• Tissue and organ systems:
  • Cardiovascular: serotonin
    • Smooth muscle-- direct effects: contraction, 5-HT₂ receptors
    • Serotonin: vasoconstriction except:
      • skeletal muscle vasculature } vasodilation
      • heart } vascular endothelial cell-dependent vasodilation
    • Serotonin: reflex bradycardia (5-HT₃ activation of chemoreceptor nerve endings)
    • Serotonin-induced vasoconstriction: strong effects on pulmonary and renal vasculature
    • Venoconstriction with subsequent increased capillary filling causes flushing following serotonin administration
    • Serotonin: small direct positive inotropic and chronotropic cardiac effects
    •  Subendocardial fibroplasia associated with prolonged elevation of serotonin in the blood (e.g. in carcinoid syndrome) -- may result in myocardial space forelectrical or valve malfunction.
    • Serotonin: induces platelet aggregation by activation of platelet surface 5-HT₂ receptors.

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  • Gastrointestinal tract: serotonin
    • Serotonin:contraction of gastrointestinal smooth muscle
      • increased tone, increased peristalsis
      •  5-HT₂ receptor mediated:
        • direct effect on smooth muscle receptors
        • stimulation of enteric ganglia cells
      •  Serotonin: -- activation of 5-HT₄ receptor
        • increased acetylcholine release (increased motility, prokinetic)
        • Example:   Serotonin over production (carcinoid tumor) -- severe diarrhea

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  • Nervous System:
    • Serotonin: stimulates itch and pain sensory nerve endings.
    • Serotonin:activates chemosensitive nerve endings in coronary vessels
    • 5-HT₃ receptor activation on these chemosensitive vagal nerve endings:causes chemoreceptor reflex {Bezold-Jarisch reflex}
      • Reflex response: significant negative chronotropic (bradycardic response) with hypotension:
        • bradycardia -- vagal mediated (blocked by atropine)
        • Other agents that activate chemoreceptor reflex include:
          1. nicotinic cholinergic receptor agonists
          2. some cardiac glycosides
    •   5-HT₃ receptor activation in the gastrointestinal tract and in the medullary vomiting center: vomiting reflex:
      • This system is important in vomiting caused by chemotherapeutic (anticancer) drugs

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• Clinical Pharmacology:
  • Serotonin Agonists

• Sumatriptan: (Imitrex)
  • Relief of migraine symptoms for most patients
  • Efficacy greater than or equal to other drug treatments (including parenteral agents or oral ergot alkaloids)
  • Multiple dosing may be required (headache lasts longer than single dose duration)
  •  Adverse Effects: Sumatriptan
    •   generally mild
    •   altered sensations (tingling, warmth, etc.)
    •   dizziness
    •   muscle weakness
    •   neck pain
    •   Chest pain (frequency: 5%)
  •  Contraindications:
    • in patients with ischemic heart disease
    • in patients with Prinzmetal's angina (variant angina)

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• Serotonin Antagonists

• Cyproheptadine (Periactin)
  • Overview
    • blocks serotonergic and histaminergic affects on smooth muscle
    • no effect on histamine-stimulated gastric secretion
    •  significant antimuscarinic effects
    •  sedation
  • Clinical Use: cyproheptadine
    • Major Use: cyproheptadine
      •   reduces smooth muscle effects of carcinoid tumor
      •   reduces postgastrectomy dumping syndrome
• Ketanserin
  • Overview
    • blocks 5-HT_1c and 5-HT₂ receptors (no activity another 5 HT or H₁ histamine receptors
    • blocks a₁ adrenergic receptors
    • blocks platelet 5-HT₂ receptors (inhibits serotonin-mediated platelet aggregation)
    • effective antihypertensive drug (probably acting through a₁ adrenergic receptors
• Ritanserin
  • Blocks 5-HT₂ receptors (no alpha blocking properties)
  • May alter platelet function

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• Ondansetron (Zofran)
  • 5-HT₃ receptor blocker
    • minimal effects on dopamine, histamine, adrenergic or cholinergic receptor activity
  • very effective for prevention of nausea and vomiting caused by chemotherapy or surgery. -- major role in management of severe nausea and vomiting due to anticancer drugs
  • Clinical Use:
    • Dosage: 4-8 mg IV (administered over 2-5 minutes just before anesthesia induction)
    • Highly effective in reducing postoperative nausea/vomiting incidence -- particularly in susceptible patient groups:
      • ambulatory gynecologic surgery
      • middle ear surgery
    • Oral or IV reduces incidence of postoperative vomiting and preadolescent children undergoing:
      • ambulatory surgery, e.g. tonsillectomy, strabismus surgery
    • Ondansetron (Zofran): effective both for prophylaxis and treatment of postoperative nausea/vomiting
      • decreases incidents & intensity of postoperative nausea & vomiting -- but does not totally eliminate this problem
      • Major advance: reduced side effects compared to previously used antiemetic drugs such as:
        • phenothiazines, antihistamines, butyrophenones
    • Propofol (Diprivan) for induction and maintenance of anesthesia may be as effective as ondansetron (Zofran) in reducing/preventing postoperative nausea & vomiting
  •  Side Effects:
    • Surgical patients:
      • 3% increased liver transaminase enzyme levels
      • 3% headache
    • No sedation, hypotension, dysphoria, extrapyramidal reactions -- side effects associated with other antiemetic drugs

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• Tropisetron:
  • 5-HT₃ receptor blocker
  • Effective in managing symptoms induced by carcinoid syndrome-- also some gastrokinetic characteristics
  • Effective in preventing chemotherapy/radio therapy-induced emesis
  • Effective in preventing postoperative nausea/vomiting when administered before general anesthetic induction

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• Granisetron (Kytril)
  • More selective 5-HT₃ receptor blocker compared to ondansetron
  • Clinical Use:
    • Effective in the chemotherapy-induced emesis prevention
    • Effective in preventing postoperative nausea/vomiting
  • Elimination half-life: nine hours, compared to about three hours for ondansetron: suggesting less frequent dosing with granisetron.
  • Significantly higher cost-- could limit clinical use

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• Dolasetron:
  • Highly potent/selective 5-HT₃ receptor blocker
  • Clinical Use:
    • Effective in preventing chemotherapy-induced nausea/vomiting
    • Effective in reducing likelihood of postoperative nausea & vomiting
    • Antiemetic effect due to long-acting, active metabolite (hydrodolasetron; elimination half-life = approximately 8 hours)

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