55 yr old male k

1. 55 yr old male k/c/o Multiple System Atrophy with Neurogenic Orthostatic Hypotension had supine hypertension Treated with an anti-hypertensive Developed erectile failure Depressed ! ! !

2. Went to a doctor � Prescribed a tricyclic antidepressant Patient was still depressed Over the counter � took a aphrodisiac Developed severe headache BP : 220 / 140 mm Hg And DIED �.

3. WHY ? Possibly due to harmful interaction b/w aphrodisiac and drugs used to treat autonomic failure syndrome Tricyclics block neuronal reuptake of norepinephrine Aphrodisiac ( yohimbine ) releases norepinephrine from sympathetic nerves This combination increases norepinephrine delivery to its receptors � In the setting of baroreflex failure, the NE-induced increase in BP is unopposed and lethal .

4. Autonomic Nervous System Basic Anatomy & Physiology

5. Introduction The critical component of central network involved in homeostasis & adaptation 3 subdivisions : Sympathetic Nervous System Parasympathetic Nervous System Enteric Nervous System

6. Peripheral Autonomic Network Central Autonomic Network

7. Peripheral Autonomic Network

8. Anatomical & Functional Organization Sympathetic & Parasympathetic efferent pathways � carry signals from brain to periphery. Consisting of 2 neurons Pre ganglionic neuron Autonomic ganglion that innervates target organ

9. Pre ganglionic neurons send myelinated axons to peripheral autonomic ganglia and to enteric nervous system. Neurons of the sympathetic or parasympathetic ganglia send unmyelinated axons ( post ganglionic axons ) that innervate heart, smooth muscle and exocrine glands. Peripheral parasympathetic ganglia are located close to target organs and send short axons to innervate these visceral effectors.

11. Sympathetic System Sympathetic preganglionic neurons are primarly located in intermediolateral nucleus at the T1 to L2 levels of spinal cord Distribution of preganglionic fibers does not follow dermatomal pattern of somatic nerves.

13. Preganglionic sympathetic axons exit through ventral roots and pass via white rami communicantes on corresponding spinal nerve to reach the paravertebral sympathetic chain Majority of them run rostrally or caudally along the sympathetic chain and synapse on large paravertebral ganglia. Remaining fibers pass through paravertebral chain without synapsing and form splanchnic nerves that innervate prevertebral ganglia & adrenal glands

14. Paravertebral sympathetic ganglia � primary relay stations for preganglionic inputs They innervate all tissues and organs except those in abdomen, pelvis and perineum Eg : superior cervical ganglion stellate ganglion prevertebral ganglion

15. Superior Cervical Ganglion Sends postganglionic axons that follow branches of carotid arteries Innervate eye, facial sweat glands, salivary glands, blood vessels of face & brain, pineal gland, thyroid and parathyroid glands Elicit pupil dilatation contraction of muller muscle facial sweating vasoconstriction-facial & cerebral circulation complex effects on salivary & lacrimal secretion

17. Stellate Ganglion Recieves preganglionic inputs from T2 � T6 segments It sends postganglionic axons that join peripheral nerve via gray rami communicantes & follow the distribution of corresponding somatic nerve to innervate blood vessels and sweat glands in upper limbs & trunk Elicit vasoconstriction / vasodilatation in skin and muscle, sweating, piloerection

18. Stellate Ganglion Stellate ganglion together with other cervical ganglion & thoracic ganglia provides input to esophageal plexus, pulmonary plexus, cardiac plexus. Elicit cardiac acceleration bronchodilatation

20. Prevertebral Ganglia Located anterior to abdominal aorta close to origin of celiac & mesenteric arteries Innervate all abdominal, pelvic & perineal organs Preganglionic input from spinal seg T5 � L2 are carried by splanchnic nerves to celiac and superior mesenteric ganglia Provide postganglionic fibers to celiac plexus that innervates all abdominal viscera except descending colon and rectum Outputs � vasoconstriction , inhibition of GI MOTILITY

21. Preganglionic axons from spinal seg L1 � L2 travel in lumbar splanchnic nerves Synapse in inferior mesenteric ganglion Provide axons to hypogastric plexus innervating descending colon, rectum, bladder & sexual organs Elicit vasoconstriction smooth muscle relaxation constriction of internal sphincters of bladder and rectum ejaculation

22. The prevertebral sympathetic ganglia integrate preganglionic with afferent inputs from dorsal root and enteric nervous system And they innervate the viscera and blood vessels of the abdomen and pelvis .

23. Parasympathetic System Parasympathetic outputs arise from preganglionic neurons located in nuclei of the brain stem & sacral spinal cord Preganglionic parasympathetic axons travel a long distance before eventually reaching their target ganglia which are located close to or even within the target end organs

24. Cranial preganglionic parasympathetic nuceli project via CN III, VII, IX, X Westphal nucleus is a part of occulomotor complex in midbrain � sends preganglionic axons that occupy peripheral portion of the occulomotor nerve and synapse on the neurons of ciliary ganglion in the orbit These neurons innervate iris and ciliary muscles Eliciting pupil constriction accomodation of eye

25. Superior salivatory nucleus � In pons projects via facial nerve to sphenopalatine ganglion, which innervates - lacrimal gland ( lacrimation ) cerebral blood vessels ( vasodilatation ) to submandibular ganglion � secretomotor & vasodilator inputs to corresponding salivary glands

26. Inferior salivatory nucleus � In medulla Sends axons via glossopharyngeal nerve Synapse on Otic ganglion Stimulate parotid gland secretion

27. Most preganglionic parasympathetic output from brain stem is mediated by Vagus nerve Vagus innervates heart, respiratory tract and entire gastrointestinal tract except descending colon and rectum Most vagal preganglionic neurons � situated in dorsal motor nucleus of vagus provides input to git and respiratory tracts , heart Vagal preganglionic output to heart - Neurons in ventrolateral portion of nucleus ambiguus Vagus � cardioinhibitory, visceromotor and secretomotor effects

29. Sacral preganglionic output � Arises from neurons of sacral preganglionic nucleus located in lateral gray matter of spinal segments S2 & S3 Their axons pass via ventral roots of pelvic splanchnic nerves which join inferior hypogastric plexus Innervate colon, bladder, sexual organs Parasympathetic output � contraction of bladder detrussor muscle & circular smooth muscle of rectum.

30. Sacral parasympathetic output elicits Vasodilatation of cavernous tissue of penis required for penile erection , whereas sympathetic output controls ejaculation

31. Enteric Nervous System Consists of sensory neurons, interneurons and motor neurons located in the myenteric and the submucosal plexus within the walls of the gut They form local reflex circuits that mediate motility, secretion and blood flow throughout gut Also the inputs from vagus and prevertebral ganglia modulate it .

32. Visceral Afferents Inform CNS about Mechanical & Chemical events in internal organs This information is conveyed to produce conscious visceral sensation and initiate visceral reflex responses Spinal visceral afferents innervate all peripheral organs Their cell bodies are in dorsal root ganglion

33. Brain stem visceral afferents are carried primarily by glossopharyngeal and vagus nerves Cell bodies in petrosal & nodose ganglia All brain stem visceral afferent nerves relay in nucleus of solitary tract ( NTS ) NTS is a major site of information integration of many bodily functions

34. Rostral portion of NTS � receives taste afferents via facial nerve( geniculate ganglion ) , glossopharyngeal & vagus nerves Intermediate portion � receives gastrointestinal afferents Caudal portion of the NTS recieves afferent information from baroreceptors, cardioreceptors, chemoreceptors and pulmonary receptors

35. Neurochemical Transmission Cholinergic Transmission Adrenergic Transmission

36. Cholinergic Transmission Ach - neurotransmitter in all pre-ganglionic neurons, parasympathetic ganglion neurons, sympathetic neurons innervating sweat glands, most enteric nervous system neurons Effects of Ach are mediated by Nicotinic and Muscarnic Receptors

37. Adrenergic Transmission With exception of the sweat glands , Norepinephrine is the primary neurotransmitter in sympathetic ganglionic neurons Epinephrine is released from chromaffin cells of adrenal medulla and acts as a circulating hormone Norepinephrine & Epinephrine act via Alpha1, Alpha2, Beta receptors Smooth muscle contraction � Alpha1 receptors Stimulation of heart � Beta1 receptors Smooth muscle relaxation � Beta2 receptors Lipolysis in brown fat � Beta3 receptors

38. Denervation Supersensitivity In response to loss of innervation by postganglionic sympathetic or parasympathetic axons � there is increased responsiveness of visceral target organ to neurotransmitter or agonist that stimulates adrenergic / muscarnic receptors. Leads to exagerrated pressor responses to adrenergic agonists. Indicates a postganglionic lesion

39. Lets see a case ?

40. A 65 yr old male h/o Diabetes mellitus admitted for severe headache On ex : Pulse : 90 / min BP 180/100 mm Hg patient had no h/o HTN , but had respiratory infection and took decongestant � pseudoephedrine 1 hour prior to development of symptoms

41. This a case of�. Diabetic autonomic neuropathy with denervation supersensitivity !!! Affecting adrenergic vasomotor fibers � which leads to up-regulation of vascular Alpha1 -adrenergic receptors Here even a minimal blood levels of alpha1 agonist ( pseudoephedrine) lead to exagerrated pressor responses.

42. Other Peripheral Autonomic Neurotransmitters ATP Nitric oxide Neuropeptide Y Substance P Calcitonin gene related peptide

43. Physiology

44. Sympathetic Outflow Sympathetic preganglionic neurons � organized into different functional units which control specific targets � Muscle vasomotor Splanchnic vasomotor Skin vasoconstrictor Skin vasodilator Cardiomotor Visceromotor preganglionic neurons

45. Sympathetically induced vasoconstriction of skeletal muscle and splanchnic vessels is critical to avoid orthostatic hypotension ( alpha 1 ) Sympathetic outflow to skin blood vessels and sweat glands is critical for thermoregulation � exposure to cold � skin vasoconstriction piloerection ( alpha 1 ) exposure to heat � sweating skin vasodilatation ( M3 )

46. Parasympathetic Outflow Main brain stem parasympathetic outflow is mediated by vagus nerve Has cardioinhibitory effect ( M2) It is critical for beat to beat control of heart rate Constriction of bronchial smooth muscle Stimulate bronchial gland secretion Normal motility of oesophagus and stomach (M3) Facilitatory role in intestinal motility

47. Sacral parasympathetic is critical for micturition ( M3 ) defecation ( M3 ) penile erection ( NO ) Nociceptive & Visceral afferents � substance P, tachykinin A, CGRP

48. Enteric Nervous System Includes several types of sensory neurons, interneurons, motor neurons � which form integrative local reflex circuits Controlling motility, secretion, blood flow throughout the gut The activity of enteric nervous system is largely independent of extrinsic innervation but is modulated by both vagal inputs from dorsal vagal nucleus and sympathetic inputs from prevertebral ganglia

51. Another Case :

52. 55 yr old male k/c/o insulin dependent diabetes mellitus c/o light headedness upon standing particularly early morning and after eating h/o nausea after eating + h/o constipation , erectile dysfunction + On ex : Pupils fail to dilate in dim light Weakness of foot dorsiflexors Absent ankle jerks Loss of all sensation modalities below mid calf Postural hypotension +

53. Autonomic lab tests : impaired sudomotor axon reflex response reduced variation of heart rate to deep breathing reduced valsalva ratio orthostatic hypotension gi motility � delayed gastric emptying usg post void urine � 250 cc

54. A CASE OF DIABETIC AUTONOMIC NEUROPATHY Sympathetic failure � orthostatic hypotension impaired sweating abnormal BP during valsalva Vagal impairment � delayed gasstric emptying constipation reduced variability of hr urinary retention erectile dysfunction

55. Central Autonomic Network

56. Components Telencephalic structures � insular cortex ant cingulate cortex amygdala - integration of bodily sensation, emotion, decision making - anterior cingulate cortex � motivation, goal directed behavior - amygdala � conditioned fear responses

57. Hypothalamus � central role in integrating autonomic and endocrine responses Hypothalmus � critical role in adaptation to internal / external stimuli, while maintaining homeostasis 3 zones Paraventricular zone � neuroendocrine control via connections to pituitary Medial zone � thermoregulation, osmoregulation, food intake, response to stress Lateral zone � arousal behaviour, sleep wake cycle

58. Brain Stem Components � Periaqueductal gray � integration of autonomic, somatic and antinociceptive responses to external stress. coordinates cardiovascular, respiratory, thermoregulatory, urinary, reproductive and pain control systems Parabrachial nucleus � taste, salivation, gi activity, cardiorespiratory activity, thermoregulation NTS � 1st relay center for taste and visceral afferent information carried in CN VII,IX,X And also for all medullary, cvs, rs, gi reflexes

59. Autonomic dysreflexia Interruption of descending inputs to preganglionic sympathetic neurons by lesions above T5 level may lead to unpatterned excessive sympathoexcitation in response to visceral / somatic stimuli Eg : severe hypertension in response to bladder distention or other peripheral inputs

60. Baroreceptor reflex Powerful moment to moment negative feedback loop that regulates arterial blood pressure . It minimizes fluctuations in arterial pressure during standing, exercise or emotion

61. RISE IN BP DISTENSION OF BLOOD VESSEL MECHANOSENSITIVE BARORECEPTORS SITTING IN WALLS OF CAROTID SINUS AND AORTIC ARCH Afferent information travels from carotid baroreceptors in glossopharyngeal n aortic arch baroreceptors in vagus To NTS 3 BARORECEPTIVE PATHWAYS FROM NTS

62. 1. Projections to cardiac vagal neurons - HR 2. Neurons in VLM � inhibit sympathetic outflow to decrease peripheral vasomotor tone 3. Ascending projections to Supraoptic and Paraventricular nuclei to inhibit vasopressin release. THE COMBINATION OF BRADYCARDIA & PERIPHERAL VASODILATATION RESTORES BLOOD PRESSURE