Serotonin 5-HT

Chapter 22: Serotonin Pharmacology

Serotonin
Chemistry Storage Major site-ECC CNS locations CNS effects Degradation Pharmacodynamics-Mechanisms of Action Serotonin Receptor Subtypes Tissue and Organ Systems Cardiovascular Actions Gastrointestinal Effects Nervous System	Clinical Pharmacology Serotonin Agonists Buspirone (BuSpar) Sumatriptan (Imitrex) Serotonin Antagonists Cyproheptadine (Periactin) Clinical Use Ketansarin Ritanserin Ondansetron (Zofran) Granisetron (Kytril) Tropisetron Dolasetron Clinical Uses

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:
        
        synthesize
        
        store
        
        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

**Some Serotonin Receptor Subtypes**
Receptor subtype	Distribution	Coupling mechanism; comments
5-HT_1A	Raphe nuclei, hippocampus	cAMP, potassium channels:partially selective agonist: 8-OH-DPAT
5-HT_1D(a,b)	brain	cAMP,partially selective agonist: sumatriptan (Imitrex)
5-HT₃	area postrema, sensory and enteric nerves	receptor:Na-K ion channel: partially selective antagonists ondansetron (Zofran), ggranisetron (Kytril), tropisetron
5-HT₄	CNS, ,smooth muscle	cAMP; partially selective agonists: metoclopramide (Reglan)

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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:
        
        nicotinic cholinergic receptor agonists
        
        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

**Buspirone (BuSpar)**

**Sumatriptan (Imitrex)**

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

**Ondansetron**

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)

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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.