2. CHOLINERGIC AGONISTS
ALSO KNOWN AS : CHOLINERGIC AGENTS / CHOLINOMIMETIC /
PARASYMPATHOMIMETIC.
» These are drugs which produce actions similar to that of ACh, either
by directly interacting with cholinergic receptors or by increasing
availability of ACh at these sites (anticholinesterases).
2
3. Synthesis and Release of ACh
Synthesis of ACh
Uptake and Storage
Release
Binding
Recycling
Degradation
3
8. 2. Smooth Muscles
(a) abdominal cramps, diarrhoea due to relaxed peristaltic movement
spincture.
(b) relaxes trigone and spincture causes urination.
(c) bronchospasm, contraindicated in asthma.
3. Exocrine Glands : increases salivary, lacrimal, sweat, bronchial, gastric, and
other GI secretions.
4. Eye : contracts spincture pupillae (miosis)
: contracts ciliary muscle »» spasm of accomodation
: increases aqueous outflow » reduces IOP
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9. Nicotinic Actions
1. Autonomic ganglia : higher dose of Acetyl choline stimulates both
sympathetic and parasympathetic ganglia
2. Skeletal muscle : at high conc, Acetyl choline initially produces twitching,
facsiculation followed by prolonged depolarization of NMJ and paralysis.
3. CNS : poor BBB penetration.
Use : ACh is used topically for the induction of miosis during ophthalmologic
surgery, instilled into the eye as a 1% solution.
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10. Bethanecol
It is not hydrolyzed by AChE due to the esterification of carbamic acid, although
it is inactivated through hydrolysis by other esterases. It has about a 1-hour
duration of action.
» selective muscarinic action on GIT and urinary bladder.
» preferred in postoperative urinary retention and paralytic ileus.
» its muscarinic side effect is antagonized by atropine.
» relaxes trigone spincture and stimulates peristaltic movement.
» also be used to treat neurogenic atony as well as megacolon.
Adverse effects : sweating, salivation, flushing, decreased blood pressure,
nausea, abdominal pain, diarrhea, and bronchospasm.
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11. Carbachol / Carbamylcholine
It has both Muscarinic and Nicotinic action, it is an ester of Carbamic acid and a
poor substrate for AChE but bio transformed by other esterases.
Actions : It can cause release of epinephrine from the adrenal medulla by its
nicotinic action. Locally instilled into the eye, it mimics the effects of ACh,
causing miosis.
Use : Glaucoma
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12. Cholinomimetic alkaloids
Pilocarpine
» obtained from pilocarpus plant. it is a tertiary amine.
» it has predominant muscarinic action especially on
secretory activity.
» vasodilatation
» high dose cause High BP and tachycardia
Uses
» Pilocarpine is used to treat glaucoma and is the drug of choice for emergency
lowering of intraocular pressure of both open-angle and angle-closure
glaucoma.
» Pilocarpine is extremely effective in opening the trabecular meshwork around
the Schlemm canal, causing an immediate drop in intraocular pressure as a
result of the increased drainage of aqueous humor. 12
13. » to reverse mydriatic effect of
atropine
» oral pilocarpine tablets and
cevimeline » Sjogren syndrome,
characterized by dry mouth and lack
of tears.
Adverse effects : blurred vision, night
blindness, and brow ache, profuse
lacrimation, salivation, sweating.
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14. Muscarine
obtained from Amanita muscaria.
Mushroom poisioning types..
1. Rapid onset type
» caused by Inocybe species.
» characterized by excessive muscarinic effect, vomiting, diarrheoa, salivation,
bradycardia, sweating, bronchospasm, hypotension.
2. Hallucinogen type
» caused by amanita muscaria and pscilocybe species, toxin is muscimol.
» it produces mainly central effect.
» no specific antidote available, atropine contraindicated, supportive care
should be taken.
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15. 3. Delayed onset type
» caused by amanita phalloides.
» toxin is amatoxin.
» causes delayed gastroenteritis, renal, and hepatic damage.
» treated with thioctic acid.
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16. INDIRECT ACTING CHOLINERGIC AGONISTS /
Anticholinesterase Agents
They inhibit the enzyme
cholinesterase that is responsible for
hydrolysis of ACh, thus acetylcholine
not metabolized, it gets accumulated
at the muscarinic and nicotinic sites.
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17. Reversible Anticholinesterase
Physostigmine : obtained from Physostigma venenosum, it is a tertiary
amine, it forms a relatively stable carbamoylated intermediate with the enzyme,
which then becomes reversibly inactivated. The result is potentiation of
cholinergic activity.
» stimulates not only the muscarinic and nicotinic sites of the ANS but also the
nicotinic receptors of the NMJ.
» Its duration of action is about 30 minutes to 2 hours
Uses
1. Glaucoma : reduces IOP by producing miosis, thus facilitates the drainage of
aqueous humour.
2. Atropine poising : it competetively reverses the effect of atropine poisioning,
but it should be used cautiously by slow I,V injection.
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18. Adverse effects : Convulsion due to high dose, Bradycardia, Inhibition of AChE
at the skeletal NMJ causes the accumulation of ACh and, ultimately, results in
paralysis of skeletal muscle.
18
19. Neostigmine : it is synthetic anticholinesterase, Unlike physostigmine,
neostigmine has a quaternary nitrogen. Therefore, it is more polar, is absorbed
poorly from the GI tract, and does not enter the CNS.
Uses
» stimulate the bladder and GI tract
» antidote for competitive neuromuscular-blocking agents.
» manage symptoms of myasthenia gravis.
Indirect Action
» by inhibiting cholinesterase neostigmine increases ACh conc at NMJ.
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20. Direct Action
» because of structural similarity, neostigmine also directly stimulates Nm
receptor at NMJ thus, it improves muscle power in patient with myesthenia
gravis.
» does not cross BBB, therefore neostigmine is preferred over physostigmine in
myesthenia gravis.
» available for oral, sc, i.v, and im.
Adverse effects : salivation, flushing, decreased blood pressure, nausea,
abdominal pain, diarrhea, and bronchospasm. No CNS side effects,
Neostigmine is contraindicated when intestinal or urinary bladder obstruction is
present.
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21. Physostigmine Neostigmine
Natural (Physostigma venenosum) Synthetic
Tertiary amine Quaternary amine
Good oral absorption Poor oral absorption
Good tissue penetration Poor
Crosses BBB, CNS effects No CNS effects
Main Indication - Glaucoma Myasthenia Gravis
Used in atropine poisioning Used in curare poisioning
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22. Pyridostigmine
» same feature as neostigmine, has longer duration of action.
» it is preferred over neostigmine.
» used in the chronic management of myasthenia gravis.
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23. Edrophonium
» a quarternary ammonium compound, on iv administration it has rapid onset
but shorter duration of action 10-20 mints.
Uses
» diagnosis of MG.
» differentiate myesthenic crisis from cholinergic crisis.
» in curare poisioning it is preferred because of rapid onset of action.
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24. Rivastigmine : This lipophilic relatively cerebroselective ChE inhibitor has
been introduced for Alzheimer’s disease.
Galantamine : This natural alkaloid inhibitor of cerebral AChE has in addition
weak agonistic action on nicotinic receptors. It is being used to afford
symptomatic relief in AD.
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25. GLAUCOMA
Glaucoma is a progressive optic neuropathy, leads to damage of optic nerve
with loss of visual function associated with increased IOP.
» Normal IOP range is 10 - 20 mmHg.
» management of this disorder is directed at lowering the existing IOP either by
improving the drainage or by decreasing the formation of aqueous humour.
Drugs used in Glaucoma
1. Drugs decreases the aqueous secretion
Beta 1 blocker : Timolol, Levobunalol, carteolol, betoxalol
Alpha 2 agonist : brimonidine, aproclonidine
Carbonic anhydraze inhibitor : acetazolamide, brinzolamide, dorzolamide
Osmotic diuretic : mannitol
2. Drugs increases the aqueous outflow
prostaglandins, miotic - pilocarpine, physostigmine, Alpha 2 agonist -
dipevefrine 25
27. MYASTHENIA GRAVIS
It is an autoimmune disorder whereby antibodies are produced which bind to
the nicotinic receptor of the skeletal muscle end plate (Nm).
Therefore, ACh produced at the NMJ is unable to bind to Nm receptor.
» Myasthenia gravis is diagnosed by :
1. signs and symptoms : weakness and fatigability.
2. Edrophonium test : 2- 10 mg i.v slowly.
3. demonstration of Ab.
Treatment
Neostigmine, pyridostigmine, ambenonium inhibits
metabolism of ACh thereby prolonging the action
at receptor, pyridostigmine is most commonly used.
corticosteroids :- pridnisolone 30 - 60 mg/day.
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28. Irriversible Anticholinesterase
A number of synthetic organophosphate compounds have the capacity to bind
covalently to AChE. The result is a long-lasting increase in ACh at all sites
where it is released. Related compounds, such as parathion and malathion, are
used as insecticides.
Echothiophate : It is a long acting Cholinesterase inhibitor, increases ACh in
iris, ciliary muscle, and other parasympathetically innervated structures of eye.
Increases outflow of aqueous humor, fall in intraocular pressure, and
potentiation of accomodation.
Used in subacute or chronic angle-closure glaucoma.
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29. .
Organophosphorus insecticides
Organophosphorus poisioning is one of the most common poisioning. Common
OP compounds are Parathion, malathion, dyflos etc.
Signs and Symptoms
1. Muscarinic effect : profuse sweating, salivation, lacrimation, increased
tracheobronchial secretion, bronchospasm, vomiting, bradycardia, involuntary
urination.
2. Nicotinic effect : Twitching effect, fasciculation, muscle weakness, paralysis.
3. Central effect : Headache, restlessness, confusion, convulsion, coma, death
due to respiratory failure.
Diagnosis
» History of exposure.
» characteristics signs and symptoms.
» estimate the cholinesterase activity in blood. 29
30. .
TREATMENT
» remove the contaminated clothes, wash skin with soap and water.
» airway should be maintained
» artificial respiration should be given if necessary
» diazepam should be used cautiously by slow i.v, injection to control
convulsion
Atropine : Atropine is the first drug is given in organophosphorus poisioning.
Inject atropine 2 mg i.v and it should be repeated every 5 - 10 minutes
doubling the dose, should be contnd for 7 days.
Oximes : atropine is not effective for reversal of neuromuscular paralysis.
Neuromuscular transmission can be improved by giving cholinesterase
reactivators --- pralidoxime, obidoxime,
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31. References
- Lippincott Illustrated Reviews: Pharmacology Sixth Edition - Karen Whalen
- Essentials of Medical Pharmacology - K.D Tripathi
- Basic and Clinical Pharmacology - Bertram G Katzung
THANK YOU
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