Autonomic Nervous SystemSlide 2Slide 3Adrenergic SystemSlide 5Adrenergic System - AgonistsSlide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Adrenergic System - AntagonistsSlide 17Slide 18Slide 19Slide 20Slide 21BIMM118Autonomic Nervous SystemBIMM118Autonomic 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!BIMM118Autonomic Nervous SystemTransmitters:•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!)BIMM118Adrenergic SystemTermination 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 2-receptors–Negative feedback that inhibits norepinephrine releaseBIMM118Adrenergic SystemAdrenergic receptors:•alpha 1 –most vascular smooth muscles–Activate PLCCa++ => Contraction•alpha 2 –mostly presynaptic –Inhibit adenylate cyclase (Gi)•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)BIMM118Adrenergic System - AgonistsSympathomimeticsIndirect 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•MoclobemidePossibility of severe adverse interactions of MAO inhibitors with numerous other drugs => fatal hypertensionBIMM118Adrenergic System - AgonistsSympathomimeticsIndirect 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 HuangThe 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. In Feb ‘04, the agency has banned the marketing of dietary supplements containing ephedrine alkaloids (ban challenged by court order in April ‘05).Epinephrine EphedrineBIMM118Adrenergic System - AgonistsSympathomimeticsIndirect 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!EphedrineBIMM118Adrenergic System - AgonistsSympathomimeticsNon-selective agonists:•Epinephrine (Adrenaline) –Activates both and 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 receptors => systolic and diastolic blood pressure increase–Very potent vasopressor => Clinical uses limited to severe shock treatmentBIMM118Adrenergic System - AgonistsSympathomimetics1 - selective agonists Clinical applications:•Methoxamine–Treatment of hypotensive state•Phenylephrine–(Local) vasoconstrictor nasal decongestantEpinephrine PhenylephrineBIMM118Adrenergic System - AgonistsSympathomimetics - 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 mucosaBIMM118Adrenergic System - AgonistsSympathomimetics - selective agonists Phenotypically produce sympatholytic effects!Activate presynaptic receptors in the cardiovascular control center in the CNS => reduced sympathetic nervous system activity => blood pressure decrease Clinical applications:Hypertension•Clonidine•GuanfacineBIMM118Adrenergic System - Agonists1 - receptors•Mostly in heart•Increase contractility = “positive inotrope”•Increase heart rate = “positive chronotrope” - receptors•Respiratory system – located in bronchial smooth muscle•Produce bronchial dilationBIMM118Adrenergic System - AgonistsSympathomimetics - 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 exerciseEpinephrine DobutamineBIMM118Adrenergic System - AgonistsSympathomimetics - selective agonists Clinical applications:Asthma:•Non-selective sympathomimetics => strong cardiac side effects• - 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
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