Autonomic Nervous System

1. Autonomic Nervous System Introduction

2. The nervous system is divided into: 1- The central nervous system (CNS; the brain and spinal cord) 2- The peripheral nervous system (PNS; neuronal tissues outside the CNS). The motor (efferent) portion of CNS is divided to: Autonomic(ANS) and Somatic. ANS is independent (autonomous), its activities are not under direct conscious control.

3. It is modulated by the symp. & parasymp systems.

4. ANS Neurons 4

5. Anatomy of ANS. 5

6. Parasympathetic cell bodies in brainstem and sacral spinal cord: craniosacral outflow. Parasympathetic Division: postganglionic neurons are short (ganglia located near effectors), stimulation involves only one visceral effector (organ) Sympathetic cell bodies located T1-L2 levels: thoracolumbar outflow. One sympathetic preganglionic neuron may have many branches and may synapse with 20+ postganglionic neurons. Projection of divergence explains why sympathetic responses can affect many effectors at once

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8. Sympathetic and parasympathetic systems have antagonistic effects

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10. Norepinephrine synthesis

12. Storage: NE is stored in vesicles bound to cAMP (4:1) + protein Release: 1- Calcium dependent exocytosis. NE + cAMP + protein + Dopamine-β- hydroxylaes are released.

13. 2-Calcium independent release. Tyramine, amphetamine are transported by NET (NE Transporter) into the neuron then transported by VMAT into the vesicles. They displaces NE from the vesicular stores, into the cytoplasm. Ne is transported into the synaptic cleft by reverse transport via NET. They produce an indirect sympathomimetic effect

14. NE effects are not terminated by metabolism, but by neuronal reuptake (uptake1). 80 % of the released NE are transported into the neuron by MAT (Mono amine Transporter). 2 enzymes metabolize NE & EP: MAO: monoamine oxidase COMT: Catechol o methyl transferase VMA is the end product of metabolism, measured in urine for the diagnosis of pheochromocytoma. Metabolism of Catecholamines:

15. Cholinoceptors Muscarinic M1: CNS neurons, sympathetic postganglionic neurons, some presynaptic sites. Muscarinic M2:   Myocardium, smooth muscle, some presynaptic sites; CNS Muscarinic M3: Exocrine glands, vessels (smooth muscle and endothelium); CNS Muscarinic M4 and M5 : mainly in CNS Nicotinic NN: Postganglionic neurons, some presynaptic cholinergic terminals.Nicotinic NM: Skeletal muscle neuromuscular end plates.

16. Adrenoceptors Alpha1 (α)1 Postsynaptic.increase intracellular Ca producing smooth muscle contraction. Alpha2(α)Presynaptic adrenergic nerve terminals, Inhibits NE release.

17. Beta1 (β1) Heart, lipocytes, brain, juxtaglomerular apparatus of renal tubules. Stimulation of adenylyl cyclase, increased cAMP Beta2 (β2)smooth muscle &cardiac muscle. Stimulation of adenylyl cyclase and increased cAMP. Beta3 (β3)lipocytes; Stimulation of adenylyl cyclase & increased cAMP

18. Dopamine receptors D1  Brain, especially smooth muscle of the renal vascular bed. Stimulation of adenylyl cyclase and increased cAMP  D2  Brain, especially smooth muscle; presynaptic nerve terminals. Inhibition of adenylyl cyclase; increased potassium conductance.

19. Dual innervations of most organs by Sym & Parasym sytems. Sympathetic tone and parasympathetic tone. Baro receptor reflex.

20. Direct Effects of Autonomic Nerve Activity Organ Sympathetic Activity Parasympathetic Eye, Iris. radial muscle Contracts  (α1) mydriasis. circular muscle. M3 Contractsmiosis Ciliary muscle Contracts M3. near vision.   Heart  Sinoatrial node Accelerates β1 Decelerates M2 Ectopic pacemakers Accelerates β1  Contractility Increases β1 Decreases (atria) M2 Blood vessels   Skin, splanchnic vessels Contracts α1   Skeletal muscle vessels Relaxes β2   Endothelium (drug effect) Releases EDRF (NO) M3, M5 5

21. Bronchiolar smooth muscle  Relaxes β2 Contracts M3 Gastrointestinal tract  Smooth muscle Walls Relaxes β2, α2 Contracts M3     Sphincters Contracts α1 Relaxes M3   Secretion Increases M3 Genitourinary smooth muscle  Bladder wall Relaxes β2 Contracts M3 Sphincter Contracts α1 Relaxes M3  Uterus, pregnant Relaxes β2 Contracts α Contracts M3   Penis, seminal vesicles Ejaculation α Erection M Skin   Pilomotor smooth muscle Contracts α   Sweat glands Increase M Metabolic functions   Liver Glycogenolysis, β2 α Glyconeogenolysis β2 α   Fat cells Lipolysis β3  Kidney Renin release β1

22. 22 Parasympathomimetic (cholinergic) Drugs Acetylcholine is the neurotransmitter in the parasympathetic (cholinergic) portion of the autonomic nervous system. Cholinergic drugs divided to 2 classes: 1- Directly acting drugs that mimic the action of acetylcholine. 2- Indirectly acting drugs that increase the concentration of acetylcholine by inhibiting acetylcholinestrase.

23. Effects: 1- GIT: - Enhance secretion by gastric & other glands & this may cause: Belching, heartburn, nausea & vomiting. 2- Increase smooth muscle tone & bowel movement. 3. Stimulation of ureter & relaxation of urinary bladder resulting in micturation . 4. Cardiac muscle: - Slowing heart rate (Bradycardia). - Decrease atrial contractility & conductivity. 5. Blood vessels: Vasodilation skin temperature & local flushing. 6. Respiration: Mucus secretion & bronchial constriction wheezing. coughing, shocking. 7. Eyes: Pupillary constriction (miosis), lower intraocular pressure. 8. Skin: activation of sweat & salivary glands. 23

24. The major groups of cholinoceptor-activating drugs, receptors, and target tissues.

25. Cholinergic Agonists or Parasympathomimetcs, cont… A - Directly acting 1- Choline Esters: Acetylcholine: Naturally released from the cholinergic nerve endings, is very short acting because of rapid hydrolysis by acetylcholine esterase enzyme. Used only in experimentation. Methacholine. Carbachol Bethanechol : Synthetic, long acting. Used in postoperative atony. Cause flushing, sweating, colic.

26. Cholinergic Agonists or Parasympathomimetcs, cont 2- Alkaloids: Muscarine: obtained from the poisonous mushroom amanita mascara. Nicotine: obtained from Tobacco plant Pilocarpine: obtained frompilocarpus plant used to treat glaucoma

27. B - Indirectly acting drugs: Cholinesterase Inhibitors or Anticholinesterases Prevent breakdown of ACh by cholinestearse. Reversible: Neostigmine: Uses: Myasthenia and postoperative atony of the bladder. Pyridostigmine slower onset, longer duration & fewer side effects than Edrophonium very short acting cholinesterase inhinitor Physostigmine Natural alkaloid, more toxic and short duration used to treat glaucoma.

28. Irreversible: Organophosphate Very potent agricultural insecticides and lethal war weapons. Very easily absorbed through all parts of the skin. Inhibit the enzyme and cause accumulation of ACh at all sites. Parathion, Malathion Used as potent insecticides Tabun, Sarin, Soman: Used as war or nerve gases.

29. Parasympatholytics, Cholinergic Blockers A- Ganglion-Blocking Drugs Block nicotinic receptors in autonomic ganglia (Nn). Hexamethonium Trimethaphan A short-acting ganglion blocker, is inactive orally Occasionally used in the treatment of hypertensive emergencies and is given by IV infusion. B- Neuromuscular blockers (Nm) 1- Depolarizing blockers, e.g. Succinylcholine. 2- Non depolarizing blockers, e.g. Curare. Used to produce muscle relaxation during operations. 29

30. C- Muscarinic blockers, e.g. Atropine The main effects: 1- Reduce spasm of smooth muscle such as spasm of the urinary bladder or intestines. 2- block vagal impulses to the heart which will increase heart rate & conductivity. 3- decrease gastric secretions, sweating, salivation and secretion of bronchial mucus. 4- relax the sphincter muscles of the iris & cause pupillary dilation (mydriasis) & loss of accommodation for near vision. 5- Act on CNS producing depression (scoplamine) or stimulation (toxic dose of atropine). 30

31. Clinical Uses: Smooth muscle spasm. Eye examination. Preoperative medication. Organophosphate poisoning Side effects: dry mouth, constipation, heartburn, dizziness, drowsiness, headache, insomnia, blurring of vision, photophobia, euphoria, hallucination flushing of the skin. Antidote for atropine poisoning is physostigmine

32. Atropine –like Drugs Hyoscine (Scopolamine): Also natural product. Similar peripheral effects. CNS depressant leading to drowsiness and sleep. Used for motion sickness Propantheline synthetic. Was used in peptic ulcer disease. Still used for irrtiable bowel syndrome (combined with anxiolytic). Also used for irritable bladders.

33. Adrenoceptor Agonists & Sympathomimetic Drugs

34. Organ System Effects of Sympathomimetics. Cardiovascular System. The net effect of a Sympathomimetic drugdepends on: its relative selectivity for α or β adrenoceptors the compensatory baroreflex mechanisms aimed at restoring homeostasis.

35. Effects of Alpha1-Receptor Activation A pureα agonist such as phenylephrine causes: arterial and venoconstriction, increases peripheral arterial resistance leading to a rise in blood pressure (BP) The rise in BP elicits a baroreceptor - mediated increase in vagal tone with slowing of the heart rate.

36. The skin vessels & the splanchnic vessels constriction (alpha receptors ). Vessels in skeletal muscle may constrict or dilate depending on whether alpha or beta 2 receptors are activated. The blood vessels of the nasal mucosa have alpha receptors, and local vasoconstriction induced by sympathomimetics produces a decongestantaction.

37. Effects of Alpha2-Receptor Activation When given systemically, the central effects of α 2 receptors leads to inhibition of sympathetic tone and a decrease in BP. Hence, α 2 agonists are used in the treatment of hypertension .

38. Effects of Beta-Receptor Activation Stimulation of β receptors in the heart increases cardiac output by stimulating contractility and by increasing the heart rate. Beta agonists also decrease peripheral resistance by activating β 2 receptors, leading to vasodilation in certain vascular beds (in sk muscles).

39. Effects of Dopamine-Receptor Activation At LOW DOSES (1-2 ug /kg/min) DA IV promotes vasodilation of renal, splanchnic, coronary, and cerebral vessels, via activation of D1 receptors & also induce natriuresis. DA is used to improve perfusion to the kidney in oliguria (abnormally low urinary output).

40. Noncardiac Effects of Sympathomimetics -Activation of β 2 receptors leads to bronchodilation, -In the eye,α receptors activation causes mydriasis. -alpha receptors in bladder base, urethral sphincter, and prostate mediate contraction & control urination. -Alpha-receptor in the ductus deferens, seminal vesicles, & prostate plays a role in normal ejaculation. -Renin secretion is stimulated by β 1& inhibited by α 2 receptors.

41. CNS CA are almost completely excluded by BBB. Peripheral effects of β agonists. e.g. tachycardia and tremor are similar to the manifestations of anxiety. Noncatecholamines with indirect actions, such as amphetamines stimulate CNS. Metabolism. β 3 receptors in fat cells increases lipolysis & release of free fatty acids & glycerol into the blood. Activation of β receptors enhance glycogenolysisinthe liver, increasing glucose release into the blood.

42. Specific Sympathomimetic Drugs Endogenous Catecholamines Epinephrine(adrenaline) Epinephrine stimulates both αandβ receptors. it is a very potent vasoconstrictor and cardiac stimulant. It increases HR and ventricular contractilityl eading to increasing cardiac output and systolic BP.The rise in diastolic pressure results from stimulation of α1 receptor mediated vasoconstriction .

43. Activation of β 2 receptors in skeletal muscle increases blood flow during exercise. β2 stimulation will cause bronchodilation in the lung and activate glycogenolysis in the liver Uses: used in the emergency management of complete heart block and cardiac arrest. to prolongs the duration of local anesthesia Treatement of anaphylactic sgock and alergic reactions.

44. Norepinephrine (noradrenaline) Agonist at α1,α 2 and β 1 receptors but has little effect on β 2 receptors. Itincreases peripheral resistance and both diastolic and systolic blood pressure. Compensatory baroreflex activation causes a decrease in HR nut the positive inotropic effects on the heart are maintained. Used to raise the blood pressure in surgical operations.

45. Dopamine is the immediate precursor of norepinephrine have important effects in regulating sodium excretion and renal function. Its deficiency in the basal ganglia leads to Parkinson's disease, which is treated with its precursor levodopa. Dopamine antagonists are antipsychotic drugs.

46. Dopamine At LOW DOSES activates D1 receptors in vascular beds (e.g. kidney) resulting in vasodilation & increase renal blood flow (used in the treatment of shock). At INTERMEDIATE DOSES dopamine activates β1 receptors in the heart. At HIGH DOSES dopamine activates alpha receptors leading to vasoconstriction, including the renal vascular bed.  Used to treat Cardiogenic shock and acute heart failure (IV infusion).

47. Direct-Acting Sympathomimetics Phenylephrine A relatively pure α 1 agonist. has a longer duration of action than the catecholamines. Effective mydriatic and decongestant and can be used to raise the blood pressure. Methoxamine A direct-acting α 1 receptor agonist. Causes a prolonged increase in BP due to vasoconstriction & a vagally mediated bradycardia. Clinical uses are rare and limited to hypotensive states.

48. Clonidine Stimulates α2A adrenoceptors in CNS causing a decrease in BP and cardiac output and bradycardia. It also causes sedation. Uses: ADHD in children, opioid withdrawal, restless legs, hypertension, alcohol withdrawal Low dose of Clonidine is used in migraine prophylaxis, menopausal flushing and chorea Abrupt withdrawal causes rebound hypertension Side effects: Sedation, dry mouth, dizziness and constipation

49. Methyldopa Metabolized to α-methyl norepinephrine, which activats α2 receptors in the brainstem which reduce sympathetic outflow, lowering BP. Used for treatment of hypertension during pregnancy Guanfacine Centrally acting α 2-selective agonist. used in the treatment of hypertension

50. Isoproterenol (isoprenaline) Very potentβ -receptor agonist and has little effect on α receptors. it is a potent vasodilator and bronchodilator. causes marked increases in HR & cardiac output and a fall in diastolic and mean arterial Pressure. Used to treat heart block