Cholinergic agent: Autonomic Drugs According to the M. Optom curriculum, we have prepared a concise presentation on Cholinergic or parasympathomimetic or cholinomimetic drugs

1. Cholinergic Agent:
an autonomic drug
Rabindra Adhikary
Rama Rokka
M. Optom 1st Batch
TIO, PU
Ocular Pharmacology, M. Optom
Unit III, Chapter 3
According to the M. Optom Curriculum
Facilititator
Parashuram Adhikari

3. CB & ISM Innervations
Edinger-Westphal Nucleus
3rd Cranial Nerve
Ciliary Ganglion synapse here with post-
ganglionic fibres
Short ciliary nerves
Muscarinic receptors of Ciliary Body and Iris
Sphincter Muscle
Pre-ganglionic
Parasympathetic fibres

5. Neurotransmitter
– Chemical messengers
– Transmits signal from a neuron to a target cells
across a synapse
– Lies in the pre-synaptic side of a synapse
• Excitory (Glutamate, aspartate, nitrous oxide)
• Inhibitory (GABA, Serotonin, dopamine)
• Both (Ach, nor-epinephrine)

7. SynthesisStoreReleaseBindingDisintegration

8. Cholinergic drug
• a/c/a
– Parasympathomimetics
– Cholinomimetics
• Acetyl Choline (Ach)
– stimulates PSNS just like ACh

9. Acetylcholine
• First neurotransmitter discovered
– 1921, German Biologist Otto Loewi
• Quarternary ammonium compound can’t
penetrate the cell membrane
• Uses choline as a precursor
• No therapeutic value
– Multiplicity of actions
– Quick disintegration by cholinesterase

10. Cholinergic Receptors
Recptors Location Actions
M1 Secretary gland Salivation, stomach
acid,sweating, lacrimation
M2 Heart decreases heart rate-
bradycardia
M3 Smooth muscles (
GI,GU,Resp)
Pupillary and cilliary muscle
Contraction of smooth
muscles- diarrhea, urination,
bronchospasm
Contraction – miosis which
help to increase the flow of
aqueous humor
N1 Skeletal muscle end plate Contraction of skeletal
muscle
N2 Autonomic ganglia
Aderenal gland
Secretion of epinephrine
which controls ANS

11. • Cholinergic Innervation in the eye
– Ciliary Body
– Iris Sphincter muscle
– Lacrimal gland

13. Types
• Direct Acting Cholinergic Agonist
– Binds directly to cholinocepters
– Can’t be metabolized by achetylcholinesterase
except Ach
• Ach
• Methylcholine
• Pilocarpine
• Carbachol
• Eserine
• Indirect Acting Cholinergic Agonist (contd…)

14. Indirect Acting
• Destroys Acetyl cholinesterase (AChE)
• Reversible
– Cycle repeats
• Physostigmine
• Neostigmine
• Endrophonium
• Demacarium
• Irreversible
– Permanent deactivation of AChE by covalent bond
• Di-isopropyl Fluorophosphate (DFP)
• Echothiophate Iodide (Phospholine Iodide)

15. Indirect Acting
• Inhibits the action of cholinesterase enzyme
– a/c/a anti-cholinesterase
– Produce accumulation of ACh at myoneural
synapses of the ciliary muscles which produces a
peripheral or end-organ increase in
accommodation without the cortical effort
• Di-isopropyl Fluorophosphate (DFP)
• Echothiophate Iodide (Phospholine Iodide)

16. • Thus, the cortical nerve-impulse needed for
accommodation is reduced
– Less convergence output via AC/A ratio
– Reduced Esodeviation
• Similarly, accumulation of Ach at the
myoneural synapse stimulates Iris Sphincter
muscle resulting in
– Pupil constriction

17. • Pilocarpine, carbachol, and echothiophate are
formulated for topical use to treat elevated
IOP in patients with ocular hypertension and
glaucoma
– Of late, only pilocarpine finds its application in
clinical practice

18. 1. Pilocarpine
• alkaloid with a tertiary amine
– Extracted from South American plant
• Pilocarpus jaborandi (1875)
• stable to hydrolysis by acetyl cholinesterase
• The response of intraocular smooth muscle to
pilocarpine
– pupillary constriction
– spasm of accommodation
– reduction of IOP
• Action both in peripheral and cental muscarinic
sites

19. Steps of Pilocarpine Action
• Pilocarpine binds to muscarinic receptors
• Activates receptors binds g-protein
• Removal of GDP and addition of GTP to G- protein
• Dissociation of G- protein from muscarinic receptor
• Separation of G- protein into alpha and beta- gamma subunits
• Alpha subunit interacts with and activates phospholipase C-
Phosphatidyl inositol biphosphate(PIP) complex
• Phospholipase breaks down PIP into inositol 1,4,5- triphosphate
(IP3) and diacylglycerol
• IP3 interacts wither membrane whicg release Ca2+
• Muscle action : Ca2+ binds to calmodulin forming a complex and
this complex binds to caldesmon. When caldesmon is bounded by
Ca2+/calmodulin complex this allow myosin – actin interactions to
occur Muscle ( pupil) contraction

20. Clinical Use
• Drug of choice for immediate control of IOP
– Direct stimulation of the longitudinal muscles of the cillary
bodyCauses the scleral spur to widen the trabecular spaces
and increase aqueous out flow
– Pilocarpine appears to reduce IOP to same degree in both
healthy and glaucomatous eye including those with ocular
hypertension
• Since Pilocarpine is the most potent stimulator of
secretion
– Used as tablets in Sjogren’s Syndrome
• It is a disease characterized by lack of tears and xerostomia

21. Adverse Effects
• It may enter into CNS
– Nervous disturbances
• May cause excessive
– Salivation
– Sweating, etc.
• Drug interactions:
– Minimal drug interactions with topical
aminoglycosides

22. Ocular
• Disrupts blood retinal barrier
• Brow ache
• Ciliary spasm causes induced myopia
– Blurring of vision
• Punctal stenosis
• Retinal Detachment

23. Contraindications
• Neovascular glaucoma and uveitis
• History of retinal detachments
• Asthma or history of asthama
• Surgical procedure using succinycholine
• Pupillary Block glaucoma
• Known history of pilocarpine hypersensitivity

24. 2.Carbachol
• Also called as carbamylcholine (carbamate)
• Has both actions
– muscarinic as well as nicotinic
• Like bethanecol, Carbachol is an ester of
carbamic acid and poor substrate for
acetylcholinesterase
• It is bio-transformed by other esterases, but at
a much slower rate

25. 2.Carbachol
• When instilled into the eye
– it mimics the effect of acetylcholine, causing
miosis and a spasm of accomodation in which the
cillary muscle of the eye remains in constant state
of contraction.
• Cardiovascular and GI tract
– First stimulate and then depress these systems

26. Therapeutic use
• It has little therapeutic value because
– Nonselective
– Longer acting
• However, used sometimes in eye for
immediate glaucoma management in place of
Pilocarpine
– When Pilocarpine contraindicated
– When Pilocarpine not available

27. Adverse effects of Carbachol
• At the doses used in ophthalmology
– Very little or no effect due to the lack of systemic
absorption

28. Anticholinesterase
• Indirect Acting cholinergic drug
• Systemic Side Effects
– Perspiration
– Nausea and vomitting
– Abdominal cramping
• Ocular S/E
– Pain and burning in instillation
– Conj. Irritation
– Spasm of accommodation induced myopia
– Eye or brow pain & Headache
– Iris Cysts
– Anterior subcapsular cataracts
Headache
Abdomenal
cramp

29. 3.Physostigmine
• It is a reversible anti-cholinesterase
• Nitrous carbamate ester found in natural
plants and is tertiary amine
• Can enter into cholinergic sites of CNS
• Therapeutic Use
– Eye: miosis, spasm of accommodation and
lowering of IOP. Less effective than Pilocarpine
– Treating overdose of anticholinergic drugs like
atropin or phenothiazines

31. 4.Endrophonium
• Reversible Indirect Acting cholinergic agonist
• Short duration of action
• Rapidly absorbed
• Used in the diagnosis of Myasthenia gravis
– IV injection leads to immediate revival of muscle
strength
• Caution:
– Excess dose may lead to cholinergic crisis
• Atropin is the antidote

32. Echothiophate:
Irreversible indirect Acting

35. • There are many other drugs
– MOA are similar according to the group (direct or
indirect acting, reversible or irreversible nature,
etc) in which they fall

36. Thank You