BIMM 118 Autonomic Nervous System Autonomic Nervous System

BIMM 118 Autonomic Nervous System

Autonomic Nervous System • Ganglia close to the innervated organs • Ganglia close to the spinal column • Myelinated axons • Preganglionic axons are myelinated; postganglionic axons are unmyelinated BIMM 118 • Note: Somatic nervous system has no ganglia!

Autonomic Nervous System Transmitters: • Acetylcholine: – ALL preganglionic neurons – ALL parasympathetic postganglionic neurons • Norepinephrine (= Noradrenalin): – MOST sympathetic postganglionic neurons – Exceptions: Sweat glands (Acetylcholine); Renal arteries (Dopamine) • Epinephrine (= Adrenalin): BIMM 118 – Adrenal medulla upon sympathetic impulses (no ganglion!)

Adrenergic System Termination of (nor)epinephrine action: • Reuptake into presynaptic nerve ending – Predominant mechanism – active transport; inhibited by Cocaine • Catechol-O-methyltransferase (COMT) – In the cytoplasm of post-junctional cells • Monoamino-oxidase (MAO) – In mitochondria of nerve and post-junctional cells • Presynaptic a 2 -receptors BIMM 118 – Negative feedback that inhibits norepinephrine release

Adrenergic System Adrenergic receptors: • alpha 1 – most vascular smooth muscles – Activate PLCb => Ca++ => Contraction • alpha 2 – mostly presynaptic – Inhibit adenylate cyclase (Gai) • beta 1 – mostly heart – Activate adenylate cyclase • beta 2 – respiratory and uterine smooth muscle – Activate adenylate cyclase • beta 3 BIMM 118 – mostly adipocytes – Activate adenylate cyclase => lipolysis • (Dopamine)

Adrenergic System - Agonists Sympathomimetics Indirect Sympathicomimetics: MAO - Inhibitors: – Inhibition of MAO causes increase in free Norepinephrine – In the CNS, MAO also metabolizes dopamine and serotonin => MAO inhibitors trigger increase in these “happy hormones” => uses as antidepressants – Irreversible inhibition of MAO => long-lasting effect (weeks!) • Tranylcypromine • Moclobemide BIMM 118 Possibility of severe adverse interactions of MAO inhibitors with numerous other drugs => fatal hypertension

Adrenergic System - Agonists Sympathomimetics Epinephrine Ephedrine Indirect Sympathicomimetics : • Ephedrine – – Chief alkaloid in Ephedra, no clinical use Displace norepinephrine in storage vesicle => forced norepinephrine release Found in many dietary supplements: “Energy-Boosters”, Diet pills (Metabolife®) etc. Ingredient in many herbal preperations: Ephedra, Ma Huang The FDA has received more than 800 reports of adverse effects associated with use of products containing ephedrine alkaloid since 1994. These serious adverse effects, include hypertension (elevated blood pressure), palpitations (rapid heart rate), neurophathy (nerve damage), myopathy (muscle injury), psychosis, stroke, memory loss, heart rate irregularities, insomnia, nervousness, tremors, seizures, heart attacks, and death. BIMM 118 In Feb ‘ 04, the agency has banned the marketing of dietary supplements containing ephedrine alkaloids (ban challenged by court order in April ‘ 05).

Adrenergic System - Agonists Sympathomimetics Indirect Sympathicomimetics : Amphetamines – Displace norepinephrine in storage vesicle => forced epinephrine release – Also inhibit norepinephrine re-uptake and degradation by MAO (“triple action”) • Methylphenidate (Ritalin®) – Treatment of ADD • Fenfluramine – Appetite suppressant (now banned in US) (combined with Phentermine = “Fen. Phen”) • Metamphetamine/MDMA BIMM 118 – Effectiveness disappears due to catecholamine depletion of vesicles => post-use depression => urge for re-administration! Ephedrine

Adrenergic System - Agonists Sympathomimetics Non-selective agonists: • Epinephrine (Adrenaline) – – – • Activates both a and b receptors; Blood pressure increase, but effect on systolic pressure dominant Dilates bronchii Potent vasopressor => Clinical uses limited Used for: symptomatic treatment of anaphylactic shock (Epi-Pen®) adjuvant in local anesthetics (increases duration, reduces bleeding) Norepinephrine (Noradrenaline) BIMM 118 – Activates mostly a receptors => systolic and diastolic blood pressure increase – Very potent vasopressor => Clinical uses limited to severe shock treatment

Adrenergic System - Agonists Sympathomimetics a 1 - selective agonists Clinical applications: • Methoxamine – Treatment of hypotensive state • Phenylephrine – (Local) vasoconstrictor nasal decongestant BIMM 118 Epinephrine Phenylephrine

Adrenergic System - Agonists Sympathomimetics a 1 - selective agonists (cont’d) Clinical applications: Nasal decongestants (mostly OTC): • Naphazoline (Privine®, Rhinon®) • Oxymetazoline (Afrin®, etc. ) • Xylometazoline (Privin®) BIMM 118 Should be used less than 10 days, otherwise reactive hyperemia (“rhinitis medicamentosa”) develops! Continued used can result in local hypoxia => atrophic damage of the nasal mucosa

Adrenergic System - Agonists Sympathomimetics a 2 - selective agonists Phenotypically produce sympatholytic effects! Activate presynaptic a 2 receptors in the cardiovascular control center in the CNS => reduced sympathetic nervous system activity => blood pressure decrease BIMM 118 Clinical applications: Hypertension • Clonidine • Guanfacine

Adrenergic System - Agonists b 1 - receptors • • • Mostly in heart Increase contractility = “positive inotrope” Increase heart rate = “positive chronotrope” b 2 - receptors BIMM 118 • • Respiratory system – located in bronchial smooth muscle Produce bronchial dilation

Adrenergic System - Agonists Sympathomimetics b 1 - selective agonists Clinical applications: • Dobutamine – Strong inotropic effect with little chronotropic effect => increase in cardiac output without significant increase in heart rate – Short-term treatment of impaired cardiac function after cardiac surgery, MI etc. – Also used in “Dobutamine Stress Test” = Heart sonogram: Dobutamine mimics exercise BIMM 118 Epinephrine Dobutamine

Adrenergic System - Agonists Sympathomimetics b 2 - selective agonists Clinical applications: BIMM 118 Asthma: • • Non-selective sympathomimetics => strong cardiac side effects b 2 - selective agonists target predominantly the respiratory system Drugs differ in speed of onset and in duration of action => acute vs. long-term treatment Additionally, preferential activation of pulmonary receptors due to application as aerosols • • • Metaproterenol (Alupent®) Albuterol = Salbutamol (Ventolin®) Formoterol (Foradil®) • Etc…

Adrenergic System - Antagonists Sympatholytics a - selective antagonists Promote vasodilation => decreased peripheral resistance => blood pressure (Side effects: reflex tachycardia and postural hypotension) Relaxation of the smooth muscles in the bladder neck Clinical applications: Hypertension; Urinary retention Non-selective a-antagonist: • • Phentolamine (for pheochromocytoma) Ergot alkaloids see 5 HT receptor a 1 -selective antagonists: • Prazosin (Minipress®) BIMM 118 first a 1 - selective antagonist • • Terazosin longer half-life Doxazosin longer half-life

Adrenergic System - Antagonists Sympatholytics a 2 - selective antagonists • Yohimbine BIMM 118 – Chief active compound in Pausinystalia yohimbine (bark) – Effects opposite of Clonidine – Enters CNS => increased sympathetic output => increased heart rate, blood pressure, can cause severe tremors – Ingredient in many weight loss products – Extensive (past) use in treatment of male sexual dysfunction

Adrenergic System - Antagonists Sympatholytics b - selective antagonists (”b - blockers”) b 2 - selective antagonists would trigger bronchial constriction => no clinical use b 2 - antagonism is mostly an “undesired side effect” of b-selective antagonists (goal is to antagonize b 1 - receptors) Non-cardiac effects: CNS - anxiolytic; skeletal muscle - reduction of tremor BIMM 118 Clinical applications: • Angina pectoris • Hypertension • Cardiac dysrhythmias • MI • Heart failure • Familial tremor • “Stage fright”

Adrenergic System - Antagonists Sympatholytics b - selective antagonists • • • First-generation b-receptor antagonists blocked b 1 and b 2 -receptors = noncardioselective (b-receptors in the heart are b 1 - receptors). Many b-receptor antagonists posses intrinsic agonist activity Basic conserved structure: Norepinephrine side chain linked to aromatic structure by a methylene-oxygen bridge. Prototype: • Propranolol BIMM 118 Epinephrine

Adrenergic System - Antagonists Sympatholytics b - selective, noncardioselective antagonists (cont’d): • • Nadolol Pindolol Timolol Labetalol - also antagonistic on a 1 - receptors => potent antihypertonic drug b 1 - specific “cardioselective” antagonists: BIMM 118 • • • Metoprolol Atenolol Esmolol - quick onset / short duration => used in urgent settings

Adrenergic System - Antagonists b-Sympatholytics BIMM 118 Epinephrine