6

• Sympathetic Nervous System


  • Important regulator of virtually all organ systems
  • Crucial for the maintenance of blood pressure even under relatively minor situations of stress
  • Mediated by the release of NE from nerve terminals, which then activates postsynaptic sites
  • Adrenal medulla releases Epi, in response to stimuli (stress)
• Epinephrine acts as hormone, whereas norepinephrine acts as neurotransmitter
• Norepinephrine Transporter (NET)


  The principal route by which norepinephrine is removed after its release from the synaptic cleft
• Sympathomimetic Drugs


  Drugs that mimic the actions of epinephrine or norepinephrine
• Types of Sympathomimetic Drugs

  • Direct Agonists (Norepinephrine and Epinephrine)
  • Indirect Agonists
• Indirect Agonists


  • Actions are dependent on the release of endogenous catecholamines
  • Displacement of stored catecholamines from the adrenergic nerve ending (e.g. Tyramine)
  • Inhibition or reuptake of catecholamines already released (e.g. cocaine and tricyclic antidepressants)
• Types of Receptors


  • Alpha Receptors (Alpha 1, Alpha 2)
  • Beta Receptors (Beta 1, Beta 2, Beta 3)
  • Dopamine Receptors
• Receptor Selectivity


  A drug may preferentially bind to one subgroup of receptors at concentrations too low to interact extensively with another subgroup
• Receptor Selectivity Examples


  • NE - Alpha 1 = Alpha 2; Beta 1 >> Beta 2
  • Epi - Alpha 1 = Alpha 2; Beta 1 = Beta 2
• Alpha Receptors


  Epinephrine ≥ Norepinephrine >> Isoproterenol
• Beta Receptors


  Isoproterenol > Epinephrine ≥ Norepinephrine
• Desensitization


  Tissues may become less responsive to further stimulation by a given agonist after long exposure from it
• Homologous desensitization


  Loss of responsiveness exclusively of the receptors that have been exposed to repeated or sustained activation by the agonist
• Heterologous desensitization


  Desensitization of one receptor by its agonists also results in desensitization of another receptor that has not been directly activated by the agonist in question
• Phenylethylamine


  The parent compound of all sympathomimetics
• Sympathomimetic Drug Structure


  • Consist of a benzene ring with an ethylamine side chain
  • Substitutions may be made on the benzene ring, terminal amino group, and alpha or beta carbons of the amino chain
• Catecholamines


  Substitutions by OH groups at the 3 and 4 positions of the benzene ring
• COMT


  Enzyme that inactivates catecholamines, found in the gut and liver
• Ephedrine and amphetamine


  Orally active, have prolonged duration of action, and produce CNS effects
• Phenylephrine


  Less potent than epinephrine
• Substitutions on the amino group

  • Increasing the length of the alkyl substituents tends to increase beta receptor activity
  • Larger substituents on the amino group lower activity at alpha receptors
• Substitution at the alpha carbon

  Blocks oxidation by MAO, prolonging the action (noncatecholamines)
• Substitution at the beta carbon


  Direct acting agonists typically have a beta hydroxyl group
• Organ System Effects of Sympathomimetic Drugs

  • Alpha 1 effects
  • Alpha 2 effects
  • Beta 1 effects
  • Beta 2 effects
  • Beta 3 effects
  • D1 effects
  • D2 effects
• Positive chronotropic effect


  Increased heart rate
• Positive dromotropic effect


  Increased conduction velocity in the AV node
• Positive inotropic effect


  Increased force of contraction
• Epinephrine


  An agonist at both alpha and beta-receptors, a very potent vasoconstrictor and cardiac stimulant
• Norepinephrine


  Agonist at both alpha 1 and 2 receptors, also has effect on beta 1 receptors but less on beta 2 than epinephrine
• Dopamine


  The immediate precursor in the synthesis of NE, important in sodium excretion and renal function, an important neurotransmitter in the CNS involved in the reward stimulus relevant to addiction
• Isoproterenol


  Very potent beta-receptor agonist and has little effect on alpha-receptors, has positive inotropic and chronotropic actions, potent vasodilator
• Alpha 1 Agonists


  Found in blood vessels
• NE


  Important in sodium excretion and renal function
• NE


  An important neurotransmitter in the central nervous system and involved in the reward stimulus relevant to addiction
• Deficiency in ganglia


  Parkinson's Disease (Levodopa)
• Cardiovascular actions


  Activates β-receptors of the heart; very high doses stimulate α-receptors causing vasoconstriction
• Renal & visceral actions


  Dilates renal & splanchic arterioles resulting to increase blood flow to the kidneys and other viscera
• Therapeutic uses of NE

  • Drug of choice for cardiogenic and septic shock
  • Superior than NE because of increased blood flow in the kidneys
  • Used to treat hypotension and severe heart failure

  
• Adverse effects of NE

  • Same effect as sympathetic stimulation
  • Nausea, hypertension, arrhythmias (short-lived)
• ISOPROTERENOL


  • Very potent B-receptor agonist and has little effect on alpha-receptors
  • Has positive inotropic and chronotropic actions; potent vasodilator