Pharmacology Continued by NgZcbk7f


									Sympathomimetic Agents

      By Jim Clarke
          The Nervous System
• Autonomic Control
  – Sympathomimetic side
     • Chief chemical neurotransmitter at the post-
       ganglionic sites is nor-epinephrine
     • Chief chemical neurotransmitter at the pre-
       ganglionic sites is acetylcholine
  – Parasympathomimetic side
     • Chief chemical neurotransmitter is acetylcholine
• Somatic Control
  – Motor control is mediated at the target organ by
Diagram of Central & Peripheral
       Nervous System
       How 2 Branches Differ
• Adrenergic                 • Cholinergic
  – Fight or Flight            – Feed or Bread
  – Gearing system up          – Increases digestive
  – Increases glycogen           functions
    breakdown                  – Increases urinary
  – Improves blood flow to       function
    major muscles & heart      – Increases bronchial
  – Dilates the eyes             secretions
  – Fast acting & very         – Slower acting & more
    widespread                   “focused”
    Nerve Signal Transmission
• Efferent limbs of nerves transmit impulses
  from the brain or spinal cord to the target
• Afferent limbs of nerves transmit impulses
  from the organ system to the brain and
  spinal cord
    Sympathetic Characteristic
• Sympathetic branch arises from thoraco-
  lumbar portion of the spinal cord
  – Postganglionic fibers may stimulate many sites
     • adrenal gland; heart; lungs; liver
     • sympathetic stimulation causes widespread effects
       because of the action of the adrenal gland on the
       entire body
 Parasympathetic Characteristics
• Arises from the cranio-sacral portions of
  spinal column
  – Postganglionic fibers are able to closely target
    effector sites (heart; lungs; gut)
  – Effects tend to be limited to the effector sites
    and are not widely distributed
      Parasympathetic Effects
• Organ Site                 • Cholinergic Effect
  – Heart
     • SA Node                    • Slowing of rate
     • Contractility              • Decreased Atrial force
     • Conduction Velocity        • Decreased conduction
  – Bronchi
                                  • Bronchoconstriction
     • Smooth Muscle

     • Mucous glands              • Increased mucus
         Parasympathetic Effects
• Organ Site
  – Vascular Smooth
    Muscle                 • Effect
     •   Skin & Mucosa          •   No direct effect
     •   Pulmonary              •   Vasodilation
     •   Skeletal muscle        •   No effect
     •   Coronary               •   No effect
       Cholinergic Receptors
• Muscarinic Receptors are located at;
  – exocrine glands (bronchial glands)
  – cardiac muscles
  – GI tract smooth muscle
• Acetylcholine working at these sites
  produce “Muscarinic” effects
  – Increase in secretions may occur when drugs
    effecting these lung sites are given
       Cholinergic Receptors
• Nicotinic Receptors are located at
  autonomic ganglia and in skeletal muscles
  – Stimulation of these receptors cause increases
    in blood pressure and muscle tremors
      Parasympathetic Agents
• Indirect acting agents inhibit the action of
  cholinestarase. This increases the action
  of the remaining acetylcholine
  – Reversible inhibitors: neostigmine
    (Prostigmine); edrophonium (Tensilon);
    pryridostigmine (Mestinon)
  – These agents are used to either reverse the
    actions of certain other drugs or to test the
    body’s ability to increase muscle strength
        Parasympathetic Agents
• Irreversible inhibitors - these are primarily the
  organophosphate pesticides (Malathion; Diazanon;
  Parathion) except for;
   – Phospholine - used as a pupillary constrictor in the
     treatment of glaucoma
  Atropine can be used to “reverse” the effects of
  both reversible and irreversible inhibitors. The
  have limited effect on organophosphates
      • Protopam may be used in first 24 hours to treat pesticide
     Parasympatholytic Agents
• These agents block acetylcholine receptors
  at the neuroeffector site
  – Atropine is the common agent in this group
  – Used to accomplish the following;
     •   Bronchodilation
     •   Antidiarrhea
     •   Tx of bradycardia
     •   Pre-operative drying of secretions
            Sympathetic Effects
• Organ Site                 • Effect
  – Heart
     • SA Node                    • Increasing of rate
     • Contractility              • Increased Atrial force
     • Conduction Velocity        • Increased conduction
  – Bronchi
                                  • Bronchorelaxation
     • Smooth Muscle

     • Mucous glands              • Increased secretion
            Sympathetic Effects
• Organ Site               • Effect
  – Vascular Smooth
     •   Skin & Mucosa          •   Vasoconstriction
     •   Pulmonary              •   Dilation/Constriction
     •   Skeletal muscle        •   Dilation
     •   Coronary               •   Dilation/Constriction
    Inactivation of Adrenergic
• Catechol-O-methyl Transferase (COMT)
  – deactivates adrenergic agents called
    catecholamines by changing one of the side-
    groups on the cathechol ring
• Mono Amine Oxidase (MAO)
  – deactivates adrenergic agents by removing the
    amine group from the side-chain
     • Since MAO is found in the stomach, many
       adrenergics cannot be orally administered
      Alpha & Beta Receptors
• Alpha receptors - generally excite (except in
  GI tract & in the CNS where inhibition or
  relaxation occurs)
  – Alpha 1 and Alpha 2 receptors
• Beta Receptors - generally inhibit or relax
  (except in the heart ---> stimulation)
  – Beta 1 and Beta 2 receptors
 Adrenergic Receptor Locations
• Receptor Type   • Location
  – Alpha 1         – Peripheral blood
  – Alpha 2         – Presynaptic receptors

  – Beta 1          – Heart
  – Beta 2          – Smooth Muscle &
                      cardiac muscle
  – Beta 3          – Lipocytes
     Key Aspects of Receptors
• Alpha 1 and Beta 1 receptors excite
• Alpha 2 and Beta 2 receptors inhibit
  Receptor Locations & Actions
• Alpha 1 receptors are located at the post-
  synaptic smooth muscle & are excitatory
• Alpha 2 receptors are located at the pre-
  synaptic ganglia & are inhibitory
Adrenergic Control in the Lungs
• There is no direct adrenergic control
  exerted in the lungs
• All control occurs through circulating
  agents like epinephrine & nor-epinephrine
  acting on alpha & beta receptors located
  throughout the lungs
        Locations of Receptors
• Beta 2 receptors exist throughout all airways in
  the lung
• Beta 1 Receptors are located primarily in the
  heart. There are some Beta 1 lung receptors
• Alpha Receptors exist in the lung in lessor
  quantity than Beta Receptors
   – Have limited airway effects (some studies
     suggest stimulation of lung alpha receptors may
     actually cause bronchospasm).
  Adrenergic Receptor Affect on
       Lung Blood Flow
• Alpha 1 stimulation will cause
  vasoconstriction resulting in decrease in
  blood flow and an increase in blood
• Beta stimulation in the lung can cause
  relaxation of vessels causing vasodilation
  and increased blood flow
     Cholinergic Lung Effects
• Vagus nerve stimulation causes Muscarinic
  receptors (located mainly in larger airways)
  to induce bronchospasm
  – Receptors active in the lung are;
     • M1
     • M2
     • M3 - responsible for causing bronchospasm
     Other Sources of Nervous
• Nonadrenergic Noncholinergic Inhibitory
  and Excitatory Nerves
  – Not well understood at this point
  – One possible neurotransmitter working in this
    system may be Nitric Oxide
  – Nitric Oxide administration causes vasodilation
    in the lungs
View of Airway Control
Adrenergic Bronchodilators
     Specific Adrenergic Agents
•   Catecholamines
•   Resourcinals
•   Saligenins
•   Other non-catecholamines
    – Pirbuterol
    – Bitolterol (pro-drug)
                Characteristics of
Name               Receptor              Duration (Hr) INH

Epinephrine        Alpha & Beta (both)          1-3

Isoproterenol      Beta 1 & 2                   .5-2

Isoetharine        Beta 2                       1-3

Bitolterol         Beta 2                       5-8
        Characteristics of Non-
Name             Receptor                   Duration (Hr) INH

Metaproterenol   Beta 2                            2-6

Terbutaline      Beta 2                            3-6

Albuterol        Beta 2                            3-8

Salmeterol       Beta 2 (3 hours to peak)          12
              Drug Names & Forms
Generic Name          Trade Name(s)        Available Form

Epinephrine           Adrenalin            Nebulizer

Racemic Epinephrine   Vaponefrin &         Nebulizer
Isoproterenol         Isuprel              Nebulizer
                      Isuprel Mistometer   MDI
Isoetharine           Bronkosol            Nebulizer
                      Bronkometer          MDI
     Drug Names & Forms Con’t
Generic Name     Trade Name(s)   Available Form

Metaproterenol   Alupent         Nebulizer
                 Metaprel        MDI
Terbutaline      Brethaire       MDI
                 Brethine        Tablets
                 Bricanyl        Syrup
Albuterol        Proventil       Nebulizer; MDI; DPI;
                 Ventolin        Syrup; Tablets
Pirbuterol       Maxair          MDI

Salmeterol       Serevent        MDI
     Advantages of Inhalation
• Quick Onset
• Smaller doses are needed compared to p.o.
• Fewer side effects
  – less Beta 1 & fewer tremors
• Direct dosing to airway
• Safe and painless
 Continuous Inhalational Dosing
• Albuterol
  –   12 mg/hr (average dose)
  –   10 - 20 mg/hr (dose ranges)
  –   Length: 4 hours (average)
  –   Length: 1 - 10 hours (range of time)
    Side Effects of Beta Agonists
• Tremors          • Tachyphylaxis
• Tachycardia &    • Decrease in PaO2
  palpitations     • Hypokalemia (only
• Headache           with continuous
• Insomnia           dosing)
• Increase in BP   • Propellant induced
• Nervousness        bronchospasm
• Nausea           • Sulfite Sensitivity
End of Week 4 - Thursday

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