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  • 1. INTRODUCTION: SYMPATHETIC AUTONOMIC PHARMACOLOGY I Philip J. Kadowitz, Ph.D.
  • 2. Learning Objectives
    • Describe the anatomy of the sympathetic nervous system.
    • Explain the actins of the transmitters of the autonomic nervous system.
    • Describe responses mediated by adrenergic receptors.
    • Describe how adrenergic receptors regulate cardiovascular function.
    • Drugs : tyramine, ephedrine, dexamphetamine, cocaine, imipramine, bretylium, reserpine, guanethidine, pargyline, methyldopa, octopamine
  • 3. A. SYMPATHETIC NEUROTRANSMITTERS
    • 1. Preganglionic - acetylcholine (nicotinic)
    • 2. Postganglionic - catecholamine (norepinephrine, epinephrine, dopamine)
    • a. Norepinephrine - primary transmitter released by sympathetic nerves
    • b. Epinephrine - released by adrenal medulla
    • - circulating hormone
    • - adrenal medulla is a nicotinic site
    • c. Dopamine - released by nerve stimulation
    • - precursor for norepinephrine
    • d. Storage of catecholamines - in dense core vesicles in nerve terminal of adrenergic nerve
    • Norepinephrine, dopamine, dopamine  -hydroxylase, ATP, chromagranin (a soluble protein)
    • All released by adrenergic stimulation (exocytosis - calcium-dependent process).
  • 4.
    • SITE OF ACTION OF CATECHOLAMINES – ADRENERGIC RECEPTORS
  • 5. C. EFFECTS ON RECEPTORS
    • 1. Norepinephrine  1 ,  2 , ß 1 >> ß 2
    • ● postganglionic neurotransmitter
    • ● activates  receptors and causes vasoconstriction, mydriasis, constriction of pyloric, intestinal and bladder sphincters
    • ● activates ß 1 receptors and increases
      • - heart rate
            • - heart contractility - inotropic action
            • - arrhythmias (ectopic beats, etc.)
        • ● stored in dense core vesicles (97%) and in cytoplasmic pools
        • (3%)
  • 6. C. EFFECTS ON RECEPTORS (cont’d)
    • 2. Epinephrine  + ß effects
    • ● ß effects occur at lower doses
    • ●  effects occur at higher doses
    • 3. Isoproterenol (ISUPREL®)
    • ● ß agonist ß 1 and ß 2 stimulant
    • ● used as a bronchodilator and cardiac stimulant
    • ● produces only vasodilation
  • 7. C. EFFECTS ON RECEPTORS (cont’d)
    • 4. Dopamine (INOTROPIN®)
    • ● acts at dopamine receptors to produce vasodilation of mesenteric and renal vessels
    • ● possesses ß 1 and  2 effects at higher doses
    • ● used in shock to support blood pressure
    • ● used in heart failure
    • 5. Dobutamine
    • ● acts at ß 1 receptors
    • ● used in cardiogenic shock
    • ● used in heart failure
  • 8.  
  • 9. Figure 6-1. Schematic diagram comparing some anatomic and neurotransmitter features of autonomic and somatic motor nerves. Only the primary transmitter substances are shown. Parasympathetic ganglia are not shown because most are in or near the wall of the organ innervated. Note that some sympathetic postganglionic fibers release acetylcholine or dopamine rather than norepinephrine. The adrenal medulla, a modified sympathetic ganglion, receives sympathetic preganglionic fibers and releases epinephrine and norepinephrine into the blood. (ACh, acetylcholine; D, dopamine; Epi, epinephrine; NE, norepinephrine; N, nicotinic receptors; M, muscarinic receptors.)
  • 10. Figure 10–2. Effects of Intravenous Infusion of Norepinephrine, Epinephrine, or Isoproterenol in Human Beings. (Modified from Allwood Et Al., 1963 , with Permission.)
  • 11. Figure 6-3. Schematic illustration of a generalized cholinergic junction (not to scale). Choline is transported into the presynaptic nerve terminal by a sodium-dependent carrier (A). This transport can be inhibited by hemicholinium drugs. ACh is transported into the storage vesicle by a second carrier (B) that can be inhibited by vesamicol. Peptides (P), ATP, and proteoglycan are also stored in the vesicle. Release of transmitter occurs when voltage-sensitive calcium channels in the terminal membrane are opened, allowing an influx of calcium. The resulting increase in intracellular calcium causes fusion of vesicles with the surface membrane and exocytotic expulsion of ACh and cotransmitters into the junctional cleft. This step is blocked by botulinum toxin. Acetylcholine's action is terminated by metabolism by the enzyme acetylcholinesterase. Receptors on the presynaptic nerve ending regulate trans-mitter release. (SNAPs, synaptosome-associated proteins; VAMPs, vesicle-associated membrane proteins.)
  • 12. The enzymes involved are shown in blue; essential cofactors, in italics. The final step occurs only in the adrenal medulla and in a few epinephrine-containing neuronal pathways in the brainstem.
  • 13. Figure 6-6. Metabolism of catecholamines by catechol- O- methyltransferase ( COMT ) and monoamine oxidase (MAO). (Modified and reproduced, with permission, from Greenspan FS, Gardner DG (editors): Basic and Clinical Endocrinology, 7th ed. McGraw-Hill, 2003.)