Autonomic Nervous System Objectives Review anatomy and function of ANS Know neurotransmitters at autonomic synapses Understand mechanism

ism of neurotransmission in the ANS Be able to describe the distribution of adrenergic and cholinergic receptors Describe general mechanisms by which drugs interact with the ANS Two systems control the body: I. Endocrine System: secretes hormones II. Nervous System a. CNS: spinal cord and brain b. PNS i. Efferent: Nerve fibers send signals from peripheral to central ii. Afferent: Nerve fibers send signals central to peripheral iii. Somatic (skeletal muscle): Voluntary movement, posture 1. Anatomy: a. Motor fiber exits at ventral horn, directly synapses with skeletal muscle 1 efferent neuron b. Acetylcholine iv. Autonomic: Involuntary, central vestibular system (CVS), digestion, respiration 1. Enteric a. Located in GI wall b. Receives inputs from i. sympathetic postganglionic fibers ii. parasympathetic preganglionic fibers iii. Sensory input from within the wall of the gut c. Controls gut motility and secretion of autoenzymes 2. Parasympathetic a. Anatomy (dont have to know cranial nerve numbers) i. Craniosacral outflow (brainstem + sacral) ii. Preganglionic fiber is longer, post is shorter iii. Preganglion: lateral medial nuclei in spinal cord ACh synapse postganglion ACh synapse smooth muscle/cardiac cells/gland cells b. Cholinergic (ACh): Muscarinic and Nicotinic receptors 3. Sympathetic a. Anatomy: i. Originate in thoracolumbar outflow ii. Preganglionic fiber is shorter iii. Preganglionic originates from lateral medial nuclei ACh synapse ganglion postganglionic NE and ACh synapse smooth muscle/cardiac cells/gland cells b. Have very wide distribution innervates many parts of body c. Activated when ready for fight/flight d. Adrenergic (NE): Alpha and Beta

Innervates Sweat glands Salivary glands Blood vessels Eye

Heart Lungs Stomach, intestines Bile duct, gall bladder, parotid gland Kidneys, pilomotor muscles Bladder Adrenal Medulla Genitalia Rectum/Anus

Parasympathetic Generalized secretion Increased salivation Dilate Lens: accommodation, near focus Ciliary muscle Sphincter muscle of iris: constricts pupil Lacrimal gland Decreased rate/force Bronchoconstriction, secretions Increased peristalsis, secretion + N/A Contraction of detrusor muscles Relaxation of internal sphincter No effect Penile erection Engorgement of clitoris/labia Increased smooth muscle tone and relaxes sphincter

Sympathetic Increased, localized in palms, feet Decreased salivation Constrict No lens effect Ciliary epithelium Radial muscle of iris: pupil dilated

Increased rate/force Vasodilation, bronchodilation Decreased peristalsis, secretion N/A + Relxation of detrusor muscles Constriction of internal sphincter Increased epinephrine secretion Ejaculation Inhibition of smooth muscle in rectum, constriction of sphincter

Neurotransmitter Chemistry of ANS I. Classification of Efferent Nerves: based on transmitter released from their terminals a. Cholinergic fibers: release ACh i. Somatic motor fibers ii. Preganglionic autonomic fibers iii. Parasympathetic fibers: all pre and postganglionic iv. Innervation of adrenal medulla v. Some sympathetic postganglionic fibers (controlling sweat gland) b. Adrenergic fibers (aka noradrenergic): release NE i. Most postganglionic sympathetic fibers c. Other fibers: i. Dopamine: renal vascular smooth muscle ii. Peptides

Neurotransmission in Autonomic Synapse I. Transmission at cholinergic and adrenergic synapses is mediated by a series of steps including: a. Synthesis, storage, release of transmitter b. Interaction of transmitter with presynaptic and postsynaptic receptors c. Activation of signal transduction mechanisms d. Elimination of transmitter II. Chemical transmission in ANS a. Synapse: the junction of nerve terminal w/ the next neuron or effector cell i. Consists of: presynaptic membrane, postsynaptic membrane, and synaptic cleft b. Transmitter: chemical agent released from nerve terminal that transmits info across synapse to effectors III. Cholinergic transmission a. Synthesis i. Choline transported into presynaptic nerve terminal by choline transporters (CHT) ii. Choline + Acetyl CoA choline acetyl-transferase Ach iii. ACh transported into vesicle by vesicle associated transporter (VAT) and packaged in the vesicle, where it is stored b. Activation i. Action potential reaches terminal, triggers influx of Ca2+ fusion of vesicular membrane with terminal membrane release of Ach into synaptic space ii. SNARE (Soluble N-ethylmalemide sensitive fusion Attachment protein REceptor) proteins regulate neurotransmitter release; important in receptor fusion process 1. Vesicle associated membrane proteins: Synaptobrevin, synaptotagmin a. Sit on synaptic vesicle membrane b. Tagmin detects Ca increase vesicle moves toward synaptic cleft c. Brevin interacts with SNARE proteins (SNAP-25 and syntaxin) on inside of presynaptic terminal membrane iii. ACh binds to and activates pre- and postsynaptic Ach receptors (cholinoceptor), exerting action of transmitter c. Termination i. ACh Acetylcholinesterase (ACHE) choline and acetate; terminates action of transmitter d. Regulation by drugs: i. Hemicholiniums: Inhibits sodium dependent choline transporter (CHT) ii. Vesamicol: blocks vesicle associated transporter (VAT) iii. Botulinum toxin: Alters SNAP-25, syntaxin to prevent docking/fusion release process iv. Neostigmine: blocks acetylcholinesterase (ACHE) increased activation of ACh receptors v. Muscarinic receptors 1. Agonist: acetylcholine, pilocarpine 2. Antagonist: atropine vi. Nicotinic receptors: 1. Agonist: Nicotine 2. Antagonist: Tubocurarine IV. Adrenergic Transmission a. Synthesis of NE i. Tyrosine actively transported into noradrenergic ending ii. Tyrosine tyrosine hydroxylase (rate limiting enzyme) dopa iii. Dopa dopa-decarboxylase decarboxylated to dopamine iv. Dopamine transported into vesicles dopamine -hydroxylase NE v. In adrenal medulla, NE is further converted to epinephrine. b. Activation

i. Action potential causes influx of Ca2+ into nerve terminal fusion of vesicle with plasma membrane exocytosis of NE ii. Activation of adrenoceptors in postsynaptic membrane action of sympathetic nerve c. Termination i. Uptake I: Norepinephrine transporters (NET) actively reuptake into presynaptic terminal and storage vesicles most important mechanism for termination 1. After transport into a cell, most of NE will be recycled. Some will be metabolized/deaminated by MAO ii. NE diffuses away from receptor site and is metabolized in tissues by MAO (monoamino oxidase) and COMT (catochol-o-methyltransferase) iii. NE can also activate presynaptic (2) receptors, to inhibit further release of NE. d. Regulation by Drugs Activation Inhibition i. Metyrosine: tyrosine hydroxylase Phentolamine antagonist ii. Reserpine alkaloids: vesicular monoamine Phenylephrine 1 Prazosin transporter (VMAT) antagonist Clonidine 2 Yohimbine iii. Guanethidine: blocks vesicle release iv. Cocaine, tricyclic antidepressants: NET Isoproterenol Propanolol antagonist Dobutamine 1 Metoprolol v. Tyramine, amphetamines, ephedrine : Atenolol compete with NE for NET Albuterol 2 vi. Norepinephrine, epinephrine, dopamine: Terbutaline adrenoceptor agonists Autonomic Receptors Receptor: receptive substance (protein) of a cell that specifically binds, interacts with ligands, and transmits information I. Types of Receptors a. Cholinoceptors: ACh receptors; parasympathetic involvement; muscarinic, nicotinic b. Adrenoceptors: NE and adrenaline receptors; sympathetic involvement; , c. Dopamine Receptors II. Types of Innervation a. Dual Innervation: i. Most organs are dually innervated. In resting state, are controlled by parasympathetic system ii. Heart, lung (bronchial smooth muscle), GI tract (smooth muscle iii. Eye: 1. Pupil a. Sympathetic: agonist contraction of radial muscle dilation (mydriasis) b. Parasympathetic: muscarinic contraction of circular muscle of ciliary body produces constriction (miosis) 2. Ciliary epithelium: receptor has permissive effect on aqueous humor secretion 3. Muscarinic agonists a. Relax lens for near vision b. Improve drainage b. Sympathetic Innervation ONLY i. Spleen ii. Sweat glands iii. Piloerector muscles iv. Most blood vessels v. Vascular smooth muscle: BP, peripheral resistance controlled by the sympathetic

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Functional Regulation of ANS a. Central Integration i. Midbrain/Medulla receives input from: 1. Cortex/hypothalamus 2. Somatosensory/ visceral sensory input ii. Midbrain/Medulla output regulates: 1. Sympathetic/parasympathetic system iii. Stress/exercise sympathetic activity b. Baroreflex i. Increased BP detected by aortic arch/carotid sinus activation of tractus solitaries (in brain stem) 1. Suppressed vasoconstrictor dilation of veins/arterioles 2. Suppressed cardiac stimulator reduced heart contraction 3. Activation of cardiac inhibitor reduced heart rate ii. Ultimate result is decreased BP iii. Suppression of reflex + addition of BP drug rise in pressure, no change in heart rate c. Hormone regulation i. Renin-angiotension-aldosterone system 1. Drop in bp decrease in renal perfusion kidney increases renin production 2. Angiotensinogen renin angiotensin I 3. Antiotensin I ACE (from lungs) Angiotensin II 4. Angiotension II: a. Increases sympathetic activity b. Increases tubular Na, Cl, water reabsorption; K excretion c. Stimulates adrenal gland cortex aldosterone secretion same tubular effects d. Arteriolar vasoconstriction increase in bp d. Synaptic regulation i. Presynaptic regulation, autoreceptors 1. Presynaptic receptors that bind the primary transmitter and regulate its release 2. Adrenergic fiber: a. Presynaptic release of NE binds to 2 receptors decreases NE release b. Presynaptic NE binds to 1 receptor increases NE release ii. Presynpatic regulation, heteroreceptors: 1. presynaptic receptors that modulate transmitter release 2. Cholinergic fiber releases ACh M2 receptor on Adrenergic fiber release of epinephrine iii. Postsynaptic regulation 1. Changes in number of receptors: +/a. Surgical denervation of motor nerve 2. Changes in receptor sensitivity a. Increased receptor sensitivity: prolonged depletion of NE induced by reserpine b. Receptor desensitization: prolonged activation of receptors

Sympathomimetic Drugs Objectives: Mode of action of sympathomimetic drugs Types and subtypes of adrenoceptors Molecular mechanisms of sympathomimetic drugs

Organ system effects of sympathomimetic drugs Pharmacokinetics of sympathomimetic drugs Clinical Application Toxicity of sympathomimetic drugs

Sympathomimetic Drugs: drugs that mimic the action of epinephrine or norepinephrine I. Mode of Action a. Direct mode: activate adrenoceptors directly b. Indirect action: dependent on release of catecholamines; 2 mechanisms: 1. Displacement of store catecholamines from adrenergic nerve ending 2. Inhibition of reuptake of catecholamines II. Types and Subtypes of Adrenoceptors a. Subtypes of adrenergic receptors involved in sympathetic nervous system response: 1. Alpha adrenergic ( receptors, 1, 2) 2. Beta adrenergic ( receptors, 1, 2, 3) 3. Dopaminergic (D1-5) b. Located on: smooth muscle, cardiac muscle, exocrine, endocrine, nerve terminals c. NE and Epi interaction w/ adrenoceptor: excitatory or inhibitory response depending on tissue III. Molecular Pharmacology a. All adrenoceptors are GPCR (G protein coupled receptors) 1. 7 transmembrane spans connect extra- and intracellular domain 2. Intracellular domain is coupled to a G-protein 3. G-protein is a heterotrimer, of 3 subunits: , , 4. + GDP= off; +GTP = on b. Mechanism of activation 1. 1: via coupling protein Gq 1. Agonist (pheylephrine) 1 GDP/ subunit dissociates GTP/ (G protein activated GTP/ activates phospholipase C Increases DAG a. IP3 increased free calcium activation of Ca2+ dependent protein kinase muscle contraction b. PKC DAG Activated PKC 2. 1 is in the vascular smooth muscle 2. 2: via Gi 1. Agonist (clonidine) presynaptic terminal 2 receptor decreased cAMP production inhibition of NE release inhibition of sympathetic nerve function 2. 2 is located presynaptically 3. 1, 2: via Gs 1. Agonist (Dobutamine) 1 increased adenylyl cycalse activity increases cAMP various effects depending on tissue 2. Heart: increased cAMP kinase activation increased Ca influx increased heart rate, contraction, conduction speed. 3. Smooth muscle/bronchioles: a. Normal: Ca influx activation of myosin light chain kinase (MLCK) phosphorylation of myosin light chain contraction of vascular smooth muscle b. Albuterol 2 increased cAMP reduced MLCK less LC phosphorylation relaxation 4. D1: Gs IV. Organ system effects a. Cardiovascular system 1. 1 (most important): Increases calcium influx in myocardium

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1. Increased pacemaker activity chronotropic 2. Increased conduction velocity dromotropic 3. Increased intrinsic contractility, accelerated relaxation ionotropic 2. 1: in smooth muscle (skin, splanchnic vessels): 1. causes contraction of vessels increase blood pressure 3. 2: in skeletal muscle 1. causes relaxation of vessels decreased blood pressure, baroreflex in HR b. Respiratory tract 1. 2: in bronchial smooth muscle 1. Causes bronchodilation 2. Albuterol (asthma): 2 agonist 2. 2: in nasal vessels 1. Cause contraction reduce congestion c. Gastrointestinal tract 1. , : on smooth muscle/neurons of enteric NS 2. Stomach and intestine 1. motility and tone (2 and 2) 2. Sphincters: contraction (1) 3. Secretion (intestine ): inhibition of salt/water secretion (2) d. Genitourinary tract 1. Urinary bladder 1. Detrusor or bladder wall: relaxes (2) 2. Trigone, sphincter, prostate gland: constricts (1) 3. Maintains continence 2. Sex organs 1. Ejaculation (1) 2. Relaxation of uterine smooth muscle (2) e. Metabolic and hormonal effects 1. Kidney: Renin release (1) increased bp 2. Pancreatic cells: Stimulate insulin release (2) 3. Liver and skeletal muscle: glycogenolysis (2) 4. Fat cells: Lipolysis (3) increased release of FFAs and glycerol into blood f. CNS 1. Catecholamines: no CNS effects (cant cross BBB) 2. Amphetamine: CNS effects (can cross BBB); depends on dosage 1. Release of dopamine in certain dopaminergic tracts 2. Beginning w/ mild alertness/reduction of fatigue 3. Progressing to anorexia, Eye Effect Action euphoria, insomnia 4. High doses lead to Iris: radial 1 Contraction Mydriasis marked anxiety or muscle aggressiveness, Ciliary muscle 2 Relaxation Far vision, paranoia, sometimes epithelium aqueous humor convulsions secretion g. Eye 1. Phenylephrine (1 agonist): mydriatic 2. Apraclonidine (2 agonist): decreased IOP, treatment of glaucoma Pharmacokinetics a. Structure activity relationship of sympathomimetic drugs 1. Responsible for: 1. Different receptor selectivity of sympathmimetics

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2. Different distribution of drugs 3. Different actions 4. Different duration b. Catecholamines: epinephrine, norepinephrine, isoproterenol, dopamine, dobutamine 1. Cant be given orally (metabolized quickly) 2. Short half life, short duration (min) 3. Cant cross BBB 4. Why? 1. Catechol group MAO, COMT degredation in liver, gut wall 2. High polarity c. Non-catecholamines Drug Oral activity Duration Amphetamine Yes Hours Phenylephrine Poor Hours Albuterol Yes Hours Terbutaline Drug Action a. Endogenous Catecholamines (direct acting) 1. Epinephrine (1 = 2; 1 = 2) 1. Pharmacologic effects: a. Cardiovascular i. Cardiac contractility, HR: increased, 1 ii. Vasoconstriction: increases, 1 increased systolic BP iii. Vasodilation in muscle: 2 decreased diastolic BP iv. Bronchodilation 2 b. Therapeutic use: i. Anaphylactic shock ii. Promotes vasoconstriction 2. Norepinephrine (1 = 2; 1 >> 2) 1. Pharmacologic effects: a. Increased: peripheral resistance, cardiac output b. Increased: diastolic, systolic BP c. Initial increase in HR baroreflex decreases heart rate 2. Therapeutic use: hypotensive emergency 3. Dopamine (DA) 1. Activates D1 receptors renal and splanchnic vasodilation 2. Dopamine activates 1 receptors in the heart 3. Vasoconstriction at high concentration 4. Phenylephrine (1 > 2 >>> ) 1. Pharmacologic effects: a. pure agonist b. Not inactivated by COMT longer duration c. Vasoconstriction, increased bp, reflex bradycardia 2. Therapeutic uses a. Nasal decongestant (due to nasal vasoconstriction) b. Pressor agent c. Mydriasis d. To provide local vasoconstriction in local anesthetics e. Postural hypotension: midodrine 5. Dobutamine: (1>2>>>) 1. Pharmacologic effects

a. Directly activate 1 b. Greater inotropic than chronotropic c. Minimal changes in HR and systolic BP 2. Therapeutic uses a. Improve myocardial function in heart failure 6. Isoproterenol (1 = 2 >>a) 1. Pharmacologic effects a. 1: increased cardiac contractility and heart rate b. 2: i. peripheral vasodilation (skeletal muscle, renal, mesenteric vascular beds ii. Decrease in mean BP; marked drop in diastolic BP iii. Muscle relaxation (bronchial and GI smooth) 2. Therapeutic uses a. Bronchodilator (asthma) b. Cardiac stimulant for heart block or severe bradycardia 7. Albuterol, terbutaline (2) 1. Pharmacologic: a. Tracheal, bronchial smooth muscle dilation b. Uterine smooth muscle dilation (terbutaline) 2. Therapeutic use: Asthma Selective Agonist 1 type 2 type 1 2 E=NE>> ISO Phenylephrine Midodrine Clonidine Dobutamine Mechanism Increase: IP3, DAG, Ca2+ Decrease: cAMP, Ca2+ Location Vascular SM Presynaptic Effect Contraction Shock Local anesthesia Antihypertensive Cardiac stimulant in heart failure Asthma Clinical Uses

Inhibition of transmitter release Increased HR, contractility Bronchodilation

Albuterol

Increased adenyl Heart cyclase, cAMP, Ca2+ Increased adenyl Bronchiole cyclase, cAMP Decreased MLCK

b. INDIRECT acting 1. Amphetamine like drugs (displacers) 1. Pharmacologic effects a. Induces NE release: Competes with NE for vesicular uptake pushes NE out of vesicles NE reverse transport occurs (NE is transported back out into synaptic cleft) b. CNS stimulant c. Resistant to COMT metabolism 2. Therapeutic uses a. Mood elevating (euphoriant) effect b. Narcolepsy: sleep deferring action (ex: modafinil) c. Treatment of ADHD (ex: methylphenidate) 2. Tyramine: tyrosine byproduct found in [high] in fermented foods (cheese) 1. Pharmacologic effects

a. Release of stored catecholamines: competes with NE in nerve terminal for transporter. Causes same effect as amphetamine, once imported. b. Normally metabolized by MAO in liver. c. MAO inhibitors + tyramine increase in BP d. MAO inhibitors i. Antidepresssants: phenelzine ii. Parkinsons diseases: selegiline 3. Cocaine 1. Pharmacologic effects a. Potent dopamine transporter block euphoria b. Block NET c. Block sodium channels in nerves local anesthetic d. Potent central nervous system stimulant e. Euphoria, increased BP, increase HR (low dose) f. Hallucinations, delusion, seizure, death (high dose) Clinical Application 1. Cardiovascular applications 1. Conditions in which blood flow or BP need to be enhanced a. Cardiogenic shock (acute heart failure), usually due to massive MI: Dopamine or dobutamine: positive inotropic agents b. Chronic Orthostatic hypotension: midodrine 2. Conditions in which blood flow needs to be reduced a. Phenylephrine: nasal decongestant spray, local anesthetics b. Epinephrine: local anesthetics 2. Pulmonary applications 1. Anaphylaxis (bronchospasm, vasodilation) a. Epinephrine reduces symptoms b. Asthma: 2 agonists (albuterol) dilates bronchioles 3. Ophthalmic applications 1. Phenylephrine: mydriatic agent 2. Apraclonidine (2): Glaucoma in IOP due to aqueous secretion 4. Genitourinary applications 1. Ritodrine, terbutaline (2): suppresses premature labor Toxicity of Sympathomimetic Drugs a. Selective 1 adrenergic agonists: hypertension b. -receptor stimulant drugs: tachycardia, arrhythmias

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