1. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. Pharmacology of Drugs Affecting Autonomic Nervous System

2. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. Basic Functions of the Nervous System  Recognizing changes in  Internal environment  External environment  Processing and integrating environmental changes  Reacting to environmental changes by producing an action or response

3. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. Two Major Divisions of the Nervous System  Central Nervous System (CNS)  Brain and spinal cord  Peripheral Nervous System  all nervous tissues outside the CNS, including sensory and motor neurons

4. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. Divisions of human nervous system Human Nervous system Central Nervous System Peripheral Nervous System

5. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. Brain & Spinal Cord Nerves enter or leave CNS Carry massage from CNS to peripheral tissues Carry massage from peripheral tissues to CNS

6. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. Divisions of the Peripheral Nervous System  Somatic nervous system  Voluntary control over skeletal muscles  Autonomic nervous system  Involuntary control over smooth and cardiac muscle and glands

7. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. Basic anatomy of ANS Sympathetic NSParasympathetic NS Enteric NS Two main differences - Origin - Function -Collection of nerve fibers that innervate GIT, pancrease & gall bladder -Called “brain of gut” -They control motility, exocrine & endocrine secretion, as well as microcirculation of gut -Modulated by sympathatic & Parasympathatic systems

8. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. Autonomic Pharmacology  Autonomic Nervous System  This system is divided into two separate systems.  These systems are called the parasympathetic nervous system and the sympathetic nervous system.  These systems often produce opposite effects, but b ranches do not always produce opposite effects.  Homeostasis – proper balance of the two branches achieved by changing one or both branches 2

9. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. Autonomic Nervous System: Sympathetic and Parasympathetic Divisions  Drugs in this group are designed to either enhance or mimic the autonomic nervous system or to block the effects of the neurotransmitters at their receptor sites.

10. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc.

11. Steps of Neurotransmission  Propagation of the nerve impulse in the preganglionic nerve fiber + + + + + + + + + + + - - - - - - - - - - - - - - - + + + + + Polarized Resting Membrane Potential + + + + - - - - + + + - - - - - + + + + - - - - + + + - - - - + + Depolarized Nerve Action Potential

12. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc.

14. Synaptic Transmission  Synapse – junction of neurons  Connection of two neurons outside CNS – ganglionic synapse.

15. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc.

17. Efferent neurons  Preganglionic neurons: Cell body within CNS Cell body within CNS  Ganglia: aggregation of nerve cell bodies located in the peripheral nervous system.  Postganglionic neurons: cell body originate in the ganglia, terminates on effector organ.  Divided into sympathatic and parasympathatic

18. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. Origin Symp. NS Thoracolumbar outflow Parasymp. NS Function Craniosacral outflow Short pre-ganglionic nerve Long post-ganglionic nerve Long pre-ganglionic nerve Short post-ganglionic nerve

19. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. Figure 13.4 Receptors in the autonomic nervous system: (a) sympathetic division; (b) parasympathetic division

20. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc.

21. Role of CNS in autonomic control functions  CNS centers in hypothalamus, medulla oblongata & spinal cord  Reflex arc  Emotions

22. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc.

23. Organs Supplied by ANS  Heart  Smooth Muscles - Eye -Bronchi - GIT - Urinary Bladder - Blood Vessels  Glands - Exocrine Glands: Lacrymal, Salivary, Sweat - Endocrine Glands: Adrenal Medulla  Metabolism  Liver  Adipose Tissue  Kidney

24. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. Sympathetic Nervous System  Sympathetic Nervous System  This nervous system is designed to cope with emergency situations.  This is commonly known as the “fright or flight” response.  Its neurotransmitters are epinephrine and norepinephrine.  Its receptors are the α and β receptors. 4

25. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. Sympathetic nervous system Fight or flight response results in: 1. Increased BP 2. Increased blood flow to brain, heart and skeletal muscles 3. Increased muscle glycogen breakdown for energy 4. Increased rate of coagulation 5. Pupil dilation

26. parasympathatic Nervous System  Parasympathetic Nervous System  This system is concerned with the conservation of the body processes.  Activated under non stressful conditions  Rest-and-digest response  Digestive processes promoted, heart rate and blood pressure decline  Its main neurotransmitter is acetylcholine.  Its receptors are muscarinic, nicotinic. 3

27. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. Figure 13.2 Effects of the sympathetic and parasympathetic nervous systems. Source: Biology Guide to the Natural World, 2 nd ed (p. 558) by David Krogh, 2002 Upper Saddle River, NJ, Prentice Hall. Reprinted by permission.

28. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. Symp. NS Parasymp. NS Single Innervations Dilator pupilae muscle Adrenal Medulla Ventricles BV Sweat Gland Kidney Constrictor pupillae muscle

29. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc.

30. Figure 13.1 Functional divisions of the peripheral nervous system.

31. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. Adrenergic & Antiadrenergic Drugs

32. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. Anatomy of the sympathetic nervous system  The origin is from thoracolumbar segments “all thoracic + lumbers L1, L2, L3 and L4 ”  They have short preganglionic fibers, and it relays in sympathetic chain ganglia & release Ach in these ganglia  They have long postganglionic fibers that innervate their body organs & release Norepinephrine as a neurotransmitter there

33. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. Neurotransmission at adrenergic neurons  Synthesis of norepinephrine (NE)  Storage of dopamine (DA) and NE in vesicles  Release of NE  Metabolism (COMT 20% + MAO 80%)  Binding to receptors  Uptake mechanism

34. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc.

36. Adrenoceptors  The adrenergic receptors are classified into  α1  α2  β1  β2  β3  There are some subtypes

37. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. Adrenergic Receptors α Subtypeβ Subtype ↑ Phospholipase C↓ Adenylate cyclase α1α1α2α2 β1, β2 & β3 ↑ Adenylate cyclase smooth muscles - Presynaptic adrenergic nerve terminal -CNS -β cells of pancreas β1 (heart) β2 (smooth muscles) β 3 (lipocytes) Adrenergic Receptors β Subtype Adrenergic Receptors α Subtype Adrenergic Receptors

38. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. Alpha1-adrenergic Receptors  In all sympathetic target organs except heart  Response  Constriction of blood vessels  Dilation of pupils

39. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. Alpha2-adrenergic Receptors  At presynaptic adrenergic neuron terminals  Activation inhibits release of norepinephrine

40. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. Beta1-adrenergic Receptors  In heart and kidneys  Response  Activation increases heart rate and force of contraction of heart.  Increases release of renin

41. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. Beta2-adrenergic Receptors  In all sympathetic target organs except the heart  Inhibit smooth muscle

42. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc.

44. OrganSympatheticRParasympatheticR HeartStimulantβ1β1Depressant of atriaM2 Smooth Muscles a- BVConstriction Dilation (BV Sk. M.) Kidney Vasculature αβ2Dαβ2D No innervation (dilation by EDRF) M3 b- BronchiNo innervationβ2β2Constriction ↑ Secretion M3 c- GIT Smooth muscle Sphincter Glands ↓ motility Constriction ----- β2α1β2α1 ↑ motility Dilation ↑ Secretion ↑Gastric acid Enteric system M3 M1 d- Urinary Bladder Smooth muscle Sphincter Relaxation Constriction β2α1β2α1 Contraction Dilation M3

45. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. OrganSympatheticRParasympatheticR e- Eye: * Iris -Radial muscle -Circular muscle *Ciliary Muscle Contraction Relaxation (slight) α1β2α1β2 Constriction Contraction M3 Glands: Salivary Glands Lacrimal Glands Sweat Glands: Thermoregulatory Apocrine (stress) ↑ Secretion No effect ↑ Secretion α1, β2 -------- M3 α1 ↑ Secretion M3 Metabolic Functions: Liver Adipose tissue Kidney Gluconeogenesis Glycogenolysis Lipolysis Renin release β2β2β3β1β2β2β3β1

46. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. α 1 – Adrenoceptors

47. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. α 1 – adrenoceptors (continue) Site of α 1 – adrenoceptors & the effects of their stimulation α 1 – adrenoceptors (continue) Site of α 1 – adrenoceptors & the effects of their stimulation  In vascular smooth muscle.  α 1 stimulation cause vasoconstriction (VC) : Vasoconstriction in the skin & viscera cause increase total vascular resistance (TVR) causing increase blood pressure (BP) Vasoconstriction in the skin & viscera cause increase total vascular resistance (TVR) causing increase blood pressure (BP)  α1 – adrenoceptors the most determine of arteriolar tone. When their stimulated no others receptors have an affects on BP. So, hypertension may be treated by blocking α1 Vasoconstriction in the nasal blood vessels cause relief of congestion Vasoconstriction in the nasal blood vessels cause relief of congestion  In the radial muscle of iris.  α1 stimulation causes contraction of the radial muscle causing mydriasis (dilation of the pupil)

48. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. Continue….  In the smooth muscle of the sphincters of GIT.  α1 stimulation cause contraction of all sphincters  In the smooth muscle of internal sphincter of urinary bladder (Very important). α 1a subtypes stimulation cause contraction and closure of the sphincters (precipitate urinary retention)  In the seminal vesicles. α stimulation cause ejaculation. Thus, all α blockers inhibit ejaculation  In the liver.  α1 stimulation causes increase glycogenolysis & gluconeogenesis

49. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. Adrenoceptors α 1 – adrenoceptors Drugs effects :  α 1 selective agonist  E.g. Phenyl ephrine Phenyl ephrine  α1 selective antagonists  E.g. Prazosin Prazosin Terazosin Terazosin Doxazosin Doxazosin Tamsolusin ( α1 a ) (has a different clinical use) Tamsolusin ( α1 a ) (has a different clinical use)

50. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. α 2 –adrenoceptors Site of α 2 – adrenoceptors & the effects of their stimulation  In adrenergic nerve terminals (presynaptic).  α 2 stimulation cause decreased Norepinephrine release (autoregulatory mechanism). It opposes the action of sympathetic stimulation.  In pancreas.  causes decreased insulin release  In platelets.  Increase platelets aggregation via c-AMP

51. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc.

52. Continue  In ciliary epithelium.  Increase the out flow of aqueous humor.(good for glaucoma)

53. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. α 2 – adrenoceptors (Continue) Drugs effects :  α 2 selective agonists  E.g. Clonidine Clonidine Methyldopa (Antihypertensive) Methyldopa (Antihypertensive) Apraclonidine (topical for eye) Apraclonidine (topical for eye)  α 2 selective antagonists  E.g. Yohimbine; Mertazapine (Antidepressant) Yohimbine; Mertazapine (Antidepressant)

54. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. β 1 – adrenoceptors  In the heart. β 1 stimulation causes  In S.A node : increase heart rate (HR) (+ve chronotropic)  In Myocardium tissue : increase contractility (+ve inotropic)  In Conducting system : increase conduction velocity (+ve dromotropic)  Increase ectopic beats  In the Juxtaglomerular Apparatus of the kidney. β 1 stimulation cause increased renin release. Then causes increase in BP

55. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. Adrenoceptors β 1 – adrenoceptor Drugs affecting them  β 1 selective agonists  E.g. Dobutamine Dobutamine  β 1 selective antagonists  E.g. Atenolol Atenolol Esmolol Esmolol Metoprolol Metoprolol

56. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. β 2 – adrenoceptors  In the bronchial smooth muscle β 2 stimulation causes relaxation of smooth muscle (bronchodilatation)  In the smooth muscle of blood vessels supplying the skeletal muscle. β 2 stimulation causes relaxation of smooth muscle  Vasodilatation(VD)  This VD effects is usually masked by the potent VC effect of α1 – receptors

57. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. Continue  In the smooth muscle of GIT wall.  β 2 stimulation cause relaxation of the wall leading to decreased peristalsis  In the smooth muscle of the wall of urinary bladder.  β 2 stimulation causes relaxation of the wall  Note: Adrenergic stimulation is opposite to the cholinergic in the wall and sphincters in GIT and genitourinary tract.

58. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. Continue  In the smooth muscle of the uterus  β 2 stimulation causes relaxation of the uterus (Ritodrine delay the labor)  In the liver.  β 2 stimulation causes increased Glycogenolysis & Gluconeogenesis  Effect on potassium.  β 2 stimulation increase potassium influx.

59. Mosby items and derived items © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. Continue….  In ciliary muscle.  β 2 stimulation causes relaxation of the ciliary muscle leading to Accommodation for far vision Accommodation for far vision Decrease outflow of aqueous humor via the canal of Schlemm Decrease outflow of aqueous humor via the canal of Schlemm  In the ciliary epithelium  β 2 stimulation causes increased production of aqueous humor