1. Pharmacology-1 PHL 313 Parasympathetic Nervous System Third Lecture By Abdelkader Ashour, Ph.D. Phone: 4677212Email: aeashour@ksu.edu.sa

2. Muscarinic Autonomic Effects of Acetylcholine  Eye (iris sphincter muscle) Contraction (miosis)  Eye (ciliary muscle) Contraction (for near vision)  SA node Bradycardia  Atrium Reduced contractility  AV node Reduced conduction velocity  Arteriole Dilation (via nitric oxide)  Bronchial muscle Muscle Contraction  Bronchial secretion Increase  GIT (motility) Increase  GIT (secretion) Increase  GIT (sphincters) Relaxation  Gallbladder Contraction  Urinary bladder (detrusor) Contraction  Urinary bladder (trigone, sphincter) Relaxation  Penis Erection (but not ejaculation)  Sweat glands Secretion (sympathetic cholinergic!)  Salivary glands Secretion  Lacrimal glands Secretion  Nasopharyngeal glands Secretion

3. Parasympathetic Nervous System, Summary of Intervention Mechanisms  Cholinergic neurotransmission can be modified at several sites, including: a)Precursor transport blockade, e.g., hemicholinium b)Choline acetyltransferase inhibition, …………no clinical example c)Promote transmitter release, e.g., choline, black widow spider venom (latrotoxin) d)Prevent transmitter release, e.g., botulinum toxin e)Prevent storage, e.g., vesamicol prevents ACh storage f)Cholinesterase inhibition, e.g., physostigmine, neostigmine g)Receptors agonists (chlinomimetic drugs) and antagonists (anticholinergic drugs)

4. Muscarinic Agonists (Cholinomimetics, Parasympathomimetics)  Acetylcholine  Acetylcholine has functions both in the CNS and in the peripheral nervous system as a neuromodulator  In the CNS, acetylcholine and the associated neurons form a neurotransmitter system, the cholinergic system, which tends to cause excitatory actions.  In the PNS, acetylcholine activates muscles, and is a major neurotransmitter in the autonomic nervous system.  Acetylcholine itself is rarely used clinically because of its rapid hydrolysis following oral ingestion and rapid metabolism following i.v. administration  A number of muscarinic agonists with resistance to hydrolysis (e.g., methacholine, carbachol, and bethanechol) are now available.  There are also several other naturally occurring muscarinic agonists such as muscarine and pilocarpine.  Use of muscarinic receptor agonists, is contraindicated in patients with asthma, coronary insufficiency, peptic ulcers, and incontinence

5. Muscarinic Agonists (Cholinomimetics, Parasympathomimetics)  Bethanechol (Urecholine ® )  Selectively stimulates muscarinic receptors (with further selectivity for M 3 receptors) without any effect on nicotinic receptors  Unlike acetylcholine, bethanechol is not hydrolyzed by cholinesterase and will therefore have a long duration of action  Indications: 1.To treat non-obstructive urinary retention resulting from general anesthetic or diabetic neuropathy of the bladder 2.To treat gastroparesis (delayed gastric emptying), because it stimulates GI motility and secretion 3.To stimulate salivary gland secretion in patients with xerostomia (dry mouth, nasal passages, and throat)  Side Effects: 1.Abdominal cramps or discomfort 2.nausea and diarrhea 3.Excessive salivation 4.Hypotension and bradycardia 5.Urinary urgency 6.bronchial constriction and asthmatic attacks

6.  Adverse Effects: (most of them are related to its non-selective action as a muscarinic receptor agonist) 1.Excessive sweating 2.Excessive salivation 3.Bronchospasm and increased bronchial mucus secretion 4.Bradycardia, hypotension 5.Nausea and diarrhea 6.It may result in miosis when used chronically as an eye drop  Pilocarpine (Salagen ® )  Indications: It is more commonly used than bethanechol to induce salivation, and also for various purposes in ophthalmology. 1.Treatment of primary open-angle glaucoma and also to lower intraocular pressure prior to surgery for acute angle-closure glaucoma (see next slide) 2.Treatment of symptoms of dry mouth from salivary gland hypofunction caused by radiotherapy for cancer of the head and neck Muscarinic Agonists (Cholinomimetics, Parasympathomimetics)