BIMM118. Autonomic Nervous System
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1 Autonomic Nervous System
2 Autonomic Nervous System Ganglia close to the innervated organs Myelinated axons Ganglia close to the spinal column Preganglionic axons are myelinated; postganglionic axons are unmyelinated Note: Somatic nervous system has no ganglia!
3 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): Adrenal medulla upon sympathetic impulses (no ganglion!)
4 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 α2-receptors Negative feedback that inhibits norepinephrine release
5 Adrenergic System Adrenergic receptors: alpha 1 most vascular smooth muscles Activate PLCβ => Ca ++ => Contraction alpha 2 mostly presynaptic Inhibit adenylate cyclase (Gα i ) beta 1 mostly heart Activate adenylate cyclase beta 2 respiratory and uterine smooth muscle Activate adenylate cyclase beta 3 mostly adipocytes Activate adenylate cyclase => lipolysis (Dopamine)
6 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 Possibility of severe adverse interactions of MAO inhibitors with numerous other drugs => fatal hypertension
7 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 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. In Feb 04, the agency has banned the marketing of dietary supplements containing ephedrine alkaloids (ban challenged by court order in April 05).
8 Sympathomimetics Adrenergic System - Agonists 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 = FenPhen ) Metamphetamine/MDMA Effectiveness disappears due to catecholamine depletion of vesicles => post-use depression => urge for re-administration! Ephedrine
9 Adrenergic System - Agonists Sympathomimetics Non-selective agonists: Epinephrine (Adrenaline) Activates both α and β 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) Activates mostly α receptors => systolic and diastolic blood pressure increase Very potent vasopressor => Clinical uses limited to severe shock treatment
10 Sympathomimetics Adrenergic System - Agonists α 1 - selective agonists Clinical applications: Methoxamine Treatment of hypotensive state Phenylephrine (Local) vasoconstrictor nasal decongestant Epinephrine Phenylephrine
11 Adrenergic System - Agonists Sympathomimetics α 1 - selective agonists (cont d) Clinical applications: Nasal decongestants (mostly OTC): Naphazoline (Privine, Rhinon ) Oxymetazoline (Afrin, etc.) Xylometazoline (Privin ) 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
12 Adrenergic System - Agonists Sympathomimetics α 2 - selective agonists Phenotypically produce sympatholytic effects! Activate presynaptic α 2 receptors in the cardiovascular control center in the CNS => reduced sympathetic nervous system activity => blood pressure decrease Clinical applications: Hypertension Clonidine Guanfacine
13 Adrenergic System - Agonists β 1 - receptors Mostly in heart Increase contractility = positive inotrope Increase heart rate = positive chronotrope β 2 - receptors Respiratory system located in bronchial smooth muscle Produce bronchial dilation
14 Adrenergic System - Agonists Sympathomimetics β 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 Epinephrine Dobutamine
15 Adrenergic System - Agonists Sympathomimetics β 2 - selective agonists Clinical applications: Asthma: Non-selective sympathomimetics => strong cardiac side effects β 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
16 Adrenergic System - Antagonists Sympatholytics α - 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 α-antagonist: Phentolamine (for pheochromocytoma) Ergot alkaloids see 5HT receptor α 1 -selective antagonists: Prazosin (Minipress ) first α 1 - selective antagonist Terazosin longer half-life Doxazosin longer half-life
17 Adrenergic System - Antagonists Sympatholytics α 2 - selective antagonists Yohimbine 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
18 Adrenergic System - Antagonists Sympatholytics β - selective antagonists ( β - blockers ) β 2 - selective antagonists would trigger bronchial constriction => no clinical use β 2 - antagonism is mostly an undesired side effect of β-selective antagonists (goal is to antagonize β 1 - receptors) Non-cardiac effects: CNS - anxiolytic; skeletal muscle - reduction of tremor Clinical applications: Angina pectoris Hypertension Cardiac dysrhythmias MI Heart failure Familial tremor Stage fright
19 Adrenergic System - Antagonists Sympatholytics β - selective antagonists First-generation β-receptor antagonists blocked β 1 and β 2 -receptors = noncardioselective (β-receptors in the heart are β 1 - receptors). Many β-receptor antagonists posses intrinsic agonist activity Basic conserved structure: Norepinephrine side chain linked to aromatic structure by a methylene-oxygen bridge. Prototype: Propranolol Epinephrine
20 Adrenergic System - Antagonists Sympatholytics β - selective, noncardioselective antagonists (cont d): Nadolol Pindolol Timolol Labetalol - also antagonistic on α 1 - receptors => potent antihypertonic drug β 1 - specific cardioselective antagonists: Metoprolol Atenolol Esmolol - quick onset / short duration => used in urgent settings
21 Adrenergic System - Antagonists β-sympatholytics Epinephrine
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