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

Bladder* and Gl hypotonia Muscarinic agonists Drug Structure Receptor specificity Hydrolysis by AChE Clinical uses   Musc Nic Acetylcholine +++ None Carbachol ++ - Methacholine + Bethanechol Bladder* and Gl hypotonia Muscarine None† Pilocarpine Glaucoma Oxotremorine

Muscarinic Effects on the Eye The parasympathetic (muscarinic) nerves to the eye supply: the ciliary muscle, which adjusts the curvature of the lens  Contraction of the ciliary muscle pulling the ciliary body forwards and inwards, thus relaxing the tension on the suspensory ligament of the lens, allowing the lens to bulge more, reducing its focal length This parasympathetic reflex is necessary to accommodate the eye for near vision the constrictor pupillae muscle, which is important not only for adjusting the pupil in response to changes in light intensity but also in regulating the intraocular pressure The main use of muscarinic agonists is in treating glaucoma, by local instillation in the form of eye drops. Pilocarpine is the most effective as, being a tertiary amine, it can cross the conjunctival membrane The anterior chamber of the eye, showing the pathway for secretion and drainage of the aqueous humor

Muscarinic Effects on the Eye Aqueous humour is secreted slowly and continuously by the cells of the epithelium covering the ciliary body, and it drains into the canal of Schlemm The intraocular pressure is normally 10-15 mmHg above atmospheric, which keeps the eye slightly distended Abnormally raised intraocular pressure (associated with glaucoma) damages the eye and is one of the commonest preventable causes of blindness In acute glaucoma, drainage of aqueous humour becomes impeded when the pupil is dilated because folding of the iris tissue occludes the drainage angle, causing the intraocular pressure to rise. Activation of the constrictor pupillae muscle by muscarinic agonists in these circumstances lowers the intraocular pressure The anterior chamber of the eye, showing the pathway for secretion and drainage of the aqueous humor

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

Muscarinic Antagonists Nonselective Muscarinic Antagonists The classical muscarinic antagonists are derived from plants and are nonselective competitive antagonists. Atropa belladonna contains atropine. Hyoscyamus niger contains primarily scopolamine and hyoscine Clinically, atropine is used for raising heart rate during situations where vagal activity is pronounced (for example, vasovagal syncope). It is also used for dilating the pupils. Its most widespread current use is in pre-anesthetic preparation of patients; in this situation, atropine reduces respiratory tract secretions and thus facilitates intubation Ipratropium is used by inhalation as a bronchodilator Cyclopentolate and tropicamide are developed for ophthalmic use and administered as eye drops (for dilating the pupil to aid examination of the eye) Oxybutinin and tolterodine are new drugs developed for urinary incontinence

Muscarinic Antagonists Side effects of muscarinic antagonists include: constipation urinary retention xerostomia (dry mouth) hypohidrosis (decreased sweating) mydriasis (dilated pupils) precipitation of glaucoma decreased lacrimation tachycardia decreased respiratory secretions Selective Muscarinic Antagonists Pirenzepine shows selectivity for the M1 muscarinic receptor Because of the importance of this receptor in mediating gastric acid release, M1 antagonists such as pirenzepine help patients with ulcer disease or gastric acid hyper-secretion Pirenzepine reduces gastric acid secretion with fewer adverse effects than atropine and other less selective agents. Pirenzepine passes the BBB, but only to a small extent, therefore it has no central effects