Cholinergics and

Anti-cholinergics
Drugs

PART 2
Cholinergic Drugs
🠶Parasympathomimetics or cholinomimetics
🠶Stimulate parasympathetic nervous system in
 same manner as does acetylcholine
🠶May stimulate cholinergic receptors directly or
slow acetylcholine metabolism at synapses
(affect the enzyme acetylcholinesterase)
Cholinergic Drugs

🠶Useful in treating Alzheimer’s Disease,

Myasthenia gravis and to tx atony of the
smooth muscle of the GI system or urinary
system
Cholinergic Drugs
🠶Normal neuromuscular function, acetylcholine binds
to nicotinic receptors on cell membranes of muscle
cells to cause contraction

🠶Myasthenia gravis = auto-antibodies presumably

destroy nicotinic receptors; thus, acetylcholine
less able to stimulate muscle contraction.
= Results in severe muscle weakness.
Cholinergic Drugs
► Acetylcholine important neurotransmitter
 affecting cognitive functioning, memory
storage and retrieval

► In Alzheimer’s disease (AD), abnormalities of

the cholinergic, serotonergic, noradrenergic,
and glutaminergic neurotransmission systems

► In cholinergic system, patient with AD found

to have loss of neurons that secrete
acetylcholine
Cholinergic Drugs—GI effects

🠶Acetylcholine stimulates cholinergic

 receptors in the gut to promote normal
secretory and motor activity
🠶Cholinergic activity in the gut will increase
peristalsis and facilitates movement of flatus
and feces
🠶The secretory functions of the salivary and
gastric glands also stimulated
Cholinergic Drugs—GU effects

🠶Acetylcholine stimulates cholinergic

receptors in the urinary system to promote
urination
🠶Results in contraction of the detrusor muscle
and relaxation of the urinary sphincter to
facilitate emptying of the urinary bladder
Acetylcholine

🠶One of the main neurotransmitters of the ANS

is acetylcholine
🠶Acetylcholine is released at preganglionic fibers
of both the sympathetic and parasympathetic
nervous system
🠶Also released from postganglionic sympathetic
neurons that innervate the sweat glands and
 from motor neurons that innervate the skeletal
muscles
Acetylcholine

🠶Sympathetic and parasympathetic divisions of

the ANS are antagonistic to each other
🠶When acetylcholine acts on body cells that
respond to parasympathetic stimulation, it
interacts with two types of cholinergic
receptors: nicotinic and muscarinic
Acetylcholine
🠶Nicotinic receptors are located in
motor nerves and skeletal muscle

🠶Stimulation results in muscle

contraction
Acetylcholine

🠶Muscarinic receptors are located in most

internal organs.
🠶This includes the cardiovascular, respiratory,
gastrointestinal, and genitourinary.
Stimulation of the muscarinic receptors may
result in either excitation or inhibition,
depending on the organ involved.
Mechanisms of Action—
Direct Acting
Cholinergics

🠶Direct acting cholinergics are lipid insoluble

🠶Do not readily enter the CNS so effects are
 peripheral
🠶Resistant to metabolism by
acetylcholinesterase
🠶Effects are longer acting than with
acetylcholine
Direct Acting Cholinergic
Drugs cont.

🠶Widespread systemic effects when they

combine with muscarinic receptors in
cardiac muscle, smooth muscle,
exocrine glands and the eye
 Direct-acting Cholinergic
Drugs Effects

🠶 Decreased heart rate, vasodilation, variable BP

effects
🠶 Increased tone and contractility in GI smooth
muscle, relaxation of sphincters, increased
salivary gland and GI secretions
🠶 Increased tone and contractility of smooth
muscle in urinary bladder and relaxation of the
sphincter
Direct Acting Cholinergic Drugs
cont.
🠶Increased tone and contractility of
bronchial smooth muscle
🠶Increased respiratory secretions
🠶Constriction of pupils (miosis) and
contraction of ciliary muscle
Direct Acting Cholinergics

🠶Bethanecol (Urecholine)—given orally.

Not given IM or IV.
🠶Used to treat urinary retention due to
bladder atony and for postoperative
abdominal distention due to paralytic
ileus
Indirect-Acting Cholinergic
Drugs

🠶Action is by decreasing the inactivation

of acetylcholine in the synapse by the
enzyme acetylcholinesterase
🠶Accumulation of acetylcholine then
occurs which enhances the activation
of the nicotinic and muscarinic
receptors
Indirect-Acting or
Anticholinesterase Drugs cont.

🠶 Anticholinesterase drugs are either reversible or

irreversible inhibitors of acetylcholinesterase
🠶 Reversible agents are such drugs as:
edrophodium (Tensilon).
🠶 Used to diagnose myasthenia gravis and for
reversal of non-depolarizing neuromuscular
blockers
Indirect-acting agents cont.

🠶 Neostigmine (Prostigmine)—prototype
anticholinesterase agent.
🠶Used for long-term tx of myasthenia gravis and as
an antidote for tubocurarine and other non
depolarizing agents in surgery.
🠶 Poorly absorbed orally so requires larger doses
than when given parenterally.
🠶 Can develop resistance to its action over time
Indirect Acting Agents

🠶Pyridostigmine (Mestinon) is the

maintenance drug of choice for patients
with Myasthenia gravis.
🠶Slow release.
Indirect Acting—Reversible
cont.

🠶 Physostigmine (Antilirium)—only
 anticholinesterase capable of crossing the
blood brain barrier.
🠶 Is more lipid soluble.
🠶 Used as an antidote for overdosage of
anticholinergics such as: atropine,
antihistamines, TCA, phenothiazines.
🠶 May also be used in tx of glaucoma.
Indirect Acting Agents used
to treat Alzheimer’s disease

► Donepezil (Aricept)—said to delay

progression of the disease by up to 55
weeks. Does not cause liver toxicity.
► Galantamine (Reminyl)—newest kid on the
 block
► Rivastigmine (Exelon) long acting. Twice a
day dosing.
► Tacrine (Cognex)—hepatoxic. Elevated liver
enzymes usu. Within 18 wks. > in women.
Specific Conditions

🠶 Distinction between cholinergic crisis and a

myasthenic crisis
🠶 Difficult to ascertain as both are characterized
by respiratory difficulty or failure
🠶 Need to distinguish as require opposite
treatment measures
 Specific Conditions—
Cholinergic vs. Myasthenic
Crisis
► Myasthenic crisis requires more
anticholinesterase drug whereas cholinergic
crisis requires discontinuation of the
anticholinesterase drugs
► Diagnosis can be made by evaluating
patient patient response to their medication
(s/s one hour after medication often is
cholinergic crisis,
► s/s 3 or more hours after medication often is
myasthenic crisis
 Myasthenia Gravis

🠶 If s/s not clearly indicative of the problem, may

have to intubate patient, inject dose of IV
edrophonium.
🠶 If dramatic improvement in breathing,
diagnosis is myasthenic crisis.
🠶 If edrophonium makes s/s worse, the diagnosis is
cholinergic crisis.
🠶 Patient must be intubated and assisted with
mechanical ventilation to perform this test.
Toxicity of Cholinergic Drugs
🠶 Atropine is the specific antidote to cholinergic
agents
🠶 Atropine reverses only the muscarinic effects of
cholinergic drugs; heart, smooth muscle, and
glands.
🠶 Atropine cannot reverse the nicotinic effects of
skeletal muscle weakness or paralysis due to
overdose of indirect cholinergic drugs.
Toxicity of Irreversible
Anticholinesterase
Agents
🠶 These agents are lipid soluble

🠶 Can enter the body by the eye,skin, respiratory

system and GI tract.

🠶 Case in point, organophosphate insecticides

(malathion, parathion) or nerve gases (sarin,
tabun, soman)

🠶 These agents cause excessive cholinergic

stimulation (muscarinic) and neuromuscular
blockade
Toxicity cont.
🠶Cholinergic crisis occurs because the
irreversible anticholinesterase poison
binds to the enzyme acetylcholinesterase
and inactivates it.

🠶Thus, acetylcholine remains in cholinergic

synapses causing excessive stimulation of
muscarinic and nicotinic receptors.
Toxicity cont.

🠶 Emergency tx includes:
1. Decontamination of clothing 2.
Flushing poison from skin and eyes
3. Activated charcoal and lavage for GI
ingestion
4. Atropine to counteract the muscarinic
effects
Toxicity cont.

► To relieve the neuromuscular blockade by

nicotinic effects, give pralidoxime
(Protopam), a cholinesterase reactivator.
► Pralidoxime causes the anticholinesterase
poison to release the enzyme
acetylcholinesterase.
► Give Pralidoxime as soon as possible as if too
much time passes, the poison bond becomes
too strong for the pralidoxime to work.
Anticholinergics
🠶Also called cholinergic blocking agents
or parasympatholytics
🠶Again, focus is on the parasympathetic
nervous system
🠶Parasympathetic system acts as a
resting and reparative function
🠶Functions include digestion, excretion,
 cardiac deceleration, anabolism and
near vision
Parasympathetic Nervous
System

🠶 75% of all parasympathetic nerve fibers are in the

vagus nerves

🠶 These nerves supply the thoracic and abdominal

organs, which innervate the heart, lungs,
esophagus, stomach, small intestine, proximal half
of the colon, liver , gallbladder, pancreas and
upper portions of the ureters
Anticholinergics
🠶 Most anticholinergic drugs interact with the
muscarinic receptors in the brain, secretory
glands, heart, and smooth muscle

🠶 A few can also affect the nicotinic receptors.

Glycopyrrolate (Robinul) is an example
Mechanism of Action and
Effects

🠶Act by occupying receptor sites at

parasympathetic nerve endings, thereby
 leaving fewer receptor sites free to
respond to acetylcholine

🠶Distribution of receptors is broad so

effects of anticholinergics will be
diffuse.
Effects on Body Tissues

1. CNS stimulation followed by depression, can

result in coma and death (atropine,
antiparkinson’s)
2. Decreased cardiovascular response to vagal
 stimulation resulting in tachycardia. Increases
vagal tone. Ex. Atropine.
3. Bronchodilation and decreased respiratory
tract secretions.
Effects on Body Tissues

🠶Antispasmotics of GI tract due to

decreased tone and motility.
🠶Mydriasis and cyclopegia. Normally do
not increase IOP but caution as can
precipitate acute glaucoma.
🠶Can cause decreased oral secretions,
decreased sweating, relaxation of
 urinary bladder
Indications for Use

🠶Uses include GI, GU, ophthalmic and

respiratory disorders, bradycardia and in
Parkinson’s disease.

🠶Used preoperatively
Use In GI Disorders
🠶Helpful in treating irritable colon or colitis
🠶Useful in gastritis, pylorospasm and
ulcerative colitis as they slow
motility
Use in GU disorders

🠶 Antispasmodic effects seen in overactive

bladder and in urinary incontinence
Ophthalmology
🠶Mydriatic and cycloplegia for
examinations and surgery

Respiratory
🠶In bronchospasm whether related to
asthma or COPD
🠶Atrovent very useful for its
bronchodilating effects
Cardiology

🠶Atropine is used to increase heart rate in

symptomatic bradycardias and higher
blocks
 Parkinson’s Disease

🠶 Useful in those with minimal side effects

🠶 Those who cannot take Levodopa
🠶 Helpful in decreasing salivation, spasticity and
tremors
Preop

🠶 Help prevent vagal stimulation and potential

bradycardia
🠶 Reduce respiratory secretions as well
Contraindications

🠶 BPH
🠶 Myasthenia gravis
🠶 Hyperthyroidism
🠶 Glaucoma
🠶 Tachydysrhythmias
🠶 Not in situations whereby delaying of gastric
emptying is a concern
Individual Anticholinergic Drugs
► Atropine—prototype. Antidote. Belladonna
alkaloid.
► Ipratropium (Atrovent). Useful in rhinorrhea.
Also excellent bronchodilator.
► Scopolamine, similar to atropine. Depresses
CNS and causes amnesia, drowsiness,
euphoria, relaxation and sleep.
= Also good for motion sickness. Given
parenterally, orally and transdermally.
Centrally Acting Anticholinergics
 🠶Benztropine (Cogentin)—temporary
use in Parkinson’s disease. Useful for
dystonic reactions caused by
antipsychotics.
🠶Trihexyphenidyl (Trihexy)—also used
for txing EPS by some antipsychotics.
*Contraindicated in glaucoma.
Urinary Antispasmotics
► Flavoxate (Urispas)—relieves dysuria, urgency,
frequency, and pain with GU infections
► Oxybutynin (Ditropan) has direct antispasmodic
effects on smooth muscle and anticholinergic
effects. Decreases frequency of voiding.
► Tolterodine (Detrol) is competitive, antimuscarinic
anticholinergic that inhibits contraction.
= More selective for this area than elsewhere in
the body.
Toxicity of Anticholinergics

🠶Anticholinergic overdose syndrome is

characterized by: Hyperthermia, delirium,
dry mouth, tacycardia, ileus, urinary
retention. Seizures, coma and respiratory
arrest may occur.
🠶Tx—activated charcoal, Antilirium,
cooling agents (ice bags, cooling
blankets, tepid baths).