Introduction to Autonomic Pharmacology by pengxiuhui


									Autonomic Pharmacology
          with a focus on
   Occupational Therapy
     Sunshine J. Yocom, Pharm.D.
  Samford University McWhorter School
             of Pharmacy
   Review of autonomic physiology
     Sympathetic nervous system (SNS)
     Parasympathetic nervous system (PNS)

   The role of cholinergic receptors in the SNS and
    the PNS
   Direct acting cholinergic agents
   Indirect acting cholinergic agents
   Anticholinergic agents
   FYI on adrenergic agents
   Case Presentation
   The human nervous system can be divided into
    two major functional areas:
     Somatic nervous system: control of skeletal
      musculature and voluntary function
     Autonomic   nervous system: control of bodily
      function that is largely involuntary
        Review of ANS Division
   The autonomic nervous system (ANS) is divided
    into 2 areas:
     Sympathetic  nervous system (SNS):
      Regulated in the thoracic and upper lumbar
      regions of the spinal cord
     Parasympathetic  nervous system (PNS):
      Regulated in the craniosacral region of the
      spinal cord
                SNS vs. PNS
                   “fight or flight”
   SNS (fight): Tends to mobilize body energy,
    and discharge is increased when the body is
    faced with a stressful situation.
     Increases cardiac output (↑ contractility and HR)
     Decreases blood flow to the GI tract

     Decreases visceral blood flow and leaves more blood
      for skeletal muscle
     Increased secretion of the sweat glands
                 SNS vs. PNS
                    “fight or flight”
   PNS: Tends to conserve and store body energy.
    Discharge tends to have the opposite effect of
    the sympathetic nervous system.
     Decreased cardiac output (↓ contractility and HR)
     Increases intestinal digestion and absorption
      (increases energy absorption for future needs)
     Causes bronchoconstriction and contraction of
      bladder smooth muscle.
    There is no innervation in the arterioles or kidney.
               SNS vs. PNS
                  “fight or flight”
   Activation of the SNS is a more comprehensive
    reaction than the PNS.
   When the SNS or “fight” reflex is activated
    multiple effects are observed throughout the
   PNS effects tend to be more discreet, and affect
    more limited organs or tissues.
    Autonomic Integration and Control
   Most ANS control is manifested through reflex.
   A peripheral sensor monitors a change in
    homeostasis, it is relayed back to the CNS, and
    an adjustment is made in autonomic discharge.
   EXAMPLE: Baroreceptors in the thorax and
    neck sense a decrease in BP and heart rate, this
    is relayed back to the brainstem, and there is a
    compensatory increase in sympathetic discharge.
            Anatomy of the ANS
Pregangliolic and postgangionic neurons
   Initially two neurons are used in both the SNS
    and PNS to extend from the CNS toward the
    periphery or organ it innervates.
   The first neuron begins in the CNS, and extends
    toward the periphery before synapsing with a
    second neuron (which then heads towards
    another synapse to complete the journey.)
   The first neuron is “pre-ganglionic”
   The second neuron is “post-ganglionic”
Pregangliolic and Postgangionic Neurons
      The Role of Acetylcholine
   The neurotransmitter used at this first synapse
    leaving the CNS is acetylcholine for both the SNS
    and ANS.
   Acetylcholine is released, travels through the
    synapse, and acts on receptors at the post-
    ganglionic end.
   The enzyme, acetylcholinesterase, is present in the
    synapse to break down any excess neurotransmitter.
   Ach is a major transmitter of the skeletal
    neuromuscular junction as well.
          Cholinergic Receptors
   The cholinergic receptors at the first juncture
    between the pre-ganglionic and post-ganglionic
    neurons is called a Type 1 (Nn) nicotinic
    cholinergic receptor.
   Remember, this receptor is present in both the
    SNS and PNS.
   Medications that act at this juncture would affect
    both the SNS and PNS.
   The ANS regulates involuntary bodily functions,
    such as our fight or flight bodily reflexes.
   The sympathetic nervous system is the “fight”
    reflex and the parasympathetic nervous system is
    more of the resting state.
   Both the SNS and PNS initially send signals
    from the CNS via preganglionic neurons, via
    acetylcholine, through a synapse, to a nicotinic
    cholinergic receptor, through a postganglionic
   From here, the pathways differentiate.
              Tip to Remember
   Both pathways initially utilize cholinergic
    receptors and acetylcholine as the

   The receptors are specifically NICOTINIC
    cholinergic receptors. You can remember the
    N, because of all the N’s used in the
    abbreviations for ANS, SNS, and PNS.
    Parasympathetic Nervous System
           (refer to page 268 of your text)

 The PNS pathway always utilizes the cholinergic
  receptors, even past the first synapse.
 The post-ganglionic neuron travels to the last
  synapse where Ach is released and acts upon the
  cholinergic receptor of the target organ or tissue.
 The cholinergic receptor of the target organ or
  tissue is a muscarinic cholinergic receptor.
  1st synapse – nicotinic 2nd synapse - muscarinic
Parasympathetic Nervous System
   When the muscarinic cholinergic receptors are
    activated at the terminal organ or cell you may
    see the following effects of the PNS:
     Decreased heart rate
     Contraction of bronchiole smooth muscle

     Increased salivation and intestinal secretion

     Contraction of GI and bladder smooth muscle
       Sympathetic Nervous System
             (refer to page 268 of your text)
   The SNS (stress reflex) initially utilizes
    acetylcholine as the neurotransmitter at junction
    one, and the cholinergic receptor.
   Sympathetic post-ganglionic neurons travel to
    the second synapse where they typically use
    norepinephrine as the transmitter.
   Norepinephrine (noradrenaline) acts upon
    “adrenergic” receptors at the target organ or
     Sympathetic Nervous System
   When the Adrenergic receptors are activated at
    the terminal organ or cell you may see the
    following effects of the SNS:
     Increased contractility and heart rate
     Relaxation of bronchiole smooth muscle

     Decreased salivation and intestinal secretion

     Decreased gastric motility

     Relaxation of the bladder
           Adrenergic Receptors
   There are four types of adrenergic receptors
    (used in the SNS at the synapse prior to the
    terminal organ or tissue):
     Alpha-1: Vasodilation and gastric relaxation
     Alpha-2: Feedback through CNS inhibition

     Beta-1: Increased heart rate and contractility

     Beta-2: Bronchodilation
Comparison of the SNS and PNS
 Pathways (refer to page 268 of your text)
   In the ANS you have the SNS and the PNS.
    Each system works through neurons that travel
    through synapses by way of neurotransmitters
    that act upon receptors.
   PNS→Acetylcholine→Nicotinic Cholinergic
    Cholinergic Receptor→Terminal tissue.
   SNS→Acetylcholine→Nicotinic Cholinergic
    Receptor (α1, α2, β1, β 2)→Terminal tissue.
   There are multiple ways that medications can be
    used to intervene in the pathways of the
    autonomic nervous system.
   Potentiate cholinergic stimulation
   Inhibit acetylcholinesterase
   Inhibit acetylcholine receptors
   Inhibit adrenergic receptors (alpha or beta)-SNS
   Potentiate adrenergic receptors (alpha or beta)-
          Cholinergic Medications
   Cholinergic stimulants
     Direct acting agents: Act directly on the cholinergic
      receptor on the post-synaptic membrane.
     Indirect agents: Inhibit acetylcholinesterase enzymes
      so there is more Ach in the synapse.
   Anticholinergic drugs
       Bind reversibly to the cholinergic receptor, but do
        not activate it, preventing a response.
Direct Acting Cholinergic Stimulants
   Direct agents bind to the cholinergic receptors
    to activate them.
   Only a few agents are used because these drugs
    must be specific for muscarinic receptors (PNS)
    or else they affect both the SNS and PNS.
   A medication that stimulates nicotinic and
    muscarinic receptors would activate both the
    fight and flight reflexes.
   This class is used mainly for PNS effects.
            * REVIEW *
    Parasympathetic Nervous System
   When the muscarinic cholinergic receptors are
    activated at the terminal organ or cell you may
    see the following effects of the PNS:
     Decreased heart rate
     Contraction of bronchiole smooth muscle

     Increased salivation and intestinal secretion

     Contraction of GI and bladder smooth muscle
              Direct Stimulants
   Bethanechol (Urecholine®)-Systemic agent
     Used to treat urinary retention and neurogenic
      bladder, works to stimulate GI tract.
     Mechanism: Stimulates cholinergic receptors in
      smooth muscle of the urinary bladder and GI tract.
     Given PO and SubCu only, cannot be given IV or
      IM because severe cholinergic response.
     Side effects include diarrhea, nausea, salivation,
      bronchoconstriction, diaphoresis, flushing, and
              Direct Stimulants
   Carbachol (Isopto®)- Opthalmic
   Pilocarpine (Pilocar®)- Opthalmic
     These agents are used topically to treat glaucoma.
     These agents work by acting on the muscarinic
      cholinergic receptors in the eye to increase the
      outflow of aqueous humor and decrease pressure.
     These agents cannot be used systemically because of
      side effects.
     SE are minimal because of topical use.
        Indirect Acting Cholinergic
   Work through inhibiting the acetylcholinesterase
   Ach increases at the synapse and there is more
    neurotransmitters to bind to the receptors.
   Some of these drugs act more centrally at the
    nicotinic receptors of both the SNS and PNS,
    and some act more peripherally at the
    muscarinic receptors of the PNS and skeletal
    neuromuscular junction, and some do both.
        Indirect Acting Stimulants
   Donepezil (Aricept®), Rivastigmine (Exelon®),
    Tacrine (Cognex®)
     Acetylcholinesterase inhibitors that work centrally to
      help increase Ach transmission across synapses.
     Use: Alzheimer’s Disease is characterized by
      neuronal atrophy, and indirect cholinergic stimulants
      can decrease symptoms in the early stages.
     These medications prolong the effects of Ach
      released in the synapse and can preserve function in
      Alzheimer’s patients, BUT they cannot cure it.
        Indirect Acting Stimulants
   Side effects of these agents used to treat
    Alzheimer’s Disease:
     > 10%: Headache, dizziness, nausea, vomiting
     < 10%: Hot flashes, frequent urination,
      incontinence, weight loss, muscle cramps,
      depression, fatigue, insomnia
     Abrupt discontinuation can result in drastic
      cognitive changes.
      -Aricept® is given QHS, which is most acceptable.
        Indirect Acting Stimulants
   Pyridostigmine (Mestinon®), Edrophonium
    (Enlon®), Neostigmine (Prostigmin®)
     Acetylcholinesterase inhibitors that work at the
      skeletal neuromuscular junction to allow Ach to be
      present for longer periods of time.
     These agents are used in Myasthenia Gravis, which is
      a disease characterized by a decrease in cholinergic
      receptors at the skeletal neuromuscular junction.
     Therefore in MG you have less functioning
      receptors, and these medications let the Ach stay
      present in the synapse for longer periods of time to
      act on the functional cholinergic receptors.
        Indirect Acting Stimulants
   Side effects of these agents used to treat
    Myasthenia Gravis:
     >10%: Diarrhea, salivation, nausea, stomach
      cramps, diaphoresis
     <10%: Incontinence, lacrimation, increased
      bronchial secretions, and bronchoconstriction
    -Given PO, IM, or IV infusion,
    -Onset of action is 15-30 minutes, and duration of
      action is 3-4 hours.
       Indirect Acting Stimulants
   In some patients the muscarinic side effects
    (diarrhea, abdominal cramps, salivation, nausea)
    of these agents may limit the dose tolerated.
   Propantheline bromide (cholinergic receptor
    blocking agent) may be used to block the
    muscarinic autonomic side effects without
    altering effects on skeletal muscle.
   Loperamide may be used to treat diarrhea.
         Indirect Acting Stimulants
   Acetylcholinesterase inhibitors (in general, as a
    class) may be used for 2 other functions:
       To treat a patient who has received neuromuscular
        blocking agents, to reverse the symptoms (for
        example, a patient in surgery or who is intubated).
       To treat a patient who was overdosed on an
        anticholinergic medication, as an antidote.
Summary of Cholinergic Stimulants
   Act either directly on the receptor or by
    inhibiting acetylcholinesterase.
   Systemic direct stimulants are used for GI and
    urinary atony, but are limited due to side effects.
   There are 2 main uses of indirect stimulants,
    those that act centrally to help neural
    transmission and improve symptoms of
    Alzheimer’s patients, and those that work at the
    skeletal neuromuscular junction to improve
    symptoms of Myasthenia Gravis.
Summary of Cholinergic Stimulants
   The main side effects of the cholinergic
     GI disturbances, including cramping, diarrhea,
      nausea and vomiting
     Dizziness
     Bradycardia
     Flushing
     Bronchoconstriction
     Headache
     Incontinence
      Anticholinergic Medications
   These medications diminish the response of
    tissues to cholinergic stimulation.
   They bind reversibly to the cholinergic receptor,
    but do not activate it.
   These agents are typically anti-muscarinic,
    meaning they bind to the cholinergic muscarinic
    receptors to prevent stimulation of the PNS.
   You want selective binding to the muscarinic
    site, otherwise you would affect the SNS as well
    as the PNS by attaching to nicotinic receptors.
            * REVIEW *
    Parasympathetic Nervous System
   When the muscarinic cholinergic receptors are
    activated at the terminal organ or cell you may
    see the following effects of the PNS:
     Decreased heart rate
     Contraction of bronchiole smooth muscle

     Increased salivation and intestinal secretion

     Contraction of GI and bladder smooth muscle

   When you block these receptors you will see the
    opposite of these effects.
          Anticholinergic Agents
   Atropine
     Used to treat symptomatic bradycardia, increases
      heart rate and contractility.
     Inhibits salivation and secretions.

     May be used for exercise induced
     May be used to treat cholinergic poisoning.

     Dilates the eye, and is used in some eye exams.

     Side effects include constipation and dry mouth.
          Anticholinergic Agents
   Dicyclomine (Bentyl®), Hyoscyamine
    (Levsin®), and Propantheline (Pro-Banthine®):
     All three are used for IBS and GI spasms.
     They work against the muscarinic receptors to
      decrease activity in smooth muscles and decrease
     Side effects include drowsiness, and a caution is
      “may impair judgement and coordination.”
      Dizziness, dyskinesia, headache, constipation,
      blurred vision and incontinence also may be seen.
          Anticholinergic Agents
   Scopolamine
     Antimuscarinic agent that works in the brainstem to
      mediate motion related nausea and vomiting.
     May be administered PO or via patch.

     Side effects include constipation and dry mouth.

   Oxybutynin (Ditropan®)
     Anticholinergic agent specific for smooth muscle,
      with good antispasmodic potential in the bladder.
     Used for neurogenic bladder and incontinence.

     >10% incidence of drowsiness and impairment.
          Anticholinergic Agents
   Ipratropium (Atrovent®)- Inhaler / Nebulizer
     Given to block Ach at PNS sites in bronchial
      smooth muscle to induce bronchodilation.
     Effects are generally localized, side effects include
      cough, headache, and trembling.

    Antimuscarinic anticholinergic agents are not used to
     treat peptic ulcer disease at all anymore. They have
     been replaced by H-2 blockers and PPIs.
Summary of Anticholinergic Agents
   Act directly on the cholinergic receptor to bind,
    but not activate the receptor.
   Anticholinergic agents typically act on the
    muscarinic type receptors specific mostly to the
   Used mainly to increase heart rate (atropine) and
    for GI spasms and to decrease motility.
   There are several other uses including motion
    sickness, bladder spasms, and bronchodilation.
Summary of Anticholinergic Agents
   The main side effects of the anticholinergic
     Constipation and urinary incontinence
     Dry mouth

     Dizziness

     Drowsiness

     Impaired judgement

     Headache
          FYI-Adrenergic agents
   Cholinergic agents were mainly for the PNS,
    with some crossover to the SNS.
   The SNS works through the adrenergic receptor
    in the periphery (α1, α2, ß1, ß2).
   Alpha 1 blockers cause vasodilation and cause
    orthostatic hypotension (i.e., Prazosin/Hytrin®)
   Beta blockers decrease heart rate and blood
    pressure and cause fatigue (i.e.,
    Metoprolol/Toprol XL®)
     End of Formal Lecture Time
 Anything that
  needs to be
  reviewed again?
 Specific questions?

 On to the case?

   Dr. Yocom

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