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Cholinergic Agonists
“Cholinomimetics”
Lecture 2
Dr. Hiwa K. Saaed
College of Pharmacy/University of Sulaimani
2017-2018
1
Classification
Cholinergic agonists mimic the effects of Ach by binding directly to
cholinoceptors (muscarinic or nicotinic).
A. Pharmacologically: by their spectrum of action.
1. Muscarinic agonists: Bethanechol, Methacholine, Pilocarpine
2. Nicotinic agonists: Nicotine
3. Both muscarinic and nicotinic agonists: Ach, Carbachol
B. mode of action
1. Direct-acting: bind directly to and activate muscarinic or nicotinic receptors,
2. Indirect-acting: by inhibiting the hydrolysis of endogenous Ach.
Direct-acting: Also subdivided chemically:
A. Esters of choline (including acetylcholine, bethanechol, methacholine
and carbachol)
B. Alkaloids (such as muscarine, pilocarpine and nicotine).
2
2. Indirect-acting:
by inhibiting the hydrolysis of endogenous Ach.
also subdivided to
A. Reversible:
neostigmine, physostigmine, pyridostigmine,
ambenomium, edrophonium, donepezil,
galantamine, rivastigmine, tacrine.
B. Irreversible
echothiophate, isoflurophate
Indirect and direct: Some quaternary cholinesterase inhibitors also
have a modest DIRECT action as well, example, neostigmine, which
activates neuromuscular nicotinic cholinoceptors directly in
addition to blocking cholinesterase.
3
Classification-mode of action
4
Cholinergic Agonists
Basic Pharmacology of Direct-acting
Pharmacokinetics
• All the direct-acting cholinergic drugs have longer durations of
action than Ach.
• Choline esters are poorly absorbed and poorly distributed into
the CNS because they are hydrophilic.
• The tertiary cholinomimetic alkaloids (pilocarpine, nicotine,
lobeline) are well absorbed from most sites of administration.
• All are hydrolyzed in the GIT (less active by the oral route).
• They differ markedly in their susceptibility to hydrolysis by
cholinesterase.
1. Acetylcholine is very rapidly hydrolyzed.
2. Methacholine 3 times more resistant to hydrolysis
3. Carbachol & Bethanechol are extremely resistant to hydrolysis.
5
6
Pharmacology of Ach-like agonist
Although, it affects almost every system within the body, it is
therapeutically of no importance!!!?? because of its multiplicity of
actions, and its rapid inactivation by the cholinesterases.
Actions:
• CVS: it ↓s heart rate, contractility, and blood pressure.
• GIT: it ↑s motility of the GIT and bladder.
• Pulmonary system: it ↑s secretions of the bronchioles
• Eye: miosis and accommodation.
• PNS: contraction of skeletal muscle
• CNS: it affects neurotransmission
• Endocrine system: it causes release of epinephrine from the adrenal
medulla (via Nn receptors).
• Sweat gland: it stimulates sweat gland secretions.
A. Acetylcholine (Ach)
7
Response mediated by Muscarinic receptors
8
Response mediated by Nicotinic receptors
Adverse effects:
excessive generalized cholinergic stimulation
DUMBLES:
• Diarrhea and decreased BP,
• Urination,
• Miosis,
• Bronchoconstriction,
• Lacrimation,
• Excitation of skeletal muscle,
• Salivation and Sweating
9
B. Bethanechol
It has duration of action of about one hour. Its major action on the smooth
musculature of the bladder and GIT, causing increased intestinal motility and
tone. (BBB-Bethanechol stimulates the Bladder and Bowel)
Therapeutic Uses: to stimulate the atonic bladder in postoperative, non-
obstructive urinary retention.
C. Carbachol
Systemically: profound effects on both the CVS and the GIT
• because of its ganglion (Nn receptor) stimulating activity, and it may first
stimulate and then depress these systems.
• It can cause release of epinephrine from the adrenal medulla by its nicotinic
action.
Locally instilled into the eye, causing miosis and a spasm of accommodation.
is rarely used therapeutically except in the eye to treat glaucoma??
Because of its high potency, and relatively long duration of action.
D. Methacholine: Act on muscarinic receptors. Used in diagnosis of asthma
and bronchial hyperreactivity.
10
E. Pilocarpine (an alkaloid)
• is a tertiary amine, and is stable not hydrolyzed by AchE.
• It is far less potent compared with Ach and its derivatives.
• Pilocarpine exhibits muscarinic activity
• is used primarily in ophthalmology, topically produces a rapid miosis
and contraction of the ciliary muscle; a spasm of accommodation; the
vision is fixed at some particular distance, making it impossible to
focus.
Pilocarpine is one of the most potent stimulators of secretions such as
sweat, tears, and saliva, but its lack of selectivity (adverse effects)
limited its use:
1. can enter the brain and causes CNS disturbances.
2. It stimulates profuse sweating and salivation.
11
Sjogren syndrome
• Sjogren syndrome, immunologic disorder with destruction
of the exocrine glands leading to the mucosal dryness (dry
mouth and lack of tears)
• is usually treated with cevimeline, a cholinergic drug that
also has the drawback of being nonspecific.
• Recent studies have shown that mouth sprays of
Pilocarpine are beneficial in promoting salivation in
patients with Xerostomia (dryness of the mouth).
12
is the DOC in the emergency lowering of IOP of both narrow-
angle and a wide-angle glaucoma.
is extremely effective in opening the trabecular meshwork
around Schlemm canal result in an increased drainage of
aqueous humor
Therapeutic use in glaucoma:
13
Organ system effects of cholinergic agonists
14
Indirect-Acting Cholinomimetics
Q. How do they work?
By inhibiting AChE, protect Ach from hydrolysis.
Their pharmacodynamic properties are almost identical.
The chief differences between members of the group are chemical
and pharmacokinetic.
Chemistry
1. Simple alcohols bearing a quaternary ammonium group, e.g.,
edrophonium
2. Carbamic acid esters of alcohols bearing
• Quaternary ammonium groups (e.g., neostigmine)
• Tertiary ammonium groups (e.g., physostigmine).
3. Organic derivatives of phosphoric acid (organophosphates,
e.g., echothiophate).
15
Physostigma venenosum
Reversible Irreversible bind covalently to ChE.
Carbamates Acridine organophosphates
Physostigmine
Neostigmine
Pyridostigmine
Edrophonium
Rivastigmie
Donepezil
tacrine Dyflos (DFP) , Echothiophate Drug
Parathion, Malathion (insecticide)
Diazinon, Tabun, sarin, soman (nerve gases
for chemical warfare)
16
Cholinesterase inhibitors
Irreversible cholinesterase inhibitors
Irreversible: Only the organophosphate inhibitors, because
they bind covalently to AChE, and can permanently
inactivate the enzyme.
The effects of organophosphates can last as long as a week,
which is approximately the time, needed to synthesize a
new molecule of AChE.
Q. Is it at all possible to reverse the effects of
organophosphates?
In most cases, NO. However, if Pralidoxime “2-PAM” (a
cholinesterase reactivator) is given before a process called
aging.
Aging: the organophosphate binds to AChE and loses one of
its alkyl groups, then it may be possible to remove the
organophosphate from AChE.
17
• Edrophonium, Neostigmine,
Pyridostigmine:
• Absorption from the conjunctiva,
skin, and lungs is predictably poor.
• Distribution into the CNS is
negligible.
• Physostigmine (lipid
soluble):
• is well absorbed from all
sites and can be used
topically in the eye.
• It is distributed into the
CNS and is more toxic
Synthetic quaternary ammonium agents
Naturally occurring tertiary
amine:
18
Absorption, Distribution, and Metabolism
All are well absorbed from the skin, lung, gut, and conjunctiva
except for echothiophate; Therefore, dangerous to humans and
highly effective as insecticides.
The organophosphate cholinesterase inhibitors
rapidly metabolized (detoxify) to
inactive products in birds and
mammals but not in insects and
Unfortunately, fish ; these agents are
therefore considered safe enough
for sale to the general public.
is not detoxified effectively in
vertebrates; thus, it is
considerably more dangerous
than malathion to humans
and livestock and is not
available for general public
use.
Malathion and a few other
organophosphate insecticides Parathion
19
Thiohosphate (parathion, malathion)
Are quite lipid-soluble rapidly; absorbed by all routes.
They must be activated in the body by conversion to the oxygen
analogs, a process that occurs rapidly in both insects and vertebrates.
Actions of AChE Inhibitors
1. CNS:
Low doses: CNS activation
High: coma and respiratory arrest
2. Eye, respiratory tract, GI & urinary tract: The same as
muscarinic agonists
3. Cardiovascular:
Heart: Bradycardia, ↓contraction, ↓COP
Blood vessels? No effect
4. Neuromuscular junction:
low dose ↑ force of contraction
high dose Muscle fasciculation and depolarizing blockade
AChE Adverse effects: Excessive cholinergic stimulation
Treatment of AChE Poisoning
1. Atropine: Reverses muscarinic but not nicotinic
2. Pralidoxime (2-PAM):
20
The major therapeutic uses of the
cholinomimetics:
1. Eye: glaucoma, accommodative esotropia
2. Gastrointestinal & Urinary tracts: postoperative atony, neurogenic bladder
3. Neuromuscular junction: myasthenia gravis, curare-induced neuromuscular
paralysis
NB. Cholinesterase inhibitors, but not direct-acting acetylcholine receptor
agonists; are extremely valuable as therapy for myasthenia.??
Drugs Used in Myasthenia Gravis
21
Drug Duration of Action
Diagnosis:
Edrophonium I.V (improvement) 5-15 min
Treatment:
Neostigmine (do not cross BBB) 0.5-2 hours
Pyridostigmine 3-6 hours
Ambenonium 4-8 hours
Summary of actions of some cholinergic agonists

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L2 ans pharmacology 2017 2018

  • 1. Cholinergic Agonists “Cholinomimetics” Lecture 2 Dr. Hiwa K. Saaed College of Pharmacy/University of Sulaimani 2017-2018 1
  • 2. Classification Cholinergic agonists mimic the effects of Ach by binding directly to cholinoceptors (muscarinic or nicotinic). A. Pharmacologically: by their spectrum of action. 1. Muscarinic agonists: Bethanechol, Methacholine, Pilocarpine 2. Nicotinic agonists: Nicotine 3. Both muscarinic and nicotinic agonists: Ach, Carbachol B. mode of action 1. Direct-acting: bind directly to and activate muscarinic or nicotinic receptors, 2. Indirect-acting: by inhibiting the hydrolysis of endogenous Ach. Direct-acting: Also subdivided chemically: A. Esters of choline (including acetylcholine, bethanechol, methacholine and carbachol) B. Alkaloids (such as muscarine, pilocarpine and nicotine). 2
  • 3. 2. Indirect-acting: by inhibiting the hydrolysis of endogenous Ach. also subdivided to A. Reversible: neostigmine, physostigmine, pyridostigmine, ambenomium, edrophonium, donepezil, galantamine, rivastigmine, tacrine. B. Irreversible echothiophate, isoflurophate Indirect and direct: Some quaternary cholinesterase inhibitors also have a modest DIRECT action as well, example, neostigmine, which activates neuromuscular nicotinic cholinoceptors directly in addition to blocking cholinesterase. 3 Classification-mode of action
  • 5. Basic Pharmacology of Direct-acting Pharmacokinetics • All the direct-acting cholinergic drugs have longer durations of action than Ach. • Choline esters are poorly absorbed and poorly distributed into the CNS because they are hydrophilic. • The tertiary cholinomimetic alkaloids (pilocarpine, nicotine, lobeline) are well absorbed from most sites of administration. • All are hydrolyzed in the GIT (less active by the oral route). • They differ markedly in their susceptibility to hydrolysis by cholinesterase. 1. Acetylcholine is very rapidly hydrolyzed. 2. Methacholine 3 times more resistant to hydrolysis 3. Carbachol & Bethanechol are extremely resistant to hydrolysis. 5
  • 7. Although, it affects almost every system within the body, it is therapeutically of no importance!!!?? because of its multiplicity of actions, and its rapid inactivation by the cholinesterases. Actions: • CVS: it ↓s heart rate, contractility, and blood pressure. • GIT: it ↑s motility of the GIT and bladder. • Pulmonary system: it ↑s secretions of the bronchioles • Eye: miosis and accommodation. • PNS: contraction of skeletal muscle • CNS: it affects neurotransmission • Endocrine system: it causes release of epinephrine from the adrenal medulla (via Nn receptors). • Sweat gland: it stimulates sweat gland secretions. A. Acetylcholine (Ach) 7
  • 8. Response mediated by Muscarinic receptors 8 Response mediated by Nicotinic receptors
  • 9. Adverse effects: excessive generalized cholinergic stimulation DUMBLES: • Diarrhea and decreased BP, • Urination, • Miosis, • Bronchoconstriction, • Lacrimation, • Excitation of skeletal muscle, • Salivation and Sweating 9
  • 10. B. Bethanechol It has duration of action of about one hour. Its major action on the smooth musculature of the bladder and GIT, causing increased intestinal motility and tone. (BBB-Bethanechol stimulates the Bladder and Bowel) Therapeutic Uses: to stimulate the atonic bladder in postoperative, non- obstructive urinary retention. C. Carbachol Systemically: profound effects on both the CVS and the GIT • because of its ganglion (Nn receptor) stimulating activity, and it may first stimulate and then depress these systems. • It can cause release of epinephrine from the adrenal medulla by its nicotinic action. Locally instilled into the eye, causing miosis and a spasm of accommodation. is rarely used therapeutically except in the eye to treat glaucoma?? Because of its high potency, and relatively long duration of action. D. Methacholine: Act on muscarinic receptors. Used in diagnosis of asthma and bronchial hyperreactivity. 10
  • 11. E. Pilocarpine (an alkaloid) • is a tertiary amine, and is stable not hydrolyzed by AchE. • It is far less potent compared with Ach and its derivatives. • Pilocarpine exhibits muscarinic activity • is used primarily in ophthalmology, topically produces a rapid miosis and contraction of the ciliary muscle; a spasm of accommodation; the vision is fixed at some particular distance, making it impossible to focus. Pilocarpine is one of the most potent stimulators of secretions such as sweat, tears, and saliva, but its lack of selectivity (adverse effects) limited its use: 1. can enter the brain and causes CNS disturbances. 2. It stimulates profuse sweating and salivation. 11
  • 12. Sjogren syndrome • Sjogren syndrome, immunologic disorder with destruction of the exocrine glands leading to the mucosal dryness (dry mouth and lack of tears) • is usually treated with cevimeline, a cholinergic drug that also has the drawback of being nonspecific. • Recent studies have shown that mouth sprays of Pilocarpine are beneficial in promoting salivation in patients with Xerostomia (dryness of the mouth). 12
  • 13. is the DOC in the emergency lowering of IOP of both narrow- angle and a wide-angle glaucoma. is extremely effective in opening the trabecular meshwork around Schlemm canal result in an increased drainage of aqueous humor Therapeutic use in glaucoma: 13
  • 14. Organ system effects of cholinergic agonists 14
  • 15. Indirect-Acting Cholinomimetics Q. How do they work? By inhibiting AChE, protect Ach from hydrolysis. Their pharmacodynamic properties are almost identical. The chief differences between members of the group are chemical and pharmacokinetic. Chemistry 1. Simple alcohols bearing a quaternary ammonium group, e.g., edrophonium 2. Carbamic acid esters of alcohols bearing • Quaternary ammonium groups (e.g., neostigmine) • Tertiary ammonium groups (e.g., physostigmine). 3. Organic derivatives of phosphoric acid (organophosphates, e.g., echothiophate). 15 Physostigma venenosum
  • 16. Reversible Irreversible bind covalently to ChE. Carbamates Acridine organophosphates Physostigmine Neostigmine Pyridostigmine Edrophonium Rivastigmie Donepezil tacrine Dyflos (DFP) , Echothiophate Drug Parathion, Malathion (insecticide) Diazinon, Tabun, sarin, soman (nerve gases for chemical warfare) 16 Cholinesterase inhibitors
  • 17. Irreversible cholinesterase inhibitors Irreversible: Only the organophosphate inhibitors, because they bind covalently to AChE, and can permanently inactivate the enzyme. The effects of organophosphates can last as long as a week, which is approximately the time, needed to synthesize a new molecule of AChE. Q. Is it at all possible to reverse the effects of organophosphates? In most cases, NO. However, if Pralidoxime “2-PAM” (a cholinesterase reactivator) is given before a process called aging. Aging: the organophosphate binds to AChE and loses one of its alkyl groups, then it may be possible to remove the organophosphate from AChE. 17
  • 18. • Edrophonium, Neostigmine, Pyridostigmine: • Absorption from the conjunctiva, skin, and lungs is predictably poor. • Distribution into the CNS is negligible. • Physostigmine (lipid soluble): • is well absorbed from all sites and can be used topically in the eye. • It is distributed into the CNS and is more toxic Synthetic quaternary ammonium agents Naturally occurring tertiary amine: 18 Absorption, Distribution, and Metabolism All are well absorbed from the skin, lung, gut, and conjunctiva except for echothiophate; Therefore, dangerous to humans and highly effective as insecticides. The organophosphate cholinesterase inhibitors
  • 19. rapidly metabolized (detoxify) to inactive products in birds and mammals but not in insects and Unfortunately, fish ; these agents are therefore considered safe enough for sale to the general public. is not detoxified effectively in vertebrates; thus, it is considerably more dangerous than malathion to humans and livestock and is not available for general public use. Malathion and a few other organophosphate insecticides Parathion 19 Thiohosphate (parathion, malathion) Are quite lipid-soluble rapidly; absorbed by all routes. They must be activated in the body by conversion to the oxygen analogs, a process that occurs rapidly in both insects and vertebrates.
  • 20. Actions of AChE Inhibitors 1. CNS: Low doses: CNS activation High: coma and respiratory arrest 2. Eye, respiratory tract, GI & urinary tract: The same as muscarinic agonists 3. Cardiovascular: Heart: Bradycardia, ↓contraction, ↓COP Blood vessels? No effect 4. Neuromuscular junction: low dose ↑ force of contraction high dose Muscle fasciculation and depolarizing blockade AChE Adverse effects: Excessive cholinergic stimulation Treatment of AChE Poisoning 1. Atropine: Reverses muscarinic but not nicotinic 2. Pralidoxime (2-PAM): 20
  • 21. The major therapeutic uses of the cholinomimetics: 1. Eye: glaucoma, accommodative esotropia 2. Gastrointestinal & Urinary tracts: postoperative atony, neurogenic bladder 3. Neuromuscular junction: myasthenia gravis, curare-induced neuromuscular paralysis NB. Cholinesterase inhibitors, but not direct-acting acetylcholine receptor agonists; are extremely valuable as therapy for myasthenia.?? Drugs Used in Myasthenia Gravis 21 Drug Duration of Action Diagnosis: Edrophonium I.V (improvement) 5-15 min Treatment: Neostigmine (do not cross BBB) 0.5-2 hours Pyridostigmine 3-6 hours Ambenonium 4-8 hours
  • 22. Summary of actions of some cholinergic agonists