Drugs Affecting ANS

Cholinergic Agonists
 CHOLINERGIC DRUGS
• These drugs produce actions similar to that of Ach,
either by directly interacting with cholinergic receptors
(cholinergic agonists) or by increasing availablity of Ach
at these sites (anticholinesterases)
CHOLINERGIC DRUGS

Direct acting Indirect acting

Cholinergic agonists Anticholinesterases

Choline esters Alkaloids Reversible Irreversible

DIRECT ACTING CHOLINERGIC AGENTS
Cholinergic agonists (also known as parasympathomimetics) mimic the
effects of acetylcholine by binding directly to cholinoceptors.
These agents may be broadly classified into two groups:
a. Choline esters, which include acetyl-choline and synthetic esters
of choline, such as carbachol and bethanechol.
b. Naturally occurring alkaloids, such as pilocarpine constitue the
second group. All of the direct-acting cholinergic drugs have
longer durations of action than acetylcholine.

Choline Esters Alkaloids

Acetylcholine Muscarine
Methacholine Pilocarpine
Carbachol Arecoline
Bethanechol
Mehcanism of Action
• Most drugs in this class nonselectively bind to cholinergic receptors.
Some of the more therapeutically useful drugs (pilocarpine and
bethanechol) preferentially bind to muscarinic receptors and are
sometimes referred to as muscarinic agents.
• The drugs carbachol, bethananicol, metapropamide and
pilocarpine cannot be destroyed by acetylcholinesterase (AchE).
The drug methacholine can be destroyed by only plasma
cholinesterase (one form of AchE). Therefore these compounds
have a longer half-life than acetylcholine.
• Ach and methacholine are rapidly metabolized by AchE and plasma
cholinesterase respectively. The therapeutic effects of Ach and
methacholine can be extended by prior administration of
anticholinesterase agent which blocks AchE.
Pharmacologic effect:
• Most drugs in this class produce non-specific effect via cholinergic
activation in ganglia and various voluntary and involuntary muscles.
• Drugs with higher affinity for muscarinic receptors produce more
selective effects. For example, muscarinic activation of the heart
produces bradycardia; muscarine activation of sweat glands
produces increase secretion
• However, as a group, the direct-acting agonists show little specifcity
in their actions, which limits their clinical usefulness.
• Pilocarpine and arecoline have tertiary (unionized) structures which
makes it possible to cross the blood brain barrier and enter the
CNS. Pilocarpine and arecoline therefore have CNS effects.
• All other drugs listed above have quaternary structures (ionized )
which do not cross the blood brain barrier. Thus they do not have
CNS effects.
 Acetylcholine (prototype)
• 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 is therapeutically of no
importance because of its multiplicity of actions and its
rapid inactivation by the cholinesterases.
• Acetylcholine has both muscarinic and nicotinic activity. It
acts on
1. Heart
2. Blood Vessels
3. Smooth Muscles
4. Glands
5. Eye
• Decrease in heart rate and cardiac output: The actions of acetyl-
choline on the heart mimic the effects of vagal stimulation. For
example, acetylcholine, if injected intravenously, produces a brief
decrease in cardiac rate (negative chronotropy) and stroke volume
as a result of a reduction in the rate of firing at the sinoatrial (SA)
node. [Note: It should be remembered that normal vagal activity
regulates the heart by the release of acetylcholine at the SA node.]
Cardiac Muscarinic receptors are of the M2 type
• Decrease in blood pressure: Injection of acetylcholine causes
vasodilation and lowering of blood pressure by an indirect
mechanism of action. Acetylcholine activates M3 receptors found
on vascular endothelial cells lining the smooth muscles of blood
vessels. Vasodilation is primarily mediated through the release of
EDRF which is NO [Note: nitric oxide is also known as endothelium-
derived relaxing factor.]
In the absence of administered cholinergic agents, the vascular
receptors have no known function, because acetylcholine is never
released into the blood in any significant quantities.
Atropine blocks these muscarinic receptors and prevents
acetylcholine from producing vasodilation
• Smooth Muscles: In most organs smooth muscle is contracted (mainly
through M3 receptors)
Tone and peristalisis of GI tract is increased and sphincters relax -- > abd. cramps
and evacuation of bowel
Peristalisis in ureter is increased. The detrusor muscle contracts while bladder
trigone relaxes -- > voiding of bladder
Bronchial muscles constricts, asthamatics are highly sensitive -- > dyspnoea,
precipitation of an attack of asthma
• Glands: Secretion from all parasympathetic glands is increased via M3 and
some M2 receptors. This results in increased sweating, salivation,
lacrimation, tracheobronchial and gastric secretions.
Note: Secretion of Milk and Bile is not affected
• Eye: Contraction of circular (pupillae sphincter) muscles of iris, causing
Miosis (marked constriction of pupil)
Contraction of Ciliary muscles which results in spasm of accomodation,
reduction of intraocular pressure
 Bethanechol
• It is structurally related to acetylcholine. It is not hydrolyzed by
acetylcholinesterase (due to the addition of carbonic acid), although it is
inactivated through hydrolysis by other esterases. It lacks nicotinic actions
but does have strong muscarinic activity. Its major actions are on the
smooth musculature of the bladder and gastro-intestinal tract. It has a
duration of action of about 1 hour.
Actions: Bethanechol directly stimulates muscarinic receptors, causing
increased intestinal motility and tone. It also stimulates the detrusor muscles
of the bladder whereas the trigone and sphincter are relaxed, causing
expulsion of urine
Therapeutic applications: In urologic treatment, bethanechol is used to
stimulate the atonic bladder, particularly in postpartum or postoperative,
nonobstructive urinary retention. Bethanechol may also be used to treat
neurogenic atony as well as megacolon and gastro esophageal refulx.
Adverse efects: Bethanechol causes the efects of generalized cholinergic
stimulation. These include sweating, salivation, fushing, decreased blood
pressure, nausea, abdominal pain, diarrhea, and bronchospasm.
 Pilocarpine
• The alkaloid pilocarpine is obtained from the leaves of Pilocarpus
microphyllus. It is a tertiary amine and is stable to hydrolysis by
acetylcholinesterase. Compared with acetylcholine and its derivatives, it is
far less potent, but it is uncharged and will penetrate the CNS at
therapeutic doses. Pilocarpine exhibits potent muscarinic activity and is
used primarily in ophthalmology.
Actions: Applied topically to the cornea, pilocarpine produces rapid miosis
and contraction of the ciliary muscle. The eye undergoes miosis and a spasm
of accommodation; the vision is fixed at some particular distance, making it
impossible to focus. [Note the opposing effects of atropine, a muscarinic
blocker, on the eye.] 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 benefcial in
promoting salivation in patients with xerostomia resulting from irradiation of
the head and neck. Sjögren’s syndrome, which is characterized by dry mouth
and lack of tears, is treated with oral pilocarpime tablets and cevimeline, a
cholinergic drug that also has the drawback of being nonspecifc.
Therapeutic use in glaucoma: Pilocarpine is the drug of choice in the
emergency lowering of intraocular pressure of both narrow-angle (also
called closed-angle) and wide-angle (also called open-angle) glaucoma.
Pilocarpine is extremely effective in opening the trabecular meshwork
around Schlemm’s canal, causing an immediate drop in intraocular
pressure as a result of the increased drainage of aque-ous humor. This
action lasts up to 8 hours and can be repeated.
The organophosphate echothiophate inhibits acetylcholinesterase and
exerts the same efect for a longer duration. [Note: Carbonic anhy-
drase inhibitors, such as acetazolamide, as well as the β-adrenergic
blocker timolol, are efective in treating glaucoma chronically but are
not used for emergency lowering of intraocular pressure.]

Adverse efects: Pilocarpine can enter the brain and cause CNS
disturbances. It stimulates profuse sweating and salivation.
Summary of adverse
effects of cholinergic • Arecoline: Found in betel
drugs nut Areca catechu and has
both muscarinic and
nicotinic actions including
those on skeletal muscle
end plates. It has
prominent CNS effect as it
has tertiary structure and
therefore had been tried
on dementia, but not found
useful. It has no
therapeutic use.
 Indirect acting Anticholinesterases
• Acetylcholinesterase is an enzyme that specifically cleaves acetylcholine 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
acetylcholinesterase indirectly provide a cholinergic action by prolonging the
lifetime of acetylcholine produced endogenously at the cholinergic nerve endings.
This results in the accumulation of acetylcholine in the synaptic space.
They may be reversible or irreversible acting
Reversible Irreversible
Carbamates Arcidine Organophosphates Carbamates
Physostigmine Tacrine# Isofluorophate Carbaryl*
Neostigmine Isothiophate Propoxur*
Pyridostigmine Echothiophate
Ambenomium Dyflos (DFP)
Demecarium Malathion*, Parathion*
Edrophonium Diazinon*
Rivastigmine#, Donepezil#, Galantamine# Sarin^, Tabun^, Soman^
#Used in Alzhemier’s Ds *Insectides ^ Nerve gases for chemical warfare
 Anti-ChE’s
• Anti-ChEs are either esters of carbamic acid or derivatives
of phosphoric acid.
• Some carbamates are lipid-soluble (e.g. Physostigmine)
while others are lipid-insoluble (e.g. Neostigmine)
• All organophosphates are highly lipid soluble except
Echothiophate which is water soluble.
• ACTIONS: Lipid-soluble agents (physostigmine and
organophosphates) have more marked muscarinic and CNS
effects, but action on skeletal muscles in less prominent
Lipid –insoluble agents (neostigmine and other quaternary
ammonium compounds) produce more marked effect on
skeletal muscles, but muscarinic effects are less prominent.
They do not penetrate CNS and have no central effects.
 Anti-ChE’s
• CVS: CV effects are comples. Muscarinic action would produce
bradycardia and hypotension while ganglionic stimulation (through
ganglionic muscarinic receptors) would tend to increase heart rate
and BP.
• Skeletal Muscles: After treatment with anti-CHEs, the Ach released
by a single nerve impulse is not immediately destroyed --- rebinds
to the same receptor, diffuses to act on neighbouring receptors and
activates prejunctional fibers --- > repetitive firing --- > twitching
and fasciculations. Force of contraction in partially curarized
(treated with curare) and myasthenic muscles is increased. Higher
doses causes persistent depolarization of end plates resulting in
blockade of neuromuscular transmission --- > weakness and
paralysis.
• Others effects: These result from the stimulation of smooth
muscles and glands of the GI, respiratory, UT and in the eye.
 Reversible Anti-ChE’s
• Physostigmine: It is an alkaloid (a nitrogenous compound present in
plants) and a tertiary amine (that is why it is soluble in lipids and also has
CNS effects)
• Actions: It has a wide range of effects not only on the muscarinic and
nicotinic sites of the ANS but also on the nicotinic receptors of the
neuromuscular junction. It can enter and stimulate the cholinergic sites of
the CNS.
• Therapeutics uses:
a. Increase intestinal and bladder motility in atony of bladder of intestine
b. Placed topically in they eye, it produces miosis ans spasm of accomodation,
as well as lowering of i.o.p. It is used to treat Glaucoma but pilocarpine is
more effective. There fore it is used to supplement Pilocarpine.
c. Used in the tx of overdoses of drugs with anticholinergic activity, such as
atropine, phenothiazines and tricyclic antidepressants.
d. It is used as an antidote for poisoning by muscarinic antagonists
• Adverse effects:
a) May lead to convulsions when high doses r used as it has CNS penetration.
b) Bradycardia and fall in CO may also occur
c) Accumulation Ach at the skeletal neuromuscular junction results in paralysis
of skeletal muscles. However, these effects are rarely seen in therapeutic
doses.
 Reversible Anti-ChE’s
• Neostigmine: It is a synthetic compound that is also a carbamic acid
ester. Unlike physostigmine, neostigmine has a quaternary nitrogen;
hence, it is more polar and does not enter the CNS.
• Actions: Its effect on skeletal muscle is greater than that of physostigmine,
and it can stimulate contractility before it paralyzes. Neostigmine has a
moderate duration of action, usually 30 minutes to 2 hours. It is used to
stimulate the bladder and GI tract
• Therapeutic uses:
a) Neostigmine has found use in symptomatic treatment of myasthenia gravis,
an autoimmune disease caused by anti-bodies to the nicotinic receptor at
neuromuscular junctions. This causes their degradation and, thus, makes
fewer receptors available for interaction with the neurotransmitter.
b) It is also used as an antidote for tubocurarine and other competitive
neuromuscular blocking agents.
c) Neostigmine does not cause CNS side effects and is NOT used to overcome
toxicity of central-acting antimuscarinic agents such as atropine.
• Adverse effects: of neostigmine include those of generalized cholinergic
stimulation, such as salivation, flushing, decreased blood pressure,
nausea, abdominal pain, diarrhea, and bronchospasm.
 Reversible Anti-ChE’s
• Pyridostigmine & Ambenomium: They other
cholinesterase inhibitors that are used in the chronic
management of myasthenia gravis. Their durations of
action are inter-mediate (3-6 hrs and 4-8 hrs, respectively),
but longer than that of neostigmine. Adverse effects of
these agents are similar to those of neostigmine.
• Demecarium: It is another cholinesterase inhibitor used to
treat chronic open-angle glaucoma (primarily in patients
refractory to other agents) closed-angle glaucoma after
irredectomy. It is also used for the diagnosis and treatment
of accommodative esotropia. Demecarium is a quaternary
amine that is structurally related to neostigmine.
Mechanisms of actions and side effects are similar to those
of neostigmine.
 Reversible Anti-ChE’s
• Edrophonium: Its actions are similar to those of neostigmine,
except that it is more rapidly absorbed and has a short duration of
action of 10 to 20 minutes (prototype short-acting agent).
Edrophonium is a quaternary amine and is used in the diagnosis of
myasthenia gravis. Intravenous injection of edrophonium leads to a
rapid increase in muscle strength. Care must be taken, because
excess drug may provoke a cholinergic crisis. Atropine is the
antidote. Edrophonium is used to distinguish muscle weakness
caused by Cholinergic crisis (worsening is seen) and Myasthenia
Gravis (improvement is seen).
• Tacrine, Donepezil, Rivastigmine, and Galantamine: Patients with
Alzheimer’s disease have a deficiency of cholinergic neurons in the
CNS. This observation led to the development of
anticholinesterases as possible remedies for the loss of cognitive
function. Tacrine was the first to become available, but it has been
replaced by the others because of its hepatotoxicity. Despite the
ability of donepezil, rivastigmine, and galantamine to delay the
progression of the disease, none can stop its progression.
Gastrointestinal distress is their primary adverse effect.
 Irreversible Anti-ChE’s
• Echothiophate:
• Mechanism of action: It is an organophosphate that covalently binds via
its phosphate group to the serine-OH group at the active site of
acetylcholinesterase. Once this occurs, the enzyme is permanently
inactivated, and restoration of acetylcholinesterase activity requires the
synthesis of new enzyme molecules. Following covalent modification of
acetyl-cholinesterase, the phosphorylated enzyme slowly releases one of
its ethyl groups. The loss of an alkyl group, which is called aging, makes it
impossible for chemical reactivators, such as pralidoxime, to break the
bond between the remaining drug and the enzyme.
• Actions: Actions include generalized cholinergic stimulation, paralysis of
motor function (causing breathing difficulties), and convulsions.
Echothiophate produces intense miosis and, thus, has found therapeutic
use. Atropine in high dosage can reverse many of the muscarinic and some
of the central effects of echothiophate
• Therapeutic uses: An ophthalmic solution of the drug is used directly in
the eye for the chronic treatment of open-angle glaucoma. The ef ects
may last for up to one week after a single administration. Echothiophate is
not a f rst-line agent in the treatment of glaucoma.In addition to its other
side ef ects, the potential risk for causing cataracts limits the use of
echothiophate.
• Reactivation of acetyl cholin esterase: Pralidoxime can reactivate
inhibited acetylcholinesterase. However, it is unable to penetrate into the
CNS. The presence of a charged group allows it to approach an anionic site
on the enzyme, where it essentially displaces the phosphate group of the
organophosphate and regenerates the enzyme. If given before aging of the
alkylated enzyme occurs, it can reverse the effects of echothiophate,
except for those in the CNS as Pralidoxime cannot penetrate the CNS. With
the newer nerve agents, which produce aging of the enzyme complex
within seconds, pralidoxime is less effective. Pralidoxime is a weak
acetylcholin-esterase inhibitor and, at higher doses, may cause side effects
similar to other acetylcholinsterase inhibitors.
 Uses of Cholinergic Agonists
• In Glaucoma: Physostigmine, Demecarium and Echothiophate are
commonly used in the treatment of glaucoma.
• In Alzheimers Ds: It is a neurodegenerative disorder characeterized
by progressive dementia. It primarily affects cholinergic neurons of
the brain. Various measures to augment cholinergic transmission in
the brain have been tried. Tacrine, Donepezil, Rivastigmine, and
Galantamine are new agents which are used in treatment of early
stages of Alzheimer’s Disease as they are relatively
cerebroselective.
• In Myasthenia Gravis: It is an autoimmune disorder affecting about
1 in 10,000 population, due to development of antibodies directed
to nicotinic receptors at the muscle endplate --- > reduction in
number of free Nm cholinoreceptors to 1/3rd of normal or less and
structural damage to the neuromuscular junction --- > weakness
and easy fatigability on repeated activity, with recovery after rest.
• Edrophonium and neostigmine have short half-
lives and are used in the diagnosis of Myasthenia
Gravis. Ambenonium, noestigmine, and
pyridostigmine are used in the treatment of
Myasthenia Gravis.
• Neostigmine and its congeners improve muscle
contraction by allowing Ach released from
prejunctional endings to accumulate and act on
receptors over a large area, and by directly
depolarizing the endplate.
 CLINICAL APPLICATIONS OF
CHOLINESTERASE INHIBITORS