Drugs Acting on the Gastrointestinal Tract

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Drugs Acting on the Gastrointestinal Tract
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Emetics and Antiemetics
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Vomiting reflex

• The vomiting reflex is a coordinated reflex
  controlled by a bilateral vomiting center in the
  dorsal portion of the lateral reticular formation
  in the medulla.
• Pharmacologic intervention relies on inhibition
  of inputs or depression of the vomiting center.

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• The vomiting center receives inputs from several
  sources
• Chemoreceptor trigger zone (CTZ)
• Vestibular nucleus
• Peripheral afferents from the pharynx,
  gastrointestinal tract, and genitals
• Psychologic input from the central nervous system
  (CNS)
• Serotonin (5-HT3)-receptors, which are the
  predominant mediators of the reflex, are present
  in
• vomiting center
• CTZ
• periphery

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Antiemetics

• Def. Agents to treat nausea and vomiting
• Useful in the treatment of vomiting associated
  with
• motion sickness
• chemotherapy

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Cholinergic antagonists

• They reduce the excitability of labyrinthine
  receptors and depress conduction from the
  vestibular apparatus to the vomiting center.

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• Cholinergic antagonists are used to
• treat motion sickness
• in preoperative situations.
• They are not useful in treating nausea caused by
  chemotherapy.

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Scopolamine

• Inhibit cholinergic and muscarinic CNS receptors.
  
• Crosses the blood-brain barrier.
• More effective against motion-induced emesis.
• SIDE EFFECTS sedation, CNS excitation, dry
  mouth, urinary retention, blurred vision,
  confusion, disorientation, hallucinations

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Histamine1 (H1)-receptor antagonists
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Histamine1 (H1)-receptor antagonists

• diphenhydramine Benadryl
• meclizine Antivert, Bonine
• dimenhydrinate Dramamine
• promethazine Phenergan

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• These agents most likely act by inhibiting
  cholinergic pathways of the vestibular apparatus
  by receptor crossover.
• H1-receptor antagonists are used to treat motion
  sickness and vertigo.
• These agents produce sedation and dry mouth.
• Meclizine and promethazine have minimal
  anticholinergic side effects and are used most
  often.

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Dopamine antagonists

• Metoclopramide Reglan
• blocks receptors within the CTZ.
• increases the sensitivity of the gastrointestinal
  tract to the action of acetylcholine (ACh)
• this enhances gastrointestinal motility and
  gastric emptying and increases lower esophageal
  sphincter tone.
• High doses of metoclopramide antagonize serotonin
  (5-HT3)-receptors in the vomiting center and
  gastrointestinal tract.

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• Metoclopramide is used to treat
• nausea due to chemotherapy (caused by agents such
  as cisplatin and doxorubicin)
• narcotic-induced vomiting.
• Metoclopramide produces sedation, diarrhea,
  extrapyramidal effects, and elevated prolactin
  secretion.

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Phenothiazines and butyrophenones

• Phenothiazine prochlorperazine Compazine
• Butyrophenone droperidol Inapsine.

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• Phenothiazines and butyrophenones
• block dopaminergic receptors in the CTZ
• inhibit peripheral transmission to the vomiting
  center.
• These agents are used to
• treat nausea due to chemotherapy and radiation
  therapy
• control postoperative nausea.
• Adverse effects (less pronounced with
  butyrophenones) include
• Anticholinergic effects (drowsiness, dry mouth,
  and blurred vision),
• Extrapyramidal effects
• Orthostatic hypotension.

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5-HT3 antagonists

• Ondansetron Zofran
• not effective for motion-sickness-induced nausea.
• more effective against nausea induced by
  chemotherapy.
• used in postoperative nausea.
• can be administered intravenously or orally.
• Side effects may include mild constipation.

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• Granisetron Kytril
• has a greater affinity for 5-HT3 receptors.
• Granisetron is longer acting and more potent than
  ondansetron or metoclopramide.
• administered by intravenous infusion or orally.
• The most common adverse effect of granisetron is
  headache.

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Cannabinoids

• The most commonly used in the USA is dronabinol
  (?-9-tetrahydrocannabinol) Marinol.
• Acts by inhibiting the vomiting center, but the
  mechanism is unclear.
• used to control nausea induced by chemotherapy.
• administered as oral preparations.
• adverse effect produce sedation, psychoactive
  effects (high), dry mouth, orthostatic
  hypotension, and increased appetite.

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Glucocorticoids

• Dexamethasone Decadron
• Methylprednisolone Solu-Medrol.
• These agents can be effective as a treatment of
  vomiting caused by highly emetic agents.
• High doses are given as an intravenous (IV) bolus
  or orally for delayed nausea, often combined with
  metoclopramide, haloperidol, diphenhydramine, or
  ondansetron.

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Benzodiazepines

• Lorazepam Ativan
• Diazepam Valium
• act as anxiolytic agents to reduce anticipatory
  emesis.
• Diazepam is useful as a treatment of vertigo.

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• Emetrol
• Emetrol is an over-the-counter (OTC) preparation
  containing a mixture of fructose, dextrose, and
  buffered orthophosphoric acid.
• Emetrol is used to treat vomiting in morning
  sickness and in infants.

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Neurokinin 1 (NK1) antagonist

• Aprepitant Emend
• (substance P receptor antagonist) used in delayed
  nausea caused by chemotherapy.
• It can be used in a combination with
  benzodiazepines and 5-HT3 antagonists, or alone.

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Emetics agents that induce reflex vomiting.

• Ipecac
• Ipecac is a mixture of alkaloids, derived from
  the ipecacuanha plant.

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• Ipecac induces vomiting by stimulating the CTZ
  and by causing gastrointestinal irritation.
• Ipecac is administered orally and is fast acting,
  causing vomiting in 85 of patients within 20
  minutes.
• Ipecac is rarely used anymore because of its low
  effectiveness and high side effect profile.
• Cardiac toxicity caused by the emetine in ipecac
  is noted in abusers such as bulimics.