Autonomic Nervous System

1. Autonomic Nervous System Trachte gtracht1@d.umn.edu

2. Autonomic Nervous System • Autonomic Nervous System defined as nerves outside of the central nervous system (outside bony encasement of nervous system) with two efferent fibers (must have a synapse prior to the final junction with the end organ)

4. Parasympathetic Nervous System • Nicotinic Receptor- Comprised of five proteins to form a cation pore; agonists & antagonists not typically used clinically (exception is Nicotine) • Muscarinic Receptor- protein coupled to GTP-binding proteins to influence adenylyl cyclase, potassium channels or phospholipase C • Bethanecol is agonist; Atropine is antagonist • Anticholinesterases- potentiate activity of system • Example is neostigmine

6. Nicotinic Receptor • Because it consists of 5 distinct proteins, there are multiple isoforms • Ganglionic nicotinic receptors typically are composed of 2 alpha (acetylcholine binding proteins) and 3 ß proteins

9. Muscarinic Receptors • Actually five different clones exist • M1, M3 & M5 couple to Phospholipase C (stimulate it) • M2 & M4 couple to adenylyl cyclase (inhibit it)

10. Muscarinic Receptors • [Muscarinic Receptors on eye (constrict pupil), lacrimal glands (increase secretions), salivary glands (increase secretions), gut (increase secretions & motility), urinary bladder (relax sphincter & contract detrusor to promote urination), lung (contract bronchioles & increase secretions), heart (decrease rate).]

11. Parasympathetic Nervous System Can produce the following influences with the agent indicated: • augment peristalsis with bethanecol or neostigmine (promotes defecation) • contract urinary bladder with bethanecol or neostigmine • promote erection with a vasodilator (sildenafil (Viagra) preserves cGMP) • prevent urination caused by overactive bladder (usually detrusor overactivity) with Tolterodine (muscarinic antagonist- others include oxybutynin, Trospium, propantheline, hyoscyamine)

12. Q1. If you want to induce urination, which of the following strategies is best? • nicotinic agonist • nicotinic antagonist • muscarinic agonist • muscarinic antagonist • Anticholinesterase

14. Sympathetic Nervous System Nicotinic Receptor- receptor consists of 5 proteins forming a cation pore when activated by acetylcholine agonists & antagonists not used much except in anesthesia or smoking cessation Beta2 Receptor- protein coupled to GTP-binding protein to activate adenylyl cyclase; chief effects are to relax smooth muscle (bronchiole, uterine, intestinal etc) and to promote glycogenolysis • agonist is Albuterol; no specific ß2 antagonists used clinically (Propranolol is nonselective ß antagonist) Alpha1 Receptor- protein coupled to GTP-binding protein to activate phosholipase C; chief effects are to constrict smooth muscle (vascular, pupillary dilator muscle, sphincters) • agonist is phenylephrine; antagonist is terazosin Can prevent urination with agents potentiating the sympathetic nervous system (imipramine)

18. Sympathetic Nervous System After Norepinephrine (NE) exocytosis, it can do one of the following: interact with receptors (1) be reaccumulated into the nerve via the axoplasmic pump be degraded by monoamine oxidase (actually occurs inside the nerve) Drugs can affect these processes Imipramine blocks the axoplasmic pump (as does cocaine) Pargyline blocks monoamine oxidase Potentiate sympathetic effects by one of the following: add  receptor agonist block the axoplasmic pump (imipramine) block monoamine oxidase (pargyline) Inhibit sympathetic effects by antagonizing  receptor

19. Genitourinary Applications Contract Urinary Bladder by: • Muscarinic agonists (Bethanecol is example) • Anticholinesterases (Neostigmine is example)

20. Genitourinary Applications • Prevent Urination by: • blocking muscarinic receptors with Tolterodine (Detrol; 1-2 mg bid; $103/month) (others include oxybutynin (Ditropan), Trospium (Sanctura), propantheline, hyoscyamine)- Med. Let. 46: 64, 2004 • stimulating sympathetic nervous system (imipramine) (Tofranil) • used to help children with bedwetting problems • a little dangerous- can cause lethal cardiac arrhythmias, even in children • bedwetting more commonly treated with antidiuretic hormone currently • In theory, could combine phenylephrine and albuterol but not done in practice

21. Genitourinary Applications • No sympathetic nervous system agents are used to induce urination but 1 receptor blockers are used to ease urination in benign prostatic hyperplasia • Drugs include Terazosin (Hytrin); Doxazosin (cardura); Alfuzosin (uroxatral) and Tamsulosin (Flomax)

22. Q2: If a patient cannot control urination because of excessive activity of the parasympathetic nervous system, which of the following is the best strategy for treatment: 1) block sympathetic receptor (Terazosin) 2) activate sympathetics (Imipramine) 3) inhibit parasympathetic receptors (Atropine) 4) stimulate parasympathetic receptors (Bethanecol) 5) Use an anticholinesterase (Neostigmine)

23. Erectile Dysfunction treatment • Induce erection (in males) by vasodilating • Actual agents used most frequently are Sildenafil (Viagra), Tadalafil (Cialis) and Verdenafil (Levitra) • they prevent degradation of cGMP by blocking Phosphodiesterase 5

24. Erectile Dysfunction treatment • Physiologically, erections are caused by nitric oxide • Nitric Oxide (NO) interacts with soluble guanylyl cyclase to produce cGMP • cGMP interacts with protein kinase G to phosphorylate proteins • opens potassium channel to hyperpolarize smooth muscle • net effect is relaxation of smooth muscle • phosphodiesterase breaks down cGMP (this step blocked by Sildenafil)