Introduction to Autonomic Nervous System What is the autonomic (involuntary, visceral) nervous system? This is the system that regulates functions which are not under voluntary control, including: * Cardiac muscle contractions (force "inotropy" and rate "chronotropy"). *Smooth muscle contractions (visera, blood _ vessels, respiratory tree). *Exocrine gland secretions. *Metabolism, body temperature and fluid/electrolyte balance. Divisions of the autonomic nervous system: The autonomic nervous system is divided anatomically into sympathetic and parasympathetic divisions. The sympathetic nerve fibres originate from the thoracolumbar regions (thoracic segments 1, 4, 5, 11, 12 and lumbar segments 1, 3) while the parasympathetic nerve fibres originate from the craniosacral regions of the CNS (cranial nerve nuclei Ill, Vil, IX, X and sacral segments 2, 3, 4). Sympathetic nervous system is responsible for accommodation to stressful conditions while parasympathetic nervous system is responsible for maintaining normal physiology. The two systems are known to be physiological antagonists.Autonomic nerve fibres: The efferent nerve fibres of the autonomic nervous system, unlike somatic nerves, do not travel directly from the CNS to the effector organ but rather travel as two nerves separated by a synapse. The nerve fibre originating from the CNS is called the preganglionic one while the next one is the postganglionic. In the sympathetic nervous system, the preganglionic fibres are short and their synapses rely in the vertebral and paravertebral ganglia. In the parasympathetic nervous system, however, the synapses rely inside the effector organ followed by a short postsynaptic fibre. Parasympathetic a Sympathetic 3 Sheer . Dilates j pupil Stimulates flow of sali Inhibits flow of saliva Ganglion Medulla oblongata: Slows Accelerates heartbeat [ >| heartbeat ce Yagus : Constriets nerve FO Dilates_ bronchi fy a 5 bronchi Solar plexus Go) inhibits _) 4) peristalsis Gam secretion Conversion \_ REF 01 sixcosen oe te glucose Stimulates: peristalsis and secretion Stimulates release of bile 2 Secretion of 5 | adrenaline and ‘i == noradrenaline Inhibits u » Inhibit Chain of [ ) bladder sympathetic (Contraction ganolia Contracts (7 bladder ' fympathetic and parasympathetic nerve fibres Chemical transmission of the autonomic nervous system: Neurotransmission in the autonomic nervous system involves the following steps: 1) Biosynthesis of the transmitter. Acetylcholine is synthesized from choline and acetyl-CoA by the action of choline acetyl transferase enzyme. Noradrenaline is synthesized from the amino acid tryptophan as illustrated in the figure. 2) Storage in storage vesicles in the nerve ending. 3) Release from nerve ending after nerve depolarization (electric transmission). 4) Action of the transmitter on the specific receptor in the effector organ or gland. 5) Termination of action by reuptake or metabolism of the transmitter. Acetylcholine is metabolized by the action of acetylcholinesterase enzyme into _ choline and acetic acid. Noradrenaline and adrenaline are metabolized by the action of monoamine oxidase (MAO) and catechol-O- methyltransferase (COMT) enzymes.BORAT ~ : — Synthesis of adrenaline and noradrenaline Types of preganglionic and postganglionic fibres: Nerve fibres are named according to the neurotransmitter they release. Nerves that release acetylcholine as the transmitter are called cholinergic nerves while nerves that release noradrenaline are called adrenergic nerves. The following is the main classification of nerve fibres:* All somatic nerves are cholinergic. + All preganglionic nerve fibres are cholinergic. * All parasympathetic postganglionic fibres are cholinergic. * Most sympathetic postganglionic fibres are adrenergic. + Few sympathetic postganglionic fibres are cholinergic (supplying sweat glands and piloerector muscles). lypes of autonomic receptors: Acetylcholine acts on two main types of receptors: *Nicotinic receptors that are found in the autonomic ganglia (N1) as well as neuromuscular junction of skeletal muscles (N2). *Muscarinic receptors that are found in cardiac muscles, smooth muscles and exocrine glands (M1 for secretions, respiratory tract and CNS, M2 in the heart, M3 in bronchi and blood vessels, M4 that regulates dynamics of muscarinic receptors and M5 in the CNS). *Noradrenaline and adrenaline act on five receptors, namely ai, a2, B1, B2 and B3 receptors. These are listed below in detail.Sympathetic Nervous System . Sympathetic nervous system is activated all at once to prepare the body to face dangers (fear, fright and flight). . Actions of sympathetic nervous system stimulation can be summarized as follows: i) On CVS: 1-Blood vessels of skin and splanchic area are constricted (a1-mediated), while those of skeletal muscles and coronaries are dilated (682- mediated). Positive inotropic effect (increased force of contraction), poitive chronotropic effect (increased heart rate), increased cardiac output, cardiac muscle work and oxygen consumption and altered rhythmic functions of the heart leading to extrasystole (decreases the refractory period). Increased rennin release (B1) from the kidney increases blood pressure by activation of rennin- angiotensin system.ii) On Respiratory tract: * B2-stimulation: bronchodilatation. * a1-stimulation: pulmonary decongestion. On the eye: Active mydriasis (by a1-stimulation of radial muscles), accomodation of eye to far vision and increased production of aqueous humor (B2- mediated, while a1-stimulation increases outflow). * iv) On the spleen: Increases the production of erythrocyte-rich blood in circulation (a1- stimulation). * vy) OnGI Contraction of sphinctor muscles (a1), relaxation of wall muscles (a1 and B2) and inhibition of movement (a1 and B2) and secretions (a2) of stomach and intestine. vi) On the urinary bladder: Contraction of sphinctor and trigone (a1-mediated) and relaxation of wall (B2-mediated) > urine retention.vii) Exocrine glands: Reduction of all body secretions, thick viscid salivary secretions (a2). Sweating is the only secretion that is increased (Ach). viii) On CNS: Stimulation of CNS takes place. a2 stimulation decreases central sympathetic outflow. ix) Metabolic effects: B2-mediated increase in glcogenolysis in liver and skeletal muscles > hyperglycaemia. a2 stimualtion decreases insulin secretion while B2 stimulation increases insulin secretion. B3-mediated 4 in lipolysis > 4 level of plasma free fatty acids. ~x) On the uterus: Relaxation of uterus muscles and decreased uterine movement (B2). xi) Sympathetic nerve endings: Presynaptic inhibition of noradrenaline release from nerve endings (a2). Drugs affecting sympathetic nervous system: A) Sympathomimetics: These are drugs that produce effects similar to those produced by endogenous sympathetic stimulation. These include:a) Direct acting sympathomimetics that act directly on sympathetic receptors including: * Adrenaline "epinephrine" (non-selective a and B agonist). * Noradrenaline "norepinephrine" (non-selective a agonist). * Phenylephrine (a1 agonist). * Isoprenaline (non-selective B agonist). * Dobutamine (B1 agonist). * Salbutamol and terbutaline (B2 agonists). 6) Indirect acting sympathomimetics that act indirectly by stimulating the release of | neurotransmitters from adrenergic nerve endings. These include tyramine and amphetamine. ¢) Mixed action sympathomimetics that act both directly and indirectly. These include — ephedrine. d) Inhibitors of transmitter metabolism, like monoamine oxidase _ inhibitors (MAOI's), e.g. tranylcypromine.B) Sympatholytics: These are agents that depress sympathetic activity by one of the following mechanisms: a) Interference with the synthesis of neurotransmitters, eg. methyldopa. }) Inhibition of the release of neurotransmitters, or adrenergic neuron blockers, e.g. guanethidine. c) Depletion of storage of the transmitter, e.g. reserpine. d) Ganglionic blockers, that block both sympathetic and parasympathetic nerves, e.g. hexamethonium. e) Alpha-2 receptor (a2) agonists that inhibit central sympathetic outflow, e.g. clonidine.f) Adrenergic receptor blockers, including: * Prazosin (reversible selective a1 blocker). * Yohimbine (selective a2 blocker). * Phentolamine (reversible non-selective a blocker). * Phenoxybenzamine (irreversible non- _ selective a blocker). * Atenolol (selective B1 blocker). * Butoxamine (selective B2 blocker). * Propranolol (non-selective B blocker). Selected sympathomimetics: Adrenaline gives all the actions of sympathetic stimulation but it is not effective orally as it is inactivated by digestive enzymes and gastqic juice. Additionally, it is metabolized in the liver as well as metabolizing enzymes in the gut (MAO and COMT). Additionally, exogenous adrenaline has no CNS stimulant effect at normal doses as it does not pass the blood brain barrier.Adrenaline is administered by local or subcutaneous administration for the following purposes: * Decongestant and hemostatic for nasal congestion or bleeding. * With local anaesthetics to increase the action and decrease toxicity. * Bronchodilator for bronchial asthma. * Cardiac arrest in hospitalized patients. * For anaphylactic shock with an —_antihistaminic and a glucocorticoid. However, adrenaline use is associated with adverse effects like hypertension, angina attacks, arrhythmia, constipation, urine retention, hyperglycemia and dry mouth.Isoprenaline: This is a non-selective B agonist that increases heart rate, dilates coronaries and skeletal muscle blood vessels, dilates bronchi and increases glycogenolysis and lipolysis. It is used for the management of bronchial asthma and heart block. Dopamine It is an agonist on B1 receptors (so useful in cardiogenic shock), a receptors (decreases blood flow to non-essential vascular bed) and dopamine D1 receptors (vasodilation to blood vessels of coronaries, mesentry and kidney so increases blood flow to vital organs).Dobutamine It is a selective agonist on B1 receptors used to treat cardiogenic shock. It causes less reflex tachycardia compared to non-selective beta agonists. Phenylephrine This is a selective a1 agonist that lacks catecholamine nucleus. It is used as vasoconstrictor to decrease nasal congestion and symptoms of common cold. It can also be used as mydriatic. However, hypertension is a common side effect.Methoxamine It is similar to phenylephrine. It is used to treat hypotensive patients. Xylometazoline and oxymetazoline: These agents are non-catecholamine alpha-agonists used mainly as nasal decongestants. Prolonged use may cause atrophy of nasal mucosa and loss of smell sensation. Salbutamol and terbutaline: These are selective agents on B2 receptors used as bronchodilators to treat bronchial asthma. Additionally, these agents can be used to prevent premature labor through decreasing uterine contractions.Ritodrine . It is a uterine relaxant through stimulation of B2 receptors. It is used mainly to protect against premature labor. Clonidine . This is a selective a2 agonist used to treat essential hypertension by inhibition of central sympathetic outflow. Amphetamine . An indirect sympathomimetic with marked CNS stimulant effect and has the following uses: . * Anorexigenic (appetite suppressant). . * Treatment of narcolepsy. . * In nocturnal enuresis. . * Hyperactive children. . * Mental and physical fatigue and depression.Methamphetamine . It is very similar to amphetamine but with higher central to peripheral effects. Tyramine . An indirect sympathomimetic present in certain foods like old cheese and causes severe hypertension when combined with MAOI's (cheese reaction). Ephedrine . A sympathomimetic that acts both directly and indirectly. This is not a catecholamine and so it is a poor substrate to COMT and MAO resulting in a long duration of action. It is used as a bronchodilator and decongestant in addition to treatment of narcolepsy and nocturnal enuresis.Cocaine . It is a sympathomimetic agent with a local anaesthetic activity. It causes euphoria, alertness, hypertension and addiction. Selected sympatholytics: Prazosin: A selective a1-blocker used for the treatment of hypertension and peripheral vascular diseases (Raynauld's disease). It is used also to treat phaeochromocytoma (a tumor of adrenal medulla accompanied by increased levels of adrenaline and noradrenaline, severe hypertension, angina attacks and arrhythmia). It decreases pupillary dilatation and adrenergic sweating. Alpha blockers decrease smooth muscle contractions in enlarged prostate and bladder base, so help in managing urine retention. Adverse effects include reflex tachycardia, postural hypotension, nasal congestion and inhibition of ejaculation.Propranolol: . As with other beta blockers, it is well absorbed after oral administration. It is a non-selective beta-blocker that has the following actions: i) On the heart: Attenuates cardiac response to sympathetic stimulation, causing negative chronotropy, negative inotropy and decreased cardiac output. Therefore, it decreases cardiac work and myocardial oxygen consumption. It prolongs the AV-nodal refractory period and has an antiarrhythmic and quinidine-like action. ti) On blood pressure: \t reduces blood pressure by four mechanisms. a) initially the fall in blood pressure is due to the decrease in cardiac output. After some time, the cardiac output returns to normal, but the blood pressure remains low; b) inhibition of renin-release by an action on B1- receptors in the juxtaglomerular apparatus; c) CNS effect, by a decrease in the central sympathetic outflow; d) presynaptic B inhibition decreases NE release.* iii) On the respiratory system: \t causes bronchospasm specially in asthmatic patients. * iv) On the eye: \t decreases intraocular pressure without an effect on accomodation or miosis. vy) On Metabolism: \t causes inhibition of glycogenolysis and impairs recovery from hypoglycaemia caused by insulin. It also masks the warning signs of hypoglycaemia caused by adrenaline release. For these reasons, it should be used with caution in diabetic patients. Inhibition of lipolysis leads to increased level of plasma triglycerides and LDL, so it should be used with caution in atherosclerosis.It is used for the following purposes: 1-Hypertension, specially if accompanied with high renin activity. 2-Angina pectoris and myocardial infarction. 3-Cardiac arrhythmia. 4-Symptomatic control of adrenergic signs of thyrotoxicosis. 5-Glucoma, by decreasing aqueous humor formation and _ increasing outflow. 6-Migraine. 7-Antianxiety (central sedative). Its side effects include: + 1-Fatigue, cold extremities, intermittent claudication. * 2-Heart failure, heart block if combined with —__Ca?*-channel blockers. * 3-Bronchospasm, specially in asthmatics. * 4-Bradycardia and hypotension. + 5-Hypoglycemia and hypertriglyceridaemia. * 6-Sudden withdrawal causes exacerbations of anginal attacks due to receptor up- regulation during treatment.Parasympathetic Nervous System Parasympathetic nervous system is the physiological antagonist of sympathetic nervous system. This system works on separate organs and tissues towards normal physiology. Actions of parasympathetic nervous system stimulation can be summarized as follows: i) On CVS: Negative chronotropic and inotropic effects as well as increased refractory period. Vasodilation of arteries and veins is mediated by nitric oxide (NO) release.* ii) On the eye: Contraction of circular muscles (miosis, | intraocular pressure) and conraction of ciliary muscles (accomodation to near vision). * iti) On GIT: \ncreased motility and secretions and relaxation of sphinctors. * iv) On urinary bladder: Relaxation of sphinctor and trigone and contraction of detrusor and wall muscles. * v) On the respiratory tract: Bronchospasm and increased secretions. * vi) On secretions: Increases salivary, lacrimal, nasopharyngeal and sweat secretions. There are five types of muscarinic receptors, namely M1, M2, M3, M4 and M5. All of these receptors are blocked by atropine. M1 receptors {responsible for vagally-induced gastric acid secretion) are blocked by pirenzepine. M2 receptors are blocked by gallamine.Drugs affecting parasympathetic nervous system: A) Parasympathomimetics: *These are drugs that produce effects similar to those produced by endogenous parasympathetic stimulation. a) Direct acting parasympathomimetics that act directly on parasympathetic receptors including choline esters (acetylcholine, methacholine, bethanechol and carbachol) and cholinomimetic alkaloids (muscarinic agonists like pilocarpine and muscarine, and nicotinic agonists like nicotine and lobeline).2) Indirect-acting parasympathomimetics including anticholinesterases that inhibit acetylcholine degradation thus increase its effect. These may be reversible (including alcohols like edrophonium as well as carbamates like neostigmine, pyridostigmine and physostigmine) or irreversible (organophosphate insecticides that are toxic). Selected parasympathomimetics: Physostigmine: This is an indirect acting parasympathomimetic agent that increases the action of acetylcholine on both nicotinic and muscarinic receptors by inactivating cholinesterase enzyme responsible for conversion of acetylcholine into choline and acetic acid.This leads to the following effects: i) On CNS: Central stimulation of cholinergic receptors causes tremors, anxiety and restlessness. ii) On skeletal muscles: \t stimulates nicotinic receptors at the neuromuscular junction (NMJ). This prolongs the end plate potential and strengthen the muscle. The effect is clear when transmission is greatly decreased as in Myasthenia gravis (MG), or during recovery from neuromuscular blockers. tii) On the CVS, eye, GIT, urinary bladder, respiratory tract_and_secretions: As mentioned before under effects of parasympathetic nervous system. This drug is used for the following purposes: a) Myotonic to enhance neuromuscular transmission in severe muscle atony as in MG and after recovery from neuromuscular blockers after surgery; b) In severe paralytic constipation; c) in poisoning with antimuscarinics, e.g. atropine.Adverse effects include: * 1- Excessive secretions of saliva and nasopharyngeal secretions and hyperhydrosis. * 2- Diarrhea, activation of peptic ulcer and abdominal cramps. * 3- Miosis. * 4- Bronchospasm. * 5- Hypotension. * 6- Trmors, anxiety and restlessness. General clinical uses of cholinomimetics: 1-Treating glaucoma by increasing outflow of aqueous humor. This can be performed by direct-acting agents (pilocarpine, methacholine and carbachol) and indirect- acting agents (physostigmine and echothiophate). 2-Gastrointestinal disorders related to paralysis without obstruction, e.g. post-operative paralytic ileus (paralysis of stomach or bowel following surgery). Drugs of choice include choline esters (bethanechol) and anticholinesterases (neostigmine).3-Decreased tone of lower esophageal sphincter associated with reflux esophagitis. 4-Urinary tract disorders, for example urinary retention due to surgical operations, labor or spinal injury (bethanechol and neostigmine). 5-Myasthenia graevis (an auto-immune disease associated with decreased number of nicotinic receptors due to destruction by auto-antibodies). 6-Treatment of supra-ventricular tachycardia (e.g. edrophonium). 7-Treatment of anti-muscarinic drug intoxication, e.g. toxicity of atropine. Selected parasympatholytics. This is a blocker of muscarinic receptors. It reverses the actions of acetylcholine on muscarinic receptors. This leads to tachycardia, dry mouth, blurred vision, mydriasis, constipation and urine retention (these effects are called together atropine-like side effects when produced by other antimuscarinics).Atropine is used for the following purposes: *A_ pre-anaesthetic medication (bronchodilator, decreases bronchial and salivary secretions and protects the heart from excessive vagal stimulation). *Antispasmodic for renal and intestinal colic. *Peptic ulcer. * Nocturnal enuresis. * Bronchial asthma. «Antidote for anticholinesterase poisoning. Atropine substitutes: These are antimuscarinic agents used specifically for the treatment of certain conditions that require blocking of muscarinic receptors, including: * Ipratropium for bronchial asthma. * Benzatropine for parkinsonism. * Pirenzepine for peptic ulcer. * Hyoscine-N-butyl bromide for colic. * Cyclopentolate as mydriatic.