The document discusses the parasympathetic nervous system and parasympathomimetic drugs. It provides details on:
- The parasympathetic nervous system originates from the brainstem and sacral region and uses acetylcholine as a neurotransmitter.
- Parasympathomimetic drugs like acetylcholine, muscarine, and anticholinesterases act to stimulate parasympathetic responses. Direct acting drugs activate cholinergic receptors while indirect drugs inhibit acetylcholinesterase.
- These drugs have therapeutic uses for conditions like glaucoma, urinary retention, and myasthenia gravis. Combinations of drugs are sometimes used to achieve optimal effects while minimizing side effects.
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Parasympathomimetics (Cholinergic drugs)
1. Prof. Amol B. Deore
Department of Pharmacology
MVP’s Institute of Pharmaceutical Sciences, Nashik
2. Parasympathetic division
The parasympathetic division typically act in opposition
of the sympathetic autonomic nervous system through
negative feedback control.
This action is a complementary response, causing a
balance of sympathetic and parasympathetic responses.
Overall, the parasympathetic outflow results in
conservation and restoration of energy, reduction in heart
rate and blood pressure, facilitation of digestion and
absorption of nutrients, and excretion of waste products.
4. The parasympathetic nervous
system is described as
originating in the cranio-sacral
region, that is, from the
brainstem and also the sacral
region.
This parasympathetic response
is primarily mediated through
cranial nerve X, the vagus nerve,
and the S2, S3, and S4 spinal
nerves (sacral region).
7. ď‚— Parasympathetic division synthesize, store and release
the neurotransmitter Acetylcholine (ACh) hence termed
as cholinergic system.
ď‚— Acetylcholine is synthesized locally in the cholinergic
nerve endings by the following pathway:
ď‚— Acetyl-CoA + choline choline acetylase Acetylcholine
ď‚— Acetylcholine is produced throughout the neurone, and
is stored in inactive form in the synaptic vesicles which
are mainly accumulated in nerve endings.
9. ď‚— Acetylcholine is produced throughout the neurone, and is stored
in inactive form in the synaptic vesicles which are mainly
accumulated in nerve endings.
ď‚— On arrival of the action potential (nerve impulse) at the nerve
endings, in presence of Ca++, free Ach molecules are released in
to synaptic cleft by the process of exocytosis.
ď‚— The active Ach combines with the cholinergic receptors
(muscarinic and nicotinic) on the postsynaptic membrane of
innervated target organ.
10. ď‚— This ACh binds to and activates the cholinergic receptor
on the postsynaptic membrane leading to the
depolarisation of this membrane. Thus the impulse is
transmitted across the synapse.
ď‚— The Ach release in synaptic cleft is rapidly hydrolysed by
the enzyme Acetylcholinesterase (AChE) within few
milliseconds. A part of choline is reabsorbed by nerve
endings and later reused in ACh synthesis.
ď‚— A pseudocholinesterase enzyme occurs in the plasma
and liver; serves to metabolize ingested esters and Ach.
11.  There are two classes of cholinergic receptors –
muscarinic and nicotinic. Muscarinic receptors are
present in the heart, smooth muscles, secretory
glands, eyes and CNS. Three subtypes of muscarinic
receptors, M1 to M3.
ď‚— Nicotinic receptors are present in the neuromuscular
junction, autonomic ganglia and adrenal medulla.
ď‚— Two subtypes of nicotinic receptors are NM and NN. NM
receptors are present at the skeletal muscle end plate
and NN receptors at the autonomic ganglia and adrenal
Cholinergic receptors
14. PARASYMPATHOMIMETICS
ď‚— These are drugs which produce actions similar to that
of Acetylcholine hence known as
parasympathomimetics.
ď‚— They act either by directly interacting with cholinergic
receptors or by increasing availability of Acetylcholine
at these sites.
16. Acetylcholine
Ach is acetic acid ester of choline and is neurotransmitter acts on
both muscarinic and nicotinic receptors.
17. Mechanism of action of Ach
The interaction of Ach with
cholinergic receptor may produce
one of the following types of
changes in the permeability of the
postsynaptic membrane:
Increased permeability of all ions
(Na+, Ca+2, and Cl-) which result to
depolarization of postsynaptic
membrane.
18. Selective permeability changes to certain ions
(K and Cl) which produce stabilization or
hyperpolarization of postsynaptic membrane.
In general, depolarization increases cellular
activity and hyperpolarization decreases
cellular activity.
28. Therapeutic uses of Ach
Acetylcholine is not used clinically because-
ď‚— It acts on all muscarinic and nicotinic receptors throughout
the body. Thus, overall effect is irrational.
ď‚— On oral administration it is hydrolysed by gastrointestinal
enzymes.
ď‚— On intravenous administration, it is metabolised
(inactivated) in blood itself by pseudocholine esterase
enzyme before reaching site of action.
ď‚— Ach does not cross blood brain barrier hence ineffective for
CNS action.
ď‚— Only little fraction of Ach molecules may enter in CNS which
get metabolised by acetylcholinesterase enzyme.
29. Oral administration
Oral administration
of Ach
Hydrolysis by
gastrointestinal
enzymes
Low bioavailability Low
efficacy
Parenteral administration
On intravenous
administration of Ach
metabolised in blood
by pseudocholine
esterase
Low bioavailability Low efficacy
42. Mechanism of action
ď‚— Reversible anticholinesterases are the drugs that
competitively antagonise the
acetylcholinesterase (AchE) enzyme and prevent
the hydrolysis of Acetylcholine.
ď‚— Acetylcholinesterase causes metabolism
(hydrolysis) of Ach. Inhibition of AchE enzyme
increases both availability and duration of action
of acetylcholine.
54. Decontamination measures
• The patient is removed from the site of
exposure of poison and placed in fresh air.
• The skin, eyes and mouth washed with soap
and water.
• Gastric lavage to remove the poison from the
stomach; induced by warm saline solution and
activated charcoal.
55. Supportive therapies
• The artificial respiration is given by ventilator to recover
from breathlessness.
• The normal saline solution and vasoconstrictors like
noradrenaline or dopamine are administered by IV infusion
to maintain blood pressure and to prevent circulatory
collapse (shock).
• Prophylactic antibiotics like ampicillin are given to prevent
infection.
• Diazepam is given to prevent convulsions.
56. Specific measures
• To counteract/ reverse the adverse effects, specific
antidotes are administered which are-
• Anticholinergic drugs like atropine sulphate (2mg
IV or IM) to be block muscarinic receptors in order
to counteract CNS effects and other complications.
• Acetylcholinesterase reactivators like pralidoxime,
oblidoxime, & pyruvalidoxime. They reactivate the
AchE enzyme at nicotinic receptor sites on skeletal
muscles (neuromuscular junction).
57. Acetylcholine is not used clinically because-
• It acts on all muscarinic and nicotinic receptors throughout
the body. Thus, overall effect is irrational.
• On oral administration it is hydrolysed by gastrointestinal
enzymes.
• On intravenous administration, it is metabolised
(inactivated) in blood itself by pseudocholine esterase
enzyme before reaching site of action.
• Ach does not cross blood brain barrier hence ineffective
for CNS action.
• Only little fraction of Ach molecules may enter in CNS
which get metabolised by acetylcholinesterase enzyme.
58. In treatment of Myasthenia gravis, atropine
is given along with neostigmine. Why?
• Myasthenia gravis is an autoimmune disorder caused
by progressive weakness and paralysis of skeletal
muscles leading to extreme fatigue.
• Nicotinic NM (neuromuscular junction) receptors get
destroyed in myasthenia gravis.
• Neostigmine is reversible anticholinesterase which
increasing availability of endogenous Acetylcholine at
receptor sites; whereas atropine is anticholinergic
(antimuscarinic) drug.
59. ď‚— Neostigmine is parasympathomimetic drug which
increasing availability of endogenous Acetylcholine
at both muscarinic and nicotinic receptor sites.
ď‚— In myasthenia gravis, only nicotinic action is
desired hence to suppress muscarinic action
(occurring at CNS, heart, blood vessels and eye)
atropine (antimuscarinic) is administered along with
neostigmine.
60. Neostigmine and pyridostigmine combination is favoured
in the treatment of myasthenia gravis. Why?
• Neostigmine and pyridostigmine are reversible
anticholinesterases used for treatment of myasthenia gravis.
• Neostigmine is a drug of choice in myasthenia gravis, but it
requires frequent dosing 15-20 mg in every six hours.
Moreover, dose and frequency is needed to be adjusted for
unpredictable period.
• Although pyridostigmine has less potency and long duration of
action which needs less frequency of dosing.
• Hence to reduce frequency of dosing and to increase
potency, Neostigmine and Pyridostigmine combination
produces synergistic action. Thus the combination is
favoured.
61. Organophospharous compounds are not used for
therapeutic purpose. Why?
• Organophospharous compounds are irreversible
anticholinesterases like Malathion, Parathion, Ecothiopate,
TabunÂŁ, SarinÂŁ, SomanÂŁ, Carbaryl*, Propoxur*.
• They inhibit metabolism of acetylcholine hence produce
persistent action. Repeated cholinergic activity of all innervated
organs leads to toxic manifestations like spasm of
accommodation of eyes, hypotension, bradycardia,
bronchospasm, respiratory failure, convulsions, and coma
leading to death.
• Thus Organophospharous compounds are used as insecticides
and pesticides in agriculture and not for therapeutic purpose.
63. Glaucoma is characterised by rise in intraocular
pressure (>21 mmHg) associated with damage to
the optic nerve in the back of the eye.
Optic nerve transmits information from the eye to
the brain. Without treatment, glaucoma can cause
total permanent blindness within a few years.
64. Treatment of glaucoma
• The miotics: these are cholinergic drugs when applied
topically constriction of the pupil and a fall in intraocular
pressure.
• Ex. Pilocarpine, Methacholine, Carbachol,
Physostigmine, DFP
• Beta adrenoceptor blockers: these drugs act by
lowering intraoccular pressure due to constriction of
pupil.
• Ex. Timolol
66. ď‚— Myasthenia gravis (MG) is a rare autoimmune disorder in
which antibodies form against acetylcholine nicotinic
postsynaptic receptors at the neuromuscular junction of
skeletal muscles.
ď‚— Myasthenia gravis is a neuromuscular disorder that
causes progressive weakness and fatigue in the skeletal
muscles, which are the muscles your body uses for
movement.
ď‚— It occurs when communication between nerve cells and
muscles becomes impaired.
ď‚— This impairment prevents crucial muscle contractions
from occurring, resulting in muscle weakness.
67.
68. Symptoms of myasthenia
• Trouble talking
• Problems walking up stairs or lifting objects
• Facial paralysis
• Difficulty breathing because of muscle weakness
• Difficulty swallowing or chewing
• Fatigue
• Hoarse voice
• Drooping of eyelids
• Double vision
69. Treatment for Myasthenia Gravis
ď‚— There is no cure for MG. The goal of treatment is to
manage symptoms and control the activity of your
immune system.
ď‚— Corticosteroids and immunosuppressants can be
used to suppress the immune system. These
medications help minimize the abnormal immune
response that occurs in MG.
ď‚— Additionally, acetylcholinesterase inhibitors, such as
physostigmine, neostigmine, pyridostigmine can be
used to increase communication between nerves and
muscles.