1. Cholinergic Agents
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Saja Hamed, Ph.D

2. Neurotransmission at cholinergic neurons
Synthesis of acetylcholine
Storage of acetylcholine in vesicles
Release of acetylcholine
binding to receptor
degradation of acetylcholine
recycling of choline
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Saja Hamed, Ph.D

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Saja Hamed, Ph.D

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Saja Hamed, Ph.D

5. Cholinergic receptors
1. Muscarinic receptors:
- Acetylcholine
- Muscarine
M1 receptors: gastric parietal cells
M2 receptors: cardiac cells and smooth muscle
M3 receptor: exocrine glands and smooth muscle
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Saja Hamed, Ph.D

6. the nicotinic receptors of autonomic ganglia differ from those on NMJ
- Acetylcholine
- Nicotine
the nicotinic receptors of autonomic ganglia differ from those on NMJ
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Saja Hamed, Ph.D

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Saja Hamed, Ph.D

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Saja Hamed, Ph.D

9. Cholinergic drugs:
chemicals that act at the same site as the neurotransmitter acetylcholine (ACh)
10/01/1440
Saja Hamed, Ph.D

10. six category of cholinergic drugs:
1. muscarinic agonists (bethanechol): mimic the effects of acetylcholine at muscarinic receptors
2. muscarinic antagonists (atropine): block the effect of Ach at muscarinic receptors
3. Ganglionic stimulating agents (nicotine) mimic the effect of Ach at nicotinicN receptors
4. Ganglionic blocking agents (trimethaphan): block ganglionic nicotinicN receptors
5. Neuromuscular blocking agents (d-tubocurarine, succinylcholine): block the effects of ACh at nicotinicM receptors of the NMJ
6. the cholinesterase inhibitors (neostigmine, physostigmine): prevent the breakdown of ACh by acetylcholinesterase
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Saja Hamed, Ph.D

11. Muscarinic agonists and antagonists
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Saja Hamed, Ph.D

12. Muscarinic agonists: bind and activate muscarinic receptors
parasympathomimetic agents
a. Bethanechol:
direct acting muscarinic agonist
binds reversibly to muscarinic cholinergic receptors
At therapeutic doses it bind selectively at muscarinic receptors having no or little effects to nicotinic receptors
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Saja Hamed, Ph.D

13. pharmacologic effects:
bradycardia
increase sweating, salivation, bronchial secretion, and secretion of gastric acid
contraction of smooth muscles (lung, GI tract, bladder)  constriction of bronchi, increased tone motility of the smooth muscle, and contraction of the detrusor muscle of the bladder
relaxation of vascular smooth muscle  vasodilation  hypotension
miosis and accommodation for near vision  
10/01/1440
Saja Hamed, Ph.D

14. Pharmacokinetics:
Orally: effects begin in min and persist for 1 hr
SC: effects begin in 5-15 min[A1]
 Oral dose is 40 times higher than SC dose because it is a quaternary ammonium compound with positive charge
10/01/1440
Saja Hamed, Ph.D

15. Therapeutic uses: Urinary retention:
relax the urinary sphincter and increase voiding pressure by contracting the detrusor muscle
Postoperative and postpartum patients (a bedpan or urinal should be available)
Should not be used to treat urinary retention caused by physical obstruction of the urinary tract (inc. pressure with blockage cause injury)
10/01/1440
Saja Hamed, Ph.D

16. Adverse effects: Hypotension and bradycardia
Excessive salivation, increase secretion of gastric acid, abdominal cramp and diarrhea, involuntary defecation
Bronchoconstriction
Dysrhythmias in hyperthyroid patients
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Saja Hamed, Ph.D

17. C.I: Low BP or CO Gastric ulcer Intestinal obstruction
Recent surgery of the bowel
Urinary tract obstruction
Weakness of the bladder wall
Asthma
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Saja Hamed, Ph.D

18. preparations, dosage, and administration:
Tablets: dosing 1 hour before meal or 2 hours after (Can cause nausea and vomiting with meal)
Solution: for SC only. Must never be injected IM or IV
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Saja Hamed, Ph.D

19. for topical therapy of glaucoma
b. Pilocarpine:
muscarinic agonist
for topical therapy of glaucoma
oral therapy of dry mouth resulting from salivary gland damage caused by radiation therapy for head and neck cancer. 5 mg tablets (Salagen®)[A2] (At this dosage the principal adverse effect is sweating)
10/01/1440
Saja Hamed, Ph.D

20. c. Acetylcholine (Miochol®):
limited to producing rapid miosis following lens delivery in cataract surgery
limitations: lacks selectivity and rapid destruction by cholinesterase
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Saja Hamed, Ph.D

21. Toxicology of muscarinic agonists:
Poisoning results from:
- ingestion of certain mushrooms
- overdose with direct acting muscarinic agonist
- overdose with cholinesterase inhibitors
excessive stimulation of muscarinic receptors: profuse salivation, tearing, visual disturbances, bronchospasm, diarrhea, bradycardia, and hypotension
Treatment: atropine
10/01/1440
Saja Hamed, Ph.D

22. Muscarinic antagonists:
competitively block the action of ACh at muscarinic receptors
parasympatholytic drugs, antimuscarinic drugs, muscarinic blockers, and anticholinergic drugs
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Saja Hamed, Ph.D

23. found naturally in a variety of plants
Atropine:
found naturally in a variety of plants
competitively block muscarinic receptors  prevent receptor activation by ACh
at therapeutic doses it selectively block muscarinic receptors but at high doses it also block nicotinic receptors
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Saja Hamed, Ph.D

24. Pharmacologic effect:
Increases heart rate
Decreases secretion from salivary glands, bronchial glands, sweat glands, and the acid secreting cells of the stomach
Relaxation of the bronchi, decreased tone of the urinary bladder, decreased tone and motility of the GI tract
Mydriasis
Mild CNS excitation
Hallucinations and delirium
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Saja Hamed, Ph.D

25. Pharmacokinetics:
Orally (0.4 mg tab): rapidly absorbed and distribute to all tissues including the CNS
Topically to the eye (ointment or solution)
IM, SC, IV
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Saja Hamed, Ph.D

26. Therapeutic Uses:
Pre-anesthetic medication: pretreatment with atropine can prevent dangerous reduction in heart rate
Eye examination and ocular surgery
Accelerate heart rate in certain patients with bradycardia
Conditions of excessive intestinal motility
Muscarinic agonist poisoning
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Saja Hamed, Ph.D

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Saja Hamed, Ph.D

29. Adverse effect:
Xerostomia (dry mouth): patients should be informed that dryness can be alleviated by chewing gum, sucking on hard candy, and sipping fluids
Blurred vision and Photophobia: avoid hazardous activity. Wear dark glasses. Room lightening for hospitalized patients should be kept low
Elevation of IOP: C.I in glaucoma or people predisposed to glaucoma (older than 40)
Urinary retention: void just prior to take the medication. C.I in urinary tract obstruction
Constipation: inform patients to increase dietary fiber and fluids. A laxative may be needed if constipation is sever. C.I in intestinal atony
Anhidrosis  hyperthermia. Avoid activities that might lead to overheating
Tachycardia: C.I in patients with tachycardia
Asthma: in patients with asthma thickening and drying of bronchial secretions bronchial plugging
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Saja Hamed, Ph.D

30. Drug interactions:
Avoid combined use of atropine with other drugs capable of causing muscarinic blockade (antihistamines, phenothiazine antipsychotics, and TCA)
 all has antimuscarinic action
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Saja Hamed, Ph.D

31. b. Oxybutynin, Tolterodine: Muscarinic antagonists
Urge incontinence (involuntary urination occurring in association with a strong urge to void) due to involuntary contraction of the bladder detrusor muscle which is under parasympathetic control: try first behavioral therapy (bladder training exercises). Drug reserved for patients who do not respond
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Saja Hamed, Ph.D

32. muscarinic antagonists suppresses emesis and motion sickness
c. Scopolamine:
muscarinic antagonists
suppresses emesis and motion sickness
Principal uses are motion sickness, production of mydriasis for ophthalmic procedure, and production of pre-anesthetic sedation (i.e. it causes sedation at therapeutic doses while atropine cause CNS excitation)
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Saja Hamed, Ph.D

33. d. Dicyclomine (Antispas®): irritable bowel syndrome
functional bowel disorders (diarrhea, hypermotility)
e. Pirenzepine and Telenzepine:
selectively block M1-muscarinic receptors (regulate secretion of gastric acid)
suppress acid secretion in peptic ulcer
minimal incidence of dry mouth and blurred vision
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Saja Hamed, Ph.D

34. Toxicology of muscarinic antagonists:
Poisoning from:
- natural sources (Atropa belladonna)
- antimuscarinic drugs (atropine, scopolamine)
symptoms: dry mouth, blurred vision, photophobia, hyperthermia, CNS effects, hot and dry skin  death from respiratory depression due to blockade of cholinergic receptors in the brain
Treatment:
- minimize absorption of antimuscarinic agents (ipecac and activated charcoal)
- administer antidote: physostigmine: inhibitor of acetylcholinesterase
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Saja Hamed, Ph.D