5 - Cholinergic Agonists
The Parasympathetic Nervous System
1. Where do we find cholinergic neurons? Fill in the blanks: (LP p44)
2. What disease is caused by antibodies that bind to the cholinergic receptors in the muscles and cause
progressive muscle weakness with use?
3. What disease is associated with loss of cholinergic transmission in the temporal lobes? (LP p43)
4. What are the main parasympathetic nerves in the body?
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5. How do the sympathetic and parasympathetic nervous systems affect the following body structures?
Organ
Sympathetic
____________________ HR and
contractility
Mydriasis (__________________of the
pupil)
Parasympathetic
______________________ HR and
contractility
Salivary Glands
_______________________ secretions
__________________________ secretions
Bronchioles
________________________
(bronchodilation)
Contraction (______________________)
Bladder
_____________________ urination
________________________ urination
Male GU
________________________ (“shoot”)
____________________________ (“point”)
GI Tract
_______________________ digestion
___________________________ digestion
Heart
Eye
Miosis (______________________ of pupil)
6. What are the symptoms of excess cholinergic activity?
“DUMBBELSS”
• D
• Urination
• Miosis
• Bronchospasm
• B
• Excitation of skeletal muscle
• Lacrimation
• Sweating
• S
7. What two parts of the “DUMBBELSS” mnemonic are not parasympathetic effects?
8. What drugs can cause excess cholinergic activity? (LP p43)
•
•
• Carbachol
• Pyridostigmine
• Methacholine
• Physostigmine
• Pilocarpine
• Edrophonium
• Echothiophate
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Cholinergic Neurotransmission
9. What are the six steps in cholinergic neurotransmission? (LP p43-45)
10. What bacterial toxin blocks the release of acetylcholine?
11. How does black widow spider venom affect acetylcholine release?
Cholinergic Receptors
12. What are the two main types of acetylcholine receptors? (LP p46)
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13. Where are muscarinic and nicotinic acetylcholine receptors found? (LP p44)
Location
Receptor
Somatic motor nerves
Postganglionic parasympathetic
Preganglionic sympathetic
Preganglionic parasympathetic
14. Where are the five subclasses of muscarinic receptors found? (LP p46)
Receptor
Location
M1
M2
M3
M4
CNS
M5
CNS
15. How does stimulation of M1 and M3 receptors affect the postsynaptic cells? (P p46)
• M1 and M3 receptors are linked to a
protein, which
activates
• Phospholipase C increases inositol triphosphate (IP3), which increases
in the cell
• Phospholipase C also increases diacylglycerol (DAG), which activates
16. How does stimulation of M2 receptors affect the smooth muscle cells? (LP p46)
• M2 receptors are linked to a
protein, which
adenylyl cyclase
• Adenylyl cyclase is responsible for turning ATP into
(cAMP), which activates
protein kinase A
• Inhibition of adenylyl cyclase will
cAMP and decrease the activity
of
17. What is the mechanism of action of M2 receptors on cardiac muscle? (LP p46)
• Stimulate G proteins linked to
in the heart
+
• Allows for
of K into the myocardial cells
• Slows the heart rate and decreases the force of contraction
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18. What are the two types of nicotinic receptors and where are they found? (LP p47)
• NM –
• NN –
19. How does stimulation of nicotinic receptors affect the postsynaptic cell? (LP p47)
• Ligand-gated ion channels
• Allow
to flow through the cell
membrane
their concentration gradient
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Quick Review 1
1. Are the following actions produced by parasympathetic or sympathetic activation?
• Elevation of heart rate:
• Miosis:
• Erection:
• Thick viscous secretions:
• Bronchoconstriction:
• Increased digestion:
2. What degrades acetylcholine in the synaptic cleft?
3. What G protein class do the following receptors stimulate?
Neurotransmitter
Receptor
G protein
Epinephrine, norepinephrine
α1
Gq
Epinephrine, norepinephrine
α2
Gi
Epinephrine, norepinephrine
β1
Gs
Epinephrine, norepinephrine
β2
Gs
Acetylcholine
M1
Acetylcholine
M2
Acetylcholine
M3
Dopamine
D2
Gi
4. What is the rate-limiting step in acetylcholine synthesis? (LP p43)
5. What enzyme catalyzes acetylcholine synthesis? (LP p43)
6. What ion always triggers exocytosis?
7. What are the four potential fates of acetylcholine (ACh)?
• Bind to a
• Bind to an autoreceptor on the presynaptic cell, which further regulates
• Diffuse away from the synaptic cleft
• Degraded by acetylcholinesterase (AChE), which cleaves ACh into
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8. Where is the only place you will find muscarinic acetylcholine receptors?
9. What are the symptoms of excess parasympathetic activity?
“DUMBBELSS”
• Diarrhea
• Urination
•
• Bronchospasm
•
• Excitation of skeletal muscle
• Lacrimation
• Sweating
•
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Direct Cholinergic Agonists
Acetylcholine
Bethanechol
Carbachol
Methacholine
Pilocarpine
Cevimiline
1. Do the cholinergic agonists work mainly at muscarinic or nicotinic receptors? (LP p47)
Acetylcholine
2. Although acetylcholine is rarely used as a drug, when can it be used? (LP p48)
•
- Instilled into the
of the eye in order to
cause
3. What are the actions of acetylcholine? (LP p48)
• Slow
• Decrease cardiac output
• Decrease blood pressure
• IV acetylcholine increases NO
•
•
•
•
•
•
•
Increase GI motility
Increase
Increase urination
Contraction of ciliary muscle
Increase salivary secretion
Increase intestinal secretion
Bethanechol
4. Where does bethanechol act? (LP p48)
5. What are the therapeutic uses of bethanechol? (LP p48)
• Nonobstructive
•
(neurogenic gastrointestinal atony)
• Treatment of
side effects of other drugs
6. What are antimuscarinic side effects that might be treated with cholinergic agonists?
•
as a hare
• Increased body temperature
• Dry as a bone
•
mouth
• Red as a beet
• Flushed skin
•
as a bat
• Cycloplegia (paralysis of ciliary muscle)
• Mad as a hatter
•
/delirium
• Bloated as a toad
• Constipation/urinary retention
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7. Which drugs cause anticholinergic side effects?
•
(such as haloperidol)
• Tricyclic antidepressants (such as amitriptyline, nortriptyline)
8. What are the adverse effects of bethanechol? (LP p49)
•
• Salivation
• Diarrhea
•
• Abdominal pain
Carbachol
9. Which cholinergic receptors does carbachol act upon? (LP p49)
10. How is carbachol used to treat glaucoma? (LP p49)
• Cause pupillary contraction
•
in intraocular pressure
Pilocarpine
11. What mnemonic helps you remember whether or not pilocarpine crosses the blood brain barrier (BBB)?
(LP p49)
12. For what is pilocarpine the drug of choice? (LP p49)
• Drug of choice for
emergencies
• Both open-angle and closed-angle
• Causes an immediate drop in intraocular pressure, can last up to
13. What is Sjogren’s syndrome?
• Autoimmune destruction of
• Dry eyes and dry mouth
hours
and
14. Besides pilocarpine, what topical cholinergic agonist is used for Sjogren’s syndrome?
15. What are the adverse effects of pilocarpine? (LP p50)
•
• Profuse sweating and salivation
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Methacholine
16. What effect does cholinergic stimulation have on the bronchioles?
• Increased secretions
•
17. How is methacholine used?
Nicotinic Agonists
Nicotine
Varenicline
18. What are the effects of nicotine in the CNS? (LP p118)
•
• Arousal
• Alertness
• Relaxation
• Appetite suppression
• Highly
19. What are the peripheral effects of nicotine? (LP p119)
•
blood pressure and heart rate
•
• Decreased coronary blood flow
• Ganglionic
(at high doses)
20. What are the therapeutic uses of nicotine? (LP p118)
21. What is the mechanism of action of varenicline? (LP p119)
•
of nicotinic receptors
• Causes less
than nicotine
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Quick Review 2
1. What is the effect of giving acetylcholine by IV?
• It binds to
• Will increase
on the endothelium of smooth muscle of the vasculature
and cause
2. What is the mechanism of action of bethanechol? (LP p48)
• Stimulates
receptors
• Causes increased intestinal motility and tone
• Stimulates the detrusor muscles of the bladder and relaxes the trigone and
sphincter
3. A 30-year-old male with schizophrenia now has urinary retention due to his neuroleptic medication. What
drug could be given to treat his urinary retention?
4. Why is carbachol not usually given systemically? (LP p49)
• It has serious effects on the
• Causes a release of
and GI system
from the adrenal medulla
5. What is the mechanism of action for pilocarpine in the eye? (LP p49)
Produces a rapid
and contraction of the
6. Methacholine is used in the treatment of what diseases?
7. Describe the effects of nicotine on the CNS in relation to high and low doses. (LP p118)
• Low doses – arousal and
• High doses – central
and severe hypotension caused by medullary
paralysis
8. What are some adverse effects of varenicline? (LP p119)
• Nausea
• Headache
•
• May lead to suicidal behavior
9. What is the pathogenesis of glaucoma?
Blocked canal of
atrophy of optic nerve
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increased pressure
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10. What is the difference between open angle and acute angle-closure glaucoma?
• Open Angle Glaucoma
- Common, insidious form; almost always bilateral
- Obstructed outflow (problem with canal of Schlemm)
•
Risk factors: older than 40, black, diabetes
Early stagelate stage- areas of reduced/absent vision, contraction of visual field (peripheral
central)
Acute Angle-Closure Glaucoma
- Emergency
- Obstruction of flow between iris and lens
onset of pain, nausea, colored halos, rainbows around light
- Red, teary eye with hazy cornea and fixed, mid-dilated pupil (not reactive to light) that is firm to
palpation
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Indirect Cholinergic Agonists (Reversible Anticholinesterases)
Physostigmine
Neostigmine
Pyridostigmine
Edrophonium
Demecarium
Ambenomium
1. How do the so-called “indirect cholinergic agonists” increase cholinergic stimulation? (LP p50)
• Allowing acetylcholine to
• No direct effect on the acetylcholine receptor
Physostigmine
2. What is the mechanism of action of physostigmine? (LP p50)
• Substrate for
(AchE)
• Binds to AchE and
the enzyme
3. What are the therapeutic uses of physostigmine? (LP p50)
• Increases intestinal and bladder motility
• Atony of bladder or
•
• Treat overdoses of
drugs
Neostigmine
4. Does neostigmine cross the blood brain barrier (BBB)? (LP p51)
5. What are the therapeutic uses of neostigmine? (LP p51)
• Bladder atony and
• Antidote to
(tubocurarine, vecuronium, rocuronium)
• Treatment of myasthenia gravis
Demecarium
6. What are the therapeutic uses of demecarium? (LP p51)
• Chronic
in patients refractory to other drugs
•
after iridectomy
• Diagnosis and treatment of accommodative esotropia
Edrophonium
7. What is the therapeutic use of edrophonium? (LP p51)
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Myasthenia Gravis
8. What is the pathophysiology of myasthenia gravis?
9. What is the common presentation of myasthenia gravis?
•
– muscles become progressively weaker with activity
• With rest, strength improves
10. What is myasthenic crisis?
Rapidly progressive weakness, especially in
muscles
11. What is the most common presentation of myasthenia gravis as seen on tests?
(drooping of the eyelids) or
(double vision) that worsens throughout the day
12. What test can be performed to make the diagnosis of myasthenia gravis?
13. What thymus pathology is associated with myasthenia gravis?
• 50% associated with thymic
• 20% associated with thymic
• 15% associated with
14. What are the treatment options for myasthenia gravis?
•
• Corticosteroids
• Thymectomy
• Plasmapheresis
15. What is the therapeutic use of pyridostigmine? (LP p51)
of myasthenia gravis
Alzheimer’s Disease
Tacrine
Donepezil
Rivastigmine
Galantamine
16. Why is tacrine rarely used for Alzheimer’s Disease? (LP p51)
Tacrine has to be taken
times a day
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17. How do cholinesterase inhibitors affect Alzheimer’s disease? (LP p51)
• Increase acetylcholine
•
progression of Alzheimer’s disease
• Cannot
progression or
Alzheimer’s disease
Irreversible Anticholinesterases
Malathion
Echothiophate
18. What is the mechanism of action of organophosphates? (LP p52)
• Bind covalently to
• Causes
increase in acetylcholine
19. What are the uses of the organophosphates parathion and malathion? (LP p52)
•
• Malathion used for
(pediculosis) or
20. What are the effects of echothiophate? (LP p52)
• Generalized cholinergic stimulation
• Paralysis of motor function
•
21. What is the therapeutic use of echothiophate? (LP p52)
22. On tests, what two features are clues to a diagnosis of organophosphate poisoning?
• Patient is a
or
•
23. What is the treatment of organophosphate poisoning?
• Protect yourself (
• Remove patient’s clothing and
•
•
)
24. What is the name of the process by which organophosphate inactivation of acetylcholine esterase becomes
permanent? (LP p52)
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Quick Review 3
1. Physostigmine can be used as an antidote for overdoses of what drugs? (LP p50)
•
• Phenothiazines
• Neuroleptic drugs
• Tricyclic antidepressants
2. List some actions of physostigmine. (LP p51)
• Contraction of
•
• Hypotension
• Bradycardia
3. A 35-year-old patient is about to undergo surgery. Her anesthesiologist administered rocuronium (a
neuromuscular blocking agent) to temporarily paralyze the patient during surgery. Once surgery is over, what
medication can you give to reverse the paralysis that was induced?
4. What medication is used in the treatment of myasthenia gravis and what medication is used to diagnose the
disease? (LP p51)
• Treatment – neostigmine,
, ambenomium
• Diagnosis –
5. What is the antidote for edrophonium toxicity? (LP p51)
6. Alzheimer’s disease results from a decrease in acetylcholine in the CNS. What other disease also has a
decrease in acetylcholine?
7. What drug regenerates acetylcholinesterase if given early in organophosphate poisoning?
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End of Session Quiz
1. What effects do the following chemicals have on acetylcholine release? (LP p43-45)
Chemical
↑intracellular Ca2+
↑intracellular ATP
Botulinum toxin
Black widow spider venom
ACh release
2. Match the following drugs with their clinical uses.
Post-operative ileus
Smoking cessation
Sjogren’s syndrome
Reversal of neuromuscular blockade
Diagnosis of asthma
Alzheimer’s Disease
a.
b.
c.
d.
e.
f.
Bethanechol
Cevimiline
Donepezil
Methacholine
Neostigmine
Varenicline
3. What is the clinical use for the organophosphate malathion?
4. A 63-year-old black woman presents with sudden onset of pain and tearing in the right eye, with colored
“rings” in her field of vision. On examination, her right eye is red, the pupil is fixed, and the globe is firm to
palpation. What drug should be given for acute management?
5. A 30-year-old schizophrenic male now has urinary retention due to his neuroleptic. What do you treat it
with?
6. If atropine is not effective in reversal of organophosphate poisoning, then which drug would you consider
adding on? (LP p52)
7. What are the three cholinesterase inhibitors commonly used in Alzheimer’s disease treatment? (LP p51)
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8. A gardener presents with shortness of breath, salivation, miosis, and diarrhea. What is the diagnosis? What is
the mechanism of action of this condition?
9. A 52-year-old man presents with a complaint of muscle weakness and double vision that gets progressively
worse throughout the day? What drug is used to confirm the diagnosis, and what drug is used for chronic
management? (LP p51)
10. Match the agents below with their mechanism of action.
Echothiophate
a. Direct cholinergic agonist
Tacrine
b. Reversible cholinesterase inhibitor
Pralidoxime
c. Irreversible cholinesterase inhibitor
Pilocarpine
d. Reactivation of acetylcholinesterase
Galantamine
Bethanechol
Donepezil
Rivastigmine
Cevimiline
Edrophonium
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