGS 299
3. Increased tone and contractility of smooth muscle
(detrusor) in the urinary bladder and relaxation of the
sphincter
4. Increased tone and contractility of bronchial smooth
muscle
5. Increased respiratory secretions
6. Constriction of pupils (miosis) and contraction of ciliary
muscle, resulting in accommodation for near vision
Indirect-acting cholinergic or anticholinesterase drugs
decrease the inactivation of acetylcholine in the synapse by
the enzyme acetylcholinesterase. Acetylcholine can then ac-
cumulate in the synapse and enhance the activation of post-
synaptic muscarinic and nicotinic receptors (Fig. 202). This
improves cholinergic neurotransmission in the brain and the
force of muscle contraction in peripheral tissues.
Anticholinesterase drugs are classified as either reversible
or irreversible inhibitors of acetylcholinesterase. The re-
versible inhibitors exhibit a moderate duration of action and
have several therapeutic uses, as described later. The irre-
versible inhibitors produce prolonged effects and are highly
toxic. These agents are used primarily as poisons (ie, insecti-
cides and nerve gases). Their only therapeutic use is in the
treatment of glaucoma (see Chap. 65).
Indications for Use
Cholinergic drugs have limited but varied uses. A direct-
acting drug, bethanechol, is used to treat urinary retention due
to urinary bladder atony and postoperative abdominal disten-
tion due to paralytic ileus. The anticholinesterase agents are
used in the diagnosis and treatment of myasthenia gravis and
to reverse the action of nondepolarizing neuromuscular block-
ing agents (eg, tubocurarine and related drugs) used in surgery
(see Chap. 14). The drugs do not reverse the neuromuscular
blockade produced by depolarizing agents, such as succinyl-
choline. In addition, tacrine, donepezil, and rivastigmine are an-
ticholinesterase agents approved for treatment of Alzheimers
disease. Cholinergic drugs may also be used to treat glaucoma
(see Chap. 65).
Contraindications to Use
These drugs are contraindicated in urinary or GI tract
obstruction, asthma, peptic ulcer disease, coronary artery
disease, hyperthyroidism, pregnancy, and inflammatory ab-
dominal conditions. Tacrine is also contraindicated in previ-
ous users in whom jaundice or a serum bilirubin level above
3 mg/dL developed.
INDIVIDUAL CHOLINERGIC DRUGS
These drugs are described in the following sections. Trade
names, clinical indications, and dosage ranges are listed in
Drugs at a Glance: Selected Cholinergic Drugs.
 300 SECTION 3 DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM

Indirect-acting
Presynaptic vesicles cholinergic drug
containing acetylcholine
Acetyl-
cholinesterase
Nerve ending Acetylcholine

Acetylcholine

Indirect-acting Choline Acetate

cholinergic
drug bound to The rapid splitting of acetylcholine
acetylcholinesterase into choline and acetate, thus
(see inset box) terminating its ability to stimulate
cholinergic receptors, is delayed
by the slower interaction of
Cholinergic
acetylcholinesterase with the
receptor
indirect-acting cholinergic drug.
Effector organ

Figure 202 Mechanism of indirect cholinergic drug action. Indirect-acting cholinergic drugs prevent the en-
zymatic breakdown of the neurotransmitter acetylcholine. The acetylcholine remains in the synapse and contin-
ues to interact with cholinergic receptors on target effector organs, producing a cholinergic response.

Direct-Acting Cholinergics Ambenonium (Mytelase) is a long-acting drug used for

Bethanechol (Urecholine) is a synthetic derivative of choline.
Because the drug produces smooth muscle contractions, it
should not be used in obstructive conditions of the urinary or
gastrointestinal tracts. Because oral bethanechol is not well
absorbed from the GI tract, oral doses are much larger than
subcutaneous (SC) doses. Bethanechol is not given by the
intramuscular (IM) or intravenous (IV) route because it re-
sults in severe adverse effects due to excessive cholinergic
stimulation.
Reversible Indirect-Acting Cholinergics
(Anticholinesterases)
Neostigmine (Prostigmin) is the prototype anticholinesterase
agent. It is used for long-term treatment of myasthenia gravis
and as an antidote for tubocurarine and other nondepolariz-
ing skeletal muscle relaxants used in surgery. Neostigmine,
like bethanecol, is a quaternary amine and carries a positive
charge. This reduces its lipid solubility and results in poor ab-
sorption from the GI tract. Consequently, oral doses are much
larger than parenteral doses. When it is used for long-term
treatment of myasthenia gravis, resistance to its action may
occur and larger doses may be required.
Edrophonium (Tensilon) is a short-acting cholinergic drug
used to diagnose myasthenia gravis, to differentiate between
myasthenic crisis and cholinergic crisis, and to reverse the
neuromuscular blockade produced by nondepolarizing skeletal
muscle relaxants. It is given IM or IV by a physician who
remains in attendance. Atropine, an antidote, and life support
equipment, such as ventilators and endotracheal tubes, must be
available when the drug is given.
the treatment of myasthenia gravis. It is used less often than
neostigmine and pyridostigmine. It may be useful in clients
who are allergic to bromides, however, because the other
drugs are both bromide salts. Ambenonium may be useful for
myasthenic clients on ventilators because it is less likely to
increase respiratory secretions than other anticholinesterase
drugs.
Physostigmine salicylate (Antilirium) is the only anti-
cholinesterase capable of crossing the bloodbrain barrier.
Unlike other drugs in this group, physostigmine is not a qua-
ternary amine, does not carry a positive charge, and there-
fore is more lipid soluble. It is sometimes used as an antidote
for overdosage of anticholinergic drugs, including atropine,
antihistamines, tricyclic antidepressants, and phenothiazine
antipsychotics. However, its potential for causing serious
adverse effects limits its usefulness. Some preparations of
physostigmine are also used in the treatment of glaucoma
(see Chap. 65).
Pyridostigmine (Mestinon) is similar to neostigmine in ac-
tions, uses, and adverse effects. It may have a longer duration
of action than neostigmine and is the maintenance drug of
choice for clients with myasthenia gravis. An added advantage
is the availability of a slow-release form, which is effective for
8 to 12 hours. When this form is taken at bedtime, the client
does not have to take other medications during the night and
does not awaken too weak to swallow.
Donepezil (Aricept) is used to treat mild to moderate
Alzheimers disease. In long term studies, donepezil delayed
the progression of the disease for up to 55 weeks Donepezil
increases acetylcholine in the brain by inhibiting its metabo-
lism. The drug is well absorbed after oral administration and
absorption is unaffected by food. It is highly bound (96%) to
 CHAPTER 20 CHOLINERGIC DRUGS 301

Drugs at a Glance: Selected Cholinergic Drugs

Routes and Dosage Ranges

Generic/Trade Name Adults Children

Direct-Acting Cholinergics
Bethanechol (Urecholine)
Indirect-Acting Cholinergics (Anticholinesterase Drugs)
Ambenonium (Mytelase)
Edrophonium (Tensilon)
Neostigmine (Prostigmin)
Physostigmine (Antilirium)
Pyridostigmine (Mestinon) PO 60 mg tid initially, individualize dose to control
Indirect-Acting Cholinergics for Alzheimers Disease
Donepezil (Aricept)
Galantamine (Reminyl)
Rivastigmine (Exelon)
Tacrine (Cognex)
PO 1050 mg bid to qid, maximum single dose not to Safety and efficacy not established < 8 yrs. PO:
exceed 50 mg. 0.6 mg/kg tid to qid. SC: 0.2 mg/kg tid to qid.
SC: 2.55 mg tid or qid. DO NOT give IM or IV. DO NOT give IM or IV.
PO 525 mg tid to qid Safety and efficacy not established.
For diagnosis of myasthenia gravis Diagnosis of myasthenia gravis
IV route preferred: 2 mg IV over 1530 sec. 8 mg IV Infants: 0.5 mg IV. <34 kg: 1 mg IV. May titrate up to
given 45 seconds later if no response. 5 mg if no response. >34 kg: 2 mg IV. May titrate
Test dose may be repeated in 30 min. up to 10 mg if no response.
IM route: 10 mg. May follow up with an additional 2 mg IM <34 kg: give 2 mg. >34 kg: give 5 mg.
30 min later if no response.
Differentiation or myasthenic crisis from cholinergic crisis
1 mg IV, may repeat in 1 min. BE PREPARED to intubate.
Prevention/treatment of postop distention and urinary Prevention/treatment of postop retention
retention Safety and efficacy not established
0.250.5 mg IM or SC q 46 h for 23 days. Treatment of myasthenia gravis
Treatment of myasthenia gravis PO 0.30.6 mg/kg q34h SC, IV, IM 0.010.04 mg/kg/
Dosage individualized to patient needs. dose q23h as needed
PO 15375 mg/day in 34 divided doses. SC, IV, or
IM 0.5 mg initially. Individualize subsequent doses.
Diagnosis of myasthenia gravis Diagnosis of myasthenia gravis
0.022 mg/kg IM 0.04 mg/kg IM
Antidote for nondepolarizing neuromuscular blockers Antidote for nondepolarizing neuromuscular blockers
Give atropine sulfate 0.61.2 mg IV several min be- Give 0.0080.025 mg/kg atropine sulfate IV several
fore slow IV injection of neostigmine 0.52 mg. min before slow IV injection of neostigmine
Repeat as needed, total dose not to exceed 5 mg. 0.070.08 mg/kg.
IM, IV 0.52 mg. Give IV slowly, no faster than 1
mg/min to avoid adverse effects of bradycardia,
respiratory distress, and seizures.
PO 7 mg/kg/day divided into 5 or 6 doses.
symptoms. Average dose in 24 h: 600 mg. Range in Neonates of mothers with myasthenia gravis who have
24 h: 601500 mg. IM, IV slowly: 1/30th the oral difficulty with sucking/breathing/swallowing:
dose 0.050.15 mg/kg IM. Change to syrup as soon as
possible.
PO 5 mg daily hs for 46 wk, then increase to 10 mg
qd if needed.
PO 8 mg/day initially, increase to 16 mg/day after
4 wks if needed. May continue to increase q 4 wks
up to maximum dose 24 mg/day.
PO 1.5 mg bid with food initially. May titrate to higher
doses at 1.5 mg intervals q 2 wks to a maximum
dose of 12 mg/day.
PO 40 mg/d (10 mg qid) for 6 wks. If aminotransferase
levels are satisfactory after weekly monitoring, may
increase the dose to 80 mg/d (20 mg/qid). If liver
function remains normal, may increase daily dose by
10 mg q 6 wks to a total of 120160 mg/d.

plasma proteins. It is metabolized in the liver to several
metabolites, some of which are pharmacologically active;
metabolites and some unchanged drug are excreted mainly in
urine. Adverse effects include nausea, vomiting, diarrhea,
bradycardia, and possible aggravation of asthma, peptic ulcer
disease, and chronic obstructive pulmonary disease. Unlike
tacrine, donepezil does not cause liver toxicity.
Galantamine (Reminyl) is the newest long-acting
anticholinesterase agent approved by the Food and Drug
Administration for the treatment of Alzheimers disease.
Its pharmacokinetics and side effect profile are similar to
donepezil and rivastigimine.
Rivastigimine (Exelon) is a long-acting central anti-
cholinesterase agent approved for the treatment of Alzheimers
 302 SECTION 3 DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM
Nursing Notes: Apply Your Knowledge
Jill and her boyfriend ate mushrooms they picked while hiking.
They were admitted to the hospital later that afternoon with acute
cholinergic poisoning. Describe the signs and symptoms they
likely exhibited. What antidote do you think was given, and why?
disease. It lasts 12 hours, making twice a day dosing possi-
ble. Like other drugs in this class, it is not a cure for
Alzheimers disease but does slow down progression of the
symptoms. Rivastigimine is metabolized by the liver and
excreted in the feces. It has a side effect profile similar to
donepezil.
Tacrine (Cognex) is a centrally acting anticholinesterase
agent approved for treatment of clients with mild to moder-
ate Alzheimers disease. The drug does not cure the disease,
but it may delay progression in some clients. Tacrine is well
absorbed after oral administration and reaches peak plasma
levels in 1 to 2 hours. It is approximately 50% protein bound,
is extensively metabolized in the liver, is excreted in the
urine, and has an elimination half-life of 2 to 4 hours. The
initial enthusiasm for tacrine has declined because of incon-
sistent clinical trial results and the occurrence of hepatotox-
icity. Approximately 30% of patients receiving low-dose
tacrine therapy experience elevated alanine aminotrans-
ferase (ALT) values of three times normal. Ninety percent of
these patients return to normal liver function values when
the drug is discontinued.
Nursing Process
Assessment
Assess the clients condition in relation to disorders for which
cholinergic drugs are used:
In clients known to have myasthenia gravis, assess for mus-
cle weakness. This may be manifested by ptosis (drooping)
of the upper eyelid and diplopia (double vision) caused by
weakness of the eye muscles. More severe disease may be
indicated by difficulty in chewing, swallowing, and speak-
ing; accumulation of oral secretions, which the client may
be unable to expectorate or swallow; decreased skeletal
muscle activity, including impaired chest expansion; and
eventual respiratory failure.
In clients with possible urinary retention, assess for blad-
der distention, time and amount of previous urination,
and fluid intake.
In clients with possible paralytic ileus, assess for presence
of bowel sounds, abdominal distention, and elimination
pattern.
In clients with Alzheimers disease, assess for abilities and
limitations in relation to memory, cognitive functioning,
self-care activities, and preexisting conditions that may be
aggravated by a cholinergic drug.
Nursing Diagnoses
Impaired gas exchange related to increased respiratory
secretions, bronchospasm, and/or respiratory paralysis
Ineffective Breathing Pattern related to bronchoconstriction
Ineffective Airway Clearance related to increased respi-
ratory secretions
Self Care Deficit related to muscle weakness cognitive im-
pairment, or diploplia
Deficient Knowledge: Drug administration and effects
Planning/Goals
The client will:
Verbalize or demonstrate correct drug administration
Improve in self-care abilities
Regain usual patterns of urinary and bowel elimination
Maintain effective oxygenation of tissues
Report adverse drug effects
For clients with myasthenia gravis, at least one family
member will verbalize or demonstrate correct drug ad-
ministration, symptoms of too much or too little drug,
and emergency care procedures.
For clients with dementia, a caregiver will verbalize or
demonstrate correct drug administration and knowledge
of adverse effects to be reported to a health care provider.
Interventions
Use measures to prevent or decrease the need for choliner-
gic drugs. Ambulation, adequate fluid intake, and judicious
use of opioid analgesics or other sedative-type drugs help
prevent postoperative urinary retention. In myasthenia
gravis, muscle weakness is aggravated by exercise and im-
proved by rest. Therefore, scheduling activities to avoid
excessive fatigue and to allow adequate rest periods may
be beneficial.
With drug therapy for Alzheimers disease, assist and teach
caregivers to:
Maintain a quiet, stable environment and daily routines
to decrease confusion (eg, verbal or written reminders,
simple directions, adequate lighting, calendars, and
personal objects within view and reach).
Avoid altering dosage or stopping the drug without
consulting the prescribing physician.
Be sure that clients keep appointments for supervision
and blood tests.
Report signs and symptoms (ie, skin rash, jaundice,
light-colored stools) that may indicate hepatotoxicity
for clients taking tacrine.
Notify surgeons about tacrine therapy. Exaggerated
muscle relaxation may occur if succinylcholine-type
drugs are given.
Do not give cholinergic drugs for bladder atony and uri-
nary retention or paralytic ilens in the presence of an
obstruction.
For long-term use, assist clients and families to establish a
schedule of drug administration that best meets the clients
needs.

With myasthenia gravis, recommend that one or more fam-
ily members be trained in cardiopulmonary resuscitation.
Evaluation
Observe and interview about the adequacy of urinary
elimination.
Observe abilities and limitations in self-care.
Question the client and at least one family member of
clients with myasthenia gravis about correct drug usage,
symptoms of underdosage and overdosage, and emergency
care procedures.
Question caregivers of clients with dementia about the
clients level of functioning and response to medication.
PRINCIPLES OF THERAPY
Use in Myasthenia Gravis
Guidelines for the use of anticholinesterase drugs in myas-
thenia gravis include the following:
1. Drug dosage should be increased gradually until maxi-
mal benefit is obtained. Larger doses are often required
CLIENT TEACHING GUIDELINES
Cholinergic Drugs
General Considerations
Cholinergic drugs used for urinary retention usually act
within 60 minutes after administration. Be sure bathroom
facilities are available.
Wear a medical alert identification device if taking long-
term cholinergic drug therapy for myasthenia gravis, hypo-
tonic bladder, or Alzheimers disease.
Atropine 0.6 mg IV may be administered for overdose of
cholinergic drugs.
Record symptoms of myasthenia gravis and effects of
drug therapy, especially when drug therapy is initiated
and medication doses are being titrated. The amount of
medication required to control symptoms of myasthenia
gravis varies greatly and the physician needs this infor-
mation to adjust the dosage correctly.
Do not overexert yourself if you have myasthenia gravis.
Rest between activities. Although the dose of medication
may be increased during periods of increased activity, it
is desirable to space activities to obtain optimal benefit
from the drug, at the lowest possible dose, with the
fewest adverse effects.
Report increased muscle weakness, difficulty breath-
ing, or recurrence of myasthenic symptoms to the physi-
cian. These are signs of drug underdosage (myasthenic
crisis) and indicate a need to increase or change drug
therapy.
Report adverse reactions, including abdominal cramps,
diarrhea, excessive oral secretions, difficulty in breathing,
and muscle weakness. These are signs of drug over-
dosage (cholinergic crisis) and require immediate dis-
CHAPTER 20 CHOLINERGIC DRUGS 303
with increased physical activity, emotional stress, and
infections, and sometimes premenstrually.
2. Some clients with myasthenia gravis cannot tolerate op-
timal doses of anticholinesterase drugs unless atropine
is given to decrease the severity of adverse reactions
due to muscarinic activation. However, atropine should
be given only if necessary because it may mask the sud-
den increase of side effects. This increase is the first
sign of overdose.
3. Drug dosage in excess of the amount needed to main-
tain muscle strength and function can produce a cholin-
ergic crisis. A cholinergic crisis is characterized by
excessive stimulation of the parasympathetic nervous
system. If early symptoms are not treated, hypotension
and respiratory failure may occur. At high doses, anti-
cholinesterase drugs weaken rather than strengthen
skeletal muscle contraction because excessive amounts
of acetylcholine accumulate at motor endplates and re-
duce nerve impulse transmission to muscle tissue.
a. Treatment for cholinergic crisis includes with-
drawal of anticholinesterase drugs, administration
of atropine, and measures to maintain respiration.
Endotracheal intubation and mechanical ventilation
continuation of drugs and treatment by the physician. Res-
piratory failure can result if this condition is not recognized
and treated properly.
Clients taking tacrine need weekly monitoring of liver
aminotransferase levels for 18 weeks when initiating ther-
apy and weekly for 6 weeks after any increase in dose.
Caregivers should report any signs or symptoms of ad-
verse drug reactions such as nausea, vomiting, diarrhea,
rash, jaundice, or change in the color of stools. The drug
should not be suddenly discontinued.
If dizziness or syncope occurs when taking tacrine
donepezil, or other anticholinesterase drugs, ambulation
should be supervised to avoid injury.
Caregivers should record observed effects of anti-
cholinesterase medications given to treat Alzheimers
disease. These medications are often titrated upward to
improve cognitive function and delay symptom progres-
sion, and this information will be helpful to the prescriber.
Self- or Caregiver Administration
Take drugs as directed on a regular schedule to maintain
consistent blood levels and control of symptoms.
Do not chew or crush sustained-release medications.
Take oral cholinergics on an empty stomach to lessen
nausea and vomiting. Also, food decreases absorption of
tacrine by up to 40%.
Ensure adequate fluid intake if vomiting or diarrhea occurs
as a side effect of cholinergic medications.
St. Johns wort should be avoided because concurrent
use may reduce blood levels of donepezil.
 304 SECTION 3 DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM
may be necessary due to profound skeletal muscle
weakness (including muscles of respiration), which
is not counteracted by atropine.
b. Differentiating myasthenic crisis from cholinergic
crisis may be difficult because both are characterized
by respiratory difficulty or failure. It is necessary to
differentiate between them, however, because they
require opposite treatment measures. Myasthenic cri-
sis requires more anticholinesterase drug, whereas
cholinergic crisis requires discontinuing any anti-
cholinesterase drug the client has been receiving.
The physician may be able to make an accurate di-
agnosis from signs and symptoms and their timing
in relation to medication; that is, signs and symptoms
having their onset within approximately 1 hour after
a dose of anticholinesterase drug are more likely to be
caused by cholinergic crisis (too much drug). Signs
and symptoms beginning 3 hours or more after a drug
dose are more likely to be caused by myasthenic
crisis (too little drug).
c. If the differential diagnosis cannot be made on the
basis of signs and symptoms, the client can be intu-
bated, mechanically ventilated, and observed closely
until a diagnosis is possible. Still another way to dif-
ferentiate between the two conditions is for the
physician to inject a small dose of IV edrophonium.
If the edrophonium causes a dramatic improvement
in breathing, the diagnosis is myasthenic crisis; if it
makes the client even weaker, the diagnosis is cholin-
ergic crisis. Note, however, that edrophonium or any
other pharmacologic agent should be administered
only after endotracheal intubation and controlled
ventilation have been instituted.
4. Some people acquire partial or total resistance to anti-
cholinesterase drugs after taking them for months or
years. Therefore, do not assume that drug therapy that
is effective initially will continue to be effective over
the long-term course of the disease.
Use in Children
Bethanechol is occasionally used to treat urinary retention
and paralytic ileus, but safety and effectiveness for children
younger than 8 years of age have not been established.
Neostigmine is used to treat myasthenia gravis and to re-
verse neuromuscular blockade after general anesthesia but is
not recommended for urinary retention. Pyridostigmine may
be used in the neonate of a mother with myasthenia gravis to
treat difficulties with sucking, swallowing, and breathing.
Other indirect-acting cholinergic drugs are used only in the
treatment of myasthenia gravis. Precautions and adverse
effects are the same for children as for adults.
Use in Older Adults
Indirect-acting cholinergic drugs may be used in myasthenia
gravis, Alzheimers disease, or overdoses of atropine and
other centrally acting anticholinergic drugs (eg, those used
for parkinsonism). Older adults are more likely to experience
adverse drug effects because of age-related physiologic
changes and superimposed pathologic conditions.
Use in Renal Impairment
Because bethanechol and other cholinergic drugs increase
pressure in the urinary tract by stimulating detrusor muscle
contraction and relaxation of urinary sphincters, they are
contraindicated for clients with urinary tract obstructions or
weaknesses in the bladder wall. Administering a cholinergic
drug to these people might result in rupture of the bladder.
Some aspects of the pharmacokinetics of cholinergic drugs
are unknown. Many of the drugs are degraded enzymatically
by cholinesterases. However, a few (eg, neostigmine and pyri-
dostigmine) undergo hepatic metabolism and tubular excretion
in the kidneys. Renal impairment may result in accumulation
and increased adverse effects, especially with chronic use.
Use in Hepatic Impairment
The hepatic metabolism of neostigmine and pyridostigmine
may be impaired by liver disease, resulting in increased ad-
verse effects.
Tacrine is contraindicated in liver disease. Approxi-
mately 20% to 50% of clients experience an increase in liver
aminotransferase levels after beginning therapy with tacrine.
Most enzyme elevation occurs in the first 18 weeks of ther-
apy and is more common in female clients. When tacrine
is started, serum ALT should be monitored weekly for
18 weeks. Then, if values are within normal limits and signs
of liver damage do not occur, the test can be done every
3 months. Immediate withdrawal of the medication usually
restores liver enzymes to normal levels with no permanent
liver injury.
Use in Critical Illness
Cholinergic drugs have several specific uses in critical ill-
ness. These include:
1. Use of neostigmine, pyridostigmine, and edrophonium
to reverse neuromuscular blockade (skeletal muscle
paralysis) caused by nondepolarizing muscle relaxants.
2. Anticholinesterase drugs are used to treat myasthenic
crisis and improve muscle strength.
3. Physostigmine may be used in severe cases as an anti-
dote to anticholinergic poisoning with drugs such as
atropine or tricyclic antidepressants.
Toxicity of Cholinergic Drugs:
Recognition and Management
Atropine, an anticholinergic (antimuscarinic) drug, is a specific
antidote to cholinergic agents. The drug and equipment for in-

jection should be readily available whenever cholinergic drugs
are given. It is important to note that atropine reverses only the
muscarinic effects of cholinergic drugs, primarily in the heart,
smooth muscle, and glands. Atropine does not interact with
nicotinic receptors and therefore can not reverse the nicotinic
effects of skeletal muscle weakness or paralysis due to over-
dose of the indirect cholinergic drugs.
Management of Mushroom Poisoning
Muscarinic receptors in the parasympathetic nervous system
were given their name because they can be stimulated by mus-
carine, an alkaloid that is found in small quantities in the
Amanita muscaria mushroom. Some mushrooms found in
North America, such as the Clitocybe and Inocybe mushrooms,
however, contain much larger quantities of muscarine. Acci-
dental or intentional ingestion of these mushrooms results in
intense cholinergic stimulation (cholinergic crisis) and is po-
tentially fatal. Atropine is the specific antidote for mushroom
poisoning.
Toxicity of Irreversible Anticholinesterase
Agents: Recognition and Management
Most irreversible anticholinesterase agents are highly lipid
soluble and can enter the body by a variety of routes includ-
ing the eye, skin, respiratory system and gastrointestinal tract.
Since they readily cross the bloodbrain barrier, their effects
are seen peripherally as well as centrally.
Exposure to toxic doses of irreversible anticholinesterase
agents, such as organophosphate insecticides (malathion,
parathion) or nerve gases (sarin, tabun, soman), produces a
cholinergic crisis characterized by excessive cholinergic (mus-
carinic) stimulation and neuromuscular blockade. This cholin-
ergic crisis occurs because the irreversible anticholinesterase
poison binds to the enzyme acetylcholinesterase and inactivates
it. Consequently, acetylcholine remains in cholinergic synapses
and causes excessive stimulation of muscarinic and nicotinic
receptors.
Emergency treatment includes decontamination proce-
dures such as removing contaminated clothing, flushing the
poison from skin and eyes, and using activated charcoal and
lavage to remove ingested poison from the GI tract. Pharma-
cologic treatment includes administering atropine to counter-
act the muscarinic effects of the poison (eg, salivation,
CHAPTER 20 CHOLINERGIC DRUGS 305
urination, defecation, bronchial secretions, laryngospasm,
bronchospasm).
To relieve the neuromuscular blockade produced by nico-
tinic effects of the poison, a second drug, pralidoxime, is
needed. Pralidoxime (Protopam), a cholinesterase reactiva-
tor, is a specific antidote for overdose with irreversible anti-
cholinesterase agents. Pralidoxime treats toxicity by causing
the anticholinesterase poison to release the enzyme acetyl-
cholinesterase. The reactivated acetylcholinesterase can then
degrade excess acetylcholine at the cholinergic synapses, in-
cluding the neuromuscular junction. Because pralidoxime
cannot cross the bloodbrain barrier, it is effective only in the
peripheral areas of the body. Pralidoxime must be given as
soon after the poisoning as possible. If too much time passes,
the bond between the irreversible anticholinesterase agent
and acetylcholinesterase becomes stronger and pralidoxime
is unable to release the enzyme from the poison. Treatment
of anticholinesterase overdose may also require diazepam or
lorazepam to control seizures. Mechanical ventilation may be
necessary to treat respiratory paralysis.
Home Care
Medications to treat long-term conditions such as myasthe-
nia gravis or Alzheimers disease are often administered in
the home setting. The person using the drugs may have diffi-
culty with self-administration. The client with myasthenia
gravis may have diplopia or diminished muscle strength that
make it difficult to self-administer medications. The client
with Alzheimers disease may have problems with remem-
bering to take medications and may easily underdose or
overdose himself or herself. It is important to work with re-
sponsible family members in such cases to ensure accurate
drug administration.
Nursing Notes: Apply Your Knowledge
Answer: Excessive stimulation of the parasympathetic nervous
system causes decreased heart rate and cardiac contractility,
hypotension, bronchial constriction, excessive saliva and mucus
production, nausea, vomiting, diarrhea, and abdominal cramping.
Because these symptoms are a result of excessive stimulation of
cholinergic receptors, treatment includes administration of an anti-
cholinergic drug such as atropine.
306 SECTION 3 DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM

NURSING
ACTIONS Cholinergic Drugs

NURSING ACTIONS RATIONALE/EXPLANATION

1. Administer accurately
a. Give oral bethanechol before meals.
b. Give parenteral bethanechol by the subcutaneous route only.
c. With pyridostigmine and other drugs for myasthenia gravis,
give at regularly scheduled intervals.
d. Give tacrine on an empty stomach, 1 hour before or 2 hours
after a meal, if possible, at regular intervals around the clock
(eg, q6h). Give with meals if GI upset occurs.
2. Observe for therapeutic effects
a. When the drug is given for postoperative hypoperistalsis,
observe for bowel sounds, passage of flatus through the rectum,
or a bowel movement.
b. When bethanechol or neostigmine is given for urinary reten-
tion, micturition usually occurs within approximately 60 min-
utes. If it does not, urinary catheterization may be necessary.
c. When the drug is given in myasthenia gravis, observe for
increased muscle strength as shown by:
(1) Decreased or absent ptosis of eyelids
(2) Decreased difficulty with chewing, swallowing, and
speech
(3) Increased skeletal muscle strength, increased tolerance
of activity, less fatigue
d. With cholinergic drugs to treat Alzheimers disease (tacrine,
donepezil, galantamine, and rivastigmine) observe for im-
provement in memory and cognitive functioning in activities of
daily living.
3. Observe for adverse effects
a. Central nervous system effectsconvulsions, dizziness,
drowsiness, headache, loss of consciousness
b. Respiratory effectsincreased secretions, bronchospasm,
laryngospasm, respiratory failure
c. Cardiovascular effectsdysrhythmias (bradycardia, tachy-
cardia, atrioventricular block), cardiac arrest, hypotension,
syncope
d. GI effectsnausea and vomiting, diarrhea, increased peri-
stalsis, abdominal cramping, increased secretions (ie, saliva, gas-
tric and intestinal secretions)
e. Other effectsincreased frequency and urgency of urina-
tion, increased sweating, miosis, skin rash
If these drugs are given after meals, nausea and vomiting may occur
because the drug stimulates contraction of muscles in the GI tract.
IM and IV injections may cause acute, severe hypotension and cir-
culatory failure. Cardiac arrest may occur.
For consistent blood levels and control of symptoms
Food decreases absorption and decreases serum drug levels by
30% or more.
Regular intervals increase therapeutic effects and decrease adverse
effects.
These are indicators of increased GI muscle tone and motility.
With neostigmine, onset of action is 24 hours after oral adminis-
tration and 1030 minutes after injection. Duration is approximately
34 hours. With pyridostigmine, onset of action is approximately
3045 minutes after oral use, 15 minutes after IM injection, and
25 minutes after IV injection. Duration is approximately 46 hours.
The long-acting form of pyridostigmine lasts 812 hours.
Improved functioning is most likely to occur in patients with mild
to moderate dementia.
Adverse effects occur with usual therapeutic doses but are more
likely with large doses. They are caused by stimulation of the
parasympathetic nervous system.
These may be detected early by regular assessment of blood
pressure and heart rate.
Bradycardia is probably the most likely dysrhythmia to occur.
GI effects commonly occur.
Skin rashes are most likely to occur from formulations of neostig-
mine or pyridostigmine that contain bromide.

(continued )

NURSING ACTIONS
4. Observe for drug interactions
a. Drug that increases effects of tacrine:
(1) Cimetidine
b. Drugs that decrease effects of cholinergic agents:
(1) Anticholinergic drugs (eg, atropine)
(2) Antihistamines
c. Drugs that decrease effects of anticholinesterase drugs
(1) Corticosteroids
(2) Aminoglycoside antibiotics (eg, gentamicin)
Review and Application Exercises
1. What are the actions of cholinergic drugs?
2. Which neurotransmitter is involved in cholinergic (para-
sympathetic) stimulation?
3. When a cholinergic drug is given to treat myasthenia gravis,
what is the expected effect?
4. What is the difference between cholinergic crisis and myas-
thenic crisis? How are they treated?
5. When tacrine is given to treat Alzheimers disease, what
is the desired effect?
6. Is a cholinergic drug the usual treatment of choice for uri-
nary bladder atony or hypotonicity? Why or why not?
7. What are the adverse effects of cholinergic drugs?
8. How are overdoses of cholinergic drugs treated?
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CHAPTER 20 CHOLINERGIC DRUGS 307
RATIONALE/EXPLANATION
Slows metabolism of tacrine in the liver, thereby increasing risks
of accumulation and adverse effects
Antagonize effects of cholinergic drugs (miosis, increased tone
and motility in smooth muscle of the GI tract, bronchi, and urinary
bladder, bradycardia). Atropine is the specific antidote for over-
dosage with cholinergic drugs.
Most antihistamines have anticholinergic properties that antago-
nize effects of cholinergic drugs.
Steroids may antagonize anticholinesterase agents and increase
muscle weakness in the patient with myasthenia gravis.
Aminoglycoside antibiotics (eg, gentamicin) can product a neuro-
muscular blockade that antagonizes the effects of anticholinesterase
drugs and causes muscle weakness in patients with myasthenia
gravis.
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