Autonomic Nervous

System Drugs
Dr. Valdez
 ANS- Review
• Sympathetic NS- generally catabolic, expending energy (the
“fight or flight” system), increases the HR, dilates the
bronchi, and decreases secretions
• Parasympathetic NS- anabolic, conserving energy, decreases
HR, stimulates GI function, increase secretions
• Autonomic neurotransmission involves two neurons:
presynaptic and post synaptic
• Preganglionic neuron extend from the brain to the
autonomic ganglia where they transmit CNS signals to
postsynaptic neurons by releasing Ach into the synaptic cleft
which is a space between the two neurons.
• Postganglionic neurons subsequently transmit impulses to
end organs (heart, stomach etc) by releasing NE (SYMP
neuron) or Ach (PARA)
•
• Catecholamines ( NE and E ) transmit most impulses of the
SYMP system
• Upon release from postganglionic neurons ,NE diffuses across
the synaptic cleft binds to adrenergic ( α1, α2, β1 or β2)
receptors .
• During times of stress, the adrenal gland releases
Epinephrine (80%) and NE into the blood (Adrenaline surge)
• Exception to NE neurotransmission in the SYMP system is the
Sweat gland
( Ach which is often considered a PARA neurotransmitter,
conveys sympathetic signals to sweat glands)
Other exception: Kidney-renal vascualr smooth muscle -
Dopamine D1
• Acetyl choline (Ach) transmits PARA signals to end organs
(heart lungs etc) by binding to muscarinic (M) receptors
• Acetylcholine also plays three other important roles in
neurotransmission
1. Ganglionic transmission
-Ach transmit both SYMP and PARA impulses from the
preganglionic neurons in the brain and spinal cord to nicotinic
ganglionic (NN) receptors on post ganglionic neurons
-This occurs in SYMP ganglia located along the spinal cord
(preganglionic) and in PARA ganglia which lie near the end
organs (postganglionic).
-Because all ganglionic transmission is cholinergic, drugs which
block ganglionic transmission inhibit either SYMP or PARA
depending on which system is predominant at the moment
2. Neuromuscular transmission
-Ach released from neurons causes muscle
contraction by binding to Nicotinic muscle (NM )
located in NMJ
Receptors on muscle cells causing calcium influx
3. Central neurotransmission
-Ach is a neurotransmitter in the brain acting
predominantly via muscarinic receptors
 Processes involved in neurotransmission
1. The neurotransmitter is synthesized from chemical precursors
2. It is packaged into vesicles in the presynaptic terminals
3. The presynaptic nerve is stimulated causing the synaptic
vesicles to fuse with the synaptic membrane and release the
neurotransmitter
4. The neurotransmitter diffuses across the synaptic cleft and
may bind to postsynaptic receptors
5. Binding of neurotransmitter to receptor results in either
opening an ion channel or activation of second messenger
cAMP or IP
6. The resulting ion influx or second messenger activation
causes an action (ex. depolarization) of the post synaptic cell
-Neurotransmitter molecules which fail to bind to postsynaptic
receptors are destroyed or degraded by enzymes are taken up
into the presynaptic neuron to be recycled or diffuse away from
 Cholinergic drugs
(Cholinomimetic)
• Cholinergic drugs promote the action of the neurotransmitter
Ach.
• Also called Parasympathomimetic drugs because they produce
effects that imitate parasympathetic nerve stimulation.
• Two major classes :
 Cholinergic agonists (Direct-acting) produce actions similar
neurotransmitter Ach
 Anticholinesterase drugs (Indirect-acting)work by inhibiting
the destruction of Ach at the cholinergic receptor sites
-drugs inhibit acetylcholinesterase
- Ach is not broken down and begins to accumulate prolonged
Ach effects
Pharmacokinetics
• Cholinergic agonists –Direct acting
-When a neuron in the PNS is stimulated, the neurotransmitter
Ach is released.
-Ach crosses the synapse and interacts with receptors in an
adjacent neuron.
- Cholinergic agonists stimulate cholinergic receptors, mimicking
the action of Ach
Choline esters (Receptor affinity) Alkaloids-not metabolized by
Acetylcholine (N/M) cholinesterases
Muscarine (M)
Bethanechol (M) Pilocarpine (M)
Carbachol (N/M) Nicotine (N)
Methacholine (M) Lobeline (M)
Ceviimeline (M)
• Cholinergic agonists are usually administered:
- topically as eye drop (pilocarpine)
- orally (bethanecol)
- subcutaneous (subQ) injection
(bethanecol)
• Pilocarpine -obtained from the leaves of
Pilocarpus microphylus, has prominent
muscarinic actions
- applied to the eye, penetrates the cornea and
causes miosis, ciliary muscle contraction and fall in
IOP lasting 4-8 hrs
• Nicotine is among the most commonly abused
drugs.
• Smokers become tolerant to and dependent on
its effects
• Nicotine stimulates the CNS releases Epi from
adrenal glands , stimulates and then blocks
receptors in ganglia and at the NMJ
• Nicotine is used therapeutically to help patient
stop smoking
Metabolism and excretion
• All cholinergic agonists are metabolized by
cholinesterases:
o at the muscarinic and nicotinic receptor sites
o in the plasma
o in the liver
• All drugs in this class are excreted by the
kidneys.
 Pharmacodynamics (how drugs act)
• Cholinergic agonists act by mimicking the action of Ach on
the neurons in certain target organs.
- When they combine with receptors on the cell membranes of
target organs, they stimulate the smooth muscle and
produce:
Muscarinic Actions:
• Glands : increased secretion from all
parasympathetically innervated glands via M3 and
some M4 >> Salivation, sweating,lacrimation
increased tracheobronchial and gastric secretion
• Heart: Ach hyperpolarizes the SAN via M2 and
decreases their rate of diastolic depolarization >>
Bradycardia and slowed AV conduction
• Blood vessels : M3 receptors are present on vascular
endothelial cells produce NO, a potent vasodilator
>>> Dilation of blood vessels
• Smooth muscles: smooth muscle in most organs is
contracted mainly through M2 receptors>>>
Constriction of the bronchioles,
Increased activity of the GI tract, Increased
tone and contraction of the bladder muscles
• Eye: contraction of circular muscle of iris via M3
>>Constriction of the pupils (miosis); contraction of
ciliary muscle>> spasm of accomodation, reduction of
IOP
Nicotinic actions:
1. Autonomic ganglia: both sympathetic and
parasympathetic ganglia are stimulated (this
effect is manifested at higher doses)>>
tachycardia,rise in BP
2. Skeletal muscles: Contraction of muscle
fiber>> twitching and fasciculation
CNS actions: cholinergic drugs which enter brain
produce complex behavioral and neurological
effects
 Pharmacotherapeutics
CLINICAL USES:
• Cholinergic agonists choline esters -are rarely if ever clinically
used to:
- treat atonic bladder conditions (bethanecol)
- postoperative and postpartum urinary retention
- treat GI disorders, such as postoperative abdominal
distension and GI atony (ileus)
• Cholinomimetic alkaloids - Pilocarpine
- reduce eye pressure in patients with glaucoma and during
eye surgery
-treat salivary gland hypofunction caused by radiation therapy
or Sjögren’s syndrome.
 Drug interactions
Cholinergic agonists have specific interactions
with other drugs.
• Anticholinesterase drugs (such as
pyidostigmine neostigmine etc), boost the
effects of cholinergic agonists and increase the
risk of toxicity.
• Cholinergic blocking drugs (such as atropine
etc) reduce the effects of cholinergic drugs.
• Quinidine reduces the effectiveness of
cholinergic agonists
 Adverse reactions to cholinergic agonists
Because they bind with receptors in the PNS, cholinergic agonists can
produce adverse effects in any organ innervated by the
parasympathetic nerves.
• nausea and vomiting
• cramps and diarrhea
• miosis, blurred vision
• decreased HR and low BP
• shortness of breath (bronchospasm)
• urinary frequency
• salivation
• sweating
• lacrimation
 Anticholinesterase (Cholinesterase
inhibitors) drugs- Indirect acting
• Anticholinesterase drugs block the action of the
enzyme Acetylcholinesterase (which breaks down the
neurotransmitter Ach) at cholinergic receptor sites,
preventing the breakdown of Ach.
-As Ach builds up, it continues to stimulate the
cholinergic receptors.
• Anticholinesterase drugs are divided into two categories
:
reversible
irreversible
Reversible anticholinesterase drugs have a short duration of action
Carbamates
Neostigmine
Physostigmine Myasthenia gravis
Pyridostigmine
Ambenonium
Edrophonium (an alcohol)
Donepezil Alzheimer disease
Rivastigmine
Galantamine
Tacrine (Acridine)
Irreversible anticholinesterase drugs have long-lasting effects
Organophosphates Carbamates
Echothiophate Propoxur (Baygon)
Malathion /Paratihion Carbaryl
Sarin
Soman
• Pharmacokinetics
Absorption:
• Most Anticholinesterase drugs are readily absorbed from
the GI tract, subcutaneous tissue, and mucous membranes
except neostigmine
• Neostigmine duration of action for an oral dose is longer
about 4 hrs , the patient does not need to take it as
frequently.
• When a rapid effect is needed, neostigmine should be
given by the I.M. or I.V. route
• Pyridostigmine duration of action 8 hrs- used for long
term therapy
• Edrophonium –the shortest acting of the
anticholinesterase inhibitors (15 min)
Distribution
• Physostigmine can cross the BBB

• Donepezil is highly bound to plasma proteins

• Tacrine is about 55% bound
• Rivastigmine is 40% bound
• Galantamine is 18% bound
Metabolism and Excretion
• Most anticholinesterase drugs are metabolized by
enzymes in the plasma and excreted in urine.
• Donepezil, Galantamine, Rivastigmine, and Tacrine
are metabolized in the liver.
• Pharmacodynamics
-Anticholinesterase drugs promote the action of Ach at
receptor sites by inhibiting cholinesterase.
• Reversible anticholinesterase drugs block the
breakdown of Ach for minutes to hours
• Irreversible anticholinesterase drugs block the
breakdown of Ach for days or weeks
• Lipid soluble agents (physostigmine, organophosphates)
have more marked muscarinic and CNS effects., stimulate
the ganglia but action on skeletal muscle is less prominent
• Lipid insoluble agents (neostigmine ) produce more
marked effect on skeletal muscles, stimulate ganglia but
muscarinic effects less prominent, no CNS effects
•
Pharmacotherapeutics
Anticholinesterase drugs are used to :
• reduce eye pressure in patients with glaucoma and during
eye surgery
• increase bladder tone
• improve tone and peristalsis through the
GI tract in patients with reduced motility or paralytic ileus
• Treat patients with Myasthenia gravis (Neostigmine)
• Diagnose Myasthenia gravis (Edrophonium)
• antidote to cholinergic blocking drugs (atropine) , TCA,
belladonna alkaloids, and narcotics
• Treat dementia and Alzheimer’s disease
( donepezil, galantamine, rivastigmine, and tacrine)
Organophosphates uses:
Malathion, Parathion, Propoxur, Carbaryl
• used primarily as insecticides and pesticides in
agriculture
Sarin, Soman
• as nerve gas in chemical warfare
Echothiophate
• The only one has therapeutic usefulness in
organophosphate poisoning
Drug interactions
• Cholinergic agonists –direct acting, increase the
risk of a toxic reaction when taken with
anticholinesterase drugs.
• CYP 450 enzyme inducers such as Carbamazepine,
rifampicin, phenytoin, and phenobarbital may
increase donepezil’s rate of elimination.
• Aminoglycoside , anesthetics, cholinergic
antagonists , magnesium, corticosteroids,
procainamide and quinidine can reduce the effects
of anticholinesterase drugs and can mask early
signs of a cholinergic crisis.
• TCA’s, and antipsychotics, can counteract the
effects of anticholinesterase drugs.
• CYP-450 inhibitors such as cimetidine and
erythromycin when combined with tacrine,
donepezil, and galantamine their effects may
be increased
• Cigarette use increases the clearance of
Rivastigmine.
• Adverse reactions
Adverse reactions caused by anti-cholinesterase
drugs
• Bradycardia
• Nausea , vomiting, diarrhea
• Bronchoconstriction-Wheezing
• Seizures -(Nicotinic effects)
• Insomnia (Nicotinic effects)
• Urinary frequency
• Blurred vision
 Recognizing a toxic response
• It is difficult to predict adverse reactions to anti-
Cholinesterase drugs in a patient with
myasthenia gravis because the therapeutic dose
varies from day to day.
Increased muscle weakness can result either
from:
• resistance to the drug
• receiving too little of the anticholinesterase
• receiving too much of the anticholinesterase
• Deciding whether a patient is experiencing a
cholinergic crisis (toxic drug reaction) or a
myasthenic crisis (extreme muscle weakness
and severe respiratory difficulties) can be
difficult.
• Edrophonium can be used to distinguish
between a cholinergic reaction and a
myasthenic crisis.
• When edrophonium is used, suction, oxygen,
mechanical ventilation, and emergency drugs,
such as atropine, must be readily available in
case a cholinergic crisis occurs.
Summary of actions of some cholinergic agonists
 Cholinergic Antagonists
• Cholinergic antagonists interrupt
parasympathetic nerve impulses in the CNS
and ANS.
• Also referred to as anticholinergic drugs
because they prevent Ach from stimulating
cholinergic receptors.
• Cholinergic antagonist drugs block just the
muscarinic receptor sites.
- Muscarinic receptors are cholinergic receptors
are blocked by atropine.
 Muscarinic Antagonists
Antimuscarinic non- selective
• Belladonna alkaloids –are the major
cholinergic blocking drugs
o Atropine (the prototype muscarinic
antagonist -an alkaloid isolated from Atropa
belladona-deadly nightshade )
o Homatropine
o Hyoscyamine sulfate
o Methscopolamine
o Scopolamine
• Synthetic Quaternary ammonium drugs :
o Glycopyrrolate
o Propantheline
• Synthetic Tertiary amines :
o Benztropine
o Dicyclomine
o Oxybutynin
o Trihexyphenidyl

• Synthetic Quaternary amines :

o Trospium
• Ipratropium
• Tropicamide
Antimuscarinic, selective
• Darifenacin
• Fesoterodine
• Solifenacin
• Tolterodine
Like atropine ,modest selectivity for M3 receptors ,
-Use for urinary urgency, incontinence,
- Administered oral,
-Duration of action12-24 hrs,
-Excessive parasympatholytic effects
• Perenzepine, telenzepine
-significant M1 selectivity
-use for peptic disease
-orally administered
Distribution
• The belladonna alkaloids are distributed
more widely throughout the body than
other cholinergic blockers.
• The belladonna alkaloids readily cross
the BBB; the other cholinergic blockers
do not.
• Metabolism and excretion
o The belladonna alkaloids are slightly to
moderately protein-bound which means that a
moderate to high amount of the drug is active and
available to produce a therapeutic response.
o The belladonna alkaloids are metabolized in the
liver and excreted by the kidneys as unchanged
drug
o Metabolism of Glycopyrrolate and propantheline
is through hydrolysis, occurs in the GI tract and
the liver; the drugs are excreted in stool and urine
-Dicyclomine’s metabolism is unknown, but it
is excreted equally in stool and urine
Pharmacotherapeutics
Cholinergic blockers are often used to treat GI
disorders and complications.
• treat GI spasm and reduce GI secretions.
• treat urinary incontinence.

Propantheline are the drugs of choice for

these conditions because they cause fewer
adverse reactions than belladonna alkaloids.
• Atropine with morphine are used to treat
biliary colic.
• Atropine may also be used as an antidote for
nerve agents
• Benztropine and trihexyphenidyl are
exclusively treatments for Parkinson’s disease
• Cholinergic blocking drugs are given by
injection before such diagnostic procedures as
endoscopy and sigmoidoscopy to relax the GI
smooth muscle
• Cholinergic blockers such as atropine are given
before surgery to:
-reduce oral, gastric, and respiratory secretions
-prevent a drop in heart rate caused by vagal nerve
stimulation during anesthesia.
• The belladonna alkaloids can affect the brain.
Example: scopolamine, given with the pain
relievers morphine or meperidine, causes
drowsiness and amnesia in a patient having surgery.
- Scopolamine also used to treat motion sickness.
• Atropine have important therapeutic effects
on the heart.
o treat symptomatic sinus bradycardia when
the heart beats too slowly, causing low blood
pressure or dizziness
o treat arrhythmias resulting from the use of
anesthetics, choline esters, or succinylcholine
• How atropine speeds the heart rate :
Without the drug : When the neurotransmitter Ach is
released, the vagus nerve stimulates the sinoatrial (SAN)
node and the atrioventricular (AVN) node, which controls
conduction between the atria and the ventricles of the
heart.
This inhibits electrical conduction and causes the heart
rate to slow down.
With the drug Atropine, competes with Ach for
cholinergic receptor sites on the SAN and AVN. By
blocking Ach, atropine speeds up the heart rate.
• Cholinergic blockers also are used as cycloplegics. -
paralyze the ciliary muscles of the eye (used for fine
focusing) alter the shape of the eye lens.
• Cholinergic blockers act as mydriatics to dilate the
pupils, making it easier to measure refractive errors
during an eye examination or to perform eye surgery.
Atropine and hyoscyamine, are effective antidotes to
cholinergic and anticholinesterase drugs.
-Atropine is the drug of choice to treat poisoning from
organophosphate pesticides.
-Atropine and hyoscyamine also counteract the effects of
the neuromuscular blocking drugs by competing for
the same receptor sites.
• n
Uses of other antimuscarinic drugs
• Benztropine – antiparkinsonism, oral parenteral
• Dicyclomine, Glycopyrrolate,- for GI applications,
oral, parenteral
• Homatropine, Cyclopentolate, Tropicamide-
topical opthalmic use to produce mydriasis,
cycloplegia
• Trospium- oral for urinary urgency
• Oxybutinin- oral, transdermal, promoted for
urinary urgency, incontinence
Drug interactions
• Because cholinergic blockers slow the passage of food
and drugs through the stomach, drugs remain in
prolonged contact with the mucous membranes of the GI
tract.
• This increases the amount of the drug that is absorbed
and, therefore, increases the risk of adverse effects.
• Drugs that increase the effects of cholinergic blockers
o disopyramide
o antiemetics and antivertigo drugs (buclizine, cyclizine,
meclizine, and diphenhydramine )
o antipsychotics ( haloperidol, phenothiazines, and
thioxanthenes )
o cyclobenzaprine orphenadrine, TCAs
• Drugs that decrease the effects of cholinergic
blockers are cholinergic agonists and
anticholinesterase drugs
• digoxin toxicity increases when digoxin is taken
with a cholinergic blocker.
• Opiate-like analgesics further slow the
movement of food and drugs through the GI
tract when taken with a cholinergic blocker.
• Absorption of sublingual NTG tablets reduced
when this drug is taken with a cholinergic blocker
• Adverse reactions to cholinergic
blockers closely related to the drug dose.

• Dry mouth
• Reduced bronchial secretions
• Increased heart rate
• Decreased sweating
• Blurred vision
• Adverse
reactions w/
muscarinic
antagonist
 Nicotinic Antagonist
• Ganglion blocking drugs- Site of action of ganglionic
blockers is the nicotinic receptors act like competitive
antagonist
- Hexamethonium –selective block of
NN ,obsolete ,adverese effects severe, no longer use, block all
autonomic effects
- Mecamylamine-enters CNS, investigational use for
smoking cessation
- Trimethaphan-short acting, was used for hypertensive
emergencies and controlled hypotension
- Varenicline-nicotine in form of gum or patches
 Cholinesterase regenerators
• Pralidoxime (2-PAM) chemical antagonist of
organophosphates
-can reactivate inhibited acetylcholinesterase
- It contains oxime group which has an extremely high affinity
for the phosphorus atom in organophosphate insecticides
• It is unable to penetrate the CNS therefore it is not useful in
treating the CNS effects of organophosphate poisoning
• It is useful in patient exposed to parathion or to nerve gas
• Side effects- muscle weakness