M.

Babbini, MD, PhD Anticholinergic Drugs

Anticholinergic Drugs

Drug Classes and Drugs to consider *

Antimuscarinic Drugs Ganglionic blocking Drugs
Tertiary amines Quaternary ammonium Mecamylamine
compounds
(Glycopyrrolate)
Atropine Glycopyrrolate (Ipratropium)
Scopolamine Ipratropium
Homatropine
Darifenacin
(Benztropine)
* Drugs in brackets have been already mentioned elsewhere

Learning Objectives
Mechanism of action
- Explain the mechanism of action of antimuscarinic drugs.
- Explain the difference between the mechanism of action of tertiary amines and that of quaternary ammonium
compounds.
- Explain the mechanism of action of ganglionic blocking drugs

Actions on organ system s

- Describe the sensitivity of different organs to the action of antimuscarinic drugs.
- Describe the actions of antimuscarinic drugs upon various organ systems.
- Relate the action of antimuscarinic drugs to the blockade of specific receptors.
- Describe the actions of ganglionic blocking drugs upon various organ systems.
- Relate the action of ganglionic blocking drugs to the blockade of specific receptors.

Pharmacokinetics
- Describe the route of administration of antimuscarinic drugs.
- Contrast the pharmacokinetics of tertiary amines and that of quaternary ammonium compounds.

Adverse effects, drug interactions and contraindications

- Describe the adverse effects antimuscarinic drugs.
- Describe the acute poisoning by antimuscarinic drugs.
- Outline the contraindications of antimuscarinic drugs.
- Outline the effects of different autonomic drugs in a subject pretreated with a ganglionic blocking drug.

Therapeutic uses
- Describe the main therapeutic uses of antimuscarinic drugs.
- Describe the main therapeutic uses of ganglionic blocking drugs.

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M. Babbini, MD, PhD Anticholinergic Drugs

PHARMACOLOGY OF ANTIMUSCARINIC DRUGS

Source and chemistry
- Atropine and scopolamine are natural alkaloids found in several
plants (Atropa belladonna, Datura stramonium, Hyoscyamus niger, etc.)
- All other compounds are synthetic drugs (tertiary or quaternary
amines)

Mechanism of action
- All antimuscarinic drugs competitively block muscarinic
receptors
- The effectiveness of this blockade (that is the affinity for the receptor)
varies with the antagonist and with the sensitivity of the tissue.
- Atropine and scopolamine block all subgroups of M receptors
- Other antimuscarinic drugs may have selectivity for one or another
subgroup of M receptors.

- Tertiary antimuscarinic drugs have negligible blocking activity at

ganglionic Nn receptors.

- Quaternary compounds mainly block muscarinic receptors but

also exhibit a significant blocking activity at ganglionic Nn
receptors.

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M. Babbini, MD, PhD Anticholinergic Drugs

RELATIVE RECEPTOR AFFINITY OF ANTIMUSCARINIC DRUGS

Drug Receptors
M1 M2 M3 Nicotinic
Atropine +++ +++ +++ 0,+
Tertiary amines
Darifenacin 0,+ 0,+ +++ 0,+

Quaternary Glycopyrrolate, +++ +++ +++ ++

ammonium Ipratropium, etc.
compounds

SENSITIVITY OF DIFFERENT ORGANS TO ATROPINE

Dose (mg) Affected organs
low Heart (M2 autoreceptors on parasympathetic
terminals); lacrimal, salivary and sweat glands.

Intermediate Above organs affected; heart (M2 receptors);

sphincter muscle of iris ; ciliary muscle ;
CNS(depression).

High Above organs more affected; intestinal, bronchial and

bladder smooth muscle; gastric glands;
CNS(excitation).

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M. Babbini, MD, PhD Anticholinergic Drugs

PHARMACODYNAMICS OF ANTIMUSCARINIC DRUGS (1)

[The following effects are referred to atropine and scopolamine, unless
otherwise specified]

Central nervous system

1) After intermediate doses:
- Mild central vagal stimulation.
- Fatigue, sedation, drowsiness, dreamless sleep
- Depression of the vestibular function (blockade of M receptors in
vestibular nuclei) (this effect is more pronounced with scopolamine)
- Reduction of parkinsonian tremor and rigidity.

2) After high doses:

- Amnesia, malaise, restlessness, irritability, disorientation,
hallucinations, delirium. Central stimulation is followed by depression
(coma).
(old and very young patients are particularly prone to CNS effects)

Cardiovascular system (heart)

- S-A node:
1) after low doses:
decrease in heart rate (likely due to blockade of M2 presynaptic
autoreceptors located on postganglionic cholinergic terminals and to
central vagal stimulation)
2) after intermediate doses: tachycardia (mild or absent in infancy and
old age). Many types of reflex vagal cardiac slowing can be abolished.

- Atria: increase in automaticity and contractility.

- A-V node: increase in conduction and automaticity; decrease in
refractoriness.
- Ventricles: minimal direct effects on myocardial cells (postsynaptic
muscarinic receptors are very few in the ventricles)

Cardiovascular system (vessels)

- 1) after therapeutic doses:
negligible effects on circulation (but vasodilation and hypotension
caused by choline esters are readily antagonized)
- 2) after high doses: dilatation of cutaneous blood vessels (mechanism
unknown). In children even therapeutic doses can cause this ‘atropine
flush’.

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M. Babbini, MD, PhD Anticholinergic Drugs

PHARMACODYNAMICS OF ANTIMUSCARINIC DRUGS (2)

Gastrointestinal system
- Decreased gastric secretion.(secretion of H+ as well as of HCO3- is
blocked, so concentration of gastric acid is not necessarily lowered).
- Decreased tone, amplitude of contractions, peristaltic activity and
secretions of intestinal tract.
- Relaxation of the lower esophageal sphincter.
- Mild relaxation of gallbladder and bile ducts.

(since noncholinergic neurons also modulate GI functions the effects of

vagal nerve stimulation are less effectively blocked than the effects of
exogenous muscarinic stimulants)

Genitourinary system
- Relaxation of pelves, calyces and ureters.
- Decreased ureteral peristalsis.
- Relaxation of detrusor muscle (which leads to an increased capacity of
the bladder).

Respiratory system
- Bronchial smooth muscle relaxation.
- Decreased tracheobronchial secretions (not with ipratropium).
- Decreased mucociliary clearance (not with ipratropium).

Eye
- Relaxation of the sphincter of iris (mydriasis).
- Relaxation of the ciliary muscle which leads to cycloplegia
(accommodation for near vision is lost) and hinders the outflow of
aqueous humor through the Schlemm’s canal.
-When atropine is given locally the mydriatic and cycloplegic effects are
long-lasting (3 days or more)
- Decreased secretion of lacrimal glands.

Skin
- Decreased secretion of sweat glands (this decrease can raise body
temperature, especially in hot climates. Infants and children are
particularly prone to ‘atropine fever’)

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M. Babbini, MD, PhD Anticholinergic Drugs

PHARMACOKINETICS OF ANTIMUSCARINIC DRUGS

ABSORPTION
- Oral bioavailability: variable
(atropine .50%; ipratropium >1%)

DISTRIBUTION
- Tertiary amines distribute in all tissues.
- Quaternary derivatives do not enter the CNS.

BIOTRANSFORMATION
- About 50% of atropine and 90% of scopolamine are metabolized by
the liver.
EXCRETION
- About 60% of atropine is excreted by the kidney.
Half-lives: Atropine and scopolamine: . 3 hours;
Glycopyrrolate: . 10 hours

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M. Babbini, MD, PhD Anticholinergic Drugs

TOXICITY OF ANTIMUSCARINIC DRUGS

Side effects
- They are unwanted effects that occur after the administration of
therapeutic doses and are consequences of the pharmacological actions
of these drugs. They largely depend on the therapeutic uses of the drug.
Thus, when atropine is used to treat diarrhea, the appearance of
tachycardia is considered a side effect, but when the same drug is used
to counteract sinus bradycardia, the appearance of constipation is
regarded as a side effect.

Allergic reactions
- Skin rashes , urticaria, fever.

Acute poisoning
- Atropine has a good therapeutic index (>100) in adults, but a dose of 5
mg can be lethal for children.

- Symptoms and signs are due to:

a) peripheral muscarinic receptor blockade
b) central muscarinic receptor blockade

- In case of serious atropine poisoning symptoms and signs appears

within 30-60 minutes after ingestion and may last 2-7 days.

- The death, due to respiratory failure, may follow a period of circulatory

collapse and coma.

- Diagnosis is easy in severe cases. An IM injection of physostigmine

may be used for confirmation. If signs of muscarinic activation do not
occur poisoning with antimuscarinic drug is almost certain.

- Treatment is mainly symptomatic. Physostigmine rapidly abolish the

delirium and coma but is reserved for severe cases since some experts
consider the drug more dangerous and no more effective than
symptomatic treatment, in mild intoxication.

- Symptomatic treatment usually include:

a) Maintenance of vital signs
b) Alleviation of convulsion with diazepam
c) Temperature control with ice bags and alcohol sponges.

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M. Babbini, MD, PhD Anticholinergic Drugs

POISONING BY ANTIMUSCARINIC DRUGS

Organ or system Symptoms and signs
Body temperature Hyperthermia can be very high (104.9° F, 40.5° C)
Eye Mydriasis (iris practically obliterated), blurring of
near vision, dryness of conjunctiva.
Respiratory system Difficulty in speaking, dyspnea, respiratory
depression.
Skin Dry, hot, and red skin.
GI systems Dryness of mouth; thirst; difficulty in swallowing;
absence of bowel sounds; paralytic ileus.
Urinary system Difficulty in micturition.
Cardiovascular Tachycardia, palpitations, arrhythmias.
system
CNS Fatigue, ataxia, headache, restlessness,
hallucinations, delirium, generalized convulsions,
coma.

CONTRAINDICATIONS AND PRECAUTIONS

OF ANTIMUSCARINIC DRUGS
- Glaucoma
- Prostatic hypertrophy
- Urinary tract obstruction
- Gastrointestinal tract obstruction
- Adynamic ileus
- Gastric ulcer
- Severe infectious diarrhea
- Reflux esophagitis
- Ulcerative colitis, Crohn’ disease (toxic megacolon can ensue)
- Tachyarrhythmias
- Coronary artery disease, cardiac failure
- Hyperthyroidism
- Children
- Elderly

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M. Babbini, MD, PhD Anticholinergic Drugs

THERAPEUTIC USES OF ANTIMUSCARINIC DRUGS

Eye
- For funduscopic examination (mydriasis)
- For measurements of refractive errors (cycloplegia)
- Iritis, iridocyclitis, choroiditis (to prevent adhesion formation)

Gastrointestinal system
- Irritable bowel syndrome (when diarrhea is the prevalent symptom)
- Abdominal colic, biliary colic.
- Diarrhea (from mild dysentery, traveler’s disease, diverticulitis, or drug
induced).
- Sialorrhea (due to heavy-metal poisoning or parkinsonism).
- Motion sickness prevention and treatment (scopolamine)

Urinary system
- Renal colic, enuresis.
- Urge incontinence (to reduce urinary frequency).

Respiratory system
- Preoperative use (to decrease bronchial secretions)
- Bronchial asthma and chronic obstructive pulmonary disease
(ipratropium: other antimuscarinic drugs are not indicated since, unlike
ipratropium, they decrease bronchial secretions and mucociliary
clearance)

Cardiovascular system
- Cardiopulmonary resuscitation (when vagal hyperactivity is the cause
of cardiac arrest).
- Sinus or nodal bradycardia (due to myocardial infarction, hyperactive
carotid sinus reflex, etc.)
- A-V block (due to increased vagal tone).
- Preoperative use (to block cardiovagal reflexes)

Central nervous system

- Parkinson’s disease (Benztropine)

Other uses
- To counteract the parasympathomimetic effects of neostigmine in
myasthenic patients.
- To cure poisoning by AchE inhibitors or by certain mushrooms
containing muscarine.
- To decrease sweating (glycopyrrolate applied topically or given IM)
- To decrease rhinorrhea (ipratropium by nasal spray)

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M. Babbini, MD, PhD Anticholinergic Drugs

SUMMARY OF CLINICAL USES OF ANTIMUSCARINIC DRUGS

Drug Clinical uses
Tertiary amines
Atropine -Visceral hypermotility and spasms
-Excessive salivation
-Cardiovascular disorders
-Cholinesterase inhibitor overdose
-Ophthalmology
-Preanesthetic medication
Scopolamine -Motion sickness
-Ophthalmology
-Preanesthetic medication
Homatropine -Ophthalmology

Darifenacin - Overactive bladder (urge incontinence)

Benztropine -Parkinson’s disease

Quaternary ammonium compounds

Glycopyrrolate -Visceral hypermotility and spasms
-Cardiovascular disorders
-Preanesthetic medication

Ipratropium -Bronchospastic disorders

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M. Babbini, MD, PhD Anticholinergic Drugs

CLASSIFICATION OF GANGLIONIC BLOCKING DRUG

Main drugs with ganglionic blocking activity
Mecamylamine
(Nicotine)
Other drugs with significant ganglionic blocking activity
- Glycopyrrolate
- Ipratropium

- Tubocurarine

PREDOMINANT TONE (PT) OF THE AUTONOMIC NERVOUS

SYSTEM AND EFFECTS OF GANGLIONIC BLOCKADE
Site PT Effect of ganglionic blockade
Heart P Tachycardia
Arterioles Sa Vasodilation, orthostatic
hypotension
Veins Sa Vasodilation; venous pooling;
decreased cardiac output
Iris P Mydriasis
Ciliary muscle P Cycloplegia
GI tract P Decreased motility and tone
(constipation, gas accumulation)
Urinary bladder P Urinary retention
Exocrine glands P Reduced secretion
Sweat glands Sc Reduced secretion (anhidrosis)
Sex organs (Male)
Erection P Impaired erection
Ejaculation Sa Impaired ejaculation
P = Parasympathetic system
S c = Sympathetic system (cholinergic)
S a = Sympathetic system (adrenergic)

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M. Babbini, MD, PhD Anticholinergic Drugs

PHARMACOLOGY OF GANGLIONIC BLOCKING DRUGS

Drugs
-Mecamylamine, a secondary amine, is the only compound still on the
market in USA.

Mechanism of action
-Competitive blockade of nicotinic receptors (Nn) in:
a) autonomic ganglia
b) adrenal medulla
c) presynaptic nerve terminals
d) central nervous system (mecamylamine)

Pharmacological effects
Cardiovascular system
- Moderate increase in heart rate
- Decreased cardiac output (in spite of the increase in heart rate,
because the peripheral venous pooling decreases the preload).
- Marked decrease in venous tone and peripheral vascular resistance
(which leads to hypotension, mainly in the upright position).
- Skin blood flow is increased, splanchnic and renal blood flow are
decreased.

Other systems
- Effects on other systems can be predicted by knowing which division of
the autonomic nervous system exercises dominant controls of various
organs (see table above).

Pharmacokinetics
-Mecamylamine is is active by oral route and can enter the brain.

Therapeutic uses
- Because of the availability of more selective autonomic blocking agents
the therapeutic applications of ganglionic blockers have virtually
disappeared.
- Low dose mecamylamine has been proposed recently as an adjunct to
nicotine preparations to reduce nicotine craving in patient’s attempting to
quit smoking.

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M. Babbini, MD, PhD Anticholinergic Drugs

Anticholinergic Drugs
(Practice questions)

1) A 28-year-old woman experienced severe motion sickness whenever she traveled by air
or sea. She feels much better after using a transdermal scopolamine patch before traveling.
The blockade of receptors located in which of the following structures most likely
contributed to the therapeutic effect of the drug in the patient’s disorder?

A) Intestinal submucosal plexus

B) Vestibular nuclei
C) Intestinal myenteric plexus
D) Smooth muscles of the stomach wall
E) Motor nucleus of vagus nerve
F) Parasympathetic ganglia

2) Pretreatment with mecamylamine will most effectively counteract which of the following
drug-induced effects?

A) Neostigmine-induced increase in intestinal peristalsis

B) Nicotine-induced contraction of skeletal muscle
C) Norepinephrine-induced bradycardia
D) Epinephrine-induced tachycardia
E) Propranolol-induced hypotension

3) Which of the following drugs can most likely prevent the fast EPSP in an autonomic
ganglion cell?

A) Atropine
B) Neostigmine
C) Atropine
D) Pilocarpine
E) Dopamine
F) Ipratropium

4) A 45-year-old man collapsed at work and was found to be unresponsive. When the
paramedics arrived he had ventricular fibrillation and was cardioverted successfully. He was
admitted to the coronary unit but shortly thereafter he developed asystole. Cardiopulmonary
resuscitation was started and escalating doses of epinephrine were given without success.
Another drug was tried. Which of the following drugs was most likely administered?

A) Neostigmine
B) Norepinephrine
C) Dopamine
D) Atropine

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M. Babbini, MD, PhD Anticholinergic Drugs

E) Ipratropium

5) Which of the following molecular actions can result from the blockade of M3 receptors by
antimuscarinic drugs in non-vascular smooth muscle?

A) Less negative resting membrane potential

B) Binding of Ca++ to troponin C
C) Increased concentration of cytosolic calcium
d) Decreased synthesis of intracellular IP3
E) Direct opening of K+ channels

6) Which of the following is an effects of atropine upon the respiratory system?

A) Increased contraction of airway smooth muscle

B) Increased secretion of bronchial glands
C) Decreased mucociliary clearance
D) Decreased pulmonary vital capacity
E) Decreased diaphragmatic performance

7) Which of the following is a common side effect of quaternary ammonium antimuscarinic

drugs?

A) Urge incontinence
B) Drowsiness
C) Difficulty in near vision
D) AV block
E) Hallucinations

8) Antimuscarinic drugs usually increase the heart rate because they can counteract which
of the following acetylcholine-induced actions?

A) Release of nitric oxide

B) Opening of K+ channels in SA node
C) Decrease in cardiac contractility
D) Opening of Na+ channels in ganglionic neurons
E) Activation of cardiac presynaptic autoreceptors

9) Which of the following statements correctly pairs the antimuscarinic drug with one of its
common adverse effects?

A) Atropine - cough
B) Darifenacin - constipation
C) Glycopyrrolate -insomnia

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M. Babbini, MD, PhD Anticholinergic Drugs

D) Ipratropium -restlessness
E) Scopolamine - impairment of far vision

10) Antimuscarinic drugs are contraindicated, or should be used with caution, in which of the
following disease states?

A) Irritable bowel syndrome

B) Sialorrhea
C) Travelers’ diarrhea
D) Urinary urge incontinence
E) Sinus bradycardia
F) Ulcerative colitis

11) Pretreatment with atropine can most effectively counteract which of the following drug-
induced effects?

A) Physostigmine-induced sweating
B) Epinephrine-induced increased in blood pressure
C) Nicotine-induced increase in peripheral vascular resistance
D) Prazosin-induced reflex tachycardia
E) Scopolamine-induced sleepiness

12) A 87-year-old woman recently developed urinary incontinence. She was treated with
darifenacin, which was able to decrease the urge to urinate and the pain associated with it.
Which of the following molecular actions on detrusor muscle cells most likely mediated the
therapeutic effect of the drug in this patient?

A) Decreased potassium efflux

*) Decreased cytosolic calcium
C) Increased cAMP synthesis
D) Increased cGMP synthesis
E) Increased sodium influx

14) A 48-year-old man was admitted to the coronary unit with an acute myocardial infarction.
He had been suffering from a left bundle branch block which now changed into a Mobiz 1 AV
block. His heart rate decreased from 70 bpm to 45 bpm. Which of the following drugs would
be appropriate to manage the patient’s bradycardia?

A) Epinephrine
B) Propranolol
C) Clonidine
D) Phenylephrine
E) Atropine

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M. Babbini, MD, PhD Anticholinergic Drugs

15) A 35-year-old woman has been recently diagnosed with gastroesophageal reflux disease.
Which of the following drug classes would be contraindicated in this patient?

A) Beta-1 antagonists
B) Beta-1 agonists
C) M3-antagonists
D) M3-agonists
E) Alpha-2 agonists

16) A new synthetic drug was studied for its cardiovascular effects. The drug was given IV
to three laboratory animals while the blood pressure is recorded. The first animal received
no pretreatment, the second received an effective dose of mecamylamine before drug X, and
the third received an effective dose of atropine before drug X. The NET CHANGES (+ or -) in
mean blood pressure induced by drug X (not by the pretreatment) are shown in the following
table.

X Mecamylamine + X Atropine + X
Mean blood - 20 - 25 ±2
pressure (mm Hg)

Which of the following agents does the new drug most closely resemble?

A) Epinephrine
B) Acetylcholine
C) Propranolol
D) Nicotine
E) Histamine

17) A new synthetic drug was studied for its cardiovascular effects. The drug was given IV
to four laboratory animals while the heart rate was recorded. The first animal received no
pretreatment, the second received an effective dose of mecamylamine before drug X, the third
received an effective dose of atropine before drug X and the fourth received effective dose
of prazosin before drug X . The NET CHANGES (+ or -) in heart rate induced by drug X (not
by the pretreatment) are shown in the following table.

X Mecamylamine + X Atropine + X Prazosin + X

Heart rate (bpm) +50 +50 +50 +50

Which of the following agents does the new drug most closely resemble?

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M. Babbini, MD, PhD Anticholinergic Drugs

A) An anticholinesterase agent
B) A M2 receptor agonist
C) An alpha-1 antagonist
D) An alpha-2 agonist
E) A beta-1 agonist

18) A new synthetic drug was studied for its cardiovascular effects. The drug was given IV
to three laboratory animals while the blood pressure is recorded. The first animal received
no pretreatment, the second received an effective dose of mecamylamine before drug X, and
the third received an effective dose of atropine before drug X. The NET CHANGES (+ or -) in
mean blood pressure induced by drug X (not by the pretreatment) are shown in the following
table.

Pretreatment X Mecamylamine + X Atropine + X

Mean blood +20 ±2 + 25
pressure (mm Hg)

Which of the following agents does the new drug most closely resemble?

A) Acetylcholine
B) Nicotine
C) Epinephrine
D) Angiotensin II
E) Neostigmine

19) A new synthetic drug was studied for its cardiovascular effects. The drug was given IV
to four laboratory animals while the heart rate and blood pressure is recorded. The first
animal received no pretreatment, the second received an effective dose of prazosin before
drug X, third received an effective dose of propranolol before drug X and the fourth received
an effective dose of atropine before drug X. The net CHANGES (+ or -) in heart rate and mean
blood pressure induced by drug X (not by the pretreatment) are shown in the following table.

X Prazosin + X Propranolol + X Atropine + X

Heart rate (bpm) - 10 ±2 - 10 ±2
Diastolic blood +20 ±2 +20 +20
pressure
(mm Hg)

Which of the following agents does the new drug most closely resemble?

A) Norepinephrine

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M. Babbini, MD, PhD Anticholinergic Drugs

B) Epinephrine
C) Isoproterenol
D) Phenylephrine
E) Acetylcholine

20) A 32-year-old woman was in the ophthalmologist's office for an eye examination. The
ophthalmologist instilled a drug into the conjunctival sac in each eye. A few minutes later the
woman experienced photophobia and difficulty in near vision. Which of the following drugs
was most likely given to the patient?

A) Epinephrine
B) Homatropine
C) Carbachol
D) Phenylephrine
E) Physostigmine
F) Timolol

Anticholinergic Drugs
(Answers and explanations)

1) Answer: B
Antimuscarinic drugs are used in certain vestibular disorders including motion sickness and
Meniere’s disease. Their mechanism of action is most likely related to blockade of M1 receptors
located in the vestibular located, in chemoreceptor trigger zone and in solitary tract nucleus. This
blockade decreases the firing from these regions nuclei to the vomiting center, so nausea and
vomiting are prevented.
A, C, D, E, F) Nausea and vomiting due to motion are mediated mainly by central, not peripheral
effects.

2) Answer: C
Norepinephrine increases the mean blood pressure. This increase causes a stimulation of aortic
baroreceptors which activates the baroreceptor reflex. The increased vagal discharge overcomes
the direct effect of norepinephrine on the heart rate (an increase due to the activation of beta-1
receptors), so the final effects is a decrease in heart rate. Mecamylamine is a ganglionic blocker.
That impairs the baroreceptor reflex and therefore bradycardia is abolished.
A) Neostigmine is a cholinesterase inhibitor that increases the availability of acetylcholine at every
cholinergic synapse. Acetylcholine activates M3 receptors in the gut and Nn receptors in the
autonomic ganglia. Both actions contribute to the increase in intestinal peristalsis. A ganglionic
blocker can prevent the activation of Nn receptors but has no effect on the activation of M3 receptors.
Therefore peristalsis will be decreased, but not completely abolished.
B) Nicotine-induced contraction of skeletal muscle is due to activation of Nm receptors. Ganglionic
blockers have negligible activity on these receptors.

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M. Babbini, MD, PhD Anticholinergic Drugs

D) Epinephrine induced tachycardia is due to the activation of cardiac beta-1 and beta-2 receptors.
A ganglionic blocker cannot block these receptors.
E). Ganglionic blockers actually cause hypotension by blocking the sympathetic discharge to the
vessels. Therefore the propranolol-induced hypotension is in fact enhanced, not prevented.

3) Answer: F
Ipratropium is an antimuscarinic drug that also has significant Nn receptor blocking activity.
Since the activation of Nn receptor in autonomic ganglia mediates the fast EPSP production,
blockade of these receptors can prevent the EPSP.
B) Neostigmine is a cholinesterase inhibitor and therefore it increases acetylcholine availability at all
cholinergic synapses. As a consequence the fast EPSP would be enhanced, not, prevented.
A, C, D, E) These drugs have negligible blocking activity on Nn receptors and therefore have no
effect on fast EPSP.

4) Answer: D
Asystole is the complete ECG absence of electrical activity. Its development usually indicates a
prolonged cardiac arrest and carries a very grave prognosis.
In the treatment of asystole epinephrine is the initial agent of choice to hopefully generate a rhythm.
Since enhanced parasympathetic tone, possibly also due to chest compression, may play a role in
inhibiting supraventricular and ventricular pacemakers, anticholinergic drugs may be beneficial, and
atropine is usually tried when epinephrine fails.
A) Neostigmine increases cholinergic activity and is therefore absolutely contraindicated in this
setting.
B, C) When epinephrine does not work, the choice of other sympathomimetic drugs is irrational.
E) Ipratropium is an anticholinergic agent but is only used by inhalatory route in bronchospastic
disorders.

5) Answer: D
The postreceptor mechanism triggered by activation of M3 receptors is the stimulation of
phospholipase C which in turn increases the synthesis of IP3. By blocking M3 receptors the opposite
occurs.
A) When M3 receptors are activated by acetylcholine the membrane potential of a smooth muscle
becomes less negative, that is the muscle is more excitable. This explains the increase in tonic
tension and in the number of contractions brought about by acetylcholine. By blocking M3 receptors
antimuscarinic drugs cause the opposite, that is the resting membrane potential becomes more
negative, not less negative, and the muscle is less excitable.
B) In smooth muscle CA++ binds to calmodulin, not to troponin C.
C) Since the synthesis of intracellular IP3 is decreased concentration of cytosolic calcium is
decreased, not increased.
E) Potassium channels are mainly regulated by M2 receptors, not by M3 receptors.

6) Answer: C
Antimuscarinic drugs (except ipratropium and tiotropium) decrease mucociliary clearance, an effect
that contraindicates these drugs in asthmatic patients.

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M. Babbini, MD, PhD Anticholinergic Drugs

A, B, D) Actually antimuscarinic drugs do the opposite.

E) Diaphragm is a skeletal muscle and therefore is not under the control of the autonomic nervous
system.

7) Answer: C
Quaternary ammonium antimuscarinic drugs mainly block muscarinic receptors but also exhibit a
significant blocking activity at ganglionic Nn receptors. The blockade of M3 receptors in the ciliary
muscle and of Nn receptors in the ciliary ganglion cause cycloplegia with loss of accommodation for
near vision.
A) Urge incontinence is due to contraction of the detrusor muscle. By blocking M3 receptors
antimuscarinic drugs actually cause relaxation, not contraction, of the detrusor muscle.
B, E) Quaternary ammonium antimuscarinic drugs do not cross the blood brain barrier so these
effects are unlikely.
D) By blocking M2 receptors in the heart antimuscarinic drugs increase AV conduction, so AV block
is unlikely.

8) Answer: B
By activating M2 receptors acetylcholine opens K+ channels in the SA node. This increases the
outward K+ current and the membrane becomes hyperpolarized. The result is a decrease in firing
rate of the SA node. By blocking M2 receptors antimuscarinic drugs counteract the acetylcholine-
induced opening of K+ channels in the SA node. The firing rate of the SA node is increased so
causing an increase in heart rate.
A) Acetylcholine-induced release of nitric oxide causes vasodilation which could lead to reflex
tachycardia. By counteracting this action antimuscarinic drugs would decrease, not increase ,the
heart rate.
C) Antimuscarinic drugs can counteract acetylcholine-induced decrease in cardiac contractility, but
this has nothing to do with the increase in heart rate.
D) Acetylcholine-induced Opening of Na+ channels in ganglionic neurons is mediated by the
activation of Nn receptors. Antimuscarinic drugs have weak or negligible blocking activity on these
receptors.
E) The blockade of presynaptic autoreceptors increases the release of acetylcholine from cholinergic
terminals. This would decrease, not increase, the heart rate.

9) Answer: B
Darifenacin is a selective M3 receptor antagonist. The drug-induced decrease in intestinal peristalsis
can lead to constipation.
A) By causing bronchodilation atropine can actually relieve cough.
C, D) Ipratropium and glycopyrrolate are quaternary ammonium compound that do not enter the
brain. Therefore central adverse effects are quite unlikely.
E) By causing cycloplegia scopolamine impairs the near, not the far vision.

10) Answer: F
Antimuscarinic drugs decrease intestinal peristalsis. In case of severe inflammatory bowel diseases,

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M. Babbini, MD, PhD Anticholinergic Drugs

this can cause toxic megacolon.

A, B, C, D, E) These options are indications, not contraindications, to the use of antimuscarinic drugs

11) Answer: A
Physostigmine is a cholinesterase inhibitors and therefore it can increase the availability of
acetylcholine at cholinergic neuroeffector junctions. Activation of M3 receptors in sweat glands
promotes sweating. By blocking these receptors atropine can counteract this action.
B) Epinephrine increase blood pressure by activating alpha-1 and beta-1 receptors. These receptors
are not affected by atropine.
C) Nicotine can increase peripheral vascular resistance by activating Nn receptors at sympathetic
ganglia. Atropine has negligible effects on Nn receptors.
D) Prazosin can cause reflex tachycardia by blocking alpha-1 receptors which in turn decreases the
blood pressure. Atropine actually can cause tachycardia and therefore it can increase, not
counteract, the action of prazosin.
E) Scopolamine and atropine are belladonna alkaloids with very close pharmacological properties.
Therefore the effects of the two drugs enhance, not antagonize, each other.

12) Answer: B
Darifenacin is a relatively selective M3 antagonist currently used to treat urge incontinence.
Activation of M3 receptors by acetylcholine increases the synthesis of IP3 which in turn triggers the
release of calcium from storage vesicles. Blockade of M3 receptors does the opposite, so the
availability of cytosolic calcium in smooth muscle cells is decreased and the muscle relaxes.
Relaxation of the detrusor muscle of the bladder relieves the urge to urinate.
A, C, D, E) (see explanation above)

13) Answer: B
Darifenacin is a selective M3 antagonist currently used to treat urge incontinence. Activation of M3
receptors by acetylcholine increases the synthesis of IP3 which in turn triggers the release of calcium
from storage vesicles. Blockade of M3 receptors does the opposite, so the availability of cytosolic
calcium in smooth muscle cells is decreased and the muscle relaxes. Relaxation of the detrusor
muscle of the bladder relieves the urge to urinate.
A) This effect is caused by blockade of M2 receptors, not by blockade of M3 receptors.
C, D, E) Antimuscarinic drugs do not cause any of these effects.

14) Answer: E
When complicating an inferior myocardial infarction, AV block often results from an increased
parasympathetic tone and usually respond to atropine. Sometimes the block resolve spontaneously,
but in the present case the block must be treated since the heart rate is too low for a sufficient
cardiac output.
A) Epinephrine can increase the heart rate but is usually contraindicated in myocardial infarction,
since it increases the heart workload and oxygen consumption. Moreover in this case bradycardia
is due to acetylcholine. Epinephrine is a physiologic antagonist of acetylcholine whereas atropine is
a pharmacological antagonist. As a general rule, pharmacological antagonism is much better than

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M. Babbini, MD, PhD Anticholinergic Drugs

physiologic antagonism, in most cases.

B, D, E) These drugs are actually contraindicated because they decrease, not increase, the heart
rate.

15) Answer: C
Gastroesophageal reflux disease is one of the most prevalent gastrointestinal disorders. Population
based studies show that it affects up to 15% of individuals. The disease is due to incompetence of
the lower esophageal sphincter. This sphincter receives mainly parasympathetic innervation and
remains tonically constricted. When this constriction is insufficient the gastric content can go back
into the esophagus. The esophageal mucosa is not capable of resisting the digestive action of gastric
secretion and erosion occurs. This explains the heartburn, which is the most prominent symptom of
the disease.
All drugs that relax smooth muscle are contraindicated in gastrointestinal reflux disease.
Antimuscarinic drugs can be especially dangerous, since the sphincter is rich of M3 cholinergic
receptors.
A, B) Contraction of the smooth muscle is not mediated by beta-1 receptors.
D) M3-agonist increase the contraction of lower esophageal sphincter. Therefore these drugs would
be indicated, not contraindicated, in gastroesophageal reflux disease.
E) Alpha-2 agonists have negligible effects on nonvascular smooth muscle.

16) Answer: B
Blood pressure (BP) is equal to cardiac output (CO) by total peripheral resistance (TPR). Therefore,
in order to decrease the mean BP a drug must decrease either CO or TPR or both. Among the listed
drugs, acetylcholine and propranolol ( mainly by decreasing CO) and histamine ( mainly by
decreasing TPR) would cause a fall in mean blood pressure. The fall is not blocked by a pretreatment
with a ganglion blocker, suggesting that the depressor effect must be evoked at a site distal to the
ganglia. The fall is instead blocked by atropine and therefore a direct acting muscarinic stimulant like
acetylcholine must be the drug under study. The drop in BP is actually greater in the present of
ganglion blockade. Likely the acetylcholine-induced vasodilation has elicited a reflex sympathetic
discharge that has blunted the full depressor action of the drug in the untreated animal.
A, D) Epinephrine and nicotine usually increase, not decrease, the mean blood pressure.
C) Propranolol-induced decrease of blood pressure would not be antagonized by atropine. In fact,
by blocking the parasympathetic action in the heart atropine can cause a sympathetically-mediated
increase in cardiac rate (and therefore in cardiac output) but this cannot occur when the animal is
treated with propranolol.
E) Histamine-induced decrease of blood pressure would not be antagonized by atropine. In fact the
decrease is due to peripheral vasodilation and atropine has very little effect on vessels.

17) Answer: E
The drug causes an increase in heart rate that is not influenced by any of the blockers. Therefore
the drug must activate directly beta-1 receptors in the heart.
A, B) Drugs that activate indirectly (anticholinesterase drugs) or directly (M2 receptor agonists)
muscarinic receptors on the heart would tend to cause a decrease, not an increase, in heart rate.
C) A drug that activates alpha-1 receptors causes vasodilation and therefore a decrease in blood

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M. Babbini, MD, PhD Anticholinergic Drugs

pressure. This decrease in turn can cause reflex tachycardia. However this tachycardia would have
been prevented by a pretreatment with a ganglionic blocker, which blocks the neuronal transmission
in the efferent portion of the reflex arch.
D) A drug that activate alpha-2 receptors causes a decreased release of norepinephrine from cardiac
adrenergic terminals, therefore causing a decrease, not an increase, in heart rate.

18) Answer: B
The drug causes an increase in mean blood pressure when given alone. This suggests that it must
be similar to nicotine, angiotensin II or epinephrine. The increase is blocked by a ganglion blocker
and is instead increased by atropine. This indicated that the increase is due to ganglionic
sympathetic stimulation which is more evident when the vagal activity to the heart is blocked by
atropine.
A, E) Acetylcholine and neostigmine usually cause a decrease of mean blood pressure.
C) Epinephrine-induced increase of mean blood pressure is due to beta-receptor activation on the
heart and alpha-receptor activation on he vessels. Therefore it would not be prevented by ganglionic
blockade.
D) Angiotensin II- induced increase of mean blood pressure is due to activation of angiotensin
receptors in the vessel. Therefore it would not be prevented by ganglionic blockade.

19) Answer: D
The drug causes an increase in diastolic blood pressure and a decrease in heart rate. This suggests
that the increased blood pressure has caused a reflex bradycardia. Among the listed drugs only
norepinephrine and phenylephrine can cause these effects, due in both cases to alpha-1 receptor
activation. In fact both effects are prevented by a pretreatment with prazosin and unaffected by
pretreatment with propranolol or atropine.
A) Norepinephrine-induced decrease in heart rate is due to reflex bradycardia which overcomes the
direct tachycardic effect due to beta-receptor activation. A pretreatment with atropine would
antagonize the reflex bradycardia (which is vagal-mediated) so unmasking the direct tachycardic
effect. By the same token a pretreatment with propranolol would antagonize the direct tachycardic,
effect so enhancing the reflex bradycardia. This does not occur with phenylephrine which is a pure
alpha agonist with no direct effects on the heart.
B) Epinephrine usually does not cause an increase in diastolic blood pressure since the alpha-1
mediated vasoconstriction is counterbalanced by the beta-2 mediated vasodilation.
C, E) Isoproterenol and acetylcholine decrease, not increase, the diastolic blood pressure.

20) Answer: B
Homatropine is an antimuscarinic drug that blocks M3 receptors in the sphincter muscle of iris and
in ciliary muscle. The relaxation of the sphincter muscle of iris increased pupillary diameter, thus
causing photophobia. The relaxation of ciliary muscle stretches the zonula fibers, which in turn pull
the lens capsule, thus decreasing lens curvature, which in turn causes difficulty in near vision.
A, C, D, E). (see explanation above)

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M. Babbini, MD, PhD Anticholinergic Drugs

ANTIMUSCARINIC AND
GANGLIONIC-BLOCKING DRUGS
Answer key
1) B 6) C
2) C 7) E
3) F 8) B
4) D 9) B
5) D 10) F
11) A 16) B
12) B 17) E
13) B 18) B
14) E 19) D
15) C) 20) B

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