The Autonomic Nervous System

1. The Autonomic Nervous System

2. Organization of The Nervous System Central Nervous System Peripheral Nervous System Autonomic Nervous System Somatic Nervous System Sympathetic Parasympathetic

3. How do we define neuron types in the ANS? Parasympathetic Sympathetic Acetylcholine Norepinephrine (Noradrenaline) Muscarine Epinephrine (Adrenaline) Nicotine

4. a b a Parasympathetic Ganglionic Synapse Acetylcholinesterase Ca2+ Na+ ACH Action Potential Nicotinic Receptor Na+ Preganglionic neuron Postganglionic neuron

5. Na+ Parasympathetic Organ Synapse Acetylcholinesterase Ca2+ Effector Organ K+ G Action Potential ACH Muscarinic Receptor Postganglionic neuron

6. Summary of parasympathetic neurons and synapses Preganglionic neurons • Long • Synapse with postganglionic neurons at or near organ • Release acetylcholine (ACH) to activate nicotinic receptors on postganglionic neurons Postganglionic neurons • Short • Synapse on the target organ • Release acetylcholine (ACH) to activate muscarinic receptors on the target organ

7. a b a Sympathetic Ganglionic Synapse Acetylcholinesterase Ca2+ Na+ ACH Action Potential Nicotinic Receptor Na+ Preganglionic neuron Postganglionic neuron

8. Na+ Sympathetic Organ Synapse Ca2+ Effector Organ G NE Action Potential Adrenergic Receptor Postganglionic neuron

9. Summary of sympathetic neurons and synapses Preganglionic neurons • Short • Synapse with postganglionic neurons near spinal cord • Release acetylcholine (ACH) to activate nicotinic receptors on postganglionic neurons Postganglionic neurons • Long • Synapse on the target organ • Release norepinephrine to activate adrenergic receptors on target organs

10. Exceptions in the sympathetic nervous system: • Sweat glands: • Postganglionic neurons involved with stress-related excretion release norepinephrine (“sweaty palms”) • Postganglionic neurons involved with thermoregulation release acetylcholine

11. Exceptions in the sympathetic nervous system: • Kidneys: • Postganglionic neurons to the smooth muscle of the renal vascular bed release dopamine • Adrenal gland: • Preganglionic neurons do not synapse in the paraverterbral sympathetic ganglion • Preganglionic neurons synapse directly on the adrenal gland, release acetylcholine, and activate nicotinic receptors on the adrenal gland • Adrenal glands release epinephrine into systemic circulation Most postganglionic sympathetic neurons release what neurotransmitter?

12. How do drugs influence the ANS? • Mimic or block the effects of the two primary neurotransmitters, Acetylcholine and Norepinephrine/Epinephrine • Drugs that mimic neurotransmitters are referred to as “receptor agonists” • These drugs activate receptors • Drugs that block neurotransmitters are referred to as “receptor antagonists” • These drugs block the endogenous neurotransmitters from activating receptors

13. Classification of drugs affecting the ANS • Parasympathetic nervous system Mimic acetylcholine = cholinergic = muscarinic agonists = parasympathomimetic Block acetylcholine = anticholinergic = muscarinic antagonist = parasympatholytic • Sympathetic nervous system Mimic norepinephrine = adrenergic = adrenergic agonist = sympathomimetic Block norepinephrine = antiadrenergic = adrenergic antagonist = sympatholytic

14. Receptors and signal transduction in the ANS Cholinergic Receptors Nicotinic Muscarinic Ganglionic Skeletal Muscle Neuronal CNS

15. Receptors and signal transduction in the ANS: Nicotinic Receptors

16. g d a a b Receptors and signal transduction in the ANS: Nicotinic Receptors

17. Receptors and signal transduction in the ANS Cholinergic Receptors Nicotinic Muscarinic M1 M3 M5 M2 M4

18. Receptors and signal transduction in the ANS: Muscarinic receptors are 7 transmembrane domain, G-protein coupled receptors

19. Receptors and signal transduction in the ANS: Muscarinic receptors(M1, M3, M5) NH 3 Phospho - (+) G lipase C q PIP 2 IP Diacylglycerol COOH 3 2+ Increase Ca Activate Protein Kinase C Response

20. Receptors and signal transduction in the ANS: Muscarinic Receptors (M2 and M4)

21. a1 a2 b a1B a1D a2A a2B a2C b1 b2 Receptors and signal transduction in the ANS Adrenergic Receptors a1A b3

22. Receptors and signal transduction in the ANS: a1-AdrenergicReceptors

23. Receptors and signal transduction in the ANS: a2-AdrenergicReceptors

24. Receptors and signal transduction in the ANS: b-AdrenergicReceptors

26. b 1 b 1, Functional Responses Mediated by the ANS Adrenergic Cholinergic Effector Organ Response Receptor Response Receptor Heart Rate of Contraction Increase Decrease M 2 Force of Contraction Increase Decrease M 2

27. Functional Responses Mediated by the ANS Adrenergic Cholinergic Effector Organ Response Receptor Response Receptor a Arteries (most) Vasoconstriction ---------- -- 1 a Veins Vasoconstriction ---------- -- 2 b Skeletal Muscle Vasodilation ---------- -- 2 Endothelium ---------- -- Release EDRF M 3

28. b 2 Functional Responses Mediated by the ANS Adrenergic Cholinergic Effector Organ Response Receptor Response Receptor Lung Bronchiolar smooth muscle Bronchodilation Bronchoconstriction M3

29. a a 1 1 Functional Responses Mediated by the ANS Adrenergic Cholinergic Effector Organ Response Receptor Response Receptor Genitourinary, smooth muscle b2 Bladder wall Relaxation Contraction M3 a Ureter Contraction Relaxation M3 1 a Sphincter Contraction Relaxation M3 1 Uterus (pregnant) Relaxation b2 Variable Contraction M 3 Erection Penis/vas deferens Ejaculation M3

30. a 1 M M 3 3 Functional Responses Mediated by the ANS Adrenergic Cholinergic Effector Organ Response Receptor Response Receptor Gastrointestinal Tract Salivary Glands Increase secretion Increase secretion Smooth Muscle: a b Walls Contraction Relaxation M3 , 2 2 a Sphincters Contraction Relaxation M3 1 Secretion ---------- -- Increase secretion

31. Functional Responses Mediated by the ANS Adrenergic Cholinergic Effector Organ Response Receptor Response Receptor Skin a1 Hair follicles, Smooth muscle Contraction, Piloerection -------------- -- Sweat glands -------------- M3 Thermoregulation Increase secretion -- -------------- a1 Apocrine (stress) Increase secretion --

32. Functional Responses Mediated by the ANS Adrenergic Cholinergic Effector Organ Response Receptor Response Receptor Eye Iris -------------- a1 Radial muscle Contraction -- Contraction -- Circular muscle ------------- M3 Contraction b2] [Relaxation Ciliary muscle M3 -------------- b2 Increase secretion of aqueous humor Ciliary epithelium --

33. Functional Responses Mediated by the ANS Adrenergic Cholinergic Effector Organ Response Receptor Response Receptor Metabolic functions a1,b2 Liver Glycogenolysis -------------- -- Gluconeogenesis b1,b3 Fat cells Lipolysis -------------- -- b Kidney -------------- -- Increase renin secretion 1 -------------- Pancreas a2 Decrease insulin release --

34. Cholinergic Pharmacology

35. a b a Action Potential Pharmacologic manipulation of the cholinergic system Ca2+ Na+ Muscarinic Receptor ACH Choline Acetyltransferase Acetylcholinesterase Acetyl CoA + Acetylcholine Choline Na+ H+ Nicotinic Receptor ACH Choline Acetate Choline Presynaptic neuron Postsynaptic target

36. NH 3 Phospho - (+) G lipase C q PIP 2 IP Diacylglycerol COOH 3 2+ Increase Ca Activate Protein Kinase C Response Receptor agonists activate signal transduction pathways O C H 3 C C H C H N C H 2 2 3 C H O 3 C H Acetylcholine 3 M3 muscarinic receptor

37. Cholinergic agonist for treatment of Sjogren’s Syndrome—autoimmune destruction of moisture-producing glands • Use Increase saliva production • Warnings/precautions: heart disease, night driving, urinary tract obstruction, GI tract obstruction • Contraindicated: uncontrolled asthma, when miosis is undesirable (narrow-angle glaucoma)

38. Clinical pharmacology of cholinergic receptor agonists Cholinesterase Drug Receptor Sensitivity Clinical Use Acetylcholine M, N Yes Intraocular use for miosis during surgery Carbachol M, N No Intraocular use for miosis during surgery, glaucoma Pilocarpine M No Glaucoma Bethanechol M No Urinary retention, post-operative ileus Varenicline N No Smoking cessation M=Muscarinic N=Nicotinic

39. Action Potential Pharmacologic manipulation of AChE: No inhibition Ca2+ Na+ Muscarinic Receptor ACH ACH Acetylcholinesterase ACH ACH ACH ACH ACH ACH ACH ACH ACH Choline Acetate Presynaptic neuron Postsynaptic target

40. Action Potential Pharmacologic manipulation of AChE: Inhibition by drugs Ca2+ ACH ACH Na+ ACH Muscarinic Receptor ACH ACH Acetylcholinesterase ACH ACH ACH ACH ACH ACH ACH ACH ACH ACH ACH ACH Presynaptic neuron Postsynaptic target

41. Clinical pharmacology of acetylcholinesterase inhibitors Type of Route of Drug inhibition administration Clinical Use Edrophonium Rev IM or IV Diagnostic for Myasthenia Gravis Neostigmine Rev IM, IV, or oral Myasthenia Gravis, post-operative ileus and bladder distention, surgical adjunct Physostigmine Rev IM, IV, or local Glaucoma, Alzheimer’s disease, antidote to anticholinergic overdose Tacrine Rev Oral Alzheimer’s disease Donepezil Rev Oral Alzheimer’s disease Isofluorophate Irrev Local Glaucoma Echothiophate Irrev Local Glaucoma

42. Contraindications to the use of parasympathomimetic drugs • Asthma • COPD • Peptic ulcer • Obstruction of the urinary or GI tract

43. Cholinergic agent side effects and toxicity SLUD • Salivation • Lacrimation • Urination • Defecation Also: • Increased sweating • Decreased heart rate • Pupils constricted • CNS activation • Treatment: • Cholinergic receptor antagonist (Atropine) • If irreversible AChE inhibitor, 2-PAM (Pralidoxime)

44. Clinical Correlation:Alzheimer’s Disease • Most common cause of dementia after age 50 • Atrophy of brain • Widening of sulci and thinning of gyri • Improper processing of b-amyloid precursor protein (b-APP) leads to toxic form (b-A42) that promotes apoptosis • On pathological exam: • Senile plaques: b-amyloid • Neurofibrillary tangles • Loss of cholinergic neurons in brain

45. Treatment of Alzheimer’s Disease • Bind to anionic site and block ACh binding • Reversible • Non-covalent • Enhances cognitive ability • Does not slow progression of disease • Newer agent: Donepezil (Aricept)

46. Treatment of Alzheimer’s Disease • Reversible carbamate AChE inhibitor • Enhances cognitive ability by increasing cholinergic function • Loses effectiveness as disease progresses • Side Effects: Nausea, vomiting, anorexia, and weight loss • Newer long-acting carbamate: Eptastigmine

47. Treatment of Alzheimer’s Disease • Reversible competitive AChE inhibitor • Extract from daffodil (Narcissus pseudonarcissus) bulbs • Loses effectiveness as disease progresses • May be a nicotinic receptor agonist • Inhibitors of P450 enzymes (3A4, 2D6) will increase galantamine bioavailability

48. Treatment of Alzheimer’s Disease • N-methyl-D-aspartate (NMDA) receptor antagonist • NMDA receptors are activated by glutamate in the CNS in areas associated with cognition and memory • Neuronal loss in Alzheimer’s may be related to increased activity of glutamate • May slow progression of the disease • Favorable adverse effect profile

49. Adrenergic Pharmacology

50. Organization of The Nervous System Central Nervous System Peripheral Nervous System Autonomic Nervous System Somatic Nervous System Sympathetic Parasympathetic