INTRODUCTION TO THE AUTONOMIC NERVOUS SYSTEM

1. INTRODUCTION TO THE AUTONOMIC NERVOUS SYSTEM Subdivisions of the Peripheral Nervous System • Somatic nervous system • (voluntary) • Autonomic nervous system • (involuntary)

2. Somatic nervous system • innervation of skeletal muscles (movement) • CNS control (corticospinal or pyramidal tracts)

3. Somatic nervous system • somatic innervations consist of a single neuron (final common motor neuron) arising in spinal cord and extending via the ventral root to the skeletal muscles • releases acetylcholine (ACh)

4. Autonomic nervous system • Functional considerations: • mediates control of vegetative or involuntary functions • innervation of cardiac muscle, vascular and nonvascular smooth muscle and exocrine glands • functions in these systems often occur without conscious control

5. Autonomic nervous system • Anatomical considerations: • In contrast to somatic efferents, autonomic innervations consist of 2 sequential neurons • These sequential neurons are the preganglionic and postganglionic neurons which synapse at autonomic ganglia

6. Autonomic nervous system • Anatomical considerations: • The autonomic nervous system consists of two divisions: • sympathetic • parasympathetic

7. Somatic MotorFiber Skeletal Muscle Ach Ganglion Sympathetic Smooth Muscle Cardiac Cells Gland Cells Postganglionic Fiber; Adrenergic Ach NE Ganglion Sympathetic Sweat Glands Ach Ach Preganglionic Fiber; Cholinergic Postganglionic Fiber; Cholinergic Sympathetic EPI/NE Ach Smooth Muscle Cardiac Cells Gland Cells Adrenal Gland Para- sympathetic Ganglion Ach Ach

8. Sympathetic nervous system • preganglionic neurons exit the spinal cord at the thoraco-lumbar level to synapse with postganglionic nerves at para-vertebral ganglia (22 pairs on each side of spinal cord) or prevertebral ganglia (celiac, mesenteric) in the abdomen.

9. Sympathetic nervous system • The adrenal medulla is considered to be a modified sympathetic ganglion; the medulla is embryonically and anatomically homologous to the sympathetic ganglia

10. Sympathetic nervous system • Sympathetic innervations usually consist of one short preganglionic fiber synapsing with several (one or more) long postganglionic fibers in the sympathetic ganglia

11. Sympathetic nervous system • there is a greater ramification of sympathetic fibers compared to the parasympathetic system (the ratio of pre to postganglionic fibers  1:20) • diffuseaction; “fight or flight” responses (i.e., stress)

12. Sympathetic nervous system • this system is normally active with the degree of activity varying from moment to moment and organ to organ • this system constantly adjusts to a changing environment, especially during rage or fright

13. Sympathetic nervous system Typical sympathetic responses include: • increase in heart rate • shift in blood flow to muscles • increase in blood glucose levels • dilation of the pupils

14. Parasympathetic nervous system • preganglionic neurons originate in the cranial nerves of the brain stem and the sacral portion of the spinal cord • these neurons synapse with post-ganglionic neurons in ganglia very close or in the organs innervated

15. Parasympathetic nervous system • Parasympathetic innervations typically consist of one longpreganglionic fiber synapsing with one shortpost-ganglionic fiber in the parasympathetic ganglia.

16. Parasympathetic nervous system • this system is more circumscribed than the sympathetic system, although a 1:1 ratio of pre to postganglionic fibers is not always the case • discreteaction; conservation and restoration of energy, localized control of discrete functions • essentialforlife

17. Parasympathetic nervous system Typical parasympathetic responses include: • slowing the heart rate • lowering blood pressure • protecting the retina from light • emptying the bladder

18. Physiological antagonism • The sympathetic and parasympathetic systems usually do not function independently; i.e., they are physiologicalantagonists.

19. Physiological antagonism • Often when one system inhibits a process, the other system will augment the level of activity so that the total response depends on the influence of both systems, although this is not always the case. • The integration of these system regulates functions below the level of consciousness.

20. Neurochemical classification of Peripheral Nervous System Acetylcholine (ACh or Cholinergic) synapses include: • Allpreganglionic fibers outside CNS (sympathetic & parasympathetic) • Allparasympatheticpostganglionic nerve endings (ACh is the transmitter) • Exception: sympathetic postganglionic nerve endings of sweat glands • somatic motor neurons innervating skeletal muscle

21. Neurochemical classification of Peripheral Nervous System • Noradrenergic (NE) synapses: • all postganglionic sympathetic fibers (except those to sweat glands) • adrenal medulla (norepinephrine & epinephrine)

22. Acetylcholine Chemistry • acetylcholine is synthesized from acetyl co-enzyme A and choline using the enzyme choline acetyl transferase • the major means of inactivation of acetylcholine is degradation in the synapse using the enzyme acetylcholine esterase

23. Acetylcholine • Acetylcholine (Cholinergic) Receptors • Muscarinic • Nicotinic

24. Acetylcholine • Muscarinic receptors • postganglionic parasympathetic fibers innervating heart, smooth muscle and exocrine glands • exception: postganglionic sympathetic fibers innervating sweat glands • blocked by antimuscarinic agents (e.g., atropine)

25. Acetylcholine • Nicotinic receptors • classically a biphasic response is observed with stimulation at low doses and inhibition at high doses • sympathetic and parasympathetic auto-nomic ganglia and the adrenal medulla • effects blocked with ganglionic blockers (e.g., trimethaphan, hexamethonium)

26. Acetylcholine • Nicotinicreceptors • neuromuscular junction of skeletal muscle • effects blocked with neuromuscular blockers (e.g., curare)

27. Norepinephrine Chemistry • norepinephrine is ultimately synthesized from tyrosine using the enzyme tyrosine hydroxylase which converts tyrosine to DOPA • aromatic L-amino acid decarboxylase converts DOPA to dopamine • dopamine b-hydroxylase converts dopamine to norepinephrine

28. Norepinephrine • Phenylethanolamine N-methyl-transferase converts norepinephrine to epinephrine • the major means of inactivation of norepinephrine is reuptake back into the presynaptic neuron from which it was released

29. Norepinephrine Norepinephrine (noradrenergic) receptors: • a1 (alpha 1) • vascular smooth muscle, genitourinary smooth muscle, liver (contraction) • intestinal smooth muscle (hyperpolarization and relaxation) • heart (increased contractile force, arrhythmias)

30. Norepinephrine Norepinephrine (noradrenergic) receptors: • a2(alpha 2) • pancreatic islets (b cells, decreased insulin secretion) • platelets (aggregation) • vascular smooth muscle (contraction)

31. Norepinephrine Norepinephrine (noradrenergic) receptors • b1 (beta 1) • heart (increased force and rate of contraction, AV nodal conduction velocity) • juxtaglomerular cells (increased renin secretion)

32. Norepinephrine Norepinephrine (noradrenergic) receptors • b2 (beta 2) • smooth muscle [vascular, bronchial, gastrointestinal, genitourinary] (relaxation) • skeletal muscle (glycogenolysis; uptake of K+) • liver (glycogenolysis; gluconeogenesis)

33. Potential ways to affect autonomic neurotransmission • Synthesis • availability of precursors for the NT • availability of synthesis enzymes

34. Potential ways to affect autonomic neurotransmission • Storage (vesicles) • protects the NT from degradation • provides for the quantal release of the NT

35. Potential ways to affect autonomic neurotransmission • Release (Ca2+ dependent exocytosis) • agents could interfere with or enhance the release of the NT

36. Potential ways to affect autonomic neurotransmission • Receptor activation • Agonist- high affinity and high intrinsic activity • Antagonist - high affinity but NOintrinsic activity

37. Potential ways to affect autonomic neurotransmission • Termination of NT effect • Acetylcholine - metabolism in synaptic cleft via acetylcholine esterase • Norepinephrine - reuptake into presynaptic neuron

38. Summary---KEY POINTS: • The ANS is a rapid homeostatic and ‘autonomous’ nervous system. • The ANS is composed of 2 divisions with different anatomical and pharmacological organization. • Sympathetic and parasympathetic efferents are disynaptic. • Parasympathetic activation stimulates muscarinic cholinergic receptors. Sympathetic activation stimulates adrenergic receptors; • Afferent input to the brainstem and brain are required for ANS coordination throughout the body.

39. Where in the autonomic nervous system isnorepinephrine stored? • Preganglionic sympathetic nerve endings • Postganglionic sympathetic nerve endings • Preganglionic parasympathetic nerve endings • Postganglionic parasympathetic nerve endings • Increased parasympathetic activity results in • decreased salivary secretion. • increased cardiac contractility. • decreased gastric motility and tone. • increased bronchiolar smooth muscle contraction. .

40. Classifications of Cholinergics • Direct-acting – Act on the receptors to activate a tissue response • Indirect-acting – Inhibit the action of the enzyme cholinesterase by forming a chemical complex, thus allowing acetylcholine to persist and attach to the receptor (cholinesterase inhibitor or an anticholinesterase drug) • Reversible – bind the cholinesterase for minutes to hours • Irreversible

41. Actions of Cholinergics • Stimulate bladder and GI tone • Constrict pupils of the eyes (miosis) • Increase neuromuscular transmission • Decreased heart rate and blood pressure • Increased salivary, GI, and bronchial glandular secretions

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45. Toxic Effects • S – Salivation • L – Lacrimation • U – Urinary incontinence • D – Diarrhea • G – GI cramps • E – Emesis

46. Uses for Direct-Acting Cholinergics • Treatment of glaucoma – contricts the pupil thus opening the canal of Schlemm allowing drainage of aqueous humor and decreasing intraocular pressure (Pilocarpine) • To increase urination – Brethanechol chloride (Urecholine) increases tone of the detrusor urinae muscle. • To deter smoking – Nicoderm, Nicorette gum

47. Indirect-acting Cholinergics • Cholinesterase breaks down acetylcholine • A small amount of cholinesterase breaks down a large amount of acetylcholine • A cholinesterase inhibitor binds the cholinesterase allowing acetylcholine to activate the muscarinic and nicotinic cholinergic receptors permitting skeletal muscle stimulation and increasing the force of muscular contraction • Additional effects include increased GI motility, bradycardia, miosis, bronchial constriction, and increased micturition • Use with caution in patients with bradycardia, asthma, peptic ulcers or hyperthyroidism • Contraindicated in patients with intestinal or urinary obstruction

48. Uses for Indirect-acting Cholinergics • Reversible inhibitors • Diagnosing myasthenia gravis – Tensilon (short-acting) • Increasing muscle tone and strength in clients with myasthenia gravis (Neostigmine, pyridostigmine bromide, ambenonium chloride) • To produce pupillary constriction in glaucoma patients • Alzheimer’s disease – Cognex • Muscarinic antagonist poisoning

49. Uses for Indirect-acting Cholinergics • Irreversible inhibitors – cholinesterase has to regenerate before drug effect diminishes (days to weeks) • Pupillary constriction • Manufacture organophosphate insecticides • Pralidoxime (Protopam) is the antidote