Nursing Pharmacology:  Autonomic (ANS) Pharmacology: Introduction

• Other Autonomic Neurotransmitters/Cotransmitters

  • ATP

    • ATP and catecholamines are found together in neuronal and adrenal medullary storage granules. ATP is released along with transmitters and, in certain cases, has an important role in synaptic transmission.

  • Vasoactive Intestinal Peptide (VIP)

    • Vasoactive intestinal peptide (VIP) is found in association with ACh in autonomic parasympathetic fibers innervating blood vessels and exocrine glands and cholinergic sympathetic fibers innervating sweat glands.

    • VIP may be involved in salivation, tracheal and the GI tract responsiveness to parasympathetic input.

  • Neuropeptide Y Family

    • The neuropeptide Y family includes NPY, pancreatic polypeptide, and peptide YY.

    • NPY in the periphery is associated with sympathetic fibers and assists in maintaining vascular tone.

    • NPY is a potent, long-lasting vasoconstrictor, especially of small vessels

  • Purines

    • Purines such as ATP and adenosine may be responsible for apparent non-cholinergic, non-adrenergic autonomic neurotransmission.

  • Nitric Oxide

    • Blood vessel endothelium is required for ACh-mediated smooth muscle relaxation.

    • The endothelial cell layer modulates vessel responsiveness to autonomic and hormonal influences.

    • Endothelial cell elaborate endothelium-derived relaxing factor (EDRF, nitric oxide) and a contracting factor.

    • Pharmacological actions of serotonin, histamine, bradykinin, purines, thrombin are mediated to some degree by stimulation of EDRF release.

    • Endothelial-released nitric oxide diffuses into vascular smooth muscle and activates guanylyl cyclase which increases cGMP.

    • Clinically, hypotension associated with endotoxemia may be mediated partially by increased release of nitric oxide. A similar mechanism is proposed for hypotension induced by cytokines.

  Predominant Sympathetic or Parasympathetic Tone

  Antatomical Site	Predominant Autonomic Tone
  Arterioles	Sympathetic-adrenergic
  Veins	Sympathetic-adrenergic
  Heart	Parasympathetic-cholinergic
  Ciliary Muscle	Parasympathetic-cholinergic
  Gastrointestinal Tract	Parasympathetic-cholinergic
  Salivary Glands	Parasympathetic-cholinergic
  Sweat Glands	Sympathetic-cholinergic

  Taylor, P. Agents Acting at the Neuromuscular Junction and Autonomic Ganglia In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp.193-195. Adapted from Table 9-3

  Baroreceptor Reflexes

  A principal mechanism for arterial blood pressure control is the baroreceptor reflex. The reflex is initiated by activation of stretch receptors located in the wall of most large arteries of the chest and neck. A high density of baroreceptors is found in the wall of each internal carotid artery (just above the carotid bifurcation i.e. carotid sinus) and in the wall of the aortic arch. →   As pressure rises and especially for rapid increases in pressure: Baroreceptor input to the tractus solitarius of the medulla results in inhibition of the vasoconstrictor center and excitation of the vagal (cholinergic) centers resulting in: Vasodilatation of the veins and arterioles in the peripheral vascular beds. Negative chronotropic and inotropic effects on the heart. (slower heart rate with reduced force of contraction).

   

   

  Pharmacological Modification of Autonomic Function

  • Transmitter Synthesis: Site 1

    • Cholinergic

      • Hemicholinium (HC-3) blocks the choline transport system into the nerve ending, thus limiting acetylcholine (ACh) synthesis.

    • Adrenergic

      • α-methyltyrosine inhibits tyrosine hydroxylase thus preventing synthesis of norepinephrine.

      • Methyldopa inhibits aromatic amino acid decarboxylase and is itself decarboxylated and hydroxylated to form the "false transmitter" α-methyl norepinephrine.

       

  • Transmitter Release: Site 2

    • Cholinergic

      • Botulinum toxin can be used clinically to treat ocular muscle spasms, muscle dystonias, and spasms.

      • Botulinus toxin binding at a presynaptic site blocks ACh release.

      • Vesamicol blocks ACh transport into storage vesicles, thus limiting release.

    • Adrenergic

      • Bretylium and guanethidine prevent action-potential mediated norepinephrine release.

      • Transient release may occur with these agents because they displace norepinephrine from storage sites.

      • Tyramine, amphetamine, and ephedrine can produce a brief liberation of transmitter.

      • Reserpine, by inhibiting vesicular uptake, produces a slow, depletion of norepinephrine, ultimately causing adrenergic blockade. Cytoplasmic MAO metabolizes the neurotransmitter.

      • Reserpine similarly depletes dopamine and serotonin. Physiological effects of reserpine are due to depletion of many transmitters.

  • Receptor Interactions: Site 3

    • Cholinergic

      • Tetraethylammonium, trimethaphan and hexamethonium are nicotinic ganglionic antagonists.

      • Decamethonium, a depolarizing drug, selectively causes neuromuscular blockade.

      • All classes of muscarinic receptors are blocked by atropine.

    • Adrenergic

      •  Phenylephrine (Neo-Synephrine):  an α₁ receptor agonist.

      •  Clonidine (Catapres): an α₂ receptor agonist.

      •  Prazosin (Minipress): an example of an α₁ receptor antagonist.

      •  Yohimbine (Yocon): an example of an α₂ receptor antagonist.

      •  Isoproterenol (Isuprel): ß₁ and ß₂ receptor agonist.

      •  Dobutamine (Dobutrex):  a relatively selective myocardial ß₁ receptor agonist.

      •  Terbutaline (Brethine):  relatively selective ß₂ receptor agonist.

      •  Propranolol (Inderal):  an example of a non-selective β-adrenergic receptor blocker.

      •  Metoprolol (Lopressor):  an example of a relatively selective ß₁ receptor antagonist.

  • Termination of Transmitter Effects: Site 4

    • Cholinergic

      • Acetylcholinesterase inhibitors prevent breakdown and inactivation of acetylcholine.

        • ACh accumulation at the neuromuscular junction causes flacid paralysis.

        • ACh accumulation at postganglionic muscarinic sites results in either excessive stimulation (contraction & secretion) or inhibition (hyperpolarization), depending on the site.

        • ACh accumulation at autonomic ganglia cause increased transmission.

    • Adrenergic

      • Interference with neurotransmitter reuptake results in potentiation of catecholamine effects.

      • Cocaine and imipramine are examples of drugs that inhibit the reuptake system.

      • Monoamine oxidase (MAO) inhibitors potentiate actions of tyramine; whereas catechol-O-methyl transferase (COMT) inhibitors (pyrogallol and tropolone) only slightly increase catecholamine effects.