Lecture 5. Drugs Acting on GIT PDF

D2 – Pharmacology I Drugs acting on GIT Presented by Dr Mohammad Jaffar Department of Pharmacology, BMC, Jeddah  Antiemetic, Prokinetic and Digestant Drugs Emesis: Vomiting occurs due to stimulation of the emetic (vomiting) centre situated in the medulla oblongata. The ch...

D2 – Pharmacology I Drugs acting on GIT Presented by Dr Mohammad Jaffar Department of Pharmacology, BMC, Jeddah  Antiemetic, Prokinetic and Digestant Drugs Emesis: Vomiting occurs due to stimulation of the emetic (vomiting) centre situated in the medulla oblongata. The chemoreceptor trigger zone (CTZ) located in medulla is relay areas for afferent impulses arising in the g.i.t, throat and other viscera. 5-HT3 receptors present on extrinsic primary afferent neurons (PAN) of the enteric nervous system (ENS). However, 5-HT is not the only mediator of such signals: many peptides, e.g. substance P and other messengers are also involved.  The CTZ express a variety of receptors, e.g. histamine H1, dopamine D2, serotonin 5-HT3, cholinergic M, neurokinin NK1 (activated by substance P), cannabinoid CB1 and opioid μ-receptors through which the emetic signals are relayed and which could be targets of antiemetic drug action.  The vestibular apparatus generates impulses when body is rotated or equilibrium is disturbed or when ototoxic drugs act.  Various unpleasant sensory stimuli such as bad odor, ghastly sight, severe pain as well as fear, recall of an obnoxious event, anticipation of an emetic stimulus (repeat dose of cisplatin) cause nausea and vomiting through higher centres.  EMETICS (short information) These are drugs used to evoke vomiting. Act on CTZ : Apomorphine, Ipecacuanha Vomiting needs to be induced only when an undesirable substance (poison) has been ingested. Powdered mustard suspension or strong salts solution may be used in emergency*. Apomorphine It is a semi-synthetic derivative of morphine, dopaminergic agonist on the CTZ. Injected i.m./s.c. in a dose of 6 mg, it promptly (within 5 min) induces vomiting. It should not be used if respiration is depressed. Ipecacuanha The dried root of Cephaelis ipecacuanha contains emetine syrup ipecac (15–30 ml in adults, 10–15 ml in children, 5 ml in infants) for inducing vomiting.  ANTIEMETICS: CLASSIFICATION 1. Anticholinergics: Hyoscine, Dicyclomine 2. H1 antihistaminics: Promethazine, Diphenhydramine, Dimenhydrinate, Doxylamine, Meclozine (Meclizine), Cinnarizine. 3. Neuroleptics (D2 blockers) :Chlorpromazine, Triflupromazine, Prochlorperazine, Haloperidol, 4. Prokinetic drugs: Metoclopramide, Domperidone, Cisapride, Mosapride, Itopride. 5. 5-HT3 antagonists: Ondansetron, Granisetron, Palonosetron, Ramosetron. 6. NK1 receptor antagonists: Aprepitant, Fosaprepitant. 7. Adjuvant antiemetics: Dexamethasone, Benzodiazepines, Dronabinol, Nabilone  ANTICHOLINERGICS Hyoscine (0.2–0.4 mg oral, i.m.) is the most effective drug for motion sickness. (Short journeys) However, it has a short duration of action MOA: Blocks the nerve impulse to the brain from the vestibular apparatus (ear) Dicyclomine (10–20 mg oral) has been used for prophylaxis of motion sickness and for morning sickness. MOA: Blocks the nerve impulse to the brain from the vestibular apparatus (ear)  Anti-histaminics Promethazine, diphenhydramine, dimenhydrinate These drugs afford protection of motion sickness for 4–6 hours, but produce sedation and dryness of mouth. Their combination has been used in chemotherapy induced nausea and vomiting (CINV). Promethazine theoclate ( 25 mg tab) This salt of promethazine has been specially promoted as an antiemetic. Doxylamine It is a sedative H1 antihistaminic with prominent anticholinergic activity. (Dose: 10–20 mg at bed time) Marketed in combination with pyridoxine (Vitamin B6), it is specifically promoted ‘morning sickness’ (vomiting of early pregnancy) but with caution. Oral absorption is slow, and its t½ is 10 hr. The side effects are drowsiness, dry mouth, vertigo and abdominal upset. Meclozine (meclizine) It is less sedative and longer-acting; protects against sea sickness for nearly 24 hours. Cinnarizine It is an anti-vertigo drug having anti-motion sickness property. MOA: It probably acts by inhibiting influx of Ca2+ from endolymph into the vestibular sensory cells which mediates labyrinthine reflexes. Morning sickness (During pregnancy) The antihistaminics are suspected to have teratogenic potential Nevertheless, it is better to avoid them for morning sickness. Most cases of morning sickness can be managed by reassurance and dietary adjustment. If an antiemetic has to be used, dicyclomine, promethazine, prochlorperazine or metoclopramide may be prescribed in low doses.  NEUROLEPTICS They have broad spectrum antiemetic action effective in: (a) Drug induced and postoperative nausea and vomiting (PONV). (b) Disease induced vomiting (c) Malignancy associated and cancer chemotherapy (mildly emetogenic) induced vomiting. (d) Radiation sickness vomiting (less effective). (e) Morning sickness Prochlorperazine is a D2 receptor blocking agent is a labyrinthine suppressant, has selective Anti-vertigo and antiemetic actions. extrapyramidal side effects (Parkinson’s like symptoms) are the most important limiting features. Dose: 5–10 mg BD/TDS oral, 12.5–25 mg by deep i.m. injection.  PROKINETIC DRUGS These are drugs which promote gastrointestinal transit and speed gastric emptying by enhancing coordinated propulsive motility. Metoclopramide A ‘gastric hurrying’ agent, it is a commonly used antiemetic. Mechanism of action: Metoclopramide acts through both dopaminergic and serotonergic Receptors. D2 antagonism: Dopamine (acting through D2 receptors) normally acts to delay gastric emptying when food is present in stomach 5-HT4 agonism: Metoclopramide acts in the g.i.t. to enhance ACh release from myenteric motor neurones. 5-HT3 antagonism: At high concentrations metoclopramide can block 5-HT3 receptors GIT: Metoclopramide has more prominent effect on upper g.i.t.; increases gastric peristalsis → speeds gastric emptying. CNS: Metoclopramide is an effective antiemetic; acting on the CTZ Pharmacokinetics: Metoclopramide is rapidly absorbed orally, enters brain, crosses placenta and is secreted in milk. It is partly conjugated in liver and excreted in urine within 24 hours; t½ is 3– 6 hours. Interactions: It increases the absorption of aspirin, diazepam etc. and reduces the absorption of digoxin and cimetidine. Adverse effects: Metoclopramide is generally well tolerated. Sedation, dizziness, loose stools, muscle dystonias (especially in children) are the main side effects. Long-term use can cause parkinsonism, gynaecomastia. Domperidone: It is a D2 receptor antagonist, Domperidone crosses blood-brain barrier poorly. The antiemetic action is exerted mainly through CTZ which is not protected by blood-brain barrier. Side effects: Dry mouth, loose stools, headache, rashes. Cardiac arrhythmias have developed on rapid i.v. injection 5-HT3 ANTAGONISTS: Ondansetron It is the prototype of a distinct class of antiemetic drugs developed to control cancer chemotherapy/radiotherapy induced vomiting. It blocks the depolarizing action of 5-HT exerted through 5-HT3 receptors on the g.i.t. as well as in CTZ. Pharmacokinetics: Oral bioavailability of ondansetron is 60–70% due to first pass metabolism, followed by glucuronide and sulfate conjugation. No clinically significant drug interactions have been noted. It is eliminated in urine and faeces, mostly as metabolites; t½ is 3–5 hrs, and duration of action is 8–12 hrs In patients who do not obtain optimum protection by ondansetron alone, addition of dexamethasone, promethazine/diazepam or both dexamethasone + NK1 antagonist (aprepitant) enhances antiemetic efficacy.  NK1 RECEPTOR ANTAGONISTS Realizing that activation of neurokinin (NK1) receptor in CTZ by substance P released due to emetogenic chemotherapy causing vomiting. Selective antagonists of this receptor are being used as antiemetic. Aprepitant, It is a recently introduced selective, high affinity NK1 receptor antagonist that blocks the emetic action of substance P, with little effect on 5 HT3 and D2 or other receptors. Gastrointestinal motility is not affected.  LAXATIVES (Aperients, Purgatives, Cathartics) (a) Laxative or aperient: milder action, elimination of soft but formed stools. (b) Purgative or cathartic: stronger action resulting in more fluid evacuation. Many drugs in low doses act as laxative and in larger doses as purgative. CLASSIFICATION 4. Osmotic purgatives 1. Bulk forming Magnesium salts: sulfate, hydroxide Dietary fibre: Bran, Psyllium (Plantago), Ispaghula, Methylcellulose Sodium salts: sulfate, phosphate Sod. pot. Tartrate Lactulose 2. Stool softener: Docusates (DOSS), Liquid paraffin 3. Stimulant purgatives (a) Diphenylmethanes: Phenolphthalein, Bisacodyl, Sodium picosulfate (b) Anthraquinones (Emodins): Senna, Cascara sagrada (c) 5-HT4 agonist: Prucalopride (d) Fixed oil: Castor oil  MECHANISM OF ACTION All purgatives increase the water content of the faeces by: (a)A hydrophilic or osmotic action, retaining water and electrolytes in the intestinal lumen— increase volume of colonic content and make it easily propelled.  BULK PURGATIVES Dietary fibre: bran Dietary fibre consists of unabsorbable cell wall and other constituents of vegetable food—cellulose, lignins, gums, pectins, glycoproteins and other polysaccharides. It absorbs water in the intestines, swells, increases water content of faeces—softens it and facilitates colonic transit Increased intake of dietary fibres is the most appropriate method for prevention of functional constipation.* Disadvantage: Bran is generally safe, but it is unpalatable. Refined ispaghula husk 3–8 g is freshly mixed with cold milk, fruit juice or water and taken once or twice daily. It acts in 1–3 days. It should not be swallowed dry (may cause esophageal impaction). Ispaghula husk (refined): ISOGEL (27 g/ 30 g), NATURE CURE (49 g/100 g), FYBOGEL (3.5 g/5.4 g) powder  STOOL SOFTENER Docusates (Dioctyl sodium sulfosuccinate: DOSS) It is an anionic detergent, softens the stools by net water accumulation in the lumen by an action on the intestinal mucosa. It emulsifies the colonic contents and increases penetration of water into the faeces. Dose: 100–400 mg/day; acts in 1–3 days. Liquid paraffin It is a viscous liquid; a mixture of petroleum hydrocarbons, that was introduced as a laxative. It is pharmacologically inert. Taken for 2–3 days, it softens stools and is said to lubricate the intestine Dose: 15–30 ml/day—oil as such or in emulsified form. STIMULANT PURGATIVES They are powerful purgatives: often produce griping. They irritate intestinal mucosa and thus were thought to primarily stimulate motor activity. mechanism of action is accumulation of water and electrolytes in the lumen by altering absorptive and secretory activity of the mucosal cell. Castor oil It is one of the oldest purgatives. Castor oil is a bland vegetable oil obtained from the seeds of Ricinus communis. The primary action is now shown to be decreased intestinal absorption of water and electrolytes, and enhanced secretion by a detergent like action on the mucosa. Structural damage to the villous tips has also been observed. Peristalsis is increased secondarily. Dose: 15–25 ml (adults) 5–15 ml (children) is generally taken in the morning. Because the site of action is small intestine, purgation occurs in 2–3 hours Due to its unpalatability, frequent cramping, possibility of dehydration after-constipation.  OSMOTIC PURGATIVES Solutes that are not absorbed in the intestine retain water osmotically and distend the bowel— increasing peristalsis indirectly. Mag. sulfate (Epsom salt): 5–15 g; bitter in taste, may nauseate. Mag. hydroxide (as 8% W/W suspension—milk of magnesia) 30 ml; bland in taste, also used as antacid. Sod. sulfate (Glauber’s salt): 10–15 g; bad in taste. Sod. phosphate: 6–12 g, taste not unpleasant. Sod. pot. tartrate (Rochelle salt): 8–15 g, relatively pleasant tasting. Lactulose It is a semisynthetic disaccharide of fructose and lactose which is neither digested nor absorbed in the small intestine—retains water. In a dose of 10 g BD taken with plenty of water, it produces soft formed stools in 1–3 days. Flatulence and flatus is common, cramps occur in few. Some patients feel nauseated by its peculiar sweet taste  DRUG THERAPY for Diarrhoea Drugs used in diarrhoeas may be categorised into: 1. Specific antimicrobial drugs 2. Probiotics 3. Drugs for inflammaory bowel disease (IBD) 4. Nonspecific antidiarrhoeal drugs.  Probiotics in diarrhoea These are microbial cell preparations, either live cultures or lyophillised powders, that are intended to restore and maintain healthy gut flora or have other health benefits. Diarrhoeal illnesses and antibiotic use are associated with alteration in the population, composition and balance of gut microflora. Recolonization of the gut by nonpathogenic, mostly lactic acid forming bacteria and yeast is believed to help restore this balance. Organisms most commonly used are— Lactobacillus sp., Bifidobacterium, Streptococcus faecalis, Enterococcus sp. and the yeast Saccharomyces boulardii, etc. Loperamide It is an opiate analogue with major peripheral μ opioid and additional weak anticholinergic property. As a constipating agent it is much more potent than codeine. Because of poor water solubility—little is absorbed from the intestines. Entry into brain is negligible—CNS effects are rare and occur only with high doses; no abuse liability. The duration of action is longer (12 hr) than codeine  Antacids: Chemical antacids: CaCO3, Mgo + Mg(OH)2 – Milk of magnesia, Magnesium trisilicate, Alluminium hydroxide MOA: Antacids acts by neutralising the acid present in the stomach Simple process of chemical reaction of acids and bases Side effects: CaCO3 (Calcium carbonate) – rebound hyperacidity, Milk of magnesia- Diarrhoea, Alluminium hydroxide causes constipation. Uses: Gastritis and hyperacidity Magnesium trisilicate can form a layer around the ulcer and can act as ulcer protective* H2 receptor blockers: Ranitidine, Famotidine, Cemitidine MOA: These agents blocks the H2 receptors present on the gastric mucosa and decreases the acid secretion in the stomach Kinetics: Orally well absorbed, Distributed in the body, pass BBB, metabolised in the liver and excreted through urine Uses: Antacids, Anti ulcer Proton pump inhibitors: Omeprazole, Pantoprazole, Esomeprazole, Rabeprazole MOA: These agents blocks the Sodium-potasium ATPase present on the gastric mucosa and decreases the acid secretion in the stomach Kinetics: Orally well absorbed, Distributed in the body, pass BBB, metabolised in the liver and excreted through urine Uses: peptic ulcer, Zollinger elisson syndrome and Gastro oesophageal reflux disorder Thank You