ANS Nervous System Guide

Autonomic
NervousSystem
Gvantsa Kvariani

Tuesday, February 2, 20XX Sample Footer Text 2
The autonomic nervous system (ANS) is
part of the peripheral nervous
system and regulates
involuntary, visceral body functions in
different organ systems (e.g., the
cardiovascular, gastrointestinal,
genitourinary systems). It is divided into
the sympathetic and parasympathetic ne
rvous systems.

The sympathetic nervous system has a thoracolumbar outflow
and is activated during fight or flight response, while
the parasympathetic nervous system has a craniosacral outflow
and is activated during digestion and rest.
The sympathetic and parasympathetic nervous systems consist
of preganglionic and postganglionic neurons.
The preganglionic fibers of both ANS divisions and
the postganglionic fibers of the parasympathetic division are
cholinergic fibers (release acetylcholine) that act on cholinergic
receptors (nicotinic or muscarinic).
All postganglionic fibers of the sympathetic division are
adrenergic fibers (release norepinephrine) that act on
adrenergic alpha or beta receptors for neurotransmission, with
the exception of the fibers innervating the sweat glands, which
are cholinergic.

The adrenal medulla does not
have a postsynaptic neuron.
The sympathetic preganglionic fibe
rs stimulate the chromaffin cells of
the adrenal medulla directly
via acetylcholine on nicotinic
receptors, which results in the
release
of norepinephrine and epinephrin
e mediating the fight or flight
response.

The sympathetic and parasympathetic nervous systems have antagonistic effects in some organ systems.
The effects of the sympathetic nervous system on target organs include mydriasis, increased heart rate,
contractility, and conduction velocity, bronchodilation, sweat secretion, decreased intestinal motility, and
increased renin release.
The effect of the parasympathetic nervous system on target organs include miosis, decreased heart rate,
contractility, and conduction velocity; increased intestinal motility; and bronchoconstriction.
In addition to the sympathetic and parasympathetic nervous systems, there is the enteric nervous system,
which consists of enteric ganglia, the myenteric (Auerbach) and the submucosal (Meissner) plexuses, and
the interstitial cells of Cajal.
The enteric nervous system controls gastrointestinal motility and secretion. Autonomic function can be
affected by medications (e.g., selective serotonin reuptake inhibitors, anticholinergics) as well as diseases
(e.g., diabetes mellitus, Parkinson disease, multiple system atrophy).

1.Efferent neurons: The ANS carries nerve
impulses from the CNS to the effector organs through two
types of efferent neurons:
the preganglionic neurons and the
postganglionic neurons.
The cell body of the first nerve cell, the preganglionic neuron,
is located within the CNS. The preganglionic neurons emerge
from the brainstem or spinal cord and make a synaptic
connection in ganglia (an aggregation of nerve cell bodies
located in the peripheral nervous system).
The ganglia function as relay stations between the
preganglionic neuron and the second nerve cell, the
postganglionic neuron.
The cell body of the postganglionic neuron originates in the
ganglion. It is generally nonmyelinated and terminates on
effector organs, such as visceral smooth muscle, cardiac
muscle, and the exocrine glands.

Afferent neurons: The
afferent neurons (fibers) of
the ANS are important in the
reflex regulation of this
system (for example, by
sensing pressure in the
carotid sinus and aortic arch)
and in signaling the CNS to
influence the efferent branch
of the system to respond.

Sympathetic neurons:
• The preganglionic neurons of the sympathetic system come from the thoracic and lumbar
regions (T1 to L2) of the spinal cord
• They synapse in two cord-like chains of ganglia that run close to and in parallel on each side
of the spinal cord.
• The preganglionic neurons are short in comparison to the postganglionic ones. The axons of
the postganglionic neuron extend from the ganglia to tissues they innervate and regulate.
• In most cases, the preganglionic nerve endings of the sympathetic nervous system are highly
branched, enabling one preganglionic neuron to interact with many postganglionic neurons.
This arrangement enables activation of numerous effector organs at the same time.
[Note: The adrenal medulla, like the sympathetic ganglia, receives preganglionic fibers from the
sympathetic system. The adrenal medulla, in response to stimulation by the ganglionic
neurotransmitter acetylcholine, secretes epinephrine (adrenaline), and lesser amounts of
norepinephrine, directly into the blood.]

Parasympathetic neurons:
• The parasympathetic preganglionic fibers arise from cranial nerves III
(oculomotor), VII (facial), IX (glossopharyngeal), and X (vagus), as well
as from the sacral region (S2 to S4) of the spinal cord and synapse in
ganglia near or on the effector organs.
• The vagus nerve accounts for 90% of preganglionic parasympathetic fibers.
Postganglionic neurons from this nerve innervate most organs in the thoracic
and abdominal cavity.
• Thus, in contrast to the sympathetic system, the preganglionic fibers are long,
and the postganglionic ones are short, with the ganglia close to or within the
organ innervated.
• In most instances, there is a one-to-one connection between the
preganglionic and postganglionic neurons, enabling discrete response of this
system.

Parasympathetic preganglionic
fibers arise from cranial cranial
nerves and sacral nerves.
• Short postganglionic axons
innervate cardiac muscle,
bronchial smooth muscle, and
• exocrine glands.
• Parasympathetic innervation
predominates over sympathetic
innervation of salivary
• glands, lacrimal glands, and
erectile tissue.

Enteric neurons: The enteric nervous system is
the third division of the ANS. It is a collection of
nerve fibers that innervate the gastrointestinal (GI)
tract, pancreas, and gallbladder, and it constitutes
the “brain of the gut.” This system functions
independently of the CNS and controls motility,
exocrine and endocrine secretions, and
microcirculation of the GI tract. It is modulated by
both the sympathetic and the parasympathetic
nervous systems.

The effect of sympathetic stimulation is an increase in
heart rate and blood pressure, mobilization of energy
stores, and increase in blood flow to skeletal muscles and
the heart, while diverting flow from the skin and internal
organs.
Sympathetic stimulation results in dilation of the pupils
and bronchioles.
reduces GI motility and affects function of the bladder and
sexual organs.
Fight-or-flight response: These reactions are triggered
both by direct sympathetic activation of effector organs
and by stimulation of the adrenal medulla to release
epinephrine and lesser amounts of norepinephrine.
Hormones released by the adrenal medulla directly enter
the bloodstream and promote responses in effector
organs that contain adrenergic receptors The sympathetic
nervous system tends to function as a unit and often
discharges as a complete system, for example, during
severe exercise or in reactions to fear.

Functions of the parasympathetic
nervous system
The parasympathetic division is involved with
maintaining homeostasis within the body. It is
required for life, since it maintains essential
functions, such as digestion and elimination.
The parasympathietic division usually acts to
oppose or balance the actions of the sympathetic
division and generally predominates the sympathetic
system in "rest-and-digest" situations. Unlike the-
sympathetic system, the parasympathetic system
never discharges as a complete system. If it did, it
would produce massive, undesirable, and
unpleasant symptoms, such as involuntary urination,
defecation. Instead, parasympathetic fibers
innervating Specific organs such as the gut, heart,
or eye are activated separetely, and the system
affects these organs individually.

General information
•Exits central nervous system (dorsal motor nucleus) with cranial
nerves CN III, CN VII, CN IX, CN X, and the
sacral spinal roots(craniosacral outflow)
•Preganglionic axons (long, myelinated cholinergic
fibers): synapse in ganglia close to end organs
•Postganglionic axons (short, cholinergic fibers): leave ganglia and

Sacral outflow
•Supplies pelvis via 2nd–
4th sacral spinal nerves
•Lateral horn of the sacral segments
of S2–S4 → pelvic splanchnic
nerves → inferior hypogastric
plexus or ganglia within walls
of pelvic (e.g., descending
and sigmoid
colon, rectum, ureter, prostate, blad
der, urethra) and genital organs.
Cranial outflow
The cranial outflow supplies visceral structures of the head, neck
and face via CN III, CN VII, CN IX and of the thorax and upper
abdomen via CN X.
•Four bilateral autonomic ganglia in the head and neck:
• Edinger-Westphal nucleus → oculomotor nerve (CN III)
→ ciliary ganglion → sphincter pupillae (miosis)
and ciliary muscle(accommodation)
• Superior salivatory nucleus → facial
nerve → pterygopalatine ganglion and submandibular
ganglion → lacrimal gland, glands of the mucosa of the
oral and nasal cavity, pharynx, and sinuses
• Inferior salivatory nucleus → glossopharyngeal
nerve → otic ganglion → salivation of parotid gland
•Dorsal nucleus of the vagus nerve → CN
X → several ganglia close to/or within the walls of
the gastrointestinal tract and lungs

Dual innervation: Most organs are innervated by both
divisions
of the ANS. Thus, vagal parasympathetic innervation
slows the heart rate and sympathetic innervation
increases heart rate. Despite this dual innervation, one
system usually predominates in controlling the activity of a
given organ. For example, the vagus nerve is the
predominant factor for controlling heart rate. The dual
innervation of organs is dynamic and fine-tuned
continually to maintain homeostasis.
Sympathetic innervation: Although most tissues
receive dual innervation, some effector organs, such as
the adrenal medulla, kidney, pilomotor muscles, and
sweat glands, receive innervation only from the
sympathetic system.

III. CHEMICAL SIGNALING
BETWEEN CELLS
Neurotransmission in the ANS is an example of chemical
signaling between cells. In addition to neurotransmission,
other types of chemical signaling include the secretion of
hormones and the release of local mediators
1. Hormones
Specialized endocrine cells secrete hormones into the
bloodstream, where they travel throughout the body, exerting
effects on broadly distributed target cells (see Unit V: Drugs
Affecting the Endocrine System).
2. Local mediators
Most cells secrete chemicals that act locally on cells in the
immediate environment. Because these chemical signals are
rapidly destroyed or removed, they do not enter the blood and are
not distributed throughout the body. Histamine and prostaglandins
are examples of local mediators.

Neurotransmitters
The release is triggered by arrival of the action potential at the nerve ending, leading to
depolarization. An increase in intracellular Ca2+ initiates fusion of synaptic vesicles with the
presynaptic membrane and release of their contents. The neurotransmitters rapidly diffuse
across the synaptic cleft, or space (synapse), between neurons and combine with specific
receptors on the postsynaptic (target) cell.
Types of neurotransmitters:
Although over 50 signal molecules in the nervous system have been identified,
norepinephrine (and the closely related epinephrine), acetylcholine, dopamine, serotonin,
histamine, glutamate, and γ-aminobutyric acid are most commonly involved in the actions of
therapeutically useful drugs.
Each of these chemical signals binds to a specific family of receptors. Acetylcholine and
norepinephrine are the primary chemical signals in the ANS, whereas a wide variety of
neurotransmitters function in the CNS.

Acetylcholine:
The autonomic nerve fibers can be divided into two groups based on the type
of neurotransmitter released. If transmission is mediated by acetylcholine, the
neuron is termed cholinergic.
Acetylcholine mediates the transmission of nerve impulses across autonomic
ganglia in both the sympathetic and parasympathetic nervous systems.
It is the neurotransmitter at the adrenal medulla.
Transmission from the autonomic postganglionic nerves to the effector organs
in the parasympathetic system, and a few sympathetic system organs, also
involves the release of acetylcholine.
In the somatic nervous system, transmission at the neuromuscular junction
(the junction of nerve fibers and voluntary muscles) is also cholinergic

Norepinephrine and epinephrine:
When norepinephrine is the
neurotransmitter, the fiber is termed
adrenergic.
In the sympathetic system,
norepinephrine mediates the
transmission of nerve impulses from
autonomic postganglionic nerves to
effector organs. Epinephrine
secreted by the adrenal medulla (not
sympathetic neurons) also acts as a
chemical messenger in the effector
organs.

Dissipation of the
transmitter/termination of
neurotransmitter action: The action
of the neurotransmitter is terminated
either by destruction by enzymes
(cholinesterase destroys acetyl
choline whereas monoamine oxidase
[MAO] and catechol-o-methyl-
transferase [COMT] destroy
noradrenaline) or by reuptake of the
neurotransmitter by tissues or axonal
terminal (noradrenaline at adrenergic
endings).

SIGNAL TRANSDUCTION IN THE EFFECTOR CELL
The binding of chemical signals to receptors activates enzymatic processes within the
cell membrane that ultimately results in a cellular response, such as the
phosphorylation of intracellular proteins or changes in the conductivity of ion channels.
A neurotransmitter can be thought of as a signal and a receptor as a signal detector
and transducer. The receptors in the ANS effector cells are classified as adrenergic or
cholinergic based on the neurotransmitters or hormones that bind to them.
Epinephrine and norepinephrine bind to adrenergic receptors, and acetylcholine binds
to cholinergic receptors.

Cholinergic receptors are further classified as
nicotinic or muscarinic.
Some receptors, such as the postsynaptic
cholinergic nicotinic receptors in skeletal muscle
cells, are directly linked to membrane ion channels
and are known as ionotropic receptors. Binding of
neurotransmitter to ionotropic receptors directly
affects ion permeability.
All adrenergic receptors and cholinergic muscarinic
receptors are G protein– coupled receptors
(metabotropic receptors). Metabotropic receptors
mediate the effects of ligands by activating a second
messenger system inside the cell. The two most
widely recognized second messengers are the
adenylyl cyclase system and the
calcium/phosphatidylinositol system

Muscarinic receptors
Muscarinic receptors belong to the class of G protein–
coupled receptors (metabotropic receptors). These
receptors, in addition to binding ACh, also recognize
muscarine, an alkaloid in certain poisonous mushrooms.
By contrast, the muscarinic receptors show only a weak
affinity for nicotine, an alkaloid found in tobacco and other
plants.
There are five subclasses of muscarinic receptors; how-
ever, only M1, M2, and M3 receptors have been functionally
characterized. These receptors, in addition to binding with
acetylcholine, also recognize muscarine. Muscarine is an
alkaloid that is present in certain poisonous mushrooms.

1. Which is correct regarding the sympathetic
nervous system?
1.It generally mediates body functions in
“rest- and-digest” mode.
2.The neurotransmitter at the sympathetic
ganglion is norepinephrine (NE).
3.The neurotransmitter at the sympathetic
ganglion is acetylcholine (ACh).
4.Sympathetic neurons release ACh in the
effector organs.

C. The neurotransmitter at the sympathetic and
parasympathetic ganglia is acetylcholine. The
sympathetic system generally mediates body
functions in “fight-or-flight” mode and the
parasympathetic system generally mediates body
functions in “rest-and-digest” mode. Sympathetic
neurons release NE, and parasympathetic neurons
release ACh in the effector cells.

.2. Why does the somatic nervous system
enable a faster response compared to the
ANS?
1.Somatic motor neurons have ganglia
where neurotransmission is mediated
by ACh.
2.Somatic motor neurons have ganglia
where neurotransmission is mediated
by NE.
3.Somatic motor neurons are not
myelinated.
4.Somatic motor neurons are
myelinated and do not have ganglia.

D. Somatic motor
neurons are myelinated
and have no ganglia.
This enables faster
transmission in the
somatic neurons.

3. Which physiological change
occurs when the
parasympathetic system is
activated?
A. Increase in heart rat
B. Inhibition of lacrimation
(tears)
C. Dilation of the pupil
(mydriasis)
D. Increase in gastric motility

D. Activation of the parasympathetic
system causes an increase in gastric
motility, increase in fluid secretions,
reduction in heart rate, and constriction of
the pupil. In the “rest-and-digest” mode,
the parasympathetic system is more
active, which helps with digestion.

Which physiological change is expected
when the sympathetic system is inhibited
using a pharmacological agent?
A. Reduction in heart rate
B. Increase in blood pressure
C. Decrease in fluid secretions
D. Constriction of blood vessels

A. Activation of the sympathetic system
causes an increase in heart rate, increase
in blood pressure, reduction or thickening
of fluid secretions, and constriction of blood
vessels. Therefore, inhibition of the
sympathetic system should theoretically
cause a reduction in heart rate, decrease in
blood pressure, increase in fluid secretions,
and relaxation of blood vessels.

Which is correct regarding activation of
receptors on the effector organs in the ANS?
A. Acetylcholine activates muscarinic
receptors.
B. Acetylcholine activates adrenergic
receptors.
C. Epinephrine activates nicotinic receptors.
D. Norepinephrine activates muscarinic
receptors.

A. Acetylcholine is the
neurotransmitter in the cholinergic
system, and it activates both
muscarinic and nicotinic cholinergic
receptors, not adrenergic receptors.
Norepinephrine and epinephrine
activate adrenergic receptors, not
muscarinic receptors.

Which statement is correct regarding the autonomic nervous
system?
A. Afferent neurons carry impulses from the central nervous
system (CNS) to the effector organs.
B. Preganglionic neurons of the sympathetic system arise
from the cranial nerves, as well as from the sacral
region.
C. When there is a sudden drop in blood pressure, the
baroreceptors send signals to the brain to activate the
parasympathetic system.
D. The heart receives both sympathetic and
parasympathetic innervation.

D. The heart receives both sympathetic and parasympathetic
innervation. Activation of sympathetic neurons increases the heart
rate and force of contraction, and activation of parasympathetic
neurons reduces the heart rate and force of contraction (slightly).
Afferent neurons carry impulses from the periphery to the CNS,
and efferent neurons carry signals away from the CNS.
Preganglionic neurons of the sympathetic system arise from
thoracic and lumbar regions of the spinal cord, whereas the
preganglionic neurons of the parasympathetic system arise from
cranial nerves and the sacral region. When there is a sudden drop
in blood pressure, the sympathetic system is activated, not the
parasympathetic system.

Two families of
cholinoceptors, designated
muscarinic and nicotinic
receptors, can be
distinguished from each
other on the basis of their
different affinities for agents
that mimic the action of ACh
(cholinomimetic agents).

Where do we use Acetylcholine?
THE CHOLINERGIC NEURON
The preganglionic fibers terminating in the adrenal medulla,
the autonomic ganglia (both parasympathetic and sympathetic),
postganglionic fibers of the parasympathetic division use ACh as a neurotransmitter

Location of muscarinic receptors: These receptors are found on the autonomic effector
organs, such as the heart, smooth muscle, brain, and exocrine glands. Although all five subtypes
are found on neurons,
M1 receptors are also found on gastric parietal cells,
M2 receptors on cardiac cells and smooth muscle
M3 receptors on the bladder, exocrine glands, and smooth muscle.
[Note: Drugs with muscarinic actions preferentially stimulate muscarinic receptors on these
tissues, but at high concentration, they may show some activity at nicotinic receptors.]

Muscarinic receptors
Muscarinic receptors belong to the class of G
protein–coupled receptors (metabotropic receptors).
These receptors, in addition to binding ACh, also
recognize muscarine, an alkaloid in certain
poisonous mushrooms.
By contrast, the muscarinic receptors show only a
weak affinity for nicotine, an alkaloid found in
tobacco and other plants.
There are five subclasses of muscarinic receptors;
however, only M1, M2, and M3 receptors have been
functionally characterized. These receptors, in
addition to binding with acetylcholine, also recognize
muscarine. Muscarine is an alkaloid that is present
in certain poisonous mushrooms.

III. CHOLINERGIC
RECEPTORS
(CHOLINOCEPTORS)
Two families of cholinoceptors, designated
muscarinic and nicotinic receptors, can be
distinguished from each other on the basis
of their different affinities for agents that
mimic the action of ACh (cholinomimetic
agents).

Neurotransmission at
cholinergic neurons
Neurotransmission in cholinergic
neurons involves six sequential
steps:
1) synthesis of ACh,
2) storage,
3) release,
4) binding of ACh to the receptor,
5) degradation of ACh in the
synaptic cleft (the space between
the nerve endings and the
adjacent receptors on nerves or
effector organs)
6) recycling of choline

1.Choline is transported from the extracellular fluid into the
cytoplasm of the cholinergic neuron by an energy-dependent
carrier system that cotransports sodium and can be inhibited
by the drug hemicholinium.The uptake of choline is the rate-
limiting step in ACh synthesis.
Choline acetyl- transferase catalyzes the reaction of choline
with acetyl coenzyme A (CoA) to form ACh (an ester) in the
cytosol.

2.Storage of acetylcholine in
vesicles: ACh is packaged and
stored into presynaptic
vesicles by an active transport
process.
The mature vesicle contains
not only ACh but also
adenosine triphosphate (ATP)
and proteoglycan.

Release of acetylcholine: When an action
potential propagated by voltage-sensitive sodium
channels arrives at a nerve ending, voltage-sensitive
calcium channels on the presynaptic membrane open,
causing an increase in the concentration of intracellular
calcium. Elevated calcium levels promote the fusion of
synaptic vesicles with the cell membrane and the
release of contents into the synaptic space. This release
can be blocked by botulinum toxin. In contrast, the toxin
in black widow spider venom causes all the ACh stored
in synaptic vesicles to empty into the synaptic gap.

Binding to the receptor: ACh released from the
synaptic vesicles diffuses across the synaptic
space and binds to postsynaptic receptors on the
target cell, to presynaptic receptors on the
membrane of the neuron that released ACh, or to other
targeted presynaptic receptors. The postsynaptic
cholinergic receptors on the surface of effector organs are
divided into two classes: muscarinic and nicotinic.
Binding to a receptor leads to a biologic response within the
cell, such as the initiation of a nerve impulse in a
postganglionic fiber or activation of specific enzymes in
effector cells, as mediated by second messenger
molecules.

5.Degradation of acetylcholine:
The signal at the postjunctional
effector site is rapidly terminated,
because acetylcholinesterase
(AChE) cleaves ACh to choline and
acetate in the synaptic cleft.

6. Recycling of choline: Choline
may be recaptured by a sodium-
coupled, high-affinity uptake
system that transports the
molecule back into the neuron.
There, it is available to be
acetylated into ACh.

Mechanism of acetylcholine signal transduction:
A number of different molecular mechanisms transmit
the signal generated by ACh occupation of the
receptor.

ACh interacts with M1, M3, and M5 muscarinic
cholinoceptors to increase phosphatidylinositol (PI)
turnover and Ca mobilization
(a) By activation of G protein (Gq), the interaction of ACh
with M1 and M3 muscarinic cholinoceptors stimulates
polyphosphatidylinositol phosphodiesterase
(phospholipaseC), which hydrolyzes PI to inositol
trisphosphate (IP3) and diacylglycerol (DAG).
(b) IP3 mobilizes intracellular Ca+ from the endoplasmic
and sarcoplasmic reticula, and activates Ca+-regulated
enzymes and cell processes.
(c) DAG activates protein kinaseC, which results in
phosphorylation of cellular enzymes and other protein
substrates and the influx of extracellular calcium that
results in activation of contractile elements in smooth
muscle.

ACh also interacts with M2
and M4 muscarinic
cholinoceptors to
activate G proteins (GI),
which leads to inhibition
of adenylyl cyclase
activity with decreased
levels of cyclic AMP (cAMP)
and to increased K1
conductance with effector
cell hyperpolarization.

Nicotinic receptors
These receptors, in addition to binding ACh, also recognize nicotine but show
only a weak affinity for muscarine. The nicotinic receptor is composed of five
subunits, and it functions as a ligand-gated ion channel. Binding of two ACh
molecules elicits a conformational change that allows the entry of sodium ions,
resulting in the depolarization of the effector cell.
Nicotine at low concentration stimulates the receptor, whereas nicotine at high
concentration blocks the receptor. Nicotinic receptors are located in the CNS,
the adrenal medulla, autonomic ganglia, and the neuromuscular junction (NMJ)
in skeletal muscles. Those at the NMJ are sometimes designated NM, and the
others, NN.
The nicotinic receptors of autonomic ganglia differ from those of the NMJ. For
example, ganglionic receptors are selectively blocked by hexamethonium and
mecamylamine, whereas NMJ receptors are specifically blocked by
tubocurarine and atracurium.

Cholinergic agonists mimic the effects of ACh by binding directly to
cholinoceptors (muscarinic or nicotinic).
These agents may be broadly classified into two groups:
1) choline esters, which include endogenous ACh and synthetic
esters of choline, such as carbachol and bethanechol, and
2) naturally occurring alkaloids, such as nicotine and pilocarpine
All direct-acting cholinergic drugs have a longer duration of action
than ACh.
The more therapeutically useful drugs (pilocarpine and
bethanechol) preferentially bind to muscarinic receptors and are
sometimes referred to as muscarinic agents. However, as a group,
the direct-acting agonists show little specificity in their actions,
which limits their clinical usefulness.

Muscarinic agonists:
Pilocarpine is a nonselective
muscarinic agonist used to treat
xerostomia and glaucoma.
Attempts are currently underway to
develop muscarinic agents that are
directed against specific receptor
subtypes.

Acetylcholine
Acetylcholine is a quaternary ammonium compound that cannot penetrate membranes. Although it is the
neurotransmitter of parasympathetic and somatic nerves as well as autonomic ganglia, it lacks therapeutic
importance because of its multiplicity of actions (leading to diffuse effects) and its rapid inactivation by the
cholinesterases. ACh has both muscarinic and nicotinic activity. Its actions include the following:
1. Decrease in heart rate and cardiac output: The actions of ACh on the heart mimic the effects of vagal
stimulation. For example, if injected intravenously, ACh produces a brief decrease in cardiac rate (bradycardia)
and cardiac output, mainly because of a reduction in the rate of firing at the sinoatrial (SA) node. [Note: Normal
vagal activity regulates the heart by the release of ACh at the SA node.]
2. Decrease in blood pressure: Injection of ACh causes vasodilation and lowering of blood pressure by an
indirect mechanism of action. ACh activates M3 receptors found on endothelial cells lining the smooth muscles
of blood vessels. This results in the production of nitric oxide from arginine. Nitric oxide then diffuses to
vascular smooth muscle cells to stimulate protein kinase G production, leading to hyperpolarization and
smooth muscle relaxation via phosphodiesterase-3 inhibition. In the absence of administered cholinergic
agents, the vascular cholinergic receptors have no known function, because ACh is never released into the
blood in significant quantities. Atropine blocks these muscarinic receptors and prevents ACh from producing
vasodilation.

Pilocarpine
1.(1) Pilocarpine is occasionally used topically for open-angle
glaucoma, either as
2.eyedrops or as a sustained-release ocular insert (Ocusert). -
adrenoceptor antagonists and prostaglandin analogs are the drugs of
choice to treat open-angle glaucoma. Other drug classes used include
 -adrenergic receptor agonists and diuretics.
3.(2) When used before surgery to treat acute narrow-angle
glaucoma (a medical emergency), pilocarpine is often given in
combination with an indirectly acting muscarinic agonist such as
physostigmine.
4.(3) Pilocarpine and cevimeline (Evoxac) increase salivary
secretion. They are used to treat Sjögren syndrome-associated dry
mouth.
5.(4) Pilocarpine is a tertiary amine that is well absorbed from the GI
tract and enters the CNS.

Adverse effects and contraindications
1.The adverse effects associated with direct-acting
muscarinic cholinoceptor agonists
2.are extensions of their pharmacologic activity. The
most serious include nausea, vom- iting, sweating,
salivation, bronchoconstriction, decreased blood
pressure, and diarrhea, all of which can be blocked
or reversed by atropine. Systemic effects are minimal
for drugs applied topically to the eye.
3.These drugs are contraindicated in the presence of
peptic ulcer (because they increase acid secretion),
asthma, cardiac disease, and Parkinson disease.
They are not recommended in hyperthyroidism
because they predispose to arrhythmia; they are also
not recommended when there is mechanical
obstruction of the GI or urinary tract.

In the gastrointestinal (GI) tract, acetylcholine increases salivary secretion
increases gastric acid secretion
stimulates intestinal secretions
motility.
Respiratory tract: It also enhances bronchiolar secretions and causes
bronchoconstriction.
Methacholine, a direct-acting cholinergic agonist, is used to assist in the
diagnosis of asthma due to its bronchoconstricting properties.
In the genitourinary tract,
ACh increases the tone of the detrusor muscle, causing urination.
In the eye, ACh is involved in stimulation of ciliary muscle contraction for near
vision and in the constriction of the pupillae sphincter muscle, causing miosis
(marked constriction of the pupil). ACh (1% solution) is instilled into the
anterior chamber of the eye to produce miosis during ophthalmic surgery.

Bethanechol
Bethanechol is an unsubstituted carbamoyl ester, structurally related to ACh. It is not hydrolyzed by AChE
due to the esterification of carbamic acid, although it is inactivated through hydrolysis by other esterases.
It lacks nicotinic actions (due to addition of the methyl group), but does have strong muscarinic activity. Its
major actions are on the smooth musculature of the bladder and GI tract. It has about a 1-hour duration of
action.
1.Actions: Bethanechol directly stimulates muscarinic receptors and selectively stimulates urinary and
gastrointestinal tract. Its effect on the GI tract causes increased intestinal motility and tone. It also
stimulates the detrusor muscle of the bladder, whereas the trigone and sphincter muscles are relaxed.
These effects stimulate urination. It has persistent effects because it is resistant to cholinesterases.
2.Therapeutic applications: In urologic treatment, bethanechol is used to stimulate the atonic bladder,
particularly seen in postpartum or postoperative or with spinal cord injury, and nonobstructive urinary
retention to facilitate emptying of the neurogenic bladder. Bethanechol may also be used to treat
neurogenic atony as well as megacolon.
3.Adverse effects: Bethanechol can cause generalized cholinergic stimulation, with sweating, salivation,
flushing, decreased blood pressure (with reflex tachycardia), nausea, abdominal pain, diarrhea, and
bronchospasm. Atropine sulfate may be administered to overcome severe cardiovascular or
bronchoconstrictor responses to this agent.

Carbachol (carbamylcholine)
Carbachol has both muscarinic and nicotinic actions. Like bethanechol, carbachol is an ester of carbamic
acid and a poor substrate for AChE. It is biotransformed by other esterases, but at a much slower rate.
1.Actions: Carbachol has profound effects on both the cardiovascular and Gl systems because of its
ganglion-stimulating activity, and it may first stimulate and then depress these systems. It can cause
release of epinephrine from the adrenal medulla by its nicotinic action. Locally instilled into the eye, it
mimics the effects of ACh, causing miosis and a spasm of accommodation in which the ciliary muscle of
the eye remains in a constant state of contraction. The vision becomes fixed at some particular distance,
making it impossible to focus
2.Therapeutic uses: Because of its high potency, receptor nonselectivity, and relatively long duration of
action, carbachol is rarely used. Intraocular use provides miosis for eye surgery and lowers intraocular
pressure in the treatment of glaucoma.
3.Adverse effects: With ophthalmologic use, few adverse effects occur due to lack of systemic
penetration {quaternary amine}.

Pilocarpine
The alkaloid pilocarpine is a tertiary amine and is stable to
hydrolysis by AChE Compared with ACh and its derivatives, it is
far less potent but is uncharged and can penetrate the CNS at
therapeutic doses. Pilocarpine exhibits muscarinic activity and is
used primarily in ophthalmology.
1.Actions: Applied topically to the eye, pilocarpine produces rapid
miosis, contraction of the ciliary muscle, and spasm of
accommodation. Pilocarpine is one of the most potent stimulators
of secretions such as sweat, tears, and saliva, but its use for
producing these effects has been limited due to its lack of
selectivity. The drug is beneficial in promoting salivation in
patients with xerostomia resulting from irradiation of the head and
neck. Sjögren syndrome, which is characterized by dry mouth and
lack of tears, is treated with oral pilocarpine tablets and
cevimeline, a cholinergic drug that also has the drawback of being
nonspecific.

1.Therapeutic use in glaucoma: Pilocarpine is used to treat glaucoma and is the
drug of choice for emergency lowering of intraocular pressure of both open-
angle and angle-closure glaucoma. Pilocarpine is extremely effective in opening
the trabecular meshwork around the Schlemm canal, causing an immediate
drop in intraocular pressure because of the increased drainage of aqueous
humor. This action occurs within a few minutes, lasts 4 to 8 hours, and can be
repeated. [Note: Topical carbonic anhydrase inhibitors, such as dorzolamide
and β-adrenergic blockers such as timolol, are effective in treating glaucoma
but are not used for emergency lowering of intraocular pressure.] The miotic
action of pilocarpine is also useful in reversing mydriasis due to atropine.

Adverse effects:
Pilocarpine can cause blurred vision, night blindness, and
brow ache. Poisoning with this agent is characterized by
exaggeration of various parasympathetic effects, including
profuse sweating (diaphoresis) and salivation. The effects
are similar to those produced by consumption of
mushrooms of the genus Inocybe, which contain muscarine.
Parenteral atropine, at doses that can cross the blood–brain
barrier, is administered to counteract the toxicity of
pilocarpine.

INDIRECT-ACTING CHOLINERGIC AGONISTS:
ANTICHOLINESTERASE AGENTS (REVERSIBLE)
AChE is an enzyme that specifically cleaves ACh to acetate and choline and, thus, terminates
its actions. It is located both pre- and postsynaptically in the nerve terminal where it is
membrane bound.
Inhibitors of AChE (anticholinesterase agents or cholinesterase inhibitors) indirectly provide
cholinergic action by preventing the degradation of ACh. This results in an accumulation of
ACh in the synaptic space. Therefore, these drugs can provoke a response at all
cholinoceptors, including both muscarinic and nicotinic receptors of the ANS, as well as at the
NMJ and in the brain.
Reversible inhibitors are physostigmine, neostigmine, pyridostigmine, edrophonium,
rivastigmine, and donepeizil.
The reversible AChE inhibitors can be broadly classified as short-acting or intermediate-acting
agents.
All are poorly absorbed from conjunctiva, skin, and lungs except physostigmine which is well
absorbed from all sites. The effects are similar to direct-acting cholinergic agonists.

These agents are commonly used in the
treatment of:
• glaucoma,
• myasthenia gravis,
• stimulation of gastrointestinal and urinary tract
motility (for example,
neostigmine)—same effects as with agonists, •
reversal of neuromuscular blockade, and
• atropine poisoning.
Primary target organs of anticholineste ase drugs are eye, skeletal muscle,
neuromuscular junctions, gastrointestinal tract, urinary tract, respiratory tract, and
heart.

Myasthenia gravis (MG)
is an autoimmune neuromuscular disease characterized by generalized
muscle weakness.
The pathophysiology of MG involves autoantibodies directed against
postsynaptic acetylcholine receptors (AchR), thereby impairing
neuromuscular transmission.
Women are more frequently affected and about 10–15% of cases are
associated with thymoma. The most common initial symptoms
are ptosis and/or diplopia due to ocular muscle weakness, with the disease
usually progressing to generalized weakness within two years.
At that point, patients have difficulties standing up, climbing stairs, and
possibly even swallowing and/or chewing. Muscle weakness worsens
throughout the day with increased activity and improves after rest.

MG is diagnosed according to patient history, physical
examination, antibody testing, and electromyographic evaluation.
All patients should be screened for thymomas via CT as they can be
surgically removed, allowing for possible curative treatment.
The treatment of choice consists of acetylcholinesterase inhibitors,
possibly in combination with immunosuppressive drugs if symptoms
persist. Acute exacerbations, as seen in myasthenic crisis, should be
treated with either IV immunoglobulins or plasma exchange.

Thymus involvement
•Muscle-like (myoid) cells in the thymus express AChR → autoreactive targeting by T
cells → production of acetylcholine receptor antibodies (AChR antibodies)
Acetylcholine receptor antibodies
•Responsible for inhibition of signal transduction at the neuromuscular junction (NMJ)
•Antibodies target postsynaptic AChRs of normal muscle cells → competitive inhibition
of acetylcholine (ACh) → AChR decay through receptor internalization (↓ receptor density at the
postsynaptic membrane) and activation of complement (→ muscle cell lysis) → impaired signal
transduction at the NMJ → skeletal muscle weakness and fatigue
• Seropositive MG (80–90% of cases): positive assays for antibodies (in blood) against
the acetylcholine receptor (AChR-Ab)
• Seronegative MG (10–20% of cases): negative for AChR antibodies, but may be positive
for muscle-specific tyrosine kinase antibodies (MuSK antibodies)

•Symptoms worsen with increased muscle use throughout the
day and improve with rest.
•Sometimes associated with exacerbating factors, including:
• Medications
• Muscle relaxants
• Beta blockers
• Benzodiazepines
• Aminoglycosides, fluoroquinolones
• Low-potency antipsychotics
• Tricyclic antidepressants
• D-penicillamine
• Pregnancy
• Stress
• Infection

Clinical manifestations
Fatigable weakness of skeletal muscles in which smaller muscles responsible for
fine movements (e.g., eye muscles) tend to be affected first, while larger muscles
muscles become affected later on.
•Eye muscle weakness: most common initial symptom
• Triad of:
• Ptosis
• Diplopia
• Blurred vision
•Bulbar muscle weakness
• Slurred speech
• Difficulty chewing and/or swallowing
•Proximal limb weakness
• Rising from a chair
• Climbing stairs
• Brushing hair
• Deep tendon reflexes are not affected.
•Respiratory muscle weakness: causes dyspnea

Physical examination findings
•Curtain sign: Lifting the more ptotic eyelid reveals ptosis in the contralateral eyelid.
• According to Hering's law of equal innervation, the muscles of both eyelids receive equal
innervation.
• Manual lifting of the more ptotic eyelid → elimination of the central compensation required to
keep the more ptotic eyelidelevated → less innervation to both eyelids → relaxing of
the contralateral levator palpebrae superioris → enhancement of ptosis in contralateral eyelid
•Cogan lid twitch sign
• The patient is asked to gaze downward for 10–20 seconds and then to look straight ahead
• The affected upper eyelid briefly twitches
•Simpson test
• Provocation test used to reproduce eyelid fatigue
• Positive if looking upward for > 1 minute (without lifting the head) provokes eyelid fatigue
•Ice test: ice pack placed on one eye for 5 minutes → temporary improvement of eyelid fatigue

Approach
•Suspected cases of MG are generally confirmed via EMG and AChR
antibodies.
•Chest CT to rule out thymoma
Laboratory studies
•AChR antibody test (most specific test)
• 80–90% of patients with generalized MG have antibodies
• 100% of patients with thymoma have antibodies
•Other associated antibodies: anti-MuSK
Electrodiagnostics
•Electromyography (EMG): shows decremental response following
repetitive nerve stimulation
Imaging
•Chest CT: every newly diagnosed MG patient to rule out thymoma

•Edrophonium test (Tensilon test)
• Used to diagnose MG before AChR
antibody test became the common
method
• Symptoms improve rapidly after
administration of a short-
acting acetylcholinesterase
inhibitor
• High false positive rate

•First line: cholinesterase inhibitors
• Drug of choice: pyridostigmine
• Only improve symptoms (no causal treatment)
•Supplemental immunosuppressants: if symptoms
persist despite anticholinesterase treatment
• Glucocorticoids
• Alternatives
are azathioprine, cyclosporine, mycophenolate
mofetil

Edrophonium
Edrophonium is the prototype short-acting AChE inhibitor.
Edrophonium binds reversibly to the active center of AChE, preventing hydrolysis of ACh.
It is rapidly absorbed and has a short duration of action of 10 to 20 minutes due to rapid renal elimination.
Edrophonium is a quaternary amine, and its actions are limited to the periphery.
It is used in the diagnosis of myasthenia gravis, an autoimmune disease caused by antibodies
to the nicotinic receptor at the NMJ.
This causes the degradation of the nicotinic receptors, making fewer receptors available for
interaction with ACh. Intravenous injection of edrophonium leads to a rapid increase in muscle
strength in patients with myasthenia gravis. Care must be taken, because excess drug may
provoke a cholinergic crisis (atropine is the antidote). Edrophonium may also be used to assess
cholinesterase inhibitor therapy, for differentiating cholinergic and myasthenic crises, and for
reversing the effects of nondepolarizing neuromuscular blockers after surgery. Due to the
availability of other agents, edrophonium use has become limited.

Edrophonium is also used to diagnose myasthenia gravis.*
The Tensilon test uses the short-acting drug edrophonium
chloride, which is given intravenously, to assess the adequacy
of treatment with AChE inhibitors. Small doses of edrophonium
improve weakness, especially in the eye muscles, briefly and
temporarily in untreated myasthenia patients or in treated
patients in whom AChE inhibition is inadequate. Worsening of
muscle weakness indicates that the dose of AChE inhibitor is
too high—that is, excessive ACh stimulation at the
neuromuscular junction results in a depolarizing blockade). A
trial use of oral pyridostigmine bromide is an alternative
approach. Tolerance may develop to long-term use of the
AChE inhibitors.

Physostigmine
Physostigmine is a nitrogenous carbamic acid ester found naturally in plants and is a tertiary amine. It is
a substrate for AChE, and it forms a relatively stable carbamoylated intermediate with the enzyme, which
then becomes reversibly inactivated. The result is potentiation of cholinergic activity throughout the body.
1. Actions: Physostigmine has a wide range of effects and stimulates not only the muscarinic and
nicotinic sites of the ANS, but also the nicotinic receptors of the NMJ. Muscarinic stimulation can
cause contraction of gastrointestinal smooth muscles, miosis, bradycardia, and hypotension Nicotinic
stimulation can cause skeletal muscle twitches, fasciculations, and skeletal muscle paralysis (at
higher doses). Its duration of action is about 30 minutes to 2 hours, and it is considered an
intermediate-acting agent. Physostigmine can enter and stimulate the cholinergic sites in the CNS.
2. Therapeutic uses: Physostigmine is used in the treatment of overdoses of drugs with
anticholinergic actions, such as atropine and scopolamine, and to reverse the effects of
neuromuscular blockers (NMBs).
3. Adverse effects: Physostigmine is well absorbed orally and it enters the CNS. High doses of
physostigmine may lead to convulsions. Bradycardia and a fall in cardiac output may also occur.
Inhibition of AChE at the NMJ causes the accumulation of ACh and, ultimately through continuous
depolarization, results in paralysis of skeletal muscle. However, these effects are rarely seen with
therapeutic doses.

Neostigmine
Neostigmine [nee-oh-STIG-meen] is a synthetic compound that is also a carbamic acid
ester, and it reversibly inhibits AChE in a manner similar to physostigmine.
1. Actions: Unlike physostigmine, neostigmine has a quaternary nitrogen. Therefore, it
is more polar, is absorbed poorly from the GI tract, and does not enter the CNS. Its
effect on skeletal muscle is greater than physostigmine, and it can stimulate
contractility before it paralyzes. Neostigmine has an intermediate duration of action,
usually 30 minutes to 2 hours.
2. Therapeutic uses: Neostigmine is used to stimulate the bladder and GI tract and
as an antidote for competitive neuromuscular-blocking agents. It is also used to
manage symptoms of myasthenia gravis.
3. Adverse effects: Adverse effects of neostigmine include those of generalized
cholinergic stimulation, such as salivation, flushing, decreased blood pressure,
nausea, abdominal pain, diarrhea, and bronchospasm. Unlike physostigmine,
neostigmine is poorly absorbed from the GI tract and has negligible distribution into the
CNS; therefore, it does not cause CNS side effects and is not used to overcome
toxicity of central-acting antimuscarinic agents such as atropine. Neostigmine is
contraindicated when intestinal or urinary bladder obstruction is present.

Direct parasympathomimetics
•Local side effects: blurred vision due to miosis when applied to the eyes
•Systemic side effects: identical to those of indirect parasympathomimetics
•Indirect parasympathomimetics
•Cardiovascular symptoms
• Bradycardia
• Hypotension
•Gastrointestinal symptoms
• Diarrhea
• Nausea
• Abdominal pain
•Genitourinary symptoms: uncontrolled urination
•Exocrine glands
• ↑ Sweating
• ↑ Salivation
• ↑ Gastric secretion
•Ocular symptoms
• Miosis
• Lacrimation
•CNS-related symptoms: can culminate in coma
• Hypoventilation
• Lethargy
• Tremor
• Restlessness
• Anxiety
• Ataxia
•Musculoskeletal symptoms
• Weakness
• Paralysis → peripheral neuromuscular respiratory failure
• Spasms
• Fasciculations

Cholinergic crisis (cholinergic syndrome)
•Definition: potentially life-threatening acetylcholine receptor overstimulation
•Etiology: poisoning with organophosphates (e.g., parathion)
•Pathophysiology: irreversible acetylcholinesterase inhibition
•Epidemiology: most commonly seen in farmers, as organophosphates are used as insecticides
•Clinical presentation
• Muscarinic effects
• Excess of secretions, including salivation, sweating, lacrimation, urination,
defecation, and emesis
• Miosis and blurred vision
• Bradycardia
• Bronchospasm
• Bronchorrhea
• Nicotinic effects: blockage at the neuromuscular junction (similar mechanism observed
in succinylcholine)
• Systemic effects
• Hypoventilation
• Lethargy
• Seizures, coma
•Treatment: antimuscarinic agents
• Atropine
• Pralidoxime
DUMBBBELLSS: Diarrhea, Urination, Miosis, Bradycardia, Bronch
ospasm, Bronchorrhea, Emesis, Lacrimation, Lethargy, Sweating,
and Salivation are the main symptoms of cholinergic crisis.

Botulinum toxin blocks the release of
acetylcholine from cholinergic nerve
terminals. Which is a possible effect of
botulinum toxin?
A. Skeletal muscle paralysis
B. Improvement of myasthenia gravis
symptoms
C. Increased salivation
D. Reduced heart rate

Correct answer = A. Acetylcholine released by cho-inergic neurons acts on
nicotinic receptors in the skeletal muscle cells to cause contraction.
Therefore, blockade of ACh release causes skeletal muscle paralysis.
Myasthenia gravis is an autoimmune disease where antibodies are produced
against nicotinic receptors and inactivate nicotinic receptors. A reduction in
ACh release therefore worsens (not improves) the symptoms of this condition.
Reduction in ACh release by botulinum toxin causes reduction in secretions
including saliva (not increase in salivation) causing dry mouth and an increase
(not reduction) in heart rate due to reduced vagal activity.

1.A patient develops urinary retention after an
abdominal surgery. Urinary obstruction was ruled
out in this patient. Which strategy would be helpful
in promoting urination?
2.A. Activating nicotinic receptors
B. Inhibiting the release of acetylcholine
C. Inhibiting cholinesterase enzyme
D. Blocking muscarinic receptors

Correct answer = C.
Activation of muscarinic receptors in the detrusor muscles of
urinary bladder can promote urination in patients where the
tone of detrusor muscle is low. Inhibiting cholinesterase
enzyme increases the levels of acetylcholine, and acetylcholine
can increase the tone of the detrusor muscle.
There are no nicotinic receptors in the detrusor muscles;
therefore, activation of nicotinic receptors is not helpful.
Inhibiting the release of acetylcholine or blocking muscarinic
receptors worsens urinary retention.

Which of the following drugs
could theoretically improve
asthma symptoms?
A. Bethanechol
B. Pilocarpine
C. Pyridostigmine
D. Atropine

Correct answer = D.
Muscarinic agonists and drugs that increase acetylcholine levels
cause constriction of bronchial smooth muscles and could
exacerbate asthma symptoms. Bethanechol and pilocarpine are
muscarinic agonists, and pyridostigmine is a cholinesterase
inhibitor that increases levels of acetylcholine. Atropine is a
muscarinic antagonist and therefore does not exacerbate asthma.
Theoretically, it should relieve symptoms of asthma (not used
clinically for this purpose).

“A 25-year-old woman presents to the general medicine
clinic complaining of vision problems. She has difficulty
keeping her eyes open and complains of “seeing double.”
Her symptoms fluctuate throughout the day. Her ptosis is
more common in the left eye, but will switch over to the
right eye. Her symptoms are generally better in the
morning and worsen as the day progresses. Her ptosis
seems to get better after she rests her eyes. She
exercises regularly, but has noticed that over the past 2
months she has struggled to complete her evening run
due to fatigue in her hips.You suspect myasthenia gravis
and perform an edrophonium (Tensilon) test.The test is
positive and therefore the patient is started on
mestinon.”

Edrophonium test and diagnosis:
An intramuscular or intravenous injection of
edrophonium will alleviate ptosis by
temporarily increasing the availability of
acetylcholine at the synapse, allowing
contraction of the levator palpebrae superiorus
muscle.This test is very specific for diagnosing
myasthenia gravis.
Mechanisms of action of edrophonium and
mestinon: acetylcholinesterase (AChE) ”

Muscarinic antagonists (antimuscarinic agents) are a group of anticholinergic
drugs that competitively inhibit postganglionicmuscarinic receptors. As such, they have a variety
of applications that involve the parasympathetic nervous system.
Which organ systems are most affected by an antimuscarinic agent depends on the specific
characteristics of the agent, particularly its lipophilicity. Lipophilic agents
(i.e., atropine or benztropine) are able to cross the blood-brain barrier and therefore affect
the central nervous system (CNS) in addition to other organ systems. Less lipophilic agents
(i.e., ipratropium or butylscopolamine) are administered if the CNS does not need to be targeted,
specifically for respiratory (e.g., asthma), gastrointestinal (e.g., irritable bowel syndrome), or
genitourinary applications (e.g., urinary incontinence).
Numerous adverse effects have been reported, the most common of which is dry mouth. An
overdose can result in anticholinergic syndrome, which manifests
in disorientation, hyperthermia, tachycardia, and/or coma.To avoid toxicity, it is especially
important to consider the anticholinergic effects of other drug classes before administering
muscarinic antagonists.

Anticholinergic syndrome (overdose)
•Etiology
• Belladonna poisoning
• Jimson weed/Angel's trumpet (Datura stramonium) poisoning: The plant contains alkaloids, such
as atropine and scopolamine, which lead to anticholinergic intoxication and mydriasis (“gardener's pupil”).
• Medications
• Anticholinergic agents (e.g., atropine, benztropine, trihexyphenidyl)
• Drugs with anticholinergic properties
• Tricyclic antidepressives (predominantly doxepin, amitriptyline, imipramine, and trimipramine)
• Antipsychotics (e.g., clozapine, quetiapine)
• First-generation antihistamines (e.g., promethazine, dimenhydrinate)
•Clinical features
• Dry mouth, warm, flushed skin, thirst, tachycardia, arrhythmias, mydriasis, confusion, and agitation
• Possibly anticholinergic delirium: Excessive use of tricyclic antidepressants (or other medications with
significant anticholinergic effects) can cause life-threatening delirium, hallucinations, and psychomotor
symptoms.
•Treatment: antidote for purely anticholinergic poisoning (e.g. atropine): physostigmine

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