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. .

41. Cholinoceptive Sites: Receptor Subtypes • Muscarinic: M 1 (nerves) M 2 (cardiovascular) M 3 (glandular) all blocked by atropine • Nicotinic: NM (skeletal muscle) blocked by curare NN (nerves) blocked by hexamethonium

43. SITES OF DOMINANCE IN THE ANS Adapted from Goodman and Gilman’s The Pharmacological Basis of Therapeutics 1The vast majority of blood vessels do not receive parasympathetic innervation

44. Table 2. Muscarinic and nicotinic effects of ACH (and direct-acting M receptor

45. Cholinoceptor Activating DrugsCholinergic Agonists

46. Cholinoceptor activating drugs: • DEFINITION: Drugs that produce effects similar to those observed during the stimulation of postganglionic parasympathetic fibers, i.e., drugs which exert their effects largely via stimulation of peripheral muscarinic receptors. • Called cholinergic agonists; muscarinic agonists, parasympathomimetics

47. 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

48. Cholinomimetics (cholinergics) Direct-acting Indirect-acting Muscarinic Nicotinic Organophosphates (very long-acting) Choline esters Alkaloids Carbamates (intermediate, long-acting) parasympatimimetics Edrophonium (short-acting)

49. ACETYLCHOLINE AND ITS METABOLITES Acetylcholine Choline Acetate

50. Actions of acetylcholine: Considerations • Rapid hydrolysis in plasma by cholinesterase • Penetration to nicotinic sites is poor • Does not penetrate the CNS