A SEMINAR ON

PARASYMPATHOMIMETIC AGENTS

Presented By: Ms. Kirti Vadi Guided By: Dr. Jalpa Suthar
17MPHCT002 Assistant Professor
M.Pharm Dept. Of Pharmacology &
(pharmacolgy) Toxicology
Rpcp,changa Rpcp,changa
 CONTENT
 Organization of nervous system
 Acetycholine drug profile
 Types of cholinergic receptors
 Nicotinic receptors
 Muscarinic receptors
 Classification of drugs
 Directly acting cholinergic drugs
 Indirectly acting cholinergic drugs
 Therapeutic uses of cholinergic drugs
 AchE Poisoning (organophosphorous poisoning)
 Side effects of cholinergic drugs
 Reference

2
 ORGANIZATION OF NERVOUS SYSTEM

The chief neurotransmitter in the parasymphathetic nervous system is

acetylcholine. Hence it is also known as cholinergic system. The drugs that
produce effect similar to that of acetylcholine are termed as cholinergic agents
3 or parasympathomimetic agents.
 ACETYCHOLINE (Prototype drug) DRUG PROFILE

4
 TYPES OF CHOLINERGIC RECEPTORS
M1

M2

Muscarinic M3
receptor

M4

Cholinergic receptors
M5

NM

Nicotinic receptor
NN
5
 NICOTINIC RECEPTORS
Features NM NN
Location and function Neuromuscular junction: Autonomic ganglia:
subserved depolarization of muscle end depolarization -postganglionic
plate -contraction of skeletal impulse,
muscle Adrenal medulla:
catecholamine release
CNS: site specific excitation or
inhibition
Nature Has intrinsic ion channel, Has intrinsic ion channel,
pentamer of only α2 β Ɛ or  pentamer of only αβ subunits,
and  subunits, each subunit each subunit has 4TM
has 4TM
Transducer Opening of cation (Na+, K+) Opening of cation (Na+, K+,
mechanism channels Ca++) channel
Agonist PTMA, Nicotine DMPP, Nicotine
Antagonist Tubocurarine Hexamethonium,
Trimethaphan
6
 MUSCARINIC RECEPTORS
Features M1 M2 M3
Location and Autonomic ganglia: Heart : GIT & Gall bladder :
function sub Depolarization (late EPSP) reduces heart rate, slow Smooth muscle contraction
served Gastric glands: AV node conduction, Pupils : Regulate pupil
Hist. release, acid secretion reduces force of constriction
CNS: contraction glands : Promote mouth,
Learning, memory, motor sinus, eye, lung & skin
functions lubrication
Blood vessels : Increase
vasodilation
Nature G-protein coupled, 7-TM G-protein coupled, 7- G-protein coupled, 7-TM
TM
Transducer IP3/DAG- ↑cytosolic Ca++ K + channel opening, IP3/DAG- ↑cytosolic Ca++
mechanism PLA2 ↑- PG synthesis cAMP PLA2 ↑- PG synthesis
Agonists Oxotremorine Methacholine Bethanechol
Antagonists Pirenzepine, Telenzepine Methoctramine, Hexahydrosiladifenidol,
Tripitramine Darifenacin

7
 CLASSIFICATION OF DRUGS
The parasympathomimetic
agents are classified into the
following:

•Directly actingcholinergic
drugs-These drugs mimic the
actions of ACh at muscarinic
and nicotinic receptors by
binding directly to these
receptors.

•Indirectly acting cholinergic

drugs-These drugs act by
inhibiting the activity of
acetylcholinesterase (AchE)
enzyme which degrades ACh to
inactive products: choline and
acetic acid.

8
 DIRECTLY ACTING CHOLINERGIC DRUGS

A. CHOLINE ESTERS

9
 B. NATURAL ALKALOID
Pilocarpine
 It is chief alkaloid obtain from the leaves of shrub Pilocarpus jaborandi. It
crosses BBB.
 It has muscarinic action and also mild nicotinic action.

Therapeutic uses:-
1. Ophthalmic use:
 For initial treatment of open angle glaucoma (0.5% to 4% solution),
reduction in intraocular pressure occur within few min and lasts for 4-8 hrs.
 To counteract mydriasis produce by atropine
 To break the adhesion between the iris and lens
2. As sialagogue – used to stimulate salivary secretion in patients after laryngeal
surgery. (5-10 mg orally)

10
 C. MISCELLANEOUS AGENTS

 TREMORINE and OXOTREMORINE are not used therapeutically, but used

only as investigated research tool to stimulate Parkinsonism like symptoms in
animal models.
 Which results from activation of muscarinic receptors in basal ganglia and
elsewhere in CNS.

11
INDIRECTLY ACTING CHOLINERGIC DRUGS
Acetylcholinesterase (AchE) is an enzyme which degrades acetylcholine to inactive
products: choline and acetic acid.

These agents act by inhibiting the AchE, by reversible or irreversible binding

which indirectly increase the concentration of acetylcholine in the synaptic cleft
and ultimately at the respective cholinergic receptors.
12
 A. REVERSIBLE (COMPETITIVE) INHIBITORS OF AChE

• The reversible anticholinesterase

drugs have a similar structure to ACh.
• They combine with the anionic and
their esteric site of AChE.
• This complex is less readily
hydrolysed than AChE-ACh complex.
• It results in a temporary inhibition of
the enzyme.
• This inhibition prolong the duration of
action of ACh released in the synaptic
cleft.

13
 PHYSOSTIGMINE

 Its an alkaloid obtain from the dried ripe seeds of Physostigma venenosum.
 It is highly lipid soluble and shows better absorption in the all the body
compartments including CNS and can crosses BBB.
 It has marked muscarinic effects and also stimulate ganglia but negligible
nicotinic effects at neuromuscular junction.
 It is highly toxic and so has only limited use.
 It is having intermediate duration of action. (30min-2hr)

Therapeutic uses:
 Ophthalmic use
 To counteract the effects of mydriatics
 To prevent the adhesion between iris and the lens
 for the treatment of glaucoma
 Belladonna (atropine) poisoning

14
 Quaternary compounds

 This drugs are least absorb and do not cross BBB.

 This drugs have important therapeutic effects on skeletal muscle neuromuscular
junction.
 Low doses moderately prolong and intensify the action of released ACh at motor
endplate, this results in strengthening of muscle weakness.

EDROPHONIUM
 A quaternary ammonium compound that binds to the anionic site of the enzyme
only.
 The ionic bond formed is readily reversible, and the action of the drug is very brief.
 It is used mainly for diagnostic purposes, because improvement of muscle strength
by an anticholinesterase is characteristic of myasthenia gravis but does not occur
when muscle weakness is due to other causes.
 Duration of action: 5-15 min

15
 Neostigmine

 Hydrolysed by esterases in liver & plasma

 Short duration of action (3-5 hours)
 Direct action on nicotinic (NM) receptors present in neuromuscular junction (motor
end plate) of skeletal muscle
 Antagonizes (reverses) skeletal muscle relaxation (paralysis) caused by tubocurarine
and other competitive neuromuscular blockers
 Stimulates autonomic ganglia in small doses but Large doses block ganglionic
transmission
 No CNS side effects.

16
 COMPARATIVE FEATURES OF
PHYSOSTIGMINE AND NEOSTIGMINE

Physostigmine Neostigmine

Source Natural Synthetic

Chemistry Tertiary amine Quaternary ammonium
compound
Oral absorption Good Poor
CNS action Present Absent
Eye Penetrates cornea Poor penetration
Effect Ganglia Muscle
Uses Miotic Mysthenia gravis
Dose 0.5-1 mg oral/parenteral 0.5-2.5 mg IM/SC
0.1-1% eye drop 15-30 mg orally
Duration of action 4-6 Hrs 3-4 Hrs
17
 B. IRREVERSIBLE INHIBITORS OF AChE
 These agents are called irreversible blockers because they phosphorylated the esteratic site of
AChE irreversibly by forming a covalent bond.
 Pentavalent organo-phosphorous compounds containing fluoride or organic group.
 During the process, this group is released leaving the remaining part of drug molecule attached
covalently with the esteratic site of AChE through its phosphorous atom.
 After phosphorylation, AChE becomes inactive and very stable due to covalent bonding.
Recovery depends on new synthesis (few weeks)
 Ecothiophate (exception) : is having a quaternary nitrogen which can bind also to the anionic
site of the enzyme slow hydrolysis (few days)  not strictly irreversible
 Sometimes phosphorylated enzyme losses one alkyl group and become resistant to hydrolysis
– ageing

18
 THERAPEUTIC USES OF CHOLINERGIC
DRUGS
 Myasthenia gravis:
Edrophonium to diagnose
Neostigmine, Pyridostigmine & Distigmine to treat
 To stimulate bladder & bowel after surgery:
Bethanechol, Carbachol, Distigmine
 To lower IOP in chronic simple glaucoma:
Pilocarpine, Physostigmine
 To improve cognitive function in Alzheimer’s disease:
Rivastigmine, Gallantamine, Donepezil
 Physostigmine in Belladonna poisoning

19
 MYASTHENIA GRAVIS
 Autoimmune disorder affecting 1 in 10,000 population

Causes: Development of antibodies directed to Nicotinic receptors in muscle end plate

– reduction in number by 1/3rd of Nm receptors
 Structural damage to NM junction
Symptoms: Weakness of muscle and fatigue which worsens after the exrecise but goes
off after the rest, slurring speech, diplopia, difficulty in swallowing
Treatment:
 Neostigmine – 15 to 30 mg, orally, every 6 hrly
 Dose requirement may fluctuate time to time – adjustment required according to
the response
 Pyridostigmine – 60-120mg, 4-6hrly, orally

20
 MYASTHENIC CRISIS
 Acute weakness and respiratory paralysis
 Tracheobronchial intubation and mechanical ventilation
 Methylprednisolone IV with withdrawal of AChE
 Gradual reintroduction of AChE
 Thymectomy
 Edrophonium is used for diagnosis of Myasthenic crisis (disease itself) and
cholinergic crisis (overdose of Anti-ChE)
 Improvement of symptoms – myasthenic crisis
 Worsening – Cholinergic crisis

21
 AChE POISONING (ORGANOPHOSPHOROUS
POISONING)
 Organophosphate poisoning is poisoning due to organophosphates(OPs).
 The underlying mechanism involves the inhibition of acetylcholinesterase ,
leading to the buildup of acetylcholine in the body.
 Diagnosis is typically based on the symptoms and can be confirmed by
measuring butyryl-cholinesterase activity in the blood.
 Poisoning may be – Occupational, accidental, Suicidal

 Symptoms:
 Fall in BP, bradycardia or tachycardia, cardiac arrhythmia and vascular
collapse
 Irritation of Eye, lacrimation, salivation, involuntary defection,
breathlessness, blurring of vision
 Muscular fasciculations and weakness
 Death due to respiratory paralysis – peripheral and central

22
 The treatment consist of specific antidote or Cholinesterase Reactivators
1. Specific antidotes
 Atropine-All cases of AChE poisoning, 2mg IV every `10 minutes – till
muscarinic symptoms disappears

2. Cholinesterase Reactivators – Oximes

 Oximes have generic formula R-CH=N-OH
 Provides reactive group OH to the enzymes to reactivate the phosphorylated
enzymes eg. Pralidoxime (2-PAM), Obidoxime Diacetyl monoxime (DAM)

23
 SIDE EFFECTS OF CHOLINERGIC DRUGS

 Diarrhoea
 Urination
 Miosis, muscle weakness
 Bronchorrhea
 Bradycardia
 Emesis
 Lacrimation
 Salvation, sweating

24
 REFERENCE
1. Sharma HL, Sharma KK. Principles of pharmacology. Paras medical
publisher; 2007.
2. Tripathi KD. Essentials of medical pharmacology. JP Medical Ltd; 2013 Sep
30.
3. Goodman LS. Goodman and Gilman's the pharmacological basis of
therapeutics. New York: McGraw-Hill; 1996.
4. H. P. Shah, J. M. Ritter. Rang & Dale’s pharmacology. Elsevier Ltd; 2016

25
 THANK YOU

26