The document provides an extensive overview of parasympathomimetics or cholinergic agents, detailing their mechanisms, classifications, and effects on the body. It explains the steps involved in cholinergic neurotransmission including synthesis, storage, release, and degradation of acetylcholine. Additionally, it covers the types of cholinergic receptors, the actions of various cholinergic drugs, and their therapeutic uses and contraindications.

1. PARASYMPATHOMIMETICS/
CHOLINERGIC AGONIST
Ms. FATHIMATH RAIHANA
ASSISTANT PROFESSOR
PA COLLEGE OF PHARMACY

2. Parasympathomimetics / Cholinergic Agents / Cholinomimetics :
These are the chemicals that act at the same site as that of acetyl choline and
thereby mimic their actions.
Hence the name.

3. CHOLINERGIC TRANSMISSION :
Acetylcholine (Ach) is the neurotransmitter of the parasympathetic system.
The nerves that synthesize, store or release Ach are called cholinergic.
Neurotransmission in cholinergic neuron involves 6 steps :
i. Synthesis
ii. Storage
iii. Release
iv. Binding of Ach to a receptor
v. Degradation of the neurotransmitter in the synaptic cleft.
vi. Recycling of choline and acetate

4. i. Synthesis :
 Choline is transported from the extracellular fluid into the cytoplasm of the
cholinergic neuron by an energy-dependent carrier system.
 The uptake of choline is the rate limiting step in the Ach synthesis.
 Choline acetyl transferase catalyse the reaction of choline with acetyl coA to form
Acetyl choline.
ii. Storage :
ACh is packaged and stored into presynaptic vesicles by active transport process and
protect it from degradation.

5. iii. Release :
When an action potential arrives at the nerve ending
Voltage-gated calcium channel open, influx of calcium leads to increase in the
concentration of intracellular calcium.
Elevated calcium promotes the fusion of vesicles and release the neurotransmitters into the
synaptic cleft.
iv. Binding of ACh to a receptor :
ACh released from the vesicles diffuses across the synaptic cleft and binds to the receptor
present on the post-synaptic neuron to produce biological response.

6. v. Degradation of ACh :
Acetylcholinesterase enzyme degrades acetyl choline to choline and acetate in the
synaptic cleft.
vi. Recycling of choline and acetate :
Choline may be recycled by sodium coupled high affinity reuptake system that
transports the molecule back into the neuron.
It is acetylated to acetyl choline that is stored until released by action potential.

7. Ca2+

8. Cholinergic receptors
Nicotinic receptors (N)
Muscarinic receptors (M)
M1
Gastric ganglia
CNS
M2
Heart
CNS
M3
Eye
GIT
Bladder
Bronchus
Glands
CNS
M4
CNS
M5
CNS
NN
Ganglia
Adrenal medulla
NM
Neuromuscular
junction

9. Cholinergic Receptors :
Two types :
i. Muscarinic receptors
ii. Nicotinic receptors
i. Muscarinic receptors :
They are G-Protein coupled receptors.
These receptors are selectively stimulated by muscarine and blocked by atropine.
Types :
M1, M2, M3, M4, M5.
M1, M3 and M5 – coupled with Gq mediated G-protein
M2 and M4 – Gi mediated G-protein

10. ii. Nicotinic receptors :
 It is a ligand-gated ion channel receptor having pentameric structure.
 Their activation causes opening of the channels and rapid flow of ions.
 This results in depolarization and action potential.
Two types :
NM :
Present at skeletal muscle end plate.
NN :
Present on ganglionic cells and adrenal medulla.

11. CLASSIFICATION : Cholinergic agonist
Directly acting Indirectly acting / Anticholinesterases
Choline esters
• Acetyl choline
• Methacholine
• Carbachol
• Bethenacol
Alkaloids
• Pilocarpine
• Muscarine
• Arecoline
Reversible Irreversible
Carbamates
• Physostigmine
• Neostigmine
• Pyridostigmine
• Rivastigmine
Alcohol
Edrophonium
Others
• Donepezil
• Galantamine
• Tacrine
Organophosphorous
compound
• Parathion
• Malathion
• Sarin
• Soman
• Echothiophate
Carbamates
• Propoxur
• Carbaryl

12. I. Directly acting :
i. Choline esters :
1. Acetyl choline :
It produce muscarinic and nicotinic effects by binding to certain receptors.
Muscarinic actions :
i. CVS :
a. Heart :
Ach
+
M2
Opens K+
channel and
hyperpolarization.
Heart rate ( Negative chronotropic effect )
Force of contraction ( Negative inotropic )
AV conduction ( Negative dromotropic )
• The acetyl choline binds to the M2 receptor in the heart, which is Gi mediated G-protein coupled
receptor.
• It reduces the heart rate, force of contraction. In large doses may produce AV conduction and may
leads to partial or total AV block.

13. b. Blood vessels :
Ach Release of Nitric
oxide
Vasodilation BP
M3
+
• Acetyl choline binds to the M3 receptor, which is Gq mediated protein receptor produce action through
phospholipase C/IP3-DAG pathway.
• It relaxes the vascular smooth muscles and causes vasodilation by the stimulation of nitric oxide
production.
• This causes decrease in BP.

14. ii. SMOOTH MUSCLES :
a. GIT :
Ach M3
• Tone of gut
• Peristaltic movements
• GI secretions
• Relaxes the sphincter – may lead to defecation
+
b. Urinary bladder :
Ach
+
M3 Contracts detrusor muscle
Relaxes trigone and sphincter – causes urination.
Tone and peristalsis is enhanced, sphincters are relaxed resulting in rapid propulsion
of intestinal contents.
It leads to the contraction of detrusor and relaxation of trigonal sphincters, thereby promotes the
voiding of urine.

15. c. Bronchi :
Ach + • Bronchoconstriction or bronchospasm
• Increases tracheobronchial secretions
‘Cholinergic drugs are contraindicated in asthmatics’
iii. EXOCRINE GLANDS :
Saliva
Lacrimal secretions
Sweat
Bronchial
Gastric
GI secretions
 Enhanced bronchial secretions and bronchospasm results in dyspnoea.
 Secretions are increased through M3 receptors and some M2
receptors.
 Secretion of milk and bile is not affected.

16.  ACh stimulates the M3 muscarinic receptor causing constriction of pupil by contracting
the circular muscles of iris.(Miosis)
 Ciliary muscle contraction results in spasm of accommodation, increased outflow
thereby reduction in intraocular pressure.
iv. EYE :
Ach
No effect on topical administration because of poor penetration to the tissues.
I.V
M3
Miosis – constriction of pupil

17. II. NICOTINIC ACTION :
To elicit nicotinic action, larger doses of Ach are required.
i. Autonomic ganglia :
Higher doses of Ach produce dangerous muscarinic effects. Hence, atropine must be
given prior to the administration.
Higher doses activate both sympathetic and parasympathetic ganglia by NN receptors.
Tachycardia
Increased BP

18. ii. Skeletal muscles contraction – NM receptors :
At high conc. Produces twitching /
contraction
Prolonged
depolarization
Paralysis
iii. CNS :
I.V Ach does not cause central effects because of poor penetration to Blood Brain Barrier.

19. 2. Bethanecol :
Selective muscarinic action on GIT and urinary bladder.
Used in :
Post-operative urine retention
Paralytic ileus

20. ii. Alkaloids :
Pilocarpine :
 It is obtained from the leaves of Pilocarpus plant and other species.
 It produces muscarinic and nicotinic effects by directly interacting with the receptors.
Actions :
 Applied to the eye, pilocarpine produces rapid miosis and contraction of ciliary
muscles.
 When the eye undergoes this miosis, it experiences a spasm of accommodation.
 The vision becomes fixed at some particular distance making it impossible to focus.
 The drug promotes salivation, tears and sweating.

21. Muscarine :
 It is an alkaloid present in several species of Amanita and Inocybe species.
 It is responsible for the symptoms of mushroom poisoning.
Arecoline :
Found in areca nut (Areca catechu) - has both muscarinic and nicotinic actions but is of
no therapeutic value.

22. 2. Indirectly acting:
Anticholinesterases :
Theses are the drugs which inhibit the enzyme cholinesterase.
Acetyl choline Choline + Acetic acid
Cholinesterase
-
Mechanism of action :
Anticholinesterase resembles ACh, they binds to Acetylcholinesterase enzyme and
inactivate them.
Thus acetyl choline is not hydrolysed and accumulated.

23. The structure of AChE have an anionic site and esteratic site.

24. Physostigmine :
• Better penetration to tissues.
• Crosses BBB.
Uses :
• In glaucoma
• Used in atropine and tricyclic antidepressant poisoning.
Neostigmine :
• Poorly absorbed from gut.
• Does not cross BBB
Uses :
• To treat myasthenia gravis
• Post-operative paralytic ileus
• Atony of urinary bladder.
Pyridostigmine :
• Similar to neostigmine.
• Longer acting
• Used in myasthenia gravis.

25. Edrophonium : Diagnosis of myasthenia gravis.
Rivastigmine
Donepezil
Tacrine
Galantamine
Alzheimer’s disease

26. Uses of reversible anticholinesterases :
1. As miotic :
Physostigmine causes miosis.
It is used in :
• In glaucoma – physostigmine , pilocarpine
• Alternatively with mydriatic ( to break adhesions between the iris and lens )
• To reverse the effect of mydriatics
2. Myasthenia gravis
3. Poisoning due to anticholinergic drugs.
Physostigmine – in atropine poisoning.

27. 4. Post-operative paralytic ileus and urinary retention – Neostigmine
5. Cobra bite – IV edrophonium prevents respiratory paralysis.
6. Alzheimer’s disease - Donepezil, galantamine, rivastigmine, tacrine.
7. Curare poisoning – Neostigmine, pyridostigmine

28. Irreversible Anticholinesterases :
 Organophosphorous compounds are powerful inhibitors, binds to the enzyme by
covalent bonds.
 They bind only to the esteratic site and enzyme is phosphorylated.
 All organophosphates except echothiophate are highly lipid soluble and hence are
absorbed even through intact skin.
Uses :
Echothiophate eye drops – glaucoma.

29. ORGANOPHOSPHOROUS POISONING :
Organophosphates are used as agricultural and domestic insecticides.
Poisoning may be occupational- while spraying insecticides, accidental or suicidal.
Symptoms result from muscarinic, nicotinic and central effects.
o Vomiting
o Abdominal cramps
o Diarrhoea
o Miosis
o Sweating
o Weakness
o Coma
Death is due to respiratory paralysis.
o Tracheobronchial and gastric secretions
o Bronchospasm
o Hypotension
o Muscular twitchings
o Convulsions
o Weakness

30. TREATMENT :
Atropine
Blocks muscarinic receptors
Reverses muscarinic effects
o Life saving
o Hence drug of choice in OP poisoning.
o Nicotinic symptoms not reversed.
Pralidoxime
Binds to cholinesterase organophosphate
complex
Cholinesterase degrades to Ach
Reverses all symptoms

31. i. If poisoning is through skin, remove clothing and wash the skin with soap and water.
If consumed orally - gastric lavage.
ii. Maintain BP and patent airway.
iii. Patient should be in prone position to avoid secretions.
iv. Drug of choice – atropine IV 2mg every 10 minutes till pupil dilates.
v. Cholinesterase reactivators.