Gastrointestinal Pharmacology Lecture 1

J S Lauritzen 24/02/2010

Lecture Outline
Review of GI function
Neural and endocrine control

Stomach
Emesis and anti-emetics Ulcers and control of secretion

Intestine
Digestive transit Absorption Inflammatory disease

References
Vanders Human Physiology (11th ed)
Widmaier, EP; Raff, H; Strang, KT. McGraw-Hill (2008). For physiology review

Pharmacology (6th ed)

Rang, HP; Dale, MM; Ritter, JM; Flower, RJ. Churchill Livingstone (2007). Covers all material in these lectures

British National Formulary (BNF)

bnf.org (available online) Clinical reference for drugs used in the UK.

Guidelines for Antiemetic Treatment of Chemotherapy-Induced Nausea and Vomiting: Past, Present, and Future Recommendations (2007). Karin Jordan, Christoph Sippel and Hans-Joachim Schmoll The Oncologist September 2007 vol. 12 no. 9 1143-1150.

Learning Outcomes
Describe the neural pathway that controls vomiting. Explain the mechanisms of action of drugs used to treat vomiting (emesis). Give an account of the drugs used to treat abnormal digestive transit.

Functions of gastrointestinal tract Gastrointestinal Tract

Essential nutrients:
Carbohydrates, protein, fat, vitamins, minerals, trace elements

Food
Toxic substances

Salivary Glands Esophagus

Liver
Gallbladder Large Intestine

Stomach
Pancreas Rectum

Small Intestine

Stomach Gastrointestinal Tract

Esophagus Sphincter Duodenum

Fundus

Store, mix, dissolve food

Mucus: Pyloric Sphincter Pepsin: HCl: Lubricate / protect epithelial surface Protein digestion Activate pepsin / denature food

Stomach Stomach

Gastric Pit

Goblet Cells (Mucus) Parietal (oxyntic) Cell (HCl)

Gastric Gland Chief Cells (Pepsinogen)

Control of digestive secretions

Neural
Presence of food in tract

Hormonal

Stimulation of sensory nerve endings

Direct stimulation of endocrine cells

Activation of autonomic nervous system

Release hormone into blood

+ or Motility Exocrine secretion

Gastric secretions
3 Phases
1 2 3

Cephalic Phase
Sight Smell Taste

Gastric Phase
Presence of food

Intestinal Phase
Nutrients in small intestine

Vagus nerves

Gastrin / Histamine

Gastrin, Secretin VIP,GIP etc.

Pepsin HCl

(Pepsin) HCl

Various effects

Gastric secretions & gut hormones

Gallbladder Esophagus Stomach HCl Pepsin Gastrin

Bj
Pancreas Pj Duodenum
CCK Secretin VIP GIP Motilin + other gut hormones

Jejunum Ileum

Control of gastric acid secretion

Sight Smell Taste Presence of food
(protein)

Vagus Histamine

Release of gastrin

Secretion of HCl
CCK
GIP

Negative feedback

Somatostatin

Abnormal function of the GI tract

Nausea; Vomiting / Emesis Diarrhoea & constipation Heartburn & indigestion Gastric and duodenal ulcers Crohns disease and inflammatory bowel disease

Control of Emesis
Neural
Chemical trigger zone of the medulla oblongata (D2 and 5-HT3 receptors). Vomiting centre (H1 and mACh receptors) receives input from CTZ and the stomach and duodenum via Vagus nerve.

Local
Irritants, Histamine, 5-HT3 receptors.

Emetic effects of drugs

Side effects of some drugs, notably cytotoxics used in cancer chemotherapy.
No longer commonly used to treat poisoning due to risk of aspiration (e.g. Ipecacuanha, which irritates the stomach lining).

Antiemetics
H1 receptor antagonists:
e.g. cinnarizine, cyclizine, promethazine. Effective against motion sickness and morning sickness in pregnancy Side effects include drowsiness and sedation

Muscarinic antagonists
E.g. Hyoscine (scopolamine). Common motion sickness prophylactic Dry mouth and blurred vision, less drowsiness than antihistamines.

Antiemetics used for postoperative nausea and with cancer chemotherapy

Selective 5-HT3 receptor antagonists
E.g. ondansetron, palonosetron Side-effects relatively uncommon, include GI effects and headaches. E.g. chlorpromazine Frequent side effects include drowsiness, hypotension and motor disorders.

Antipsychotics

Benzodiazepines
Adjunct therapy in circumstances where anxiety is a factor

D2 receptor antagonists

E.g. metoclopramide, domperidone Also increase GI motility, so are used for other GI conditions Metoclopramide may have serious CNS side effects

J S Lauritzen 25/02/2009

Other antiemetics
Cannabinoids
Nabilone Sometimes effective when other drugs have failed Side effects similar to other cannabinoids

Glucocorticoids
Dexamethasone Mechanism not well understood sensitive P450 substrate

Neurokinin-1 antagonists
Aprepitant Probably by inhibiting action of substance P; inhibitor of P450

J S Lauritzen 25/02/2009

Drugs that affect digestive transit and motility

Purgatives
Accelerate passage of food through GI tract

Drugs that increase motility

Domperidone, metoclopromide

Antidiarrhoeal drugs Antispasmodic drugs

J S Lauritzen 25/02/2009

Purgatives
Bulk / osmotic laxatives:
Function by producing an indigestible, hydrated mass, which stretches gut smooth muscle and stimulates motility. Dietary fibre, ispaghula husk. Poorly absorbed salts, e.g. Magnesium sulphate Lactulose

Faecal softeners (docusate sodium, arachis oil) Stimulant laxatives

Bisacodyl; senna, dantron
J S Lauritzen 25/02/2009

Antidiarrhoeal drugs
Diarhoea may be caused by infection, toxins or some other cause Maintain fluid and electrolyte balance Combat infection (notably E.Coli) Antimotility drugs
Atropine Opiates (morphine, codeine) Loperamide Antispasmodics (e.g. Mebeverine)

Adsorbents
E.g. Activated charcoal, kaolin,

J S Lauritzen 25/02/2009

Chronic bowel disease (TDL)

Non-tropical sprue Irritable bowel syndrome Ulcerative colitis Crohns disease

Anti-inflammatories (Glucocorticoids, aminosalicylates, sulfalazine) Immunosuppressants, cytokine inhibitors (infliximab), antiallergy drugs Control motility Dietary adjustments

Review
Drugs can modify vomiting by acting on which of the following areas:
A) The vomiting centre in the medulla. B) The chemoreceptor trigger zone in the floor of the fourth ventricle. C) The nucleus of the solitary tract in the medulla. D) Visceral afferents in the gastrointestinal tract.

Drugs can modify vomiting by acting as which of the following?

A) Antagonists against 5-HT3-receptors in the chemoreceptor trigger zone (CTZ). B) Agonists for dopamine D2-receptors in the chemoreceptor trigger zone (CTZ). C) Agonists for histamine H1-receptors associated with the vestibular nuclei. D) Antagonists against muscarinic receptors in the nucleus of the solitary tract.

Which drugs have antiemetic actions?

A) B) C) D) E) 5-HT3 antagonists. Glucocorticoids. Histamine H2 antagonists. Dopamine D2 agonists. Muscarinic receptor agonists.

Which of the following is true of the H1-receptor antagonists used to treat vomiting?

A) They are strongly active against emetogenic stimuli action on the chemoreceptor trigger zone (CTZ). B) Cyclizine is effective in motion sickness. C) Cinnarizine is useful in Mnire's disease. D) Promethazine can be used for the morning sickness of pregnancy.

Which of the following can ease the passage of food through the GI tract?
A) B) C) D) E) Ispaghula husk. Codeine. Bisacodyl. Lactulose. Aluminium hydroxide.

Learning Outcomes
Describe the neural pathway that controls vomiting. Explain the mechanisms of action of drugs used to treat vomiting (emesis). Give an account of the drugs used to treat abnormal digestive transit.