Poma Autonomic Nervous System

Functional and Clinical Role of ANS

 Three division of autonomic system:
- sympathetic: originates from the thoracolumbar (T1-L3 nerves) segments and the lateral horn. Postganglionic neurons located in sympathetic ganglia
- parasympathetic: arise from craniosacral portion of the spinal cord (III, VII, IX and X cranial nerves and S2-S4 spinal segments). Ganglion are within target organs
- Enteric: intrinsic nervous system of the gastrointestinal tract. Uses multiple neurotransmitter and anatomically arranged as myenteric and submucosal plexus. The enteric system co-ordinates intestinal motility stimulated by the food bolus and secretion of digestive enzyme.
 Basal activity: sympathetic and parasympathetic are continuously operating and conducting action potential in the pre and postganglionic nerves, e.g. sympathetic innervating blood vessels (vasomotor tone regulated by the RVL nucleus in the medulla oblongata) or parasympathetic innervating gut.
 Autonomic reflexes: visceral afferent information is normally processed via the nucleus of the solitary tract and other parts of the central autonomic circuit affect autonomic, hormonal and behavioral activity
 Baroreceptor reflex:
- carotid and aortic baroreceptors sense fluctuation in BP and sends afferent signals to the NTS
- NTS acts as an inhibitor of RVL and stimulator of nucleus ambuguus (vagus nerve). Drop in BP lowers NTS activity and enhance sympathetic stimulation to increase HR, SV and TPR to restore BP.
- RVL neurons project to spinal cord and modulate vasomotor sympathetic activity by continuous excitation of preganglionc neuron.
 Chemoreceptor reflex:
- carotid and aortic bodies innervated by the IX and X cranial nerve detects O2, CO2 and pH levels in blood (stimulated by hypoxia)
- reflex effect to increase ventilation and sympathetic vasoconstrictor activity is mediated (i.e. increase BP and decrease HR)
 Diving reflex: oxygen conserving response stimulated by the afferent fibres of the 5th cranial nerve when water covers the face.
- characterized by apnea (breath holding, bradycardia (slowing of heart due to reflex increase in efferent activity of vagus nerve), peripheral vasoconstriction, and rise of blood pressure
- Blood is directed to heart and brain
 Supraventricular tachycardia: abnormally rapid beating of the heart due to excessive SA activity in the right atrium. Consequently there is insufficient time for ventricular filling/perfusion and leads to lowered cardiac output, BP and myocardial ichaemia. Administration of adenosine and using reflex activation of vagal activity, the heart rate can be brought down:
- applying cold water to the face
- massaging the carotid sinus region on one side to activate baroreceptors
- valsalva’s manouvre (increased intrathoracic pressure with closed glottis)
 Essential hypertension: abnormally high blood pressure triggered by unknown pathogenesis, i.e. could be genetic, diet, lifestyles etc.
- systolic pressure greater than 140 and diastolic greater than 90
- increase in sympathetic vasomotor tone in the initiate phases of hypertension
 Postural hypotension: lowering in blood supply to brain (cerebral perfusion) when an individual change to an upright posture thus causing dizziness or faint.
- impairment of baroreceptors to detect a lowering in BP and respond effectively to stimulate sympathetic vasoconstriction and tachycardia
- treatment: intake of fluid, pressure drugs and coffee
 Urinary bladder:
- sympathetic: neurons from the intermediolateral nucleus synapse at the inferior mesenteric ganglion with hypogastric nerve and it stimulates closure of internal urethral sphincter and relaxation of urinary bladder smooth muscles
- parasympathetic: pelvic splanchnic neurons from the sacral parasympathetic nucleus synapse with postsynaptic neuron that stimulates the constriction of urinary bladder smooth muscle
- somatic: pudental nerve from the somatic motor nucleus controls the external urethral sphincter
 Reflex control of bladder: spino-ponto-spinal reflex
- mechanoreceptor and pain receptor in the muscular walls of the bladder detect expansion of detrusor muscle and pain of pressure
- afferent signal is sent to the pontine micturition center that co-ordinates the parasympathetic pelvic nerve to constrict bladder
- somatic pathway must relax external sphincter for bladder emptying
 Horner’s syndrome: lesion in the ocuolsympathetic neurons in the upper T1 to T3 segments, or of the cervical sympathetic trunk or intracranial postganglionic pathway that controls pupil dilation. This can be caused trauma, surgery, neck injury. Symptoms include:
- miosis: papillary constriction
- ptosis: drooping of the eyelid
- anhydrosis: failure of sweat gland on the same side of the forehead
- enophthalmos: sinking of the eye
 Horner syndrome diagnosis:
- cocaine drop: inhibition of NA reuptake enhance NA effect to produce dilation. However in horner’s there is no dilation.
- tyramine drop: release of NA to produce pupil dilation only if postganglionic nerve is intact
 Pheochromocytoma: neuroendocrine tumour of the medulla of the adrenal glands due to excessive secretion of the catecholamines from the adrenal chromaffin cells.
 Sexual arousal:
- increase in parasympathetic enhance secretion from glands and blood flow into corpus cavernosum
- increase in sympathetic activity stimulate contract of smooth muscles and ejaculation
- Ach acts on muscarinic rececptors of the vascular endothelium to stimulate NO production from L-arginine by NO synthetase. NO reacts wit guanylate cyclase to increase CGMP levels
 Viagra: inhibitor of the phosphodiesterase type 5 that breaks down cGMP to prolong effects of NO and cGMP for erection
 Diabetic autonomic neuropathy: loss of preganglionic and postganglionic autonomic nerves in patients with diabetes. Clinical symptoms include:
- postural hypotension
- bradycardia
- sweating
- GI, sexual and urinary tract dysfunction
 Progressive autonomic failure: degeneration of sympathetic preganglionic cell bodies
- bladder disturbances
- decreased tear production
- erectile dysfunction
- reduced sweating
- orthostatic hypotension
 Shy-Drager syndrome: Parkinson’s disease and progressive autonomic failure with degeneration of preganglionic neurons in the lateral horn of the spinal cord as well as pyramidal and extra-pyramidal pathways

Drugs and ANS:

• Muscarinic receptors: G-protein coupled receptors with 7 transmembrane spanning domains. There are 5 subtypes of muscarinic receptors that differ in their anatomic distribution, e.g. M2 on myocardium and M3 on smooth muscles
- M1, M3, M5 receptors are linked to Gq and activates phospholipase C which leads to rises in inositol triphosphate and diacylglycerol.
- M2 and M4 receptors are link to Gi that inhibit AC and decrease cAMP and open a K+ channel
• Muscarinic effect of ACh
- eyes: miosis and promotes drainage of aqueous humour out of eyes
- heart: heart rate slowed by increasing conduction time through AV node and directly slowing SA node depolarization; reduced contractility and dilation of blood vessels.
- respiratory system: contracts smooth muscles and stimulate mucus secretion of bronchi
- GI tract: promote peristaltic activity of gut and secretions by salivary and gastric glands
- Urinary: contract smooth muscle for urine emptying
• Muscarinic agonists: not very clinically significant due to rapid metabolism and short duration of action.
- pilocarpine: treat glaucoma by increasing the outflow of aqueous humour from eyes. Eye drops
- bethanecol: treat gastroesophageal reflux by increasing the tone of oesophageal sphincter and treat atonic bladder
• Adverse effect of muscarinic agonists: similar to effect of drugs that inhibit acetylcholinesterase
- sweating
- abdominal cramps
- diarrhoea
- excessive salivation
- miosis
- bronchoconstriction
• Muscarinic antagonist:
- atropine: antagonist of all different subtypes of muscarinic receptors used to counteract transient increase of parasympathetic tone (slowing of heart rate) after heart attack
- ipratropium bromide: treat asthma by relaxing smooth muscle of airway through blocking actions of ACh on M3 receptors. The drug is poorly absorbed through GI and bronchi mucosa so avoid adverse effect.
- Benztropine: reduce the increase tone of muscle by blocking nAChR and action potential transduction
- Pirenzipine: selective M1 antagonist that block acid secretion by inhibiting release of acetylcholine from vagal nerve to treat peptic ulcer disease.
- Scopolamine: used to treat travel sickness by inhibiting cholinergic neurotransmission in the vestibular apparatus (inner ear). Applied as transdermal patches.
- Oxybutinin: treat urinary incontinence (hyperactive bladder) by reducing contractility of bladder smooth muscles.
• Adverse effect of muscarinic antagonist:
- blurred vision
- dry mouth
- constipation
- urinary retention
- delirium
• Nicotinic receptors: contains 5 subunits forming a cation channel. Binding of acetylcholine to alpha subunits opens channel allowing Na+ and other cation to flow through
- NM receptors: a pentameric structure consisting of 2 alpha subunits and beta, gamma and sigma subunits found on the neuromuscular endplate in skeletal muscles
- NN receptors: consists of only alpha and beta subunits found in autonomic ganglia
• Hexamethonium: ganglion blockers drugs that act as antagonists at NN receptor and used to treat hypertension.
- adverse effect: flushing, postural hypotension and impotence
• Tubocurarine: competitive antagonists at NM receptors cause neuromuscular blockade and used as muscle relaxants during surgery
• Cholinesterase inhibitors: used mainly in anaesthesia to reverse the effect of neuromuscular blockade by promoting acetylcholine accumulation to out compete the effect of NM antagonist
- malathion
- neostigmine
• Mechanism of catecholamine inactivation:
- Catecholamines uptake: the main mechanism by which the action of catecholamines are terminated is by reuptake of the neurotransmitter
- MAO: monoamine oxidase catalyze the breakdown of catecholamines inside neurons
- COMT: Catechol-O-Methyl Transferase is inovled in the metabolism of circulating catecholamines
• MAO inhibitor: drugs such as phenelzine are used in treatment of depression by blocking MAO. Problems with hypertensive crisis have being associated with this.
• Tyramine: an indirect sympathomimetic drug that triggers the release of catecholamines from nerve ending (instead of binding to receptors). In the presence of MAOI, catecholamines accumulate and produce hypertension.
• Adrenergic receptors:
- alpha 1: postsynaptic receptors linked through Gq to PLC on smooth muscles to produce contraction.
- alpha 2: presynaptic receptors linked to Gi to decrease in cAMP and to K+ channels and to inhibit NA release. Usually located at sites remote from adrenergic nerve terminals.
- beta 1,2,3: linked through Gs to increase in cAMP
• Effects of adrenergic receptors:
- Blood vessels: alpha-1 receptors contract vascular smooth muscles whereas beta-2 receptors relax. Thus in skin vessels, sympathetic stimulation causes vasoconstriction while in skeletal muscle, vasodilation occurs.
- Heart: heart rate increase by beta-1 receptor stimulation and increase in contractility
- Eyes: activation of alpha receptors to dilate the pupil and alpha agonist can increase outflow of aqueous humour from the eye and lower intraocular pressure
- Respiratory tract: stimulation of beta-2 receptors relaxes airway smooth muscle and leads to bronchodilation
- GI tract: stimulation of both alpha and beta receptors relaxes gastrointestinal smooth muscle and decrease motility
- Urinary tract: beta-2 receptors on the smooth muscle of the bladder mediate relaxation and alpha-1 receptors are found on urethral sphincter and contracts to help maintain continence.
- Metabolic effects: activation of beta 2 receptors in liver leads to glycogenolysis and rise in blood glucose.

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