Chapter 22:  Serotonin Pharmacology

Serotonin

• Chemistry: serotonin

  • Widely distributed indoleethylamine formed from L-tryptophan:

    • hydroxylation of the indole ring

    • decarboxylation

    • hydroxylation at C-5: rate-limiting step

      • inhibited by p-chlorophenylalanine (PCPA, fenclonine)

  • Following synthesis:

    • storage or

    • rapid inactivation-- oxidation (monoamine oxidase, MAO)

    • Pineal gland: serotonin -- precursor for melatonin (melanocyte-stimulating hormone)

  • Storage:

    • Most serotonin (> 90%):enterochromaffin cells -- GI tract

    • Blood: platelets (active carrier-mediated transport system {similar to nerve endings})

    • CNS locations:serotonin

      • raphe nuclei (brain stem)

        • localization of neuronal cell bodies that:

          1. synthesize

          2. store

          3. release

      • CNS serotonin involvement:

        • mood

        • sleep

        • appetite

        • temperature regulation

        • pain perception

        • blood-pressure regulation

        • vomiting

  • Degradation:

    • Catabolism: monoamine oxidase -- product: 5-hydroxyindoleacetaldehyde

      • 5-hydroxyindoleacetaldehyde: further oxidation catalyzed aldehyde dehydrogenase

      • amount of 5-hydroxyindoleacetic acid (5-HIAA) excreted is a measure of serotonin synthesis.

        • excessive serotonin synthesis may be helpful as a diagnostic test for certain tumors (e.g. carcinoid)

• Pharmacodynamics -- Mechanisms of Actions

  • Effects mediated through serotonin receptors:

    • At least seven major 5 HT subtypes identified

      • most: G protein coupled

      • at least one: ligand-gated channel

• 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.

  • 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

  • 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

• Clinical Pharmacology:

  • Serotonin Agonists

    • Buspirone (BuSpar)-- 5-HT_1A agonist: nonbenzodiazepine anxiolytic

    • Sumatriptan (Imitrex): 5-HT_1D agonist: acute migraine and cluster headache

• 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)

• Serotonin Antagonists

  • Cyproheptadine (Periactin)

  • Ondansetron (Zofran)

  • Ketanserin

  • Granisetron (Kytril)

  • Ritanserin

  • Dolasetron

  • Tropisetron

• 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

• 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

• 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

• 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

• 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)

Burkhalter, A, Julius, D.J. and Katzung, B. Histamine, Serotonin and the Ergot Alkaloids (Section IV. Drugs with Important Actions on Smooth Muscle), in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 261-286.