INTRODUCTION TO

AUTONOMIC
PHARMACOLOGY
Enteric division
 1.Synthesis of acetylcholine
(Ach) via ChAT (choline acetyl
transferase)

2. Transport of Ach via VAT

(vesicle-associated transporter)
then storage of acetylcholine
(Ach) in vesicles

3. Release of
acetylcholine (Ach)

4. Binding to 6. Recycling of
the receptor choline

5. Degradation of
acetylcholine by
acetylcholine
esterase
 1.Synthesis of NE:
rate limiting step!

2.Storage of NE in vesicles:
Vesicular MonoAmine
Transporter; Dopamine β-
Hydroxylase
Cotransmission!!
3. Release of NE: AP,
voltage-sensitive
calcium channels 3. Release of NE
open, Vesicle Cotransmission!!
Associated
Membrane Protein

5. Recycling of NE:
NorEpinephrine
4. Binding to
Transporter
the receptor
(post- & pre- 6. Removal of NE:
synaptically) diffusion, MAO,
COMT
Action of sympathetic and parasympathetic nervous
systems on effector organs
OVERVIEW

Drugs affecting the autonomic nervous system (ANS) are

divided into two groups according to the type of neuron
involved in the mechanism of action:

a) The cholinergic drugs: they act on receptors that

are activated by acetylcholine (Ach)
b) The adrenergic drugs: they act on receptors that
are activated by norepinephrine or epinephrine

Cholinergic and adrenergic drugs both act by either

stimulating or blocking receptors of the ANS
CHOLINOCEPTOR-
A large group of drugs that
ACTIVATING & mimic the effect of
CHOLINESTERASE-INHIBITING acetylcholine
DRUGS (cholinomimetics)
 ILO’s
1. To learn the classification of cholinoceptor-activating
drugs and mechanism of action.
2. To learn the pharmacological effects of cholinoceptor-
activating drugs.
3. To understand major adverse reactions of
cholinoceptor-activating drugs.
4. To understand the pharmacological effects, therapeutic
applications and toxicity of cholinersterase-inhibiting
drugs.
CHOLINERGIC RECEPTORS (CHOLINOCEPTORS)

Cholinoceptor denotes receptors that respond to

acetylcholine

Two families/subtypes of cholinoceptors were

named after the alkaloids originally used in their
identification: nicotinic (N) and muscarinic (M)
receptors
 I. NICOTINIC (N) RECEPTORS

 These receptors, in addition to binding ACh, also

recognize nicotine, but show a week affinity for
muscarine

 N receptors are transmembrane polypeptide whose

subunits form cation-selective ion channels

 N receptors are located on plasma membranes of

postganglionic cells in all autonomic ganglia, muscles
innervated by somatic motor fibers (i.e.
Neuromuscular junction), and of some CNS neurons
 I. NICOTINIC (N) RECEPTORS

 Binding of 2 Ach molecules causes channel opening with

a rapid influx of sodium and potassium ions (calcium ions
may also carry charge through the nicotinic receptor ion
channel)

 This triggers depolarization of the cell and elicits a

neruronal action potential (in postganglionic nerve) or
muscle contraction (in skeletal muscles)

 N receptors located at the neuromuscular junction are

sometimes designated NM and the ganglionic (neuronal)
receptors are designated NN
II. MUSCARINIC (M) RECEPTORS

 These receptors, in addition to binding acetylcholine,

also recognize muscarine, but show a weak affinity for
nicotine

 These receptors have been found in the CNS, organs

innervated by parasympathetic nerves as well as on
some tissues that are not innervated by these nerves,
(eg, endothelial tissue) and on those tissues
innervated by postganglionic sympathetic cholinergic
nerves (sweat glands)
II. MUSCARINIC (M) RECEPTORS

 Contains 7 transmembrane domains whose third

cytoplasmic loop is coupled to G proteins

 Five subclasses of muscarinic receptors: M 1, M2, M3,

M4, and M5 have been identified

 These receptors have different signal transduction

mechanisms based on the G-protein to which they
are coupled (see table
 TABLE 1: Subtypes and Characteristics of Cholinoceptors

Receptor Postreceptor
Type Other Names Location Structural Features Mechanism
M
M11 Seven
Seven transmembrane
transmembrane IP
IP33,, DAG
DAG cascade
cascade
 Neural
 Neural Nerves
Nerves segments,
   segments, G
Gq/11 protein-linked
q/11protein-linked
  
Seven
Seven transmembrane
transmembrane Inhibition
Inhibition of
of cAMP
cAMP
M
M22 Cardiac
Cardiac M
M22 Heart,
Heart, nerves,
nerves, segments, G
segments, Gi/o protein-linked production,
i/o protein-linked production,
activation
activation of
of
      smooth
smooth muscle
muscle    K ++
channels!
K channels!
M Glands,
Glands, smooth
smooth Seven
M33  Glandular muscle, vascular Seven transmembrane
transmembrane IP
IP33,, DAG
DAG cascade,
cascade,
    Glandular muscle, vascular segments,
segments, G protein-linked   Increase
endothelium!
endothelium!
Gq/11
q/11protein-linked   Increase cGMP!
cGMP!
M
M44 Seven
Seven transmembrane
transmembrane Inhibition
Inhibition of
of cAMP
cAMP
   CNS?
CNS? segments,
   segments, G
Gi/o protein-linked
i/oprotein-linked
production
production
M
M55 CNS?,
CNS?, cerebral
cerebral Seven
Seven transmembrane
transmembrane IP
IP33,, DAG
DAG cascade
cascade
   segments,
   vessels
vessels segments, G
Gq/11 protein-linked
q/11protein-linked
  

N Muscle
Muscle type,
type, Skeletal
Skeletal muscle
muscle Pentamer[()2βςγ)] Na
Na+,, K
K+ depolarizing
depolarizing ion
+ +
NM M end plate neuromuscular ion
   end plate neuromuscular   channel
channel
receptor
receptor junction
junction
Neuronal Pentamer
Pentamer withwith 2 2 subunits
Neuronal type, Na
Na+,, K
K+ depolarizing
depolarizing ion
+ +
N type, CNS subunits ion
NNN ganglion CNS postganglionic
postganglionic only,
only, eg, (4)22(2)33 (CNS) or
eg, (4) (2) (CNS) or 3
3 channel
   ganglion cell
cell body, dendrites
body, dendrites channel
receptor
receptor 5(2) (ganglia)
5(2)33 (ganglia)   
M2

The M2 receptor can be coupled via the

subunit of the G protein to potassium
channels in the heart and
elsewhere…...Muscarinic agonists facilitate
opening of these channels
OVERVIEW

 Nonselective cholinoceptor stimulants in sufficient dosage can

produce very diffuse and marked alterations in organ system
function

 Selectivity of action is based on:

 Receptor selectivity: muscarinic vs. nicotinic
 PK selectivity: using appropriate routes of administration so that desired effects can
often be achieved while minimizing systemic effects

 Cholinomimetic drugs can elicit some or all of the effects that

acetylcholine (ACh) produces

 Include agents that act directly (cholinoceptor

agonists/stimulants) or indirectly acting mechanisms
(cholinesterase inhibitors)
DIRECT ACTING CHOLINERGIC STIMULANTS

 The directly acting cholinomimetics can be

subdivided into:
I. Parasympathomimetic drugs: agents that exert
their effects primarily through stimulation of
muscarinic receptors at parasympathetic neuro-
effector junctions

II. Agents that stimulate nicotinic receptors in

autonomic ganglia and at the neuromuscular
junction
DIRECT ACTING CHOLINERGIC STIMULANTS
 Mimic the effects of ACh by binding directly to cholinoceptors

 Divided into two groups:

 Choline esters: (Ach, methacholine, carbachol, bethanechol)

 Naturally occurring cholinomimetic alkaloids: (muscarine,

nicotine, pilocarpine, lobeline)

 All of the direct-acting cholinergic drugs have longer durations

of action than Ach and are more selective
 CHOLINE ESTERS
Longer duration of action

— Permanently charged and

relatively insoluble in lipids

— The β-methyl group

(methacholine, bethanechol)
reduces the potency of these
drugs at nicotinic receptors
CHOLINOMIMETIC ALKALOIDS
DIRECT ACTING CHOLINERGIC STIMULANTS
PHARMACOKINETICS

I. Choline esters
 Poorly absorbed and poorly distributed into the CNS because they
are hydrophilic and susceptible to esterase hydrolysis in the GIT

 Acetylcholine is very rapidly hydrolyzed (short duration of action of

5-20 seconds following a large I.V bolus)
 Nevertheless ACh has some clinical applications
 Methacholine is more resistant to hydrolysis, and the carbamic acid
esters carbachol and bethanechol are still more resistant to
hydrolysis by cholinesterase and have correspondingly longer
durations of action
 DIRECT ACTING CHOLINERGIC STIMULANTS
PHARMACOKINETICS

II. Natural cholinomimetic alkaloids

 Tertiary amines (pilocarpine, nicotine, lobeline) is well absorbed

from most sites of administration, and it can cross the BBB

 Quaternary amine (muscarine) is less completely absorbed from

the GIT than the tertiary amines but is toxic when ingested and it
even enters the brain
PHARMACOLOGY OF
ACETYLCHOLINE-LIKE AGONISTS
Cholinomimetic Susceptibility to Muscarinic Nicotinic
Cholinesterase Action Action
Acetylcholine ++++ +++ +++
chloride
Carbachol Negligible ++ +++
Methacholine + +++ None
Bethanechol Negligible +++ None
Muscarine Negligible +++ None

Pilocarpine Negligible +++ None

A. EYE

Muscarinic agonists cause contraction of the smooth

muscle of the:
1) Iris sphincter* miosis (contraction of pupil)
2) Ciliary muscle* resulting in accommodation of the
eye for near vision

* activation of M3 receptor
The iris is pulled away from the angle of the anterior chamber, and
the trabecular meshwork at the base of the ciliary muscle is opened
Note: Both effects facilitate the outflow of aqueous humor into the
canal of Schlemm and decrease intraocular pressure
Structure of the anterior chamber of the eye. Aqueous humor is secreted by the epithelium of the
ciliary body, flows through the anterior chamber, and exits via the canal of Schelmm (arrow)
B. CARDIOVASCULAR SYSTEM

ACh has four primary effects on the CVS:

a) Vasodilation*
b) Decrease in heart rate (negative chronotropic
effect)**
c) Decrease in the conduction velocity in the
atrioventricular (AV) node (negative dromotropic
effect)**
d) Decrease in the force of cardiac contraction (negative
inotropic effect)**

* activation of endothelial M3

** activation of M2 receptors
B. CARDIOVASCULAR SYSTEM

 The primary effects of muscarinic agonists are reduction

in peripheral vascular resistance and changes in heart
rate
 Acetylcholine-induced vasodilation requires the
presence of intact endothelium…….release
endothelium-derived relaxing factor (EDRF), identified
as nitric oxide (NO)……increases cGMP, resulting in
relaxation
 THE DIRECT SLOWING OF SINOATRIAL RATE AND
ATRIOVENTRICULAR CONDUCTION IS OFTEN OPPOSED
BY REFLEX SYMPATHETIC DISCHARGE, ELICITED BY THE
DECREASE IN BLOOD PRESSURE
C. RESPIRATORY SYSTEM*
 bronchoconstriction & increase tracheobronchial
secretion

D. GIT**
• Increases the secretory and motor activity of the gut
• Salivary and gastric glands are strongly stimulated
• Pancreas and small intestinal glands are also stimulated
to a lower degree
• Most sphincters are relaxed

• * M3 activation **M2 and M3 activation

E. GENITOURINARY TRACT
• Stimulation of detrusor muscle (M3 activation) and
relaxation of trigone and sphincter muscles of the
bladder (M2 activation) promoting urination (voiding)

Note: human uterus is not notably sensitive to muscarinic agonists

F. MISCELLANEOUS SECRETORY GLANDS
• Muscarinic agonists increase secretion of sweat
(thermoregulatory), lacrimal, and nasopharyngeal glands
• Mediated by M3 activation

G. CNS
• Contains both muscarinic and nicotinic receptors (brain richer in
muscarinic sites, spinal cord in nicotinic)
• Activation of M1-receptors in the brain areas involved in
cognition
• Activation of M2-R cause tremor, hypothermia, antinociception
• Activation of M3-R increase appetite and increase body fat mass
H. PNS:
•Autonomic ganglia are important sites of nicotinic synaptic
action (NN)
•Activation of nicotinic receptors initiate AP in postganglionic
neurons (both parasympathetic and sympathetic)
•In CVS, the effects of nicotine are chiefly sympathomimetic:
hypertension and sympathetic tachycardia may alternate with a
bradycardia mediated by vagal discharge
•In the GIT and UT, the effects are largely
parasympathomimetic: nausea, vomiting, diarrhea, and voiding
of urine
•Prolonged exposure may result in depolarizing blockade of the
ganglia
I. NEUROMUSCULAR JUNCTION (NM)

• When a nicotinic agonist is applied directly to a NMJ, an

immediate depolarization of the end plate results (increase
in permeability to K+ and Na+), causing muscle contraction

• Depolarizing nicotinic agents that are not rapidly hydrolyzed

(like nicotine itself) cause rapid development of
depolarization blockade

• Transmission blockade persists even when the membrane

has repolarized (flaccid paralysis in skeletal muscles)
INDIRECT ACTING Acetylcholinestrase
CHOLINOMIMETICS inhibitors
INDIRECT ACTING CHOLINOMIMETICS

 Acetylcholinesterase (AChE) is an enzyme that

specifically cleaves ACh to acetate and choline
and, thus, terminates its action

 Inhibitors of AChE indirectly provide a cholinergic

action by prolonging the lifetime of acetylcholine
in synapses where acetylcholine is released
physiologically (i.e. they have both muscarinic and
nicotinic effets)
INDIRECT ACTING CHOLINOMIMETICS

There are three chemical groups of cholinesterase

inhibitors:

(1) Simple alcohols bearing a quaternary ammonium

group, e.g., edrophonium

(2) Carbamates: carbamic acid esters of alcohols

having quaternary or tertiary ammonium groups
(e.g., neostigmine, physostigmine, pyridostigmine
carbaryl)

(3) Organophosphates: organic derivatives of

phosphoric acid (e.g., echothiophate)
• Absorption of the quaternary carbamates is negligible as well as CNS
distribution
• Physostigmine is well absorbed from all site and can be used topically

Structures of some organophosphate
cholinesterase inhibitors. The dashed lines
indicate the bond that is hydrolyzed in
binding to the enzyme.
Sarin is an extremely potent “nerve gas.”
Parathion and malathion are
thiophosphate (sulfur-containing
phosphate) prodrugs that are inactive as
such; they are converted to the
phosphate derivatives in animals and
plants and are used as insecticides.
They are activated in the body by
conversion to the oxygen analogs, a
process that occurs rapidly in both
insects and vertebrates. Malathion and a
few other organophosphate insecticides
are also rapidly metabolized by other
pathways to inactive products in birds
and mammals but not in insects; these
agents are therefore considered safe
enough for sale to the general public.
INDIRECT ACTING CHOLINOMIMETICS
MECHANISM OF ACTION
AchE is the primary target of these drugs, but
butyrylcholinesterase is also inhibited
The active site of AChE comprises two distinct regions:
an anionic site and an esteratic site
1st step: ACh binds to the enzyme's active site and is
hydrolyzed, yielding free choline and the acetylated
enzyme
2nd step, the covalent acetyl-enzyme bond is split, with
the addition of water (hydration)
The entire process takes place in approximately 150
microseconds
 INDIRECT ACTING CHOLINOMIMETICS
MECHANISM OF ACTION

 Anti-cholinesterase drugs fall into three main groups

according to the nature of their interaction with the active
site:

I. Short acting anticholinesterase (quaternary alcohols ,

e.g. edrophonium):
 Reversibly bind electrostatically and by hydrogen bonds to the
active site, thus preventing access of ACh (competitive inhibition)

 The enzyme-inhibitor complex does not involve a covalent bond

and is correspondingly short-lived (on the order of 2–10 minutes)
INDIRECT ACTING CHOLINOMIMETICS
MECHANISM OF ACTION

II. Medium-duration anticholinesterase (e.g. Neostigmate,

pyridostigmate, and physostigmine):

 They undergo a two-step hydrolysis sequence analogous

to that for ACh
 The covalent bond of the carbamoylated  enzyme is
considerably more resistant to the second (hydration)
process, and this step is correspondingly prolonged (on
the order of 30 minutes to 6 hours)
INDIRECT ACTING CHOLINOMIMETICS
MECHANISM OF ACTION

III.Irreversible anticholinesterases (synthetic

organophosphate compounds):
 They undergo initial binding and hydrolysis by the
enzyme, resulting in a phosphorylated  active site
 The covalent phosphorus-enzyme bond is extremely
stable and hydrolyzes in water at a very slow rate
(hundreds of hours)
 Moreover!! Phosphorylated enzyme may undergo
Aging
 breaking one of the oxygen-phosphorus bonds of the
inhibitor, further strengthening the phosphorus-enzyme
bond and making it impossible for chemical reactivation
 INDIRECT ACTING CHOLINOMIMETICS
MECHANISM OF ACTION

Cholinesterase regenerator:

Strong nucleophiles like pralidoxime are able to split the

phosphorous-enzyme bond and can be used in reversal of
organophosphate insecticide poisoning “cholinesterase
regenerator”
BuT!!
Once aging has occurred, the enzyme-inhibitor complex is
even more stable and is more difficult to break, even
with oxime regenerator compounds
 INDIRECT ACTING CHOLINOMIMETICS
ORGAN SYSTEM EFFECT

a. Central nervous system (CNS)

At low concentrations, the lipid-soluble cholinesterase inhibitors
cause activation on the electroencephalogram and a subjective
alerting response

At higher concentrations, cause generalized convulsions, which may

be followed by coma and respiratory arrest

b. Eye, Respiratory Tract, GIT, & Urinary Tract

Quite similar to the effects of the direct-acting cholinomimetics
 INDIRECT ACTING CHOLINOMIMETICS
ORGAN SYSTEM EFFECT
c. Cardiovascular system
 The actions of anticholinesterases on the CV system are
complex
 Increase activity in both sympathetic and parasympathetic
ganglia supplying the heart AND at the Ach receptors on
neuroeffector cells that receive cholinergic innervation
 In the heart, the parasympathetic effects predominate. They
have minimal effects on vascular smooth muscle (vascular
beds lack cholinergic innervation….coronary vasculature is an
exception)
 Net cardiovascular effects: modest bradycardia, decrease CO,
increase vascular resistance and BP
d. Neuromuscular junction

 This increases the strength of contraction, especially in

muscles weakened (myasthenia gravis)

 At higher concentrations, the accumulation

of acetylcholine may result in fibrillation of muscle fibers

 With marked inhibition of AchE, depolarizing

neuromuscular blockade occurs

 Neostigmine: additional direct nicotinic agonist effect at

the NMJ; effective in the therapy of myesthenia gravis
CLINICAL USES OF THE CHOLINOMIMETICS
a. Glaucoma
 In the past, glaucoma was treated with either direct
agonists (pilocarpine, carbachol) or cholinesterase
inhibitors (physostigmine, demecarium, echothiophate,
isoflurophate)

 Reduce intraocular pressure by causing contraction of

the ciliary body so as to facilitate outflow of aqueous
humor

 For chronic glaucoma, these drugs have been largely

replaced by topical β-blockers and prostaglandin
derivatives
 GLAUCOMA

 Acute angle-closure glaucoma: a medical emergency

frequently treated initially with drugs but requires surgery
for permanent correction
 Initial therapy often consists of a combination of a direct
muscarinic agonist and a cholinesterase inhibitor (eg,
pilocarpine + physostigmine)
 Once the intraocular pressure is controlled the patient is
prepared for corrective surgery (laser iridectomy)
 Open-angle glaucoma: chronic diseases not amenable to
traditional surgical correction (now laser techniques
available!!!)
Useful glaucoma animation:
https://www.youtube.com/watch?
v=TgjdPgSxeYg
 CLINICAL USES OF THE CHOLINOMIMETICS

b. Gastrointestinal and Urinary Tracts

 Bladder and bowel atony after surgery: Bethanechol and
neostigmine are the most widely used

 Xerostomia associated with Sjögren's syndrome and that

caused by radiation damage of the salivary glands:
pilocarpine & cevimeline (a new direct-acting muscarinic
agonist)

o*Sjögren's syndrome: autoimmune disease where the immune cells attack and
destroy exocrine glands that secrete saliva
 CLINICAL USES OF THE CHOLINOMIMETICS
C. Neuromuscular Junction

 Myasthenia gravis: an autoimmune disease affecting skeletal

muscle (antibodies are produced against the nicotinic receptor)

 Symptoms: ptosis (lazy eye), diplopia, difficulty in speaking and

swallowing, and extremity weakness (may interfere with
respiration)

 Anticholinesterase agents elevate and prolong the conc. of ACh

in the synaptic cleft, producing a greater activation of the
remaining nicotinic receptors…..alleviate the weakness!
 http://www.myasthenia.org.
au/html/symptoms.htm

myasthenia gravis
Usually, weakness of the eye muscle is the first
noticeable symptom

"Sleepy" (© Disney) of Snow White and the Seven Dwarfs was

supposedly based on a friend of Walt Disney who had MG
 MYASTHENIA GRAVIS

Three different serial pictures to demonstrate fatigue of eyelid muscles as the

patient keeps looking up.
After a few minutes of rest, the eyelids have returned to near-normal position.
 CLINICAL USES OF THE CHOLINOMIMETICS

C. Neuromuscular Junction

 Edrophonium (IV) is used for the diagnosis of myasthenia gravis

and differentiating myasthenic crisis from cholinergic crisis
(how?)

 An improvement in muscle strength that lasts about 5 min. is

observed in myesthenia gravis after 2 mg dose (45 sec interval)

 Long-term therapy: pyridostigmine and neostigmine

CLINICAL USES OF THE CHOLINOMIMETICS

d. Antimuscarinic Drug Intoxication: to treat overdoses

of drug with antimuscarinic action (as atropine,
tricyclic antidepressants)

 Physostigmine has been used for this application; it

enters the CNS and reverses the central as well as the
peripheral signs of muscarinic blockade

 However, can produce dangerous CNS effects….used

only in severe cases! (dangerous elevation of body
temperature and very rapid supraventricular
tachycardia)
 CLINICAL USES OF THE CHOLINOMIMETICS

e. CNS (Alzheimer’s Disease)

 Tacrine, donepezil, galantamine, & rivastigmine
(esterase inhibitors) are approved for the palliative
treatment of Alzheimer’s disease
 These agents can cross the BBB to produce a reversible
inhibition of AChE in the CNS
 Produce modest but significant improvement in the
cognitive function of patients with mild to moderate
Alzheimer’s disease, but they do not delay progression of
the disease
 Hepatic toxicity is significant with tacrine
 TOXICITY
A. Direct-Acting Muscarinic Stimulants (pilocarpine, and the
choline esters)
 Overdosage is characterized by exaggeration of the various
parasympathomimetic effects:
 nausea, vomiting, diarrhea (N,V,D), urinary urgency
 salivation, sweating,
 hypotension with reflex tachycardia,
 bronchial constriction
 Resembles that produced by consumption of mushrooms
of the genus Inocybe
 Tx: Atropine
 TOXICITY

B. Direct-Acting Nicotinic Stimulants (nicotine)

 ACUTE TOXICITY: the fatal dose of nicotine is ~40 mg, or 1 drop
of the pure liquid (contents of two regular cigarettes)
 CHRONIC NICOTINE TOXICITY "cigarette smoking” is more
relevant!!!
 In the brain, the α4β2 oligomer is the most abundant nicotinic
receptor in the brain
 Activation of α4β2 nicotinic receptors is associated with greater
release of dopamine in the mesolimbic system: mild alerting
action and the addictive property of nicotine absorbed from
tobacco
 NICOTINIC DRUGS
 Sustained desensitization of α4β2 receptors in the CNS and
reduces the desire to smoke and the pleasurable feelings of
smoking

 Direct acting nicotine agonists have no therapeutic

applications except in smoking cessation (nicotine and
varenicline) and producing skeletal muscle paralysis
(succinylcholine)

 Several approaches to help patients stop smoking:

1. Replacement therapy with nicotine in the form of gum,

transdermal patch, nasal spray, or inhaler
 VARENICLINE (Chantix®)

2. Varenicline: a synthetic drug with partial agonist action at

α4β2 nicotinic receptors

 Prevents the stimulant effect of nicotine at presynaptic

α4β2 receptors that causes release of dopamine

 ADRs: nausea, insomnia, and exacerbation of psychiatric

illnesses, including anxiety and depression
TOXICITY

 C. Cholinesterase Inhibitors
 Major cause of toxicity is accidental intoxication from
the use pesticide use in agriculture and in the home

 With increasing inhibition of AChE and accumulation of

ACh, the first signs are muscarinic stimulation, followed
by nicotinic receptor stimulation and then
desensitization of nicotinic receptors

 CNS symptoms include agitation, dizziness, and mental

confusion (compounds of extremely high lipid solubility)
 TOXICITY

Excessive inhibition can ultimately lead to a cholinergic

crisis that includes:
1. GIT distress: NVD & excessive salivation
2. Respiratory distress: bronchospasm & increased
bronchial secretions
3. CV distress: bradycardia
4. Visual disturbance: miosis, blurred vision
5. Sweating
6. Loss of skeletal motor function: progressing
through incoordination, muscle cramps, weakness,
fasciculation, and paralysis
Q: The FDA approved during 2003 the use
pyridostigmine bromide as pretreatment against the
nerve gas Soman. Explain how pyridostigmine acts as a
protective agent against Soman intoxication.
A 30-year-old woman undergoes abdominal surgery. In spite
of minimal tissue damage, complete ileus (absence of bowel
motility) follows, and she complains of severe bloating. She
also finds it difficult to urinate. Mild cholinomimetic stimulation
with bethanechol or neostigmine is often effective in
relieving these complications of surgery. Neostigmine and
bethanechol in moderate doses have significantly different
effects on which one of the following?

(A) Gastric secretion

(B) Neuromuscular end plate
(C) Salivary glands
(D) Sweat glands
(E) Ureteral tone
Parathion has which one of the following
characteristics?
(A) It is inactivated by conversion to paraoxon
(B) It is less toxic to humans than malathion
(C) It is more persistent in the environment than
DDT
(D) It is poorly absorbed through skin and lungs
(E) If treated early, its toxicity may be partly reversed
by
pralidoxime
Ms Brown has been treated for myasthenia gravis for several
years. She reports to the emergency department complaining
of recent onset of weakness of her hands, diplopia, and
difficulty swallowing. She may be suffering from a change in
response to her myasthenia therapy, that is, a cholinergic or
a myasthenic crisis. Which of the following is the best drug
for distinguishing between myasthenic crisis (insufficient
therapy) and cholinergic crisis (excessive therapy)?
(A) Atropine
(B) Edrophonium
(C) Physostigmine
(D) Pralidoxime
(E) Pyridostigmine
A crop duster pilot has been accidentally exposed to a high
concentration of a highly toxic agricultural organophosphate
insecticide. If untreated, the cause of death from such exposure
would probably be

(A) Cardiac arrhythmia

(B) Gastrointestinal bleeding
(C) Heart failure
(D) Hypotension
(E) Respiratory failure
Mr Green has just been diagnosed with dysautonomia
(chronic idiopathic autonomic insufficiency). You are considering
different therapies for his disease. Pyridostigmine and
neostigmine may cause which one of the following?

(A) Bronchodilation
(B) Cycloplegia
(C) Diarrhea
(D) Irreversible inhibition of acetylcholinesterase
(E) Reduced gastric acid secretion
Parasympathetic nerve stimulation and a slow infusion of
bethanechol will each:
(A) Cause ganglion cell depolarization
(B) Cause skeletal muscle end plate depolarization
(C) Cause vasodilation
(D) Increase bladder tone
(E) Increase heart rate
Actions and clinical uses of muscarinic cholinoceptor agonists
include which one of the following?
(A) Bronchodilation (asthma)
(B) Improved aqueous humor drainage (glaucoma)
(C) Decreased gastrointestinal motility (diarrhea)
(D) Decreased neuromuscular transmission and relaxation of
skeletal muscle (during surgical anesthesia)
(E) Increased sweating (fever)
Which of the following is a direct-acting cholinomimetic that
is lipid-soluble and is used to facilitate smoking cessation?
(A) Acetylcholine
(B) Bethanechol
(C) Neostigmine
(D) Physostigmine
(E) Varenicline
A 3-year-old child is admitted after taking a drug from her
parents’ medicine cabinet. The signs suggest that the drug
is an indirect-acting cholinomimetic with little or no CNS
effect and a duration of action of about 2–4 h. Which of the
following is the most likely cause of these effects?

(A) Acetylcholine
(B) Bethanechol
(C) Neostigmine
(D) Physostigmine
(E) Pilocarpine
Which of the following is the primary second-messenger process
in the contraction of the ciliary muscle when focusing on
near objects?
(A) cAMP (cyclic adenosine monophosphate)
(B) DAG (diacylglycerol)
(C) Depolarizing influx of sodium ions via a channel
(D) IP3 (inositol 1,4,5-trisphosphate)
(E) NO (nitric oxide)