Drugs acting in Cholinergic system

Satarkulova A.M.

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Functional organization of the
autonomic nervous system

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Comparison of Somatic and
Autonomic Systems

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 ANS branches
cholinergic fibers - acetylcholine
adrenergic fibers noradrenaline (norepinepherine NE)

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 Role of the Parasympathetic
Division
Concerned with keeping body energy use low
Involves the D activities digestion, defecation, and
diuresis
Its activity is illustrated in a person who relaxes after
a meal
BP,HR, Resp. are low
GIT activity is high
The skin is warm and the pupils are constricted

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 Role of the Sympathetic Division
The sympathetic division is the fight-or-flight
system
Involves E activities exercise, excitement,
emergency, and embarrassment
Its activity is illustrated by a person who is
threatened
HR increases, and breathing is rapid and deep
The skin is cold and sweaty, and the pupils dilate

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 Figure 20-2.
Sympathetic and Parasympathetic Effects on
Body Tissues

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 Autonomic Nervous System
Can be divided into:
Sympathetic Nervous
System
Fight or Flight
Parasympathetic
Nervous System
Rest and Digest

These 2 systems are antagonistic.

Typically, we balance these 2 to keep
ourselves in a state of dynamic balance.

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Characteristics of a neurotransmitter
Synthesized in (or transported to) presynaptic
terminal
Stored in vesicles
Regulated release
Receptor located on postsynaptic membrane
Termination of action

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 Ion channels & NT receptors
Voltage-gated channels
Respond to AP
Fast action potentials
Ligand-gated channels (Inotropic)
opened by binding to NT
few to tens of milliseconds
G-protein coupled receptors (Metabotropic)
Modulate voltage-gated channels
Tens of milliseconds to minutes
Direct opening voltage-channel or indirectly through SM

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G proteins activate enzymes, most
commonly the following:

Adenylyl cyclase - converts ATP into cyclic

AMP (cAMP)
Phospholipase C - cleaves a lipid (inositol
phospholipid) into inositol-1,4,5-
trisphosphate (IP3, a hydrophilic sugar) and
diacylglycerol (DAG, a lipid in the
membrane)

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 Cholinergic Neurons

Na+
Choline

Acetylation

Ca++

Acetylcholinesterase

Receptor
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 Cholinergic Receptors
Muscarinic receptors come in 5 flavours
M1, M2, M3, M4, M5
Found in different locations
Muscarinic are G-protein coupled
Metabotrophic
Can be either inhibitory or excitatory

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Muscarinic AChR activate G-proteins

1999 Sinauer Associates Inc

 Nicotinic Receptors
Nicotinic receptors are found on:
Motor end plates (somatic targets)-Nm
All ganglionic neurons of both sympathetic and
parasympathetic divisions-Nn
The hormone-producing cells of the adrenal
medulla-Nn
The effect of ACh binding to nicotinic receptors
is always stimulatory
Nicotinic are ion channels
Ionotrophic
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Nicotinic AChR are sodium channels

1999 Sinauer Associates Inc

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 Autonomic Nervous System
Medications (1 of 2)
Drugs Affecting the Parasympathetic System:
Cholinergic agonist
Cholinergic antagonist
Ganglionic blocking agents
Neuromuscular blocking agents

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 Cholinergic agonists
parasympathomimetic drugs
Cholinergic drugs or cholinomimetric
Cholinergic agonists are two types :
1. Direct acting
2. Indirect acting

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 Direct acting Cholinergic agonists
They act by binding directly to cholinoceptors
Choline esters
Acetylcholine
Methacholine
Bethancol (Urecholine, others)
Carbachol
Alkaloids
Muscarine
Pilocarpine
Arecholine
Aceclidine

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 Indirect acting Cholinergic agonists
They act through inhibition of Acetyl cholinesterase
enzyme.so increases Acetylcholine level in the
synapse
Reversible: Irreversible :
Neostigmine
Physostigmine Ecothiophate
Pyridostigmine Malathion
Edrophonium Parathion
Tacrine
Sarin
Danopezil

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 Pharmacologic manipulation of the cholinergic system

Na+
Muscarinic
ACH Receptor
Choline
Acetyltransferase
Acetylcholinesterase
Acetyl CoA
+ Acetylcholine
Action Potential Choline

Na+ H+
ACH Nicotinic
Choline Acetate
Receptor
Choline

Presynaptic neuron
Postsynaptic target
 Receptor agonists activate signal transduction
pathways CH3
O
C O CH2 CH2
CH3
N CH3
NH3
CH3
Acetylcholine

M3 muscarinic
receptor

(+) Phospho-
Gq lipase C
PIP2

COOH IP3 Diacylglycerol

Increase Ca2+ Activate Protein

Kinase C

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Parasympathetic Responses

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M1 Secretory salivation, stomach acid, sweating, lacrimation
glands

M2 Heart Decreases heart rate bradycardia

M3 Smooth Contraction of smooth muscles (some)

muscle diarrhea, bronchospasm, urination
(GI/GU/Resp)
M3 Pupil and Contracts Miosis
ciliary Increased flow of aqueous humor
muscle
Nm Skeletal Contraction of skeletal muscle
muscle end
plate
Nn Autonomic Secretion of Epinephrine
ganglia, Controls ANS
Adrenal
Medulla
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 Acetylcholine

It is a quaternary ammonium compound so

Cannot penetrate the membrane
Does not have any therapeutic importance,
because rapid inactivation by ACHesterases
It has both Muscarinic & Nicotinic actions
Neurotransmitter for pre-ganglionic neuron

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 Bethanechol
Not hydrolyzed by Achesterase
It has strong Muscarinic action & no Nicotinic action
Actions
Directly stimulates M receptors causing intestinal motility & tone
It stimulates detrusor muscle of the bladder while trigone &
sphincters are relaxed causing expulsion of urine
Therapeutic Uses:
Paralytic ileus
Urinary retentions

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 Pilocarpine
An alkaloid, lipid soluble & is stable to hydrolysis by Achesterases
It has Muscarinic activity only .
Actions-
When applied locally to cornea Produces rapid moisis &
contraction of ciliary muscle produces of spasm of
accommodation.
Therapeutic Use :
In Glaucoma- opens trabecular meshwork around schlemms
canal
causes drainage of aqueous humor
IOP immediately decreases.

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Pharmacologic Actions of all Cholinergic drugs

Heart: Cardiac suppressantBradycardia,

hypotension,
Eye: Miosis, cycloplegia, facilitates aqueous
humour drainage, lacrimation
Bronchospasm
Excess secretion from glands.salivary, bronchial,
lacrimal glands etc..
GIT /bladder smooth muscle contraction and
relaxation of sphincters, increased motility,
diarrhea, vomiting , increased micturation
(urinary urgency)
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 Epidemiology of Glaucoma
About 70 million people are affected
Worldwide
10% of these (~7 million) are blind from glaucoma
US data: > 40 yrs of age, 3 million
about 120, 000 Americans are blind from it.
Most common cause of blindness among
Black-Americans.
50% of all patients, are not aware they have it,
until late

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 Two types of Glaucoma
Types of Glaucoma:
1. Open Angle Glaucoma Excessive production of Aqueous
Humour
2. Closed Angle Glaucoma Outflow obstruction of Aqueous
Humour
Two Therapy aimed at:
1. Reduce (Production, Synthesis or Secretion)
Dorzolamide, Acetazolamide, Timolol, Betoxolol and Apraclonidine
2.Facilitate the drainage: Pilocarpine, Carbachol, Ecothiopate ,Mannitol
and Latanoprost

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Courtesy : Katzung

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 Reduction of aqueous humor production
Mannitol
reduces IOP by reducing vitreous volume by inhibiting the
enzyme carbonic anhydrase
Reduces the secretion/synethesis
Timolol topical eye drops Non-selective blockade
Betaxolol eye drops Selective 1 blockade
Reduces the synthesis
Acetazolamide (oral), Dorzolamide (topical ) : reduces the
synthesis of aqueous humour, inhibits the enzyme
carbonic anhydrase
2 receptor agonist (apraclonidine 1%, topical drops).
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 Increased outflow of aqueous humor

1. Pilocarpine, Carbachol, Ecothiopate and Physostigmine :Causes

Ciliary muscle contraction, increases Irido-corneal angle and

open trabecular meshwork.

2. Prostaglandins : Latanoprost : increase the outflow through

uveoscleral meshwork

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 Uses of Indirect Cholinergic agonists

Neostigmine in M.gravis
Physostigmine in Glaucoma, atropine overdose

Ecothiopate in glaucoma
Edrophonium in M.gravis to test
Tacrin, Danopezil in Alzheimer's
Malathion, Parathion as insecticides

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 Myasthenia gravis
An autoimmune process causes production of AB that decrease the
number of functional nicotinic receptors on the postjunctional end
plates.
Frequent findings are
Double vision. diplopia,
Drooping of eyelids. ptosis,
Dysarthria Difficulty in speaking
Dysphagia ..difficulty swallowing,
Difficult in Daily routines
Day passes, limb weakness increases.
Difficulty in respiration Severe disease may affect all the muscles,
including those necessary for respiration.
Death
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 Treatment of Myasthenia Gravis

Neostigmine Has a strong influence at the

neuromuscular junction
Pyridostigmine: Has a longer duration of action than
neostigmine
Ambenonium :Available only in oral form; cannot be
used if patient is unable to swallow tablets
Edrophonium: Diagnostic agent for myasthenia
gravis and to diffrentiate myasthenic and cholinergic
crisis (Tensilon test )

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 Alzheimers Disease
A progressive disorder involving neural
degeneration in the cortex
Leads to a marked loss of memory and of the
ability to carry on activities of daily living
Cause of the disease is not yet known
?????? There is a progressive loss of ACh-
producing neurons and their target neurons

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 Drugs Used to Treat Alzheimers Disease
Rivastigmine
Available in solution for swallowing ease

Donepezil
Has once-a-day dosing advantage

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 Irreversible cholinestarse inhibitors

Only Ecothipate is used clinically in

Glaucoma. This is the long acting
drug used in glaucoma
Rest of the drugs are used as
pesticides or war gases or poisons:
Malathion and Parathion

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Features of toxicity of cholinergic drugs (organophosphorus
poisoning ) In brief .

Miosis
Excessive salivation
Bradycardia
Bronchospasm
Abdominal cramps, vomiting, diarrhea,
urination
Sweating

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 Treatment of OP poisoning
1. maintenance of vital signsrespiration in particular
may be impaired
2. decontamination to prevent further absorptionthis
may require removal of all clothing and washing of the
skin in cases of exposure to dusts and sprays
3. Atropine parenterally in large doses, given as often as
required to control signs of muscarinic excess
stimulation .
4. Therapy often also includes treatment with
pralidoxime (Acetylcholinesterase reactivator)
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 Cholinergic Blocking Agents
Drugs that block or inhibit the actions
of acetylcholine (ACh) in the
parasympathetic nervous system
(PSNS)

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Cholinergic Antagonists

Antimuscarinic agents
Atropine, ipratropium
Ganglion blockers
nicotine
Neuromuscular
blockers
Vecuronium,
tubocuarine,
pancuronium

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 Cholinergic Blocking Agents:
Mechanism of Action
Competitive antagonists
Compete with ACh
Block ACh at the muscarinic receptors
in the PSNS
As a result, ACh is unable to bind to the
receptor site and cause a cholinergic effect.

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 Cholinergic Antagonists
(Muscarinic receptor)

Postsynaptic Postsynaptic
nerve nerve

Ach
Ach Ach

Antagonist

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Cholinergic Blocking Agents: Chemical
Class
Natural Synthetic Semisynthetic
atropine anisotropine clidinium
belladonna dicyclomine glycopyrrolate
hyoscyamine hexocyclium homatropine
scopolamine ipratropium isopropamide
oxybutynin propantheline
tolterodine tridihexethyl

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 Drug Effects of
Cholinergic Blocking Agents
CV
Small doses heart rate
Large doses: heart rate
CNS
Small doses: decrease muscle rigidity
and tremors
Large doses: drowsiness, disorientation,
hallucinations

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 Drug Effects of
Cholinergic Blocking Agents
Eye
Dilated pupils (mydriasis)
Decreased accommodation due to paralysis
of ciliary muscles (cycloplegia)
GIT
Relax smooth muscle tone of GIT
intestinal and gastric secretions
motility and peristalsis

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 Drug Effects of
Cholinergic Blocking Agents
GUT
Relaxed detrusor muscle
Increased constriction of internal sphincter
Result: urinary retention
Glandular
Decreased bronchial secretions, salivation,
sweating
Respiratory
Decreased bronchial secretions
Dilated bronchial airways

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 Cholinergic Blocking Agents:
Therapeutic Uses
CNS
Parkinsons disease
Drug-induced extrapyramidal reactions

Used primarily for cardiovascular disorders

Sinus node dysfunction
Symptomatic second-degree heart block
Sinus bradycardia with hemodynamic compromise (advanced life
support)
Respiratory agents are used to treat:
Exercise-induced bronchospasms
Chronic bronchitis
Asthma
Chronic obstructive pulmonary disease
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 Cholinergic Blocking Agents:
Therapeutic Uses
GIT:
PUD
Irritable bowel disease
GI hypersecretory states
GUT:
Relaxed detrusor muscles of the bladder
Increased constriction of the internal sphincter
Reflex neurogenic bladder
Incontinence

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 Cholinergic Blocking Agents:
Side Effects
Body System Side/Adverse Effects
CVS Increased heart rate,
dysrhythmias

CNS CNS excitation, restlessness,

irritability, disorientation,
hallucinations, delirium

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 Cholinergic Blocking Agents:
Side Effects
Body System Side/Adverse Effects
Eye Dilated pupils, decreased visual
accommodation, increased intraocular pressure

Gastrointestinal Decreased salivation,

decreased gastric secretions,
decreased motility

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 Cholinergic Blocking Agents:
Side Effects
Body System Side/Adverse Effects
Genitourinary Urinary retention

Glandular Decreased sweating

Respiratory Decreased bronchial secretions

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 Cholinergic Blocking Agents:
Interactions
Antihistamines, phenothiazines,
tricyclic antidepressants, MAOIs
When given with cholinergic blocking
agents, cause ADDITIVE cholinergic
effects, resulting in increased effects

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 Trimethaphan
(yet another cholinergic antagonist)

Competitive nicotinic ganglion

blocker
Used to lower blood pressure in
emergencies

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 Neuromuscular Blockers
Look like acetylcholine
Either work as antagonists or agonists
Two flavours:
Non-depolarizing (antagonist)
Eg: tubocurarine
Block ion channels at motor end plate
Depolarizing (agonist)
Eg: succinylcholine
Activates receptor

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 Turbocurarine
Used during surgery to ACh

relax muscles Na+

Increase safety of Curare
anaesthetics
Do not cross blood-
Nicotinic Receptor
brain barrier Na+ Channel

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 Succinylcholine
Uses: Na+
- - - - - -
endotracheal intubations
What is this? + + + + + + +
Why?
Phase I
electroconvulsive shock
therapy
Na+
Problem: can cause apnea
+ + + + + +

- - - - - -
Phase II

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