1. Clinical Pharmacology Autonomic pharmacology Jane M Johnston Ph.D.

2. Efferent (motor) nerves Two systems Autonomic nerves (unconscious) Eg cardiac output, respiration, etc Somatic nerves (voluntary)

3. ANS branches cholinergic fibres - acetylcholine adrenergic fibres noradrenaline (norepinepherine NE)

4. Functions and origins of the ANS

5. Action of ANS drugs Drugs to block ANS chemical transmission Drugs to mimic ANS action ANS drugs can modify a variety of effector tissues Cardiac muscle Blood pressure Exocrine glands

6. Cholinergic transmission Acetylcholine is at motor neuron and CNS nerve terminals Synthesized from Acetyl coA (mitochondria) Choline (dietary) Catalyzed by choline acetyl transferase (ChAT) Release is dependent on Calcium (Ca 2+ ) Causes muscle contraction

7. Acetylcholine Identified 1921 Present at all NMJ and also CNS Synthesized in the axon terminal Diffuses across synaptic cleft Two receptor subtypes Nicotinic ACh receptors Muscarinic ACh receptors

8. The discovery of vagusstoff E.Chudler 2001

9. Neuromuscular Junction 1999 Sinauer Associates Inc

10. Acetylcholine and NMJ

11. Characteristics of a neurotransmitter Synthesized in (or transported to) presynaptic terminal Stored in vesicles Regulated release Receptor located on postsynaptic membrane Termination of action

12. Synaptic vesicles at the NMJ (EM) Heuser and Heuser

13. Synthesis and release of neurotransmitters Synaptic Transmission in: Basic Neurochemistry 6 th Edition

14. Presynaptic events Calcium influx releases synaptic vesicles from microtubules Movement of synaptic vesicles to sites of action Interaction of specific proteins Vesicle docking Membrane fusion Calcium dependent exocytosis

15. Fusion proteins regulate neurotransmitter release Vesicle proteins Synaptobrevin Presynaptic membrane proteins Syntaxins SNAP-25

16. The SNARE hypothesis SNARE (Soluble N’ethylmalemide sensitive fusion Attachment protein REceptor) A. Pestronk www.neuro.wustl.edu/neuromuscular 2003www.neuro.wustl.edu/neuromuscular

17. Many presynaptic proteins regulate neurotransmitter release Synaptic Transmission in: Basic Neurochemistry 6 th Edition

18. Vesicular transport of NT – drug implications Toxins targeting neurotransmitter release Spider venom (excess ACh release) Botulinum (blocks ACh release) Tetanus

19. Postsynaptic events Boutons have multiple nerve terminals Simultaneous release Stimulation of contraction via AP Acetylcholine degraded after action ACETYLCHOLINESTERASE (AChE)

20. Motor neuron innervating skeletal muscle

21. Cholinergic receptors Two classes for acetylcholine Nicotinic and muscarinic Nicotinic are ion channels Ionotrophic Muscarinic are G-protein coupled Metabotrophic

22. Nicotinic AChR are sodium channels 1999 Sinauer Associates Inc

23. Ionotropic AChR Consist of five polypeptide subunits Receptors vary in: subunit structure agonist sensitivity distribution Mediate fast synaptic transmission

24. Muscarinic AChR activate G- proteins 1999 Sinauer Associates Inc

25. Metabotropic AChR Five muscarinic AChR subtypes G protein coupled Slower synaptic transmission via intracellular signaling cascade

26. Mode of cholinergic drug action Cholinomimetics agonist antagonist Cholinesterase inhibitors Clinical applications

27. Cholinomimetics Katzung, 2001

28. AChR agonists and antagonists Nicotinic AChR agonists Nicotine Nicotinic AChR antagonists Strychnine Snake toxins Bungarotoxin Muscarinic AChR agonist Muscarine Muscarinic AChR antagonists Atropine

29. Cholinesterase inhibitors Inhibit breakdown of acetylcholine at the synapse Act by Binding to acetylcholine esterase (steric hinderance or hydrolysis) Actions of acetylcholine persist at synapse Pesticides and nerve gases

30. Clinical Implications Myasthenia Gravis Glaucoma Cholinergic poisons CNS – Alzheimer’s Disease Schizophrenia

31. Myasthenia gravis Affects skeletal muscle at NMJ Involves autoimmunity to nicotinic receptors Extreme weakness, difficulty speaking, eating, breathing Cholinesterase inhibitors for therapy

32. Adrenergic transmission Catecholamines are the neuroTs Complex synthesis Secretion at nerve terminals and adrenal glands Adrenal glands Two adrenal glands Consist of cortex (outer) medulla (inner) medulla secretes: Epinephrine (adrenaline) Norepinephrine

33. NE and E are released at nerve terminals and secreted by the adrenal medulla

34. Norepinephrine and epinephrine Catecholamines Synthesized from dopamine Present in CNS and sympathetic nerves Widely distributed, general behavioral arousal eg raise blood pressure etc Stress increases release of norepinephrine

35. Synthesis of norepinephrine (NA)

36. Synthesis of epinephrine (adrenaline)

37. Adrenergic receptors Four receptor subtypes  1,  2,  1,  2 G protein linked Bind either norepinephrine or epinephrine

38. Sympathetomimetic drugs Can act directly or indirectly Direct binding to receptors Epinepherine, dopamine (CNS and renal) Indirectly Drugs targeting synthesis and release of NE and NA eg DBH inhibitors, reserpine - depletes stores Drugs targeting reuptake at synapse eg cocaine, Tricyclic antidepressants

39. Importance of sympathetomimetic drugs Cardiovascular system Regulation of smooth muscle affects heart and blood pressure beta blockers Respiratory tract Smooth muscle relaxation – bronchodilation Isoproterenol, albuterol (asthma) Metabolic effects Liver effects, insulin secretion CNS Nervousness, emotional well-being, psychosis etc