Sympathomimetics or Adrenergic Drugs

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Sympathomimetics or Adrenergic Drugs

• These are the drugs which produce effects similar
  to the effects produced by endogenously released
  adrenergic neurotransmitters.
• These drugs can work at adrenergic receptors, as
  well as other sites of the adrenergic neuron and
  can affect various steps of the life cycle of the
  neurotransmitter.

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Life Cycle of Norepinephrine
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Life Cycle of Norepinephrine

• Tyrosine is transported into the noradrenergic
  ending or varicosity by a sodium-dependent
  carrier (A).
• Tyrosine is converted to dopamine , and
  transported into the vesicle by the vesicular
  monoamine transporter (VMAT), which can be
  blocked by reserpine. The same carrier transports
  NE and several other amines into these granules.
• Dopamine is converted to NE in the vesicle by
  dopamine- -hydroxylase.

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Life Cycle of Norepinephrine

• Physiologic release of transmitter occurs when an
  action potential opens voltage-sensitive calcium
  channels and increases intracellular calcium.
  Fusion of vesicles with the surface membrane
  results in expulsion of norepinephrine,
  cotransmitters, and dopamine- -hydroxylase.
• Release can be blocked by drugs such as
  guanethidine and bretylium.
• After release, norepinephrine diffuses out of the
  cleft or is transported into the cytoplasm of the
  terminal by the norepinephrine transporter (NET),
  which can be blocked by cocaine and tricyclic
  antidepressants, or into postjunctional or
  perijunctional cells.
• Regulatory receptors are present on the
  presynaptic terminal. SNAPs, synaptosome-associate
  d proteins VAMPs, vesicle-associated membrane
  proteins

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Biosynthesis of Catecholamines
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Metabolism of Catecholamines
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Autonomic and hormonal control of cardiovascular
function
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Autonomic and hormonal control of cardiovascular
function

• Two feedback loops are present the autonomic
  nervous system loop and the hormonal loop.
• The sympathetic nervous system directly
  influences four major variables peripheral
  vascular resistance, heart rate, force, and
  venous tone. It also directly modulates renin
  production.
• The parasympathetic nervous system directly
  influences heart rate.
• Angiotensin II stimulates aldosterone secretion,
  and directly increases peripheral vascular
  resistance and facilitates sympathetic effects
• The net feedback effect of each loop is to
  compensate for changes in arterial blood
  pressure.
• Thus, decreased blood pressure due to blood loss
  would evoke increased sympathetic outflow and
  renin release.
• Conversely, elevated pressure due to the
  administration of a vasoconstrictor drug would
  cause reduced sympathetic outflow, reduced renin
  release, and increased parasympathetic (vagal)
  outflow.

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Alpha1 receptors are coupled via G proteins in
the Gq family to phospholipase C leading to the
formation of inositol 1,4,5-trisphosphate (IP3)
and diacylglycerol (DAG)
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Alpha2 receptors inhibit adenylyl cyclase and
decrease cAMP. Beta Receptors stimulates
adenylyl cyclase and increase cAMP.
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• Dopamine Receptors
• The D1 receptor is typically associated with the
  stimulation of adenylyl cyclase for example,
  D1-receptor-induced smooth muscle relaxation is
  presumably due to cAMP accumulation in the smooth
  muscle of those vascular beds in which dopamine
  is a vasodilator.
• D2 receptors have been found to inhibit adenylyl
  cyclase activity, open potassium channels, and
  decrease calcium influx.

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Adrenergic Receptors
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Dopamine Receptors
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Dopamine Receptor Subtypes
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Catecholamines
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Noncatecholamines
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Structure Activity Relationships

• Substitution on the Benzene Ring
• Substitution on the Amino Group
• Substitution on the Alpha Carbon

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• Substitution on the Benzene Ring
• Maximal a and ß activity is found with
  catecholamines, i.e. drugs having OH groups at
  the 3 and 4 positions on the benzene ring.
• The absence of one or the other of these
  groups, particularly the hydroxyl at C3, without
  other substitutions on the ring may dramatically
  reduce the potency of the drug. For example,
  phenylephrine is much less potent than
  epinephrine indeed, a -receptor affinity is
  decreased about 100-fold and ß activity is almost
  negligible .
• No OH groups on the ring means
• 1-COMT is not effective, so the drug is
  effective orally.
• 2- Lipid solubility increases, so the drug
  has a CNS effect. For example, ephedrine and
  amphetamine are orally active, have a prolonged
  duration of action, and produce central nervous
  system effects not typically observed with the
  catecholamines.

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• Substitution on the Amino Group
• Increasing the size of alkyl substituents on the
  amino group tends to increase ß -receptor
  activity. For example, methyl substitution on
  norepinephrine, yielding epinephrine, enhances
  activity at ß 2 receptors.
• Beta activity is further enhanced with isopropyl
  substitution at the amino nitrogen
  (isoproterenol).
• Beta2-selective agonists generally require a
  large amino substituent group. The larger the
  substituent on the amino group, the lower the
  activity at a receptors for example,
  isoproterenol is very weak at a receptors.

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• Substitution on the Alpha Carbon
• Substitutions at the a carbon, block oxidation by
  monoamine oxidase (MAO) and prolong the action of
  such drugs, particularly the noncatecholamines.
• Ephedrine and amphetamine are examples of - a
  carbon substituted compounds .