Unit VIII

Cholinergics and Anticholinergics

Rogie Royce Z. Carandang, RPh, MPH

Hazel Anne L. Catublas, RPh, MS Pharm

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Objectives
At the end of the chapter, the student is expected to:
1. Know where drugs can act in acetylcholine transmission
2. List the steps in acetylcholine synthesis
3. Explain the classification of cholinergic receptors
4. Describe the pharmacodynamics and pharmacokinetics
of muscarinic antagonists
5. Know the types of nicotinic receptors
6. Describe the classification of cholinoreceptor stimulants
and their effects
7. Know and differentiate the drugs affecting autonomic
ganglia
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Biosynthesis of Acetylcholine
O

CH3 SCoA

Acetyl Co-A Choline

Acetyltransferase O CH3
+ +
N
CH3 O CH3
CH3
HO CH3 Acetylcholine
N
+ CH3
CH3

Choline

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 Cholinergic Transmission
Botulinum
Vesamicol Toxin

AP
ACh Ca+2
Ca+2
N
Acetyl Co-A (+)
ACh
+ ACh
Choline ACh M

AChE
Choline

Hemicholinium Choline + Acetate

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 Cholinergic receptors
Muscarinic Nicotinic
NT Muscarine, Ach Nicotine, Ach
Receptor type Membrane receptor linked Ion channel
to G-protein
Location Heart, vascular endothelium, Ganglia, CNS,
smooth muscles, presynaptic neuromuscular junction
nerve terminals, exocrine
glands
Subtypes M1-M5: Ganglionic receptors
M1 – gastric parietal cell -Blocked by
M2 – cardiac and smooth hexamethonium
mucles Neuromuscular receptor
M3 – exocrine glands and - Blocked by
smooth mucles tubocurarine
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 CHOLINOCEPTORS
Location Response
M1 • Gastric parietal cells HCl, pepsin secretion
• Ganglion Neuronal stimulation
• CNS Stimulation, memory,
learning
M2 • SA node K+ conduction (slow
depolarization)
• Atria contractility
• AV node conduction (AV block)
 CHOLINOCEPTORS cont’d.
Location Response
M3 • Bronchial Constriction, secretion
• Intestinal Neuronal stimulation
• Bladder Contraction
• Sphincters Relaxed
• Eyes Miosis
• Endocrine secretions
• Blood vessels Release of EDRF
(endothelium)
Nn • Neuronal junction Stimulation
• CNS Neurotransmission
Nm • Skeletal muscles Contraction
Cholinomimetic Agents

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 Cholinomimetic Agents
1. Direct acting
- Bind, activate receptor
2. Indirect acting
- Inhibits acetylcholinesterase  ACh

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 Cholinomimetic Agents
Acetylcholine
Carbachol
Choline Esters
Bethanecol
Methacoline

Direct acting

Nicotine
Muscarine
Alkaloids
Arecoline
Pilocarpine
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 CHOLINE ESTERS
 Acetylcholine, methacholine, carbachol, bethanecol
relatively insoluble in lipids
Contain a quaternary ammonium group
 poorly absorbed and hydrolyzed in the GI tract
 poorly distributed in the CNS
 presence of the beta-methyl group (methacholine,
bethanecol)
 reduces potency at the nicotinic receptor

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 CHOLINE ESTERS
1. Acetylcholine
- Prototype
- No clinical use because of widespread •D - Diarrhoea
effects and rapidly hydrolyzed by Achase •U - Urination
•M - Miosis
- S/E: DUMBELLS (small pupils)
•B - Bradycardia
•E - Emesis
2. Bethanecol (Urecholine)
•L - Lacrimation
- inc. intestinal motility after surgery •L - Lethargy
(bowel) •S - Salivation
- Urinary retention (bladder)
- can’t cross BBB (poor lipid solubility)
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- S/E: DUMBELS
CHOLINE ESTERS
3. Carbachol
- Like bethanecol
- Glaucoma

4. Methacholine
- Diagnosis of asthma

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ALKALOIDS
 Pilocarpine, nicotine, lobeline, tertiary amines
 well absorbed from most sites of administration
 Muscarine, a quaternary amine, is less completely
absorbed from the GI tract
 Chiefly excreted in the kidneys, alkaloid excretion is
enhanced through acidification of urine

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ALKALOIDS
1. Pilocarpine
- Alkaloid from Pilocarpus sp.
- Glaucoma – miosis, drains aqueous humor  dec.
ocular pressure
- S/E: enter CNS  hallucinations, seizures; DUMBELS

2. Arecoline
- From betel nut (Areca catechu)

3. Muscarine
- From mushroom Amanita muscaria

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ALKALOIDS

Betel Nut Amanita mushroom

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 Cholinomimetic Agents
4º NH4 compd Edrophonium

Physostigmine
Neostigmine
Organocarbamates Pyridostigmine
Ambenonium
Indirect Demecarium
acting
Echothiophate
Organophosphates
Parathion, Malation
Diisopropyl
Tacrine, Donepezil, flurophosphate
Rivastigmine Sarin, Tabun, Soman
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 Indirect-acting cholinomimetics or
Cholinesterase inhibitors
MOA: competes with ACh for receptors on AChE to exert
significant effects in vivo

A. Organic derivatives of phosphoric acid

(organophosphates)
1. isofluorophate, echothiophate
2. Malathion, parathion
3. Tabun, sarin, soman

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 Indirect-acting cholinomimetics or
Cholinesterase inhibitors
B. Carbamates
1. Physostigmine
2. Neostigmine
3. Pyridostigmine
4. Carbamate insecticides

C. Quarternary Amine
1. Edrophonium
2. Spider venom

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 Indirect-acting cholinomimetics or
Cholinesterase inhibitors
A. Organophosphates
1. isofluorophate, echothiophate  glaucoma
2. Malathion, parathion  pesticides; converted to the
active malaoxon and paraoxon respectively
3. Tabun, sarin, soman  chemical warfare/ “nerve gas”
- S/E: DUMBELLS
- Antidote:
a. Pralidoxime
- Reactivates Achase by removing OP; should be given
before Achase loses one of its alkyl groups
(organophosphate aging)
b. Atropine  anticholinergic/ muscarinic blocker 20
 Indirect-acting cholinomimetics or
Cholinesterase inhibitors
B. Carbamates
1. Physostigmine
- Aka eserine
- Alkaloid from calabar bean/ordeal bean/Physostigma
venenosum
- Intestinal and bowel atony, glaucoma
2. Neostigmine (Prostigmin)
- Treatment of MG (Myasthenia gravis): autoimmune
- destroys nicotinic receptors  weakness, ptosis
3. Pyridostigmine (Mestinon)
- Tx of myasthenia gravis
4. Carbamate insecticides
- carbaryl, methyl carbamate (Baygon) 21
Indirect-acting cholinomimetics or
Cholinesterase inhibitors

Calabar Bean

ptosis

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Indirect-acting cholinomimetics or
Cholinesterase inhibitors

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 Indirect-acting cholinomimetics or
Cholinesterase inhibitors
C. Quarternary Amine
1.Edrophonium (Tensilon)
-Diagnosis of MG
-Tensilon Test  Inc. strength, dec. ptosis

2.Spider Venom
- Promotes release of acetylcholine

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 Muscarinic Antagonists
1. Atropine aka hyoscyamine derived from Atropa belladona
(deadly nightshade) and Datura stramonium (jimsonweed)
2. Scopolamine (Buscopan, Transderm-Scop) aka hyoscine
from Hyoscyamus niger (henbane)
3. Chemistry:
a. Natural Alkaloids – e.g. atropine, scopolamine
b. Tertiary ammonium – e.g. Pirenzipine, Tropicamide
c. Quaternary Ammonium – e.g. Ipratropium, Benztropine
4. Many antihistamine and antidepressant drugs have similar
structures to tertiary ammoium analogs and thus, also have
significant antimuscarinic effect
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Atropa belladona Datura stramonium
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 Muscarinic Antagonists
MOA: Reversible blockade of receptors
o Most sensitive to atropine: salivary, bronchial and sweat
glands tissues
o Intermediate sensitivity: smooth muscles and cardiac
tissue
o Least sensitive: gastric parietal cells
o Atropine is highly selective for muscarinic receptors
o Synthetic anti-muscarinic drugs (e.g. 4° NH4s) less
specific and may have significant ganglion-blocking
actions (Nicotinic receptors)
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 Muscarinic Antagonists
MNEMONIC for ATROPINE TOXICITY
 Reverse of DUMBELS
“blind as a bat”
“dry as a bone”
“red as a beet”
“mad as a hatter”
“hot as a hell”
“full as a flask”

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 Antimuscarinic Agents
Organ Drugs Uses
Heart Atropine Symptomatic bradycardia
Pulseless electrical activity
CNS Scopolomine Trihexyphenidyl Wakefulness, Parkinson’s
Biperiden (Akineton) (Artane)
Benztropine (Cogentin) Orphenadrine
Procyclidine Tropicamide
Isopropamide
GIT Atropine Pirenzepine Anti-motility, Hyperacidity,
Dicyclomine Telenzepine
Oxybutinin Propantheline
GUT Dicyclomine Tolterodine Urgency, Incontinence, Over
Oxybutinin Fesoterodine active bladder
Glycopyrolate Solifenacin
Propantheline Darifenacin
Eyes Atropine Cyclopentolate Cycloplegic agents
Homatropine
Lungs Ipratropium Br (Atrovent) Bronchodilator
Oxytropium 29
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 Drugs Affecting
Autonomic Ganglia

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Ganglion Stimulants
1. Most nicotinic receptors agonists affect both
ganglionic and motor endplate receptors but show
selectivity
2. NOT used clinically
3. Used as experimental tools
4. Cause complex peripheral responses associated with
generalized stimulation of autonomic ganglia

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Ganglion Stimulants
EFFECTS:
1. Tachycardia
2. Increase in BP
3. Variable effects on GI motility and secretions
4. Increase bronchial, salivary, sweat secretions

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Ganglion Stimulants
EXAMPLES:
 Nicotine – tertiary amine; derived from tobacco
 Lobeline – tertiary amine, derived from lobelia
 Dimethylphenylpiperazinium (DMPP) – synthetic
compound selective for ganglionic receptors

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 Antinicotinic Agents
Depolarizing Nicotine

Ganglionic Mecamylamine
blockers
Non-depo Trimethaphan
Hexamethonium
Anti
nicotinic
Succinylcholine
Depolarizing
Galamine

NMBs
Tubocurarine
Non-depo Atracurium
Pancuronium
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Ganglion-Blocking Drugs
MOA:
1. Interference with ACh release
o E.g. Botulinum toxin (prevents release), hemicholinium
(blocks choline uptake), Mg+2
2. Prolonged depolarization
o E.g. nicotine
3. Interference with postsynaptic action of Ach
o E.g. blockade of nicotinic receptors/ ion channels by
tubocurarine, trimethaphan, hexamethonium
4. Block ALL autonomic ganglia and enteric ganglia
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Ganglion-Blocking Drugs
EFFECTS:
1. Hypotension
2. Loss of CV reflexes (postural hypotension)
3. Inhibition of secretions
4. GI paralysis
5. Impaired micturition

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Neuromuscular Blocking Drugs
MOA:
Drugs can block NM transmission by acting:
A. Presynaptically – inhibit ACh synthesis or release
B. Postsynaptically – act on the receptor or ion
channel
o Used in surgery, these decrease the dose of
anesthetic required
o For intubation
o Control of muscle spasms in intoxication (strychnine) or
infections (tetanus, rabies)
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Neuromuscular Blocking Drugs
Drugs that act presynaptically
o They serve useful experimental tools (no clinical
applications)
o Examples
A. Hemicholinium – blocks transport of choline
B. Triethylcholine – blocks transport of choline; forms a FALSE
NT
C. Vesamicol – blocks transport into vesicles
D. Botulinum toxin – inhibit Ach release; peptidases as active
component; causes progressive parasympathetic and motor
paralysis
E. β-bungarotoxin – cobra family venom; phospholipase as
active ingredient; similar to effect to botulinum 39
Neuromuscular Blocking Drugs
CLASSIFICATION
1. Non-depolarizing blocking drugs
o Prototype drug is tubocurarine
o Prevents access of Ach to the receptor / ion channel
o Majority of NM blockers
o E.g. tubocurarine, atracurium, doxacurium, mivacurium,
pancuronium, veruconium, pipecuronium, rocuronium

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Neuromuscular Blocking Drugs
1. Non-depolarizing blocking drugs
MOA:
1. Competitive antagonist
2. Acts mainly at nicotinic receptor site
3. Blocks the core of the ion channel
4. May block prejunctional Na+ channels

Tetanic stimulation relieves the blockade;

cholinesterase inhibitors reverse the blockade

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Neuromuscular Blocking Drugs
1. Non-depolarizing blocking drugs
EFFECTS:
1. Motor paralysis
2. Produce significant autonomic effects
3. Consciousness and awareness of pain were normal

SEQUENCE OF MOTOR PARALYSIS

Extrinsic eye muscles  small muscles of the face,
limbs and pharynx  respiratory muscles

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Neuromuscular Blocking Drugs
1. Non-depolarizing blocking drugs
ADVERSE EFFECTS:
1. Tubocurarine – fall in arterial BP secondary o
ganglion block
2. Vecuronium – less ganglion block and release of
histamine
3. Gallamine/Pancuronium – block muscarinic
receptors in heart causing tachycardia

Antidote: Neostigmine
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Neuromuscular Blocking Drugs
2. Depolarizing blocking drugs
 Agonists at Ach receptors
 Prototype drug is Ach
 Drug: Succinylcholine

ALL NM blockers bear a structural resemblance to ACh

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Neuromuscular Blocking Drugs
2. Depolarizing blocking drugs
MOA:
1. Phase 1 Block
 “Depolarization block”
 Leads to a loss of excitability
 Fasciculation due to initial depolarization
 Phase 1 Block is augmented by cholinesterase
inhibitors

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Neuromuscular Blocking Drugs
2. Depolarizing blocking drugs
MOA:
1. Phase 2 Block (Desensitizing)
 Initial end plate depolarization decreases,
membrane becomes repolarized
 Channels behave as in a prolonged closed state

Later in Phase 2 block, tetanic stimulation relieves

the blockade; cholinesterase inhibitors reverse the blockade

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Neuromuscular Blocking Drugs
2. Depolarizing blocking drugs
ADVERSE EFFECTS:
1. Bradycardia – preventable by Atropine, direct muscarinic
action
2. K release – increase in cation permeability of the motor
endplates
3. Prolonged paralysis – plasma cholinesterase is abnormal,
antocholinesterase drugs, neonates and Px with liver disease
4. Malignant Hyperthermia – intense muscle spasm, rise in
body temperature, treatment with dantrolene
5. Post-operative muscle pain

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Summary
A. Muscarinic Blockers
1. Atropine
2. Scopolamine
3. Homatropine
4. Ipratropium
5. Pirenzepine
6. Benztropine, trihexyphenidyl, Biperiden
• Other drugs that block muscarinic receptors:
7. antihistamines
8. Antipsychotics
9. TCA
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Summary
B. Neuromuscular blockers/Skeletal Muscle Relaxants
• B1. Nondepolarizing
1. Tubocurarine
2. Pancuronium, atracurium, vecuronium
• B2. Depolarizing
1. Succinylcholine

C. Ganglionic Blockers
1. hexamethonium, mecamylamine, trimethaphan
2. Nicotine
3. Lobeline
4. Botulinum toxin 49
End of Lecture! ^o^

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