Nursing Pharmacology Autonomic (ANS) Pharmacology: Introduction

• Fight or Flight: General Functions of the Autonomic Nervous System

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    "Fight or Flight Response"

    "Paul Andersen explains how epinephrine is responsible for changes in chemistry of our body associated with the fight or flight response. Epinephrine released by the adrenal medulla is received by a number of organs associated with the sympathetic nervous system." Bozeman Biology https://www.youtube.com/watch?v=m2GywoS77qc

  • ANS regulates organs/processes not under conscious control including:

    1. Circulation

    2. Digestion

    3. Respiration

    4. Temperature

    5. Sweating

    6. Metabolism

    7. Some endocrine gland secretions

  • Sympathetic system is most active when the body needs to react to changes in the internal or external environment.

    •  The requirement for sympathetic activity is most critical for:

      1. Temperature regulation

      2. Regulation of glucose levels

      3. Rapid vascular response to hemorrhage

      4. Reacting to oxygen deficiency

  • During rage or fright the sympathetic system can discharge as a unit--affecting multiorgan systems.

    • Sympathetic fibers show greater ramification.

    • Sympathetic preganglionic fibers may traverse through many ganglia before terminiating at its post-ganglionic cell. Synaptic terminal arborization results in a single preganglionic fiber terminating on many post-ganglionic cells.

    • This anatomical characteristic is the basis for the diffuse nature of sympathic response in the human and other species.

  •  Sympathetic Responses

    1. Heart rate increases

    2. Blood pressure increases

    3. Blood is shunted to skeletal muscles

    4. Blood glucose increase

    5. Bronchioles dilate

    6. Pupils dilate

  • Parasympathetic responses

    1. Slows heart rate

    2. Protects retina from excessive light

    3. lowers blood pressure

    4. Empties the bowel and bladder

    5. Increases gastrointestinal motility

    6. Promotes absorption of nutrients

Lefkowitz, R.J, Hoffman, B.B and Taylor, P. Neurotrasmission: The Autonomic and Somatic Motor Nervous Systems, 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) TheMcGraw-Hill Companies, Inc.,1996, pp.108.

• Neurotransmitters and the Autonomic Nervous System

  • Neurotransmitter Criteria: 

    • To support the idea that a chemical is a neurotransmitter, several conditions must be satisfied

    The chemical should be found in the appropriate anatomical location (e.g. synaptic terminal)

    • Enzymes that are involved in "transmitter" synthesis should also be present.

    • Where possible (as in autonomic transmission), recovery of the "transmitter" in higher quantities following nerve stimulation than in the absence of stimulation.*

    • Externally applied (e.g. iontophoretically applied) chemical produces the same effect as stimulation. For example, the reversal potential is the same.

    • Effects of antagonists influence the response to externally applied chemical in the same manner as antagonists modify responses following nerve stimulation.

    * may not be possible in many instances

  • Neurotransmission Steps

    • Axonal conduction

      • Depolarization of the axonal membrane potential results in an action potential.

      • The upstoke of the action potential is a sodium current flowing through voltage-activated sodium channels

      • As the membrane potential decreases, activation occurs of an outgoing potassium current, which opposes further depolarization and initiates repolarization.

      • Longitudinal spread of local depolarizing sodium currents results in progressive, longitudinal activation of sodium channels and new sites of depolarization. The rate of conduction is dependent on the number and synchrony of sodium channel activation.

      • Number and synchrony of sodium channel activation is membrane potential dependent.

        • As the resting membrane potential decrease (towards 0), fewer sodium channels will be activated by a depolarizing influence and conduction velocity slows.

      • In myelinated fibers, depolarization occurs at the Nodes of Ranvier.

    • Synaptic (Junctional) Activity

      • Storage and Release of Neurotransmitter

      • Small molecule neurotransmitters (e.g. acetylcholine, norepinephrine) are synthesized at axonal terminals and stored in synaptic vesicles.

      • Synaptic Vesicles: These structures contain neurotransmitter and associated molecules

        "The electron micrograph shows synaptic vesicles, purified from rat brain (negative staining, courtesy of Dr. Peter R. Maycox). Each is about 50 nm in diameter (1/20,000th of a millimeter). The inset shows a few vesicles labeled by immunogold for one of the major synaptic vesicle proteins (synaptophysin)."--Research group of Reinhard Jahn "Synaptic vesicles belong to the most abundant organelles in the body.  The human CNS contains about 1011 neurons. Each of these neuron forms on average about 1000 synapses, and each synapse contains about 500 vesicles, resulting in more than 1017 synaptic vesicles.  This is more than eight magnitudes more than the human genome has base pairs!  attribution:  Research group of Dr. Reinhard Jahn

       

      • Isolated neurotransmitter "quanta", perhaps corresponding to single vesicle neurotransmitter quantity, is randomly released in the basal state.

        • This level of release, generating miniature end-plate potentials (mepp's), is necessary for resting skeletal muscle tone.

      • Action Potentials, promoting calcium influx, induce large, synchronous release of several hundred quanta .

        • Calcium facilitates vesicular membrane-synaptic membrane fusion, resulting in vesicular content discharge into the synaptic cleft.

      • Many chemical can inhibit norepinephrine or acetylcholine release through receptor interactions at the appropriate terminal. Examples:

        1. Norepinephrine + presynaptic α₂-adrenergic receptor (autoreceptor) inhibits norepinephrine release

        2. α₂ receptor antagonists increase release of norepinephrine

        3. Neurally-mediated acetylcholine release from cholinergic neurons is inhibited by α₂-adrenergic receptor agonists

        4. Stimulation of presynaptic β₂ adrenergic receptors increases slightly norepinephrine release

      • These agents Inhibit neurally-mediated norepinephrine released by interacting with presynaptic receptors

        • Adenosine

        • Acetylcholine

        • Dopamine

        • Prostaglandins

        • Enkephalins

    • Neurotransmitter + Post-Junctional Receptors  Interactions Lead to Physiological Response

      • Neurotransmitter diffuses across the synaptic cleft and bind to post-junctional receptors causing an increase in membrane conductance (ions flow).

      • Three primary types of changes in conductance (permeability to ions) may occur:

        • Increase in Na⁺ (usually) or Ca⁺ conductance which depolarizes the membrane (EPSP), membrane potential LESS negative, towards threshold.

        • Increase in Cl^- permeability: inward hyperpolarizing flow:  membrane potential MORE negative) (IPSP)

        • Increase in K⁺ permeability; K⁺ leaves the cells, resulting in hyperpolarization (membrane potential is MORE negative), (IPSP)

      • If the EPSP is of sufficient magnitude to cause the membrane potential to reach the threshold potential, an action potential results (e.g. in skeletal or cardiac muscle).

        • In gland cells an EPSP may cause secretion; in other cells, an EPSP may increase the rate of spontaneous depolarization.

      • An IPSP (produced in neurons and smooth, but not skeletal muscle) opposes EPSPs.

      • Definitions: EPSP: excitatory postsynaptic potential; IPSP: inhibitory postsynaptic potential

    • Termination of Transmitter Action

      • Cholinergic: Termination of action of acetylcholine is acetylcholine hydrolysis. (acetylcholinesterase-catalazed)

        • If acetylcholinesterase is inhibited, the duration of cholinergic effect is increased.

      • Adrenergic: Termination of action of adrenergic neurotransmitters is by reuptake and diffusion away from receptors.

      • Amino Acids: Termination of action of amino-acid neurotransmitters is by active transport into neurons and glia

    • Other Nonelectrogenic Functions

      • Basal, quantal release of transmitter in quantities insufficient to generate an EPSP may have other actions.

        • These effects may include:

          • Regulation of neurotransmitter biosynthetic and degradative enzymes and

          • Pre- and post-synaptic receptor density.