Understanding Indirect-Acting Cholinergic Drugs and Their Mechanisms of Action

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INDIRECT ACTING
CHOLINRTGIC DRUGS
 
Ali Alhoshani
 
Objectives
 
By the end of this lecture the student should able to :
Classification of indirect acting cholinomimetics
 Mechanism of action, kinetics, dynamics and uses of
anticholinesterases
 Adverse effects & contraindications of anticholinesterases
 Symptoms and treatment of organophosphates toxicity.
 
 
Parasympathomimetic/
 cholinomimetics
 (Cholinergic Drugs )
 
Indirect-acting on Ach receptors
 
(also called anticholinesterases)
 
Mechanism of action:
 
Anticholinesterases
 
prevent hydrolysis of Ach by inhibiting
acetyl cholinesterase 
thus increase Ach concentrations and
actions at the cholinergic receptors 
(both nicotinic and
muscarinic).
 
Indirect-acting on Ach receptors
 
Mechanism of action :
Normally
 
 
 
 
 
 
 
Indirect-acting on Ach receptors
Reversible anticholinesterases
Short acting (Alcohols) 
edrophonium
Intermediate acting (Carbamates esters)
Physostigmine, Neostigmine, Pyridostigmine
I
r
r
e
v
e
r
s
i
b
l
e
 
a
n
t
i
c
h
o
l
i
n
e
s
t
e
r
a
s
e
s
L
o
n
g
 
a
c
t
i
n
g
Phosphates esters 
e.g. insecticides, gas war
e
.
g
.
 
E
c
o
t
h
i
o
p
h
a
t
e
 
&
 
I
s
o
f
l
u
r
o
p
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a
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e
 
 Indirect-acting on Ach receptors
 
Structure: (
Reversible anticholinesterases
)
1- Simple alcohols  ( 
Short Acting
 )
Forms weak hydrogen bond with
acetylcholinesterase enzyme
 
 
 
 
 
 Indirect-acting on Ach receptors
 
Structure
 (
Reversible anticholinesterases
)
2- Carbamic acid esters (
Intermediate acting
)
binds to two sites of cholinesterase enzyme
All polar and synthetic except physostigmine
Physo
stigmine
Pyrido
stigmine
Neo
stigmine
 
 
 
pyridostigmine
 
Indirect-acting on Ach receptors
 
Structure: 
Irreversible anticholinesterases
3- Organic derivatives of phosphoric acid 
( Long
Acting
)
 used as insecticides(malathion) or nerve gases
(sarin)
Form very stable covalent bond with cholinesterase
All phosphates are lipid soluble except
ecothiophate which is polar.
 
e.g. Ecothio
phate – 
Isofluro
phate
Pharmacological effects of anticholinesterases
ALL Anticholinesterases
 
Pharmacological effects of anticholinesterases
 
Neuromuscular junction
Therapeutic dose: 
muscle contraction
Toxic dose: 
relaxation or paralysis of skeletal muscles.
Ganglia:
 stimulation of sympathetic and
parasympathetic ganglia
Adrenal medulla
  release of catecholamines (A & NA).
 
Nicotinic actions
 
Pharmacological effects of anticholinesterases
 
Muscarnic actions
 
Drugs indirect-acting on Ach receptors (CHOLINOCEPTORS)
 
Edrophonium
Reversible anticholinesterase
alcohol
Polar
NOT absorbed orally 
(given by injection)
attach mainly to acetyl cholinesterase by weak hydrogen
bond.
Has short duration of action (5-15 min.)
Used for diagnosis of myasthenia gravis.
 
Drugs indirect-acting on Ach receptors (CHOLINOCEPTORS)
 
Physostigmine
Reversible anticholinesterase
Tertiary ammonium compound
Non polar (lipid soluble)
Good lipid solubility
Good oral absorption
Has muscarinic & nicotinic actions
cross BBB (has CNS effects)
Uses
Glaucoma
atropine toxicity (atropine is anticholinergic drug
)
 
Drugs indirect-acting on Ach receptors (CHOLINOCEPTORS)
 
Neostigmine
Reversible anticholinesterase
Quaternary ammonium comp.
Polar compound
Can be used orally
No CNS effect
Has muscarinic & nicotinic actions (prominent on 
GIT &
urinary tract
).
Uses
 Treatment of myasthenia gravis
Paralytic ileus & Urinary retention
Competitive neuromuscular blockers intoxication
 
Drugs indirect-acting on Ach receptors (CHOLINOCEPTORS)
 
Drugs indirect-acting on Ach receptors (CHOLINOCEPTORS)
 
Ecothiophate (
Organophosphorous compounds)
Irreversible anticholinesterase
Binds to cholinesterase by strong covalent bond.
Have very long duration of action
Aging make bond extremely stable
Not lipid soluble
Used
for glaucoma.
 
Drugs indirect-acting on Ach receptors (CHOLINOCEPTORS)
 
Organophosphates toxicity
 
 
Heart:
Lung:
GIT:
CNS:
Skeletal muscles :
 
Drugs indirect-acting on Ach receptors (CHOLINOCEPTORS)
 
OXIMES
 
Pralidoxime  (PAM)
 cholinesterase reactivator
 Acts by regeneration of cholinesterase enzyme.
 reactivates recently inhibited enzymes before aging.
 
Uses
 
I.V. 
 over 15-30 min for organophosphate
intoxication.
 
Drugs indirect-acting on Ach receptors (CHOLINOCEPTORS)
 
Donepezil
 Anticholinesterase drugs.
 Given orally.
 used for treatment of dementia of
   Alzheimer’s disease
 
Drugs indirect-acting on Ach receptors (CHOLINOCEPTORS)
 
Summary for cholinomimetics & their uses
 
Eye :
 treatment of glaucoma
Pilocarpine (direct muscarinic agonist)
Physostigmine
Ecothiophate (indirect cholinomimetics
)
Urinary retention and paralytic ileus
Bethanechol
 
(direct)
Neostigmine (indirect)
Myasthenia gravis  (only indirect cholinomimetics)
Pyridostigmine, Neostigmine, Ambenonium
Xerostomia
Pilocarpine – Cevimeline (Sjogren’s  syndrome)
Alzheimer’s disease:
Donepezil
 
Drugs indirect-acting on Ach receptors (CHOLINOCEPTORS
 
Adverse effects of cholinergic drugs:
 Bradycardia
 Sweating & Salivation
 Bronchoconstriction
 Diarrhea
 
Contraindications of cholinergic drugs
Bronchial asthma
Peptic ulcer
Angina pectoris
Incontinence
Intestinal obstruction
 
Drugs in/direct-acting on Ach receptors
 
Adverse effects:
In mid-afternoon, a coworker brings 43-year-old JM to
the emergency department because he is unable to
continue picking vegetables. His gait is unsteady and he
walks with support from his colleague. JM has difficulty
speaking and swallowing, his vision is blurred, and his
eyes are filled with tears. His coworker notes that JM was
working in a field that had been sprayed early in the
morning with a material that had the odor of sulfur.
Within 3 hours after starting his work, JM complained of
tightness in his chest that made breathing difficult, and he
called for help before becoming disoriented.
 
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This lecture covers the classification, mechanism of action, kinetics, dynamics, and uses of indirect-acting cholinomimetics. It discusses anticholinesterases, their adverse effects, contraindications, and the symptoms and treatment of organophosphates toxicity. Reversible and irreversible anticholinesterases, along with their structures and functions, are also explained in detail.


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  1. INDIRECT ACTING CHOLINRTGIC DRUGS Ali Alhoshani ahoshani@ksu.edu.sa http://fac.ksu.edu.sa/ahoshani Office: 2B 84

  2. Objectives By the end of this lecture the student should able to : Classification of indirect acting cholinomimetics Mechanism of action, kinetics, dynamics and uses of anticholinesterases Adverse effects & contraindications of anticholinesterases Symptoms and treatment of organophosphates toxicity.

  3. Parasympathomimetic/ cholinomimetics (Cholinergic Drugs )

  4. Indirect-acting on Ach receptors (also called anticholinesterases) Mechanism of action: Anticholinesterases prevent hydrolysis of Ach by inhibiting acetyl cholinesterase thus increase Ach concentrations and actions at the cholinergic receptors (both nicotinic and muscarinic).

  5. Indirect-acting on Ach receptors Mechanism of action : Normally

  6. Indirect-acting on Ach receptors Reversible anticholinesterases Short acting (Alcohols) edrophonium Intermediate acting (Carbamates esters) Physostigmine, Neostigmine, Pyridostigmine Irreversible anticholinesterases Long acting Phosphates esters e.g. insecticides, gas war e.g. Ecothiophate & Isoflurophate

  7. Indirect-acting on Ach receptors Structure: (Reversible anticholinesterases) 1- Simple alcohols ( Short Acting ) Forms weak hydrogen bond with acetylcholinesterase enzyme

  8. Indirect-acting on Ach receptors Structure (Reversible anticholinesterases) 2- Carbamic acid esters (Intermediate acting) binds to two sites of cholinesterase enzyme All polar and synthetic except physostigmine Physostigmine Pyridostigmine Neostigmine pyridostigmine

  9. Indirect-acting on Ach receptors Structure: Irreversible anticholinesterases 3- Organic derivatives of phosphoric acid ( Long Acting) used as insecticides(malathion) or nerve gases (sarin) Form very stable covalent bond with cholinesterase All phosphates are lipid soluble except ecothiophate which is polar. e.g. Ecothiophate Isoflurophate

  10. Pharmacological effects of anticholinesterases ALL Anticholinesterases Action on Yes/No muscarinic YES nicotinic YES CNS effects only lipid soluble drugs

  11. Pharmacological effects of anticholinesterases Nicotinic actions Neuromuscular junction Therapeutic dose: muscle contraction Toxic dose: relaxation or paralysis of skeletal muscles. Ganglia: stimulation of sympathetic and parasympathetic ganglia Adrenal medulla release of catecholamines (A & NA).

  12. Pharmacological effects of anticholinesterases Muscarnic actions Cholinergic actions Contraction of circular muscle of iris (miosis)(M3) Contraction of ciliary muscles for near vision (M3) Decrease in intraocular pressure bradycardia ( heart rate ) (M2) Release of NO (EDRF) Constriction of bronchial smooth muscles Increase bronchial secretion M3 Increased motility (peristalsis) Increased secretion Relaxation of sphincter M3 Contraction of muscles Relaxation of sphincter M3 Increase of sweat, saliva, lacrimal, bronchial, intestinal secretions M3 Organs Eye Heart endothelium Lung GIT Urinary bladder Exocrine glands

  13. Drugs indirect-acting on Ach receptors (CHOLINOCEPTORS) Edrophonium Reversible anticholinesterase alcohol Polar NOT absorbed orally (given by injection) attach mainly to acetyl cholinesterase by weak hydrogen bond. Has short duration of action (5-15 min.) Used for diagnosis of myasthenia gravis.

  14. Drugs indirect-acting on Ach receptors (CHOLINOCEPTORS) Physostigmine Reversible anticholinesterase Tertiary ammonium compound Non polar (lipid soluble) Good lipid solubility Good oral absorption Has muscarinic & nicotinic actions cross BBB (has CNS effects) Uses Glaucoma atropine toxicity (atropine is anticholinergic drug)

  15. Drugs indirect-acting on Ach receptors (CHOLINOCEPTORS) Neostigmine Reversible anticholinesterase Quaternary ammonium comp. Polar compound Can be used orally No CNS effect Has muscarinic & nicotinic actions (prominent on GIT & urinary tract). Uses Treatment of myasthenia gravis Paralytic ileus & Urinary retention Competitive neuromuscular blockers intoxication

  16. Drugs indirect-acting on Ach receptors (CHOLINOCEPTORS) Drug Actions Nicotinic & muscarinic M, N Kinetics Uses Neostigmine Myasthenia gravis treatment Paralytic ileus Urinary retention Curare toxicity Glaucoma atropine toxicity 0.5-2hr polar 0.5-2hr Lipid soluble Physostigmine Nicotinic muscarinic M, N, CNS Nicotinic & muscarinic M, N Nicotinic & muscarinic M, N Pyridostigmine 3-6 polar Myasthenia gravis treatment Ambenonium 4-8 polar Myasthenia gravis treatment

  17. Drugs indirect-acting on Ach receptors (CHOLINOCEPTORS) Ecothiophate (Organophosphorous compounds) Irreversible anticholinesterase Binds to cholinesterase by strong covalent bond. Have very long duration of action Aging make bond extremely stable Not lipid soluble Used for glaucoma.

  18. Drugs indirect-acting on Ach receptors (CHOLINOCEPTORS) Organophosphates toxicity Heart: Lung: GIT: CNS: Skeletal muscles :

  19. Drugs indirect-acting on Ach receptors (CHOLINOCEPTORS) OXIMES Pralidoxime (PAM) cholinesterase reactivator Acts by regeneration of cholinesterase enzyme. reactivates recently inhibited enzymes before aging. Uses I.V. over 15-30 min for organophosphate intoxication.

  20. Drugs indirect-acting on Ach receptors (CHOLINOCEPTORS) Donepezil Anticholinesterase drugs. Given orally. used for treatment of dementia of Alzheimer s disease

  21. Drugs indirect-acting on Ach receptors (CHOLINOCEPTORS) Edrophonium M, N Neostigmine M, N Very Short 5-15 min, Polar Short 0.5-2hr polar Diagnosis of Myasthenia gravis Myasthenia gravis treatment Paralytic ileus Urinary retention curare toxicity Glaucoma atropine toxicity Myasthenia gravis treatment Physostigmine M,N, CNS Ambenonium Pyridostigmine M, N Ecothiophate M, N Short 0.5-2hr Lipid soluble Short 3-6, polar Long 100hr, polar Glaucoma. Donepezil M, N dementia of Alzheimer s disease

  22. Summary for cholinomimetics & their uses Eye : treatment of glaucoma Pilocarpine (direct muscarinic agonist) Physostigmine Ecothiophate (indirect cholinomimetics) Urinary retention and paralytic ileus Bethanechol (direct) Neostigmine (indirect) Myasthenia gravis (only indirect cholinomimetics) Pyridostigmine, Neostigmine, Ambenonium Xerostomia Pilocarpine Cevimeline (Sjogren s syndrome) Alzheimer s disease: Donepezil

  23. Drugs indirect-acting on Ach receptors (CHOLINOCEPTORS Adverse effects of cholinergic drugs: Bradycardia Sweating & Salivation Bronchoconstriction Diarrhea Contraindications of cholinergic drugs Bronchial asthma Peptic ulcer Angina pectoris Incontinence Intestinal obstruction

  24. Drugs in/direct-acting on Ach receptors Adverse effects: In mid-afternoon, a coworker brings 43-year-old JM to the emergency department because he is unable to continue picking vegetables. His gait is unsteady and he walks with support from his colleague. JM has difficulty speaking and swallowing, his vision is blurred, and his eyes are filled with tears. His coworker notes that JM was working in a field that had been sprayed early in the morning with a material that had the odor of sulfur. Within 3 hours after starting his work, JM complained of tightness in his chest that made breathing difficult, and he called for help before becoming disoriented.

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