Pharmacotherapy of Gastrointestinal Motility Disorders PDF

PHARMACOTHERAPY OF GASTROINTESTINAL MOTILITY DISORDERS Prof Ahmet AKICI, MD Department of Medical Pharmacology  PHARMACOTHERAPY OF GASTROINTESTINAL MOTILITY DISORDERS Emetic Drugs Drugs Used in The Treatment of Nausea and Vomiting Prokinetic Agents...

PHARMACOTHERAPY OF GASTROINTESTINAL MOTILITY DISORDERS Prof Ahmet AKICI, MD Department of Medical Pharmacology  PHARMACOTHERAPY OF GASTROINTESTINAL MOTILITY DISORDERS Emetic Drugs Drugs Used in The Treatment of Nausea and Vomiting Prokinetic Agents Antidiarrheal Agents Laxative Drugs Uses and Abuses of Laxatives  NAUSEA AND VOMITING Vomiting is a complex clinical behaviour that results in the evacuation of stomach contents and involves coordinated activity of the GI tract and the nervous system. It is frequently preceded by nausea and retching. Vomiting center (VC) is located in the dorsal portion of the lateral reticular formation of the medulla and interacts with chemoreceptor trigger zone (CTZ), afferent nerves from gut, the vestibular system, and intracranial pressure receptors. The vomiting act is preceded by a prodrome consisting of; - Nausea - Cold sweats - Pupillary dilatation - Tachycardia - Salivation  VOMITING ACTION Vagal efferent nerve fibers relax the proximal stomach, contract the eusophagus longitudinally and pull the proximal stomach into the thorax, evacuate the upper small intestine into the stomach via a retrograde giant contraction, while emptying the lower intestine into the colon. The vomiting of the gastric contents is caused by the compression of the stomach through a strong simultaneous contraction of the diaphragm and abdominal muscles. TYPES OF SICKNESS RELATED WITH VOMITING;. Motion sickness and other vestibular problems Pregnancy (Hyperemesis gravidarum) CNS infection / increased pressure in CNS Radiation / chemotherapy Postoperative vomiting GI irritation Other GI problems (Hepatobiliary disorders, GI obstruction, Peptic ulcer, Gastritis, Ulcerative colitis, Crohn’s disease, Achalasia) Adrenal insufficiency Psychiatric disorders Chemical substances Drugs ………………… PROLONGED AND SEVERE VOMITING CAUSES; - Hypochloremia - Hypokalemia - Alkalosis - Dehydration  Is there any condition that vomiting is indicated? Can some drugs used for the purpose of vomiting?  EMETICis Dindicated Vomiting RUGS in some intoxication like ingestion of some substances but there are some rules for vomiting; -Patient must be conscious -The swallowed substance must not be alkali, acid, corrosive or petroleum product -Time (vomiting is indicated in early hours) (within 2 hours)  Apomorphine (subcutaneous): Molecular structure is like dopamine and it stimulates D2 receptors in CTZ and causes emesis. Ipecac syrup (oral): Irritates the gastric mucosa and causes emesis. Hypertonic salt solutions, antimon potassium, copper sulfate and zinc sulfate have also emetic effects on gastric mucosa but they are not been used anymore because of their side effects.  DRUGS USED IN THE TREATMENT OF NAUSEA AND VOMITING 1- Muscarinic receptor antagonist: Scopolamine 2- Histamine H1 receptor antagonists: Cyclizine Diphenhydramine Chlorcyclizine Dimenhydrinate Cinnarizine Doxylamine Meclizine Promethazine 3- Dopamine receptor antagonists: Phenothiazines: Chlorpromazine, Prochlorperazine, Perphenazine, Thiethylperazine Butyrophenones: Haloperidol, Droperidol Domperidone Metoclopramide Trimethobenzamide 4-Serotonin 5HT3 receptor antagonists: Ondansetron, Granisetron, Tropisetron, Dolasetron, Palonosetron 5- Cannabionids: Tetrahydrocannabinol, Nabilone, Levonantradol 6- Pyridoxine 7- Corticosteroids: Dexamethasone, Methylprednisolone 8- Benzodiazepines: Lorazepam, Alprazolam 9- Substance P/Neurokinin-1 receptor antagonist: Aprepitant  DRUGS USED IN THE TREATMENT OF NAUSEA AND VOMITING 1- Muscarinic receptor antagonist: Scopolamine 2- Histamine H1 receptor antagonists: Cyclizine Diphenhydramine Chlorcyclizine Dimenhydrinate Cinnarizine Doxylamine Meclizine Promethazine 3- Dopamine receptor antagonists: Phenothiazines: Chlorpromazine, Prochlorperazine, Perphenazine, Thiethylperazine Butyrophenones: Haloperidol, Droperidol Domperidone Metoclopramide Trimethobenzamide 4-Serotonin 5HT3 receptor antagonists: Ondansetron, Granisetron, Tropisetron, Dolasetron, Palonosetron 5- Cannabionids: Tetrahydrocannabinol, Nabilone, Levonantradol 6- Pyridoxine 7- Corticosteroids: Dexamethasone, Methylprednisolone 8- Benzodiazepines: Lorazepam, Alprazolam 9- Substance P/Neurokinin-1 receptor antagonist: Aprepitant  INDICATIONS 1- Muscarinic receptor antagonist: Scopolamine (transdermal therapeutic system) -Motion sickness (it is one of the best agents for the prevention of this indication) -Post-op vomiting 2- Antihistaminics: -Motion sickness -Other labyrinthine disturbances (Meniere) -Pregnancy -Uremia -Post-op vomiting Histamine H1 antagonists have significant anticholinergic properties.  INDICATIONS 3- Dopamine receptor blockers -Meniere’s disease -Radiation sickness -Post-op vomiting -Cytotoxic drug induced vomiting -………. In butyrophenones, the main agent used is droperidol, which can be given i.m. or i.v. Extrapyramidal side effects and hypotension may occur. Droperidol may prolong the QT interval.  INDICATIONS 4- 5HT3 receptor antagonists: -Cytotoxic drug induced vomiting -Radiation -Post-op vomiting Serotonin receptor antagonist are well tolerated. The most common side effects are headache, dizziness, and constipation (these drugs are expensive).  INDICATIONS 5- Cannabionids: Cytotoxic drug induced vomiting They are not first-line antiemetics because of their serious side effects, including dysphoria, hallucinations, sedation, vertigo, and disorientation. 6- Pyridoxine : Pregnancy, Radiation sickness, Meniere’s disease The vitamin B6 diminishes effectiveness of levodopa. 7- Corticosteroids: Cytotoxic drug induced vomiting and other indications. Their antiemetic mechanism is not known, but may involve blockade of prostaglandins. These drugs are commonly used in combination with other agents.  INDICATIONS 8- Lorazepam and Alprazolam: Cytotoxic drug induced vomiting Their beneficial effects may be due to their sedative, anxiolytic, and amnestic properties. But their antiemetic potency is low. 9-Substance P/Neurokinin-1 receptor antagonist: Aprepitant It is indicated as part of a multiple drug regimen for prophylaxis of nausea and vomiting associated with high dose cytotoxic drug (e.g. Cisplatin). -Side effects: constipation and fatigue /Drug-drug interactions (e.g warfarin).  PROKINETIC AGENTS Drugs that can selectively stimulate gut motor function (prokinetic agents) have significant potential clinical usefulness.  PROKINETIC AGENTS Agents that increase lower esophageal sphincter pressures may be useful for Gastroesophageal Reflux Disease. Prokinetic (or gastrokinetic) agents are useful in reducing gastric fluid volume. Reduction of gastric fluid volume is important to decrease risk of some sickness such as aspiration pneumonitis.  GASTRIC HYPOMOTILITY Gastric hypomotility with delayed emptying of the stomach contents is also a component of some GI disorders: Diabetic neuropathy Anorexia nervosa Achlorhydria Postoperative (gastric surgery) Gastric motility should be increased in these conditions too; emergency surgery but if the patient has a full stomach, patient with hiatus hernia and patient with esophageal reflux. The symptoms of such disorders may include: Nausea and vomiting Heartburn Postprandial discomfort Indigestion Gastric hypomotility may cause: Gastroesophageal reflux Esophageal ulceration Intense substernal pain Respiratory problems such as pneumonitis  Drugs: - Metoclopramide - Domperidone - Bethanechol - Cisapride - Macrolides - Antiemetic phenothiazines (minor relief and unacceptable side effects)  Metoclopramide - Cholinergic stimulation / Dopaminergic antagonist (D2) - Antiemetic effect - Accelerates the emptying of gastric contents via the serotonergic 5HT4 receptor agonism. - Relaxes the pylorus and duodenum. - Constricts the lower esophageal sphincter. - Reduces reflux from duodenum to stomach and stomach to esophagus. - Less effect on colonic motility and gastric secretion. The most common side effects; restlessness, drowsiness, insomnia, anxiety, and agitation. -Extrapyramidal side effects (symptoms like Parkinson disease). -Hyperprolactinemia (causes lactation or infertilty in women, gynecomastia in men).  METOCLOPRAMIDE WARNINGS Metoclopramide requires a boxed warning about risk for tardive dyskinesia. to warn providers and patients about the risk for tardive dyskinesia with chronic or high-dose use. Metoclopramide increases the rate of stomach emptying and is used as short-term treatment (