GASTRO INTESTINAL TRACT PHARMACOLOGY - 2 LECTURE 8

The Gastrointestinal Tract Gastroesophageal Reflux Disease (GERD) Peptic Ulcer Disease (PUD) Duodenal Ulcer Nausea Emesis Diarrhea Constipation IBS

Vomiting The act of vomiting and the sensation of nausea that accompanies it are protective reflexes that serve to rid the stomach and intestine of toxic substances and prevent their further ingestion Vomiting or throwing up is forcing the contents of the stomach up through the esophagus and out of the mouth. Nausea is the feeling of having an urge to vomit. It is often called being sick to your stomach.

Vomiting Centre (medulla) Cerebral cortex Anticipatory emesis Smell Sight Thought Vestibular nuclei Motion sickness Pharynx & GIT Chemo & radio therapy Gastroenteritis (vagus) Chemoreceptor Trigger Zone (CTZ) (Outside BBB) Cancer chemotherapy Opioids Muscarinic, 5 HT 3 & Histaminic H 1 5 HT 3 receptors Dopamine D 2 5 HT 3,,Opioid Receptors Muscarinic Histaminic H 1 Pathophysiology of Emesis

Indications of antiemetics 1- Chemotherapy-induced vomiting 2- Post irradiation vomiting 3- Postoperative vomiting 4- Vomiting of pregnancy 5- Motion sickness

Group of drugs used as antiemetics Serotonin 5 HT 3 Antagonists: Dopamine D 2 Antagonist: Anticholinergics: H 1 Antihistaminics

Serotonin 5 HT 3 Antagonist Potent antiemetics Mechanism of action: 1- Peripheral 5-HT3 receptor blockade on intestinal vagal afferents. 2- Central 5-HT3 receptor blockade in the vomiting center and chemoreceptor trigger zone Antiemetic action is mainly against: Emesis mediated by vagal stimulation (e.g. postoperative and chemotherapy) High first pass metabolism Excreted by liver & kidney No dose reduction in renal insufficiency but needed in hepatic insufficiency

Drugs Available 1.Ondansetron 2.Granisetron 3.Dolasetron 4.Palonosteron Indications 1)Chemotherapy induced nausea and vomiting 2)postradiation nausea & vomiting 3)Vomiting of pregnancy 4)Postoperative vomiting

Adverse Effects The most common adverse effects are: 1- Headache and dizziness 2- Constipation or diarrhoea

Corticosteroids Corticosteroids have antiemetic properties Mechanism of action: possibly by suppressing peritumoral inflammation and prostaglandin production. Use: to enhance efficacy of 5HT 3 receptor antagonists in the treatment of chemotherapy-induced vomiting.

Phenothiazines Phenothiazines as promethazine are antipsychotic agents Use: Chemotherapy-induced vomiting Radiotherapy-induced vomiting postoperative nausea and vomiting Mechanism of the antiemetic action: inhibition of central dopamine, muscarinic and H1 histamine receptors receptors

Butyrophenones Butyrophenones as droperidole are antipsychotic agents Mechanism of the antiemetic action: inhibition of central dopamine receptors Use: Chemotherapy-induced vomiting Radiotherapy-induced vomiting postoperative nausea and vomiting Adverse effects: droperidol may prolong the QT inter, therefore, it should not be used in patients with QT prolongation (should only be used in patients who have not responded adequately to alternative agents).

Substituted Benzamides 1- Metoclopramide 2- Trimethobenzamide Mechanism of antiemetic action: Central dopamine-receptor blockade Side effects: (mainly extrapyramidal): 1)Restlessness 2)Dystonias 3) Parkinsonian symptoms

H1 receptor antagonists and Anticholinergics Use: prevention or treatment of motion sickness. Adverse effects: sedation, dizziness,confusion, dry mouth, cycloplegia, and urinary retention.. Diphenhydramine dimenhydrinate First generation H1 receptor blockers that have anticholinergic and sedating properties MeclizineFirst generation H1 receptor blockers that have lesser anticholinergic and sedating properties HyoscineMuscarinic receptor blocker

Benzodiazepines Uses: Benzodiazepines such as diazepam are used prior to the initiation of chemotherapy to reduce anticipatory vomiting or vomiting caused by anxiety

Cannabinoids (Dronabinol) The mechanisms for the antiemetic effects is not known. Pharmacokinetics. readily absorbed after oral administration It undergoes extensive first-pass metabolism with limited systemic bioavailability after single doses Mmetabolites are excreted primarily via the biliary-fecal route Adverse effects include: 1.Euphoria or dysphoria, sedation and hallucinations 2.Abrupt withdrawal leads o withdrawal syndrome (restless, insomnia and irritability) 3.Autonomic effects (sympathetic) in the form of tachycardia, palpitation, conjunctival injection, and orthostatic hypotension. Use: For the prevention of chemotherapy-induced nausea and vomiting

LAXATIVES bulk laxatives bulk laxatives – =increasing the volume, not absorbed – methylcelulose, agar, psyllium seeds – no serious unwanted effects osmotic l. osmotic l. – not absorbed, osmosis - distension of colon – magnesium sulphate, magnesium hydroxide, lactulose – ADR: flatulence, cramps, diarhoea, electrolyte dist., tolerance stimulant l. stimulant l. – stimulation of enteric nerves -  secretion, motility – bisacodyl, senna preparations – ! only for short-term use - nerve reduction

antidiarrhoeal agents I secretion, motility, decreased absorption ! fluid and electrolyte balance - rehydration antiinfective agents…gastroenteritis – sever cases of Campylobacter - erythromycin, ciprofloxacin antidiarrhoeal agents

antidiarrhoeal agents II antimotility agents antimotility agents – opiates, morphine - constipation, sphincter contraction – codeine, diphenoxylate, loperamide – ! drowsiness, dizziness, paralytic ileus adsorbents adsorbents – adsorbing microorganisms and toxins – kaolin, pectin, charcoal

motility stimulants = prokinetic drug domperidone (Motilium) - D 2 antagonist, also antiemetic –  oesophageal sphincter pressure…GERD – ! hyperprolactinemia metoclopramide (Paspertin) - DA antagonist and Ach agonist – increases gastric emptying - GERD – ! extrapyramidal side effects cisapride (Prepulsid) - 5-HT 4 rec. agonist….Ach release –  gut motility, no antiemetic action – withdrawn due to QT prolongation

Agents that increase GIT motility 1- Cholinergic agents Stimulate cholinergic receptors. Enhance contractions in an uncoordinated manner that produces no net propulsive activity. Not useful for treating motility disorders 2- Prokinetic agents enhance coordinated GIT propulsive motility. Prokinetic agents act at receptor sites on the motor neuron itself increasing the release of acetylcholine at the motor nerve terminal without interfering with the normal physiological pattern and rhythm of motility. Useful for treating motility disorders

Cholinergic Agents Direct cholinergic agents Stimulate cholinergic receptors in the wall of the GIT. 1- ACh is not used pharmacologically because:  it affects both nicotinic and muscarinic receptors  It is degraded rapidly by acetylcholinesterase. 2- Bethanechol  Muscarinic receptor agonist  Resists enzymatic hydrolysis.  In addition, it lacks real prokinetic efficacy,

Indirect cholinergic agents: Acetylcholinesterase Inhibitors. These drugs inhibit the degradation of ACh, allowing ACh to accumulate at sites of release.  Neostigmine has been used to treat paralytic ileus.

Inflammatory bowel disease Ulcerative colitis - diffuse mucosal inflammation - limited to colon - defined by location (eg proctitis;pancolitis) Crohn’s disease - patchy transmural inflammation - fistulae; strictures - any part of GI tract - defined by location or pattern

Treatment options 1.Aminosalicylates 2.Corticosteroids 3.Thiopurines 4.Ciclosporin 5.Methotrexate 6.Infliximab 7.Surgery

Management of UC Acute to induce remission 1.oral +- topical 5-ASA 2.+- oral corticosteroids eg 40mg prednisolone 3.Azathioprine (Chronic active) 4.iv steroids/Colectomy/ ciclosporin (severe) Maintaining remission 1.oral +- topical 5-ASA 2.+- Azathioprine (frequent relapses)

Management of CD Acute to induce remission 1.oral high dose5-ASA 2.+- oral corticosteroids reducing over 8/52 3.Azathioprine (Chronic active) 4.Methotrexate (intolerant of azathioprine) 5.iv steroids/ metronidazole/elemental diet/surgery/infliximab Maintaining remission 1.Smoking cessation 2.oral 5-ASA limited role 3.+- Azathioprine (frequent relapses) 4.Methotrexate (intolerant of azathioprine) 5.Infliximab infusions (8 weekly)

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