1.Cholinergic drugs(directly acting and indirectly acting ).

2.Drugs for Myasthenia gravis

3. Drugs for Glaucoma

Pinki Verma
Associate Professor
ABIPER
 Sites of Cholinergic Transmission
Acetylcholine (Ach) is major neurohumoral transmitter at
autonomic, somatic and central nervous system:
1. All preganglionic sites (Both Parasympathetic and
sympathetic)
2. All Postganglionic Parasympathetic sites and
sympathetic to sweat gland and some blood vessels
3. Skeletal Muscles
4. CNS: Cortex Basal ganglia, spinal chord and others
Parasympathetic Stimulation – Acetylcholine (Ach) release at
neuroeffector junction - biological effects
Cholinergic Transmission – Synthesis:

•Cholinergic neurons contain large numbers of small

membrane-bound vesicles (containing ACh) concentrated
near the synaptic portion of the cell membrane
•ACh is synthesized in the cytoplasm from acetyl-CoA
and choline by the catalytic action of Choline
acetyltransferase (ChAT)
•Acetyl-CoA is synthesized in mitochondria, which are
present in large numbers in the nerve ending
•Choline is transported from the extracellular fluid into the
neuron terminal by a sodium-dependent membrane carrier
(carrier A). This carrier can be blocked by a group of
drugs called hemicholinium
 Cholinergic Transmission –
Release:
•Synthesized, ACh is transported from the cytoplasm into the
vesicles by an antiporter .This transporter can be blocked by
vesamicol
•Release is dependent on extracellular Ca2+ and occurs when an
action potential reaches the terminal and triggers sufficient influx of
Ca2+ ions
•The increased Ca2+ concentration "destabilizes" the storage
vesicles by interacting with special proteins associated with the
vesicular membrane.Fusion of the vesicular membranes with the
terminal membrane results in exocytotic expulsion of ACh into the
synaptic cleft
•The ACh vesicle release process is blocked by botulinum toxin
through the enzymatic removal of two amino acids from one or
more of the fusion proteins. Black widow spider??
 Cholinergic Transmission: Destruction
•After release - ACh molecules may bind to and
activate an ACh receptor (cholinoceptor)
•AChE very efficiently splits ACh into choline and
acetate, neither of which has significant transmitter
effect, and thereby terminates the action of the
transmitter.
•. AChE is also found in other tissues, eg, red blood
cells.
•Another cholinesterase with a lower specificity for
ACh, butyrylcholinesterase [pseudo
cholinesterase], is found in blood plasma, liver,
glial, and many other tissues.
 True Vs Pseudo AChE
True AChE Pseudo AChE

Distribution All cholinergic sites, Plasma, liver,

RBCs, gray matter Intestine and
white matter
Action on:
Acetycholine Very Fast Slow
Methacholine Slower Not hydrolyzed
Function Termination of Ach Hydrolysis of
action Ingested Esters

Inhibition More sensitive to More sensitive to

Physostigmine Organophosphates
 Cholinergic receptors - 2 types

• Muscarinic (M) and Nicotinic (N):

Nicotinic (N) –
Muscarinic ligand gated
(M) - GPCR
Muscarinic Receptors
1. Selectively stimulated by Muscarine and
blocked by Atropine – all are G-protein
coupled receptors
2. Primarily located in heart, eye, smooth
muscles and glands of GIT
3. Subsidiary M receptors are also present
in ganglia for modulation
4.Blood vessels: All blood vessels have
muscarninc receptors although no
cholinergic innervations
 Muscarinic Receptors - Subtypes

• Pharmacologically - M1, M2, M3, M4 and M5

• M4 and M5 are present in certain areas of Brain and

regulate other neurotransmitters

• M1, M3 and M5 fall in one class, while M2 and M4 in

another class
 Muscarinic Receptors - Location
• M1: Ganglion Cells and Central Neurons (cortex,
hippocampus, corpus striatum)
– Physiological Role: Mediation of Gastric acid secretion and
relaxation of LES (vagal)
• Learning, memory and motor functions
• M2: Cardiac Muscarinic receptors
– Mediate vagal bradycardia
– Also auto receptors in cholinergic nerve endings
• M3: Visceral smooth muscles, glands and vascular
endothelium. Also Iris and Ciliary muscles
 Muscarinic Receptor Subtypes
M1 M2 M3
Location Autonomic ganglia, Heart and CNS SMs of Viscera,
Gastric glands and Eye, exocrine
CNS glands and
endothelium

Functions EPSP & Histamine Less impulse generation, Visceral SM

release & acid less velocity of contraction,
secretion with CNS conduction, decreased Constriction of
learning and motor contractility, less Ach pupil, contraction
functions release of Cilliary muscle
and vasodilatation

Agonists Oxotremorine Methacholine Bethanechol

Antagonists Pirenzepine Methoctramine & Darifenacin

Triptramine

Transducer IP3/DAG and PLA2 K+ channel opening and IP3/DAG and PLA2
increase – Ca++ and decresed cAMP increase – Ca++
PG and PG
 Nicotinic (N) Receptors
• Nicotinic receptors: nicotinic actions of ACh are
those that can be reproduced by the injection of
Nicotine (Nicotiana tabacum)
– Can be blocked by tubocurarine
and hexamethonium
• ligand-gated ion channels
– activation results in a rapid increase in cellular
permeability to Na+ and Ca++ resulting -
depolarization and initiation of action
potential
Nicotinic Receptors – NM Vs NN
NM (Muscle type) NN (Ganglion type)
1. Location: Skeletal Muscle 1. Location: In autonomic ganglia of
end plates all type (ganglion type) –
Sympathetic,Parasympathetic and
2. Function: Stimulate also Adrenal Medulla
skeletal
muscle (contraction) 2 Function: Depolarization and
3. MOA: Postsynaptic and . postganglionic impulse – stimulate all
autonomic ganglia
Excitatory (increases Na+ and
K+ permeability)
3.MOA: Excitatory – Na+, K+ and Ca+
4. Agonists: ACh, carbachol channel opening
(CCh), suxamethonium 4.Agonists: ACh, CCh, nicotine
Selective stimulation by phenyl – Selectively stimulated by Dimethyl
trimethyl ammonium (PTMA) phenyl piperazinium (DMPP)
5. – Antagonists: tubocurarine, 5. Antagonists: Trimethaphan,
Mecamylamine and
Atracurium, vecuronium and Hexamethonium
pancuronium
 Cholinergic Drugs or Cholinomimetic or
Parasympathomimetics

Drugs producing actions similar to Acetylcholine by –

1) interacting with Cholinergic receptors or

2) increasing availability of Acetylcholine at these sites

 Classifiction - Direct-acting (receptor
agonists)
• Choline Esters
– Natural: Acetylcholine (Ach)
– Synthetic: Methacholine, Carbachol and
Bethanechol
• Alkaloids: Pilocarpine, Muscarine, Arecholine
– Synthetic: Oxotremorine
Cholinergic Drugs – Indirect acting
• Cholinesterase inhibitors or reversible
anticholinesterases:
1. Natural: Physostigmine
2. Synthetic: Neostigmine, Pyridostigmine, Distigmine,
Rivastigmine, Donepezil, Gallantamine, Edrophonium,
Ambenonium, Demecarium
• Irreversible anticholinesterases:
1. Organophosphorous Compounds (OPC) – Diisopropyl
fluorophosphate (DFP), Ecothiophate, Parathion,
malathion, diazinon (insecticides and pesticides)
2. Tabun, sarin, soman (nerve gases in war)
3. Carbamate Esters: Carbaryl and Propoxur
(Baygon)
 ACh actions –
Muscarinic
1. Heart: M2
– SA node hyperpolarization (decrease in rate of diastolic
depolarizaton) - reduction in impulse generation and Bradycardia
– AVN and PF – RP is increased – slowing of conduction –
partial/complete heart block
– Atrial fibres: Reduction in force of contraction and RP in fibers
abbreviated
– Decrease in ventricular contractility (less prominent)
2. Blood Vessels: M3
– M3 present in all type blood vessel – Vasodilatation by Nitric
oxide (NO) release – fall in BP and flushing
– Penile erection
Muscarinic action
– contd.
3. Smooth Muscles: M3 - All are contracted
– Abdominal cramps, diarrhoea – due to increased peristalsis and relaxed
sphincters
– Voiding of Bladder
– Bronchial SM contraction – dyspnoea, attack of asthma etc.
4. Glands: M3
– Increased secretions: sweating, salivation, lacrimation,
tracheobronchial tree and gastric glands
– Pancratic and intestinal glands – less prominen
5. Eye: M3
– Contraction of circular fibres of Iris – miosis
– Contraction of Ciliary muscles – spasm of accommodation,
increased outflow and reduction in IOP
Ach actions – Nicotinic
1. Autonomic ganglia:
– Both Sympathetic and parasympathetic ganglia are stimulated
– After atropine injection Ach causes tachycardia and rise in BP
2. Skeletal muscle
– IV injection – no effect
– Application causes contraction of skeletal muscle
3. CNS:
– Does not penetrate BBB
– Local injection in CNS – complex actions

USE:
(Acetylcholine is not used therapeutically – non specific)
 Pilocarpine
• Alkaloid from leaves of Jaborandi (Pilocarpus
microphyllus)
• Prominent muscarinic actions
• Profuse salivation, lacrimation, sweating
• Dilates blood vessels, causes hypotension
• High doses: Rise in BP and tachycardia (ganglionic action)
• On Eyes: produces miosis and spasm of
accommodation
• Lowers intraocular pressure (IOP) in Glaucoma when applied as
eye drops
• Too toxic for systemic use – CNS toxicity
• Diaphoretic (?), xerostomia and Sjögren’s syndrome
 Pilocarpine – contd.
1. Used as eye drops in treatment of wide angle glaucoma
2. To reverse mydriatic effect of atropine
3.To break adhesion between iris and cornea/lens
4.Pilocarpine nitrate eye drops ( 1 to 4% )
Cholinergic Drugs – Indirect acting
(Anticholinesterases)

• Cholinesterase inhibitors or reversible

anticholinesterases:
1. Natural: Physostigmine
2. Synthetic: Neostigmine, Pyridostigmine, Distigmine,
Rivastigmine, Donepezil, Gallantamine, Edrophonium,
Ambenonium, Demecarium

• Irreversible anticholinesterases:
1. Organophosphorous Compounds (OPC) – Diisopropyl
fluorophosphate (DFP), Ecothiophate, Parathion, malathion,
diazinon (insecticides and pesticides)
2. Tabun, sarin, soman (nerve gases in war)
3. Carbamate Esters: Carbaryl and Propoxur (Baygon)
 AChEs - MOA
• Normally Acetylcholinesterase (AchE) hydrolyses Acetylcholine
• The active site of AChE is made up of two subsites – anionic
and esteratic
• The anionic site serves to bind a molecule of ACh to the
enzyme
• Once the ACh is bound, the hydrolytic reaction occurs at a
second region of the active site called the esteratic subsite
• Anticholinesterases also react with the enzyme ChEs in
similar fashion like Acetylcholine.
• Anticholinesterases reduce activity of AchEs and
reduce hydrolysis of acetylcholine resulting into increasing
availability of Acetylcholine at these sites
Anticholinesterases – Individual Drugs
• 2 (two) important clinically used drugs –
– Physostigmine – lipid soluble, ganglion acting and
less action in skeletal muscle
• Also organophosphates
– Neostigmine – lipid insoluble, skeletal muscle
acting
 Physostigmine
• Alkaloid from dried ripe seed (Calabar bean) of African
plant Physostigma venenosum
• Tertiary amine, lipid soluble, well absorbed orally and
crosses BBB
• Hydrolyzed in liver and plasma by esterases
• Long lasting action (4-8 hours)
• It indirectly prevents destruction of acetylcholine
released from cholinergic nerve endings and causes
ACh accumulation
• Muscarinic action on eye causing miosis and spasm of
accommodation on local application
• Salivation, lacrimation, sweating and increased
tracheobronchial secretions
• Increased heart rate & hypotension
 Physostigmine - uses
1. Used as miotic drops to decrease IOP in
Glaucoma
2. To antagonize mydriatic effect of
atropine
3. To break adhesions between iris and cornea
alternating with mydriatic drops
4. Belladonna poisoning, TCAs & Phenothiazine
poisoning
5. Alzheimer’s disease- pre-senile or senile
dementia
6. Atropine is antidote in physostigmine
poisoning.
ADRs – CNS stimulation followed by
depression
 Physostigmine Vs 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 0.5-2.5 mg IM/SC
oral/parenteral 15-30 mg orally
0.1-1% eye drop
Duration of action 4-6 Hrs 3-4 Hrs
Organophosphate Poisoning

• Signs and symptoms:

1. Irritationof eye, lacrmation, salivation, tracheo-bronchial
secretions, colic, blurring of vision, defaecation and urination
2. Fall in BP, tachy or bradycardia and CVS collapse
3. Muscular fasciculations, weakness, and respiratory paralysis
4. Excitement, tremor, convulsins and coma
• Treatment:
– Decontamination – gastric lavage if needed
– Airway maintenance
– Supportive measures – for BP/fluid and electrolyte
– Specifc antidote – Atropine – 2mg IV every 10 minutes,
Pralidoxime (2-PAM) , Obidoxime and Diacetyl
monoxime (DAM)
Overall Therapeutic Uses – cholinergic drugs

1. Myasthenia gravis: Edrophonium to diagnose and

Neostigmine, Pyridostigmine & Distigmine to treat
2. To stimulate bladder & bowel after surgery:
– Bethanechol, Carbachol, Distigmine.

3 To lower IOP in chronic simple

. glaucoma:
– Pilocarpine, Physostigmine
4. To improve cognitive function in Alzheimer’s
disease: Rivastigmine, Gallantamine, Donepezil.
5. Physostigmine in Belladonna poisoning
6. Cobra Bite
 Myasthenia gravis (Myo + asthenia)
• Autoimmune disorder affecting 1 in 10,000 population (?) –
reduction in number of NM receptors
• 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 and easy fatigability – ptosis to
diaphragmatic paralysis

• Treatment:
– Neostigmine – 15 to 30 mg. orally every 6 hrly
– Pyridostigmine
– Other drugs: Corticosteroids (prednisolone 30-60 mg /day)
• Azathioprin and cyclosporin also Plasmapheresis
 Myasthenic crisis
• Acute weakness and respiratory paralysis
– Tracheobronchial intubation and mechnical ventilation
– Methylprednisolone IV with withdrawal of AChE
– Gradual reintroduction of AChE
– Thymectomy

– Diagnosis by various tests – Tensilon Test

– Injection of Edrophonium – 2 mg (observe) – after half a
minute 8 mg (observe)
• In MG – symptoms will improve
• In overtreatment – symptoms worsen
 Drugs used in glaucoma
•Glaucoma is a group of disorders characterized by a progressive
optic neuropathy resulting in a characteristic appearance of optic
disc & specific pattern of irreversible visual field defects that are
associated frequently but not invariably with ↑IOP (>21 mm Hg)
• All types of glaucoma – progressive optic neuropathy due to
the death of retinal ganglion cells .
•Therapeutic goal • Lower IOT by – Reduction of aqueous
humor secretion – Promoting aqueous drainage • Lowering of
IOT retards the progression of optic nerve damage even in
normal/low i.o.t
TYPE OF GLAUCOMA:
1.Open angle/wide angle/chronic simple glaucoma:
• Genetically predisposed degenerative disease affecting
patency of trabecular meshwork
• IOP builds up progressively
• Damage of the optic nerve
• Ocular hypotensive drugs - reduce formation of AH, increase
drainage or protect optic nerve

Available drugs:
• β-adrenergic blockers: Timolol, Betaxolol, Levobunolol
• α- adrenergic agonists: Dipivefrine, Apraclonidine, Brimonidine
• PG analogues: Latanoprost, Travoprost and Bimatoprost
• Carbonic anhydrase inhibitors: Acetazolamide
• Miotics: Pilocarpine and Physostigmine
2.Angle closure (narrow angle, acute congestive) Glaucoma
Emergency situation occurring in person with narrow iridocorneal
angle and shallow anterior
• IOT rises rapidly to very high levels (40 - 60 mmHg) • Failure to
lower IOT → loss of sight
Therapy of closed angle glaucoma:
1. Hypertonic mannitol (20%) or Glycerol (10%)
2. Glycerine 50%
3. Acetazolamide (0.5g)
4. Miotic: -topical Pilocarpine 1-4 %
5. Topical β blocker: Timolol
6. Latanaprost (0.005%) / Apraclonidine (1%)
7. Chronic narrow angle: miotic/other drugs for longer period
 Important questions
• Explain about Cholinergic tranmission
• Cholinergic receptors
• Distribution of Muscarinic and Nicotinic receptors with selective
agonist and antagonist examples.
• Short note on Pilocarpine, Neostigmine, Edrophonium
• Organ phosphorus poisoning symptoms and treatment
• Pharmacology of Anticholinesterases
• Physostigmine Vs Neostigmine
• Drugs for Myasthenia gravis
• Drugs for glaucoma