DRUGS ACTING ON THE DRUGS ACTING ON THE GASTROINTESTINAL SYSTEMGASTROINTESTINAL SYSTEM

Four Major Activities of the GI System• Secretion

• Absorption

• Digestion

• Motility

• Secretion of digestive enzymes, acid, bicarbonate, and mucus facilitates the digestion and absorption of nutrients.

• The GI system is controlled by the nerve plexus, which maintains a basic electrical rhythm and responds to local stimuli to increase or decrease activity.

• A series of local reflexes within the Gi tract helps maintain homeostasis within the system. Overstimuation of any of these reflexes can result in constipation (underactivity) or diarrhea (overactivity).

• Swallowing is a centrally mediated reflex that us important in delivering food to the GI tract for processing.

• Vomitting is controlled by the chemoreceptor trigger zone (CTZ) in the medulla or by the emetic zone in immature or injured brains.

• The H2-receptor antagonists (H2RA, often shortened to H2 antagonist) are a class of drugs used to block the action of histamine on parietal cells in the stomach, decreasing the production of acid by these cells. H2 antagonist are used in the treatment of dyspepsia, although they have largely been surpassed in popularity by the more effective proton pump inhibitors.

examples

• Cimetidine

• Famotidine

• Nizatidine

• Ranitidine

antacidantacid

• An antacid is any substance, generally a base or basic salt, which counteracts stomach acidity. In other words, antacids are stomach acid neutralizers.

Action mechanism

• Antacids perform a neutralization reaction, i.e. they buffer gastric acid, raising the pH to reduce acidity in the stomach. When gastric hydrochloric acid reaches the nerves in the gastrointestinal mucosa, they signal pain to the central nervous system. This happens when these nerves are exposed, as in peptic ulcers. The gastric acid may also reach ulcers in the esophagus or the duodenum.

• Other mechanisms may contribute, such as the effect of aluminum ions inhibiting smooth muscle cell contraction and delaying gastric emptying.

Indications

• Antacids are taken by mouth to relieve heartburn, the major symptom of gastroesophageal reflux disease, or acid indigestion. Treatment with antacids alone is symptomatic and only justified for minor symptoms. Peptic ulcers may require H2-receptor antagonists or proton pump inhibitors.

• The utility of many combinations of antacids is not clear, although the combination of magnesium and aluminium salts may prevent alteration of bowel habits.

Drug names

Examples of antacids (brand names may vary in different countries).

• Aluminium hydroxide (Amphojel, AlternaGEL) • Magnesium hydroxide (Phillips’ Milk of Magnesia) • Aluminum hydroxide with magnesium hydroxide (Maalox,

Mylanta, Diovol) • gel (Basaljel) • Calcium carbonate (Alcalak, TUMS, Quick-Eze, Rennie,

Titralac, Rolaids) • Sodium bicarbonate (Bicarbonate of soda, Alka-Seltzer) • (Mg6Al2(CO3)(OH)16 · 4(H2O); Talcid) • Bismuth subsalicylate (Pepto-Bismol) • Magaldrate with Simethicone (Pepsil)

Proton pump inhibitors

• Proton pump inhibitors (or "PPI"s) are a group of drugs whose main action is a pronounced and long-lasting reduction of gastric acid production. They are the most potent inhibitors of acid secretion available today. The group followed and has largely superseded another group of pharmaceuticals with similar effects, but different mode-of-action, called H2-receptor antagonists. These drugs are among the most widely-selling drugs in the world as a result of their outstanding efficacy and safety. The vast majority of these drugs are benzimidazole derivatives; however, promising new research indicates that imidazopyridine derivatives may be a more effective means of treatment.

Clinical use

These drugs are utilized in the treatment of many conditions such as:

• Dyspepsia • Peptic ulcer disease (PUD) • Gastroesophageal reflux disease (GORD/GERD) • Laryngopharyngeal Reflux Disease • Barrett's esophagus • prevention of stress gastritis • Gastrinomas and other conditions that cause

hypersecretion of acid • Zollinger-Ellison syndrome

Mechanism of action

• Proton pump inhibitors act by irreversibly blocking the inhibitors act by irreversibly blocking the hydrogen//potassium adenosine triphosphatase enzyme system (the system (the H+/K+ ATPase, or, more common, , or, more common, gastric gastric proton pump) of the gastric ) of the gastric parietal cell. The proton pump is the terminal . The proton pump is the terminal stage in gastric acid secretion, being directly responsible for secreting H+ ions into stage in gastric acid secretion, being directly responsible for secreting H+ ions into the gastric lumen, making it an ideal target for inhibiting acid secretion. the gastric lumen, making it an ideal target for inhibiting acid secretion. ("Irreversibility" refers to the effect on a single copy of the enzyme; the effect on the ("Irreversibility" refers to the effect on a single copy of the enzyme; the effect on the overall human digestive system is reversible, as the enzymes are naturally overall human digestive system is reversible, as the enzymes are naturally destroyed and replaced with new copies.)destroyed and replaced with new copies.)

• Targeting the terminal-step in acid production, as well as the irreversible nature of Targeting the terminal-step in acid production, as well as the irreversible nature of the inhibition, results in a class of drugs that are significantly more effective than the inhibition, results in a class of drugs that are significantly more effective than H2 antagonists and reduce gastric acid secretion by up to 99%. and reduce gastric acid secretion by up to 99%.

• The lack of the acid in the stomach will aid in the healing of The lack of the acid in the stomach will aid in the healing of duodenal ulcers, and ulcers, and reduces the pain from indigestion and reduces the pain from indigestion and heartburn, which can be exacerbated by , which can be exacerbated by stomach acid. However, lack of stomach acid is also called stomach acid. However, lack of stomach acid is also called hypochlorhydria, the , the lack of sufficient lack of sufficient hydrochloric acid, or HCl. Hydrochloric acid is required for the , or HCl. Hydrochloric acid is required for the digestion of proteins and for the absorption of nutrients, particularly of vitamin B12 digestion of proteins and for the absorption of nutrients, particularly of vitamin B12 and of calcium.and of calcium.

• The proton pump inhibitors are given in an inactive form. The inactive form is The proton pump inhibitors are given in an inactive form. The inactive form is neutrally charged (neutrally charged (lipophilic) and readily crosses ) and readily crosses cell membranes into intracellular into intracellular compartments (like the parietal cell canaliculus) that have acidic environments. In compartments (like the parietal cell canaliculus) that have acidic environments. In an acid environment, the inactive drug is protonated and rearranges into its active an acid environment, the inactive drug is protonated and rearranges into its active form. As described above, the active form will form. As described above, the active form will covalently and irreversibly bind to the and irreversibly bind to the gastric proton pump, deactivating it.gastric proton pump, deactivating it.

Examples of proton pump inhibitors

Clinically used proton pump inhibitors:• Omeprazole (brand names: Losec, Prilosec, Zegerid,

ocid, Lomac, Omepral, Omez) • Lansoprazole (brand names: Prevacid, Zoton,

Inhibitol, Levant, Lupizole) • Dexlansoprazole (brand name: Kapidex) • Esomeprazole (brand names: Nexium, Esotrex) • Pantoprazole (brand names: Protonix, Somac,

Pantoloc, Pantozol, Zurcal, Pan) • Rabeprazole (brand names: Rabecid, Aciphex, Pariet,

Rabeloc. Dorafem: combination with domperidone) All proton pump inhibitors except rabeprazole and

dexlansoprazole have intravenous formulations.

prostaglandin

• A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring. They are mediators and have a variety of strong physiological effects. Although they are technically hormones, they are rarely classified as such.

• The prostaglandins together with the thromboxanes and prostacyclins form the prostanoid class of fatty acid derivatives. The prostanoi is a subclass of eicosanoids.

FunctionThere are currently nine known prostaglandin receptors on various cell

types. Prostaglandins ligate a sub-family of cell surface seven-transmembrane receptors, G-protein-coupled receptors. These receptors are termed DP1-2, EP1-4, FP, Ip, and TP, corresponding to the receptor that ligates the corresponding prostaglandin (e.g., DP1-2 receptors bind to PGD2).

The diversity of receptors means that prostaglandins act on an array of cells and have a wide variety of effects:

• cause constriction or dilation in vascular smooth muscle cells • cause aggregation or disaggregation of platelets • sensitize spinal neurons to pain • decrease intraocular pressure • regulate inflammatory mediation • regulate calcium movement • control hormone regulation • control cell growth • Prostaglandins are potent but have a short half-life before being

inactivated and excreted. Therefore, they send only paracrine (locally active) or autocrine (acting on the same cell from which it is synthesized) signals.

Laxatives

• Laxatives (or purgatives) are foods, compounds, or drugs taken to induce bowel movements or to loosen the stool, most often taken to treat constipation. Certain stimulant, lubricant, and saline laxatives are used to evacuate the colon for rectal and bowel examinations, and may be supplemented by enemas in that circumstance. Sufficiently high doses of laxatives will cause diarrhea. Laxatives work to hasten the elimination of undigested remains of food in the large intestine and colon.

Some vegetables and foods can be eaten to cure constipation and act as laxatives, although the effectiveness may vary. These include:

• Almonds • Aloe Vera • Apples/Apple Juice • Bananas • Basil • Beets • Carob • Chicory • Coconut • Coffee • Dandelion • Dates • Dried apricots • Endive • Fenugreek • Figs • Flaxseed • Grapes • Kale

• Liquorice • Mangos • Molasses • Oranges • Papayas • Parsley • Peaches/Apricots • Pears • Persimmons • Pineapple • Plums • Prunes/Prune Juice • Rhubarb • Soybeans • Tamarind • Tea • Tomato Juice • Vanilla • Walnuts • Watercress • Yams • Olive oil

Bulk-producing agents

• Site of Action: Small and large intestine • Onset of Action: 12 - 72 hours • Examples: psyllium husk (Metamucil),

methylcellulose (Citrucel), polycarbophil, dietary fiber, apples, broccoli

• Also known as bulking agents or roughage, these include dietary fiber. Bulk-producing agents cause the stool to be bulkier and to retain more water, as well as forming an emollient gel, making it easier for peristaltic action to move it along. They should be taken with plenty of water. Bulk-producing agents have the gentlest of effects among laxatives and can be taken just for maintaining regular bowel movements.

Stool softeners / Surfactants

• Site of Action: Small and large intestine • Onset of Action: 12 - 72 hours • Examples: docusate (Colace, Diocto) • These cause water and fats to penetrate the

stool, making it easier to move along. Many of these quickly produce a tolerance effect and so become ineffective with prolonged use. Their strength is between that of the bulk producers and the stimulants, and they can be used for patients with occasional constipation or those with anorectal conditions for whom passage of a firm stool is painful.

Lubricants / Emollient

• Site of Action: Colon • Onset of Action: 6 - 8 hours • These simply make the stool slippery, so

that it slides through the intestine more easily. An example is mineral oil, which also retards colonic absorption of water, softening the stool. Mineral oil may decrease the absorption of fat-soluble vitamins and some minerals.

Hydrating agents (osmotics)These cause the intestines to hold more water within, softening the

stool. There are two principal types, saline and hyperosmotic.

SalineSite of Action: Small and large intestine • Onset of Action: 0.5 - 6 hours • Examples: Dibasic sodium phosphate, magnesium citrate,

magnesium hydroxide (Milk of magnesia), magnesium sulfate (which is Epsom salt) , monobasic sodium phosphate, .

• Saline laxatives attract and retain water in the intestinal lumen, increasing intraluminal pressure and thus softening the stool. They will also cause the release of cholecystokinin, which stimulates the digestion of fat and protein. Saline laxatives may alter a patient's fluid and electrolyte balance.

• Sulfate salts are considered the most potent.

Hyperosmotic agents• Site of Action: Colon • Onset of Action: 0.5 - 3 hours • Examples: Glycerin suppositories, Sorbitol, Lactulose, and

Polyethylene glycol (PEG). • Lactulose works by the osmotic effect, which retains water

in the colon, lowering the pH and increasing colonic peristalsis. Lactulose is also indicated in Portal-systemic encephalopathy . Glycerin suppositories work mostly by hyperosmotic action, but also the sodium stearate in the preparation causes local irritation to the colon.

• Solutions of polyethylene glycol and electrolytes (sodium chloride, sodium bicarbonate, potassium chloride, and sometimes sodium sulfate) are used for whole bowel irrigation, a process designed to prepare the bowel for surgery or colonoscopy and to treat certain types of poisoning. Brand names for these solutions include GoLytely, GlycoLax, CoLyte, NuLytely, and others.

Stimulant / Irritant • These stimulate peristaltic action and can

be dangerous under certain circumstances. Long term use can lead to 'cathartic colon'.[8] Stimulant laxatives act on the intestinal mucosa, or nerve plexus; they also alter water and electrolyte secretion. They are the most severe among laxatives and should be used only in extreme conditions. Castor oil may be preferred when more complete evacuation is required.

Castor oil

• Site of Action – Small intestine

• Castor oil acts directly on intestinal mucosa or nerve plexus and alters water and electrolyte secretion. It is converted into ricinoleic acid (the active component) in the gut.

Serotonin agonist

• Tegaserod is a motility stimulant that works through activation of 5-HT4 receptors of the enteric nervous system in the gastrointestinal tract. However caution must be taken due to potentially harmful cardiovascular side-effects.

GASTROINTESTINAL STIMULANTS

• Used for more generalized Gi stimulation that results in an overall increase in GI activity and secretions.

• These drugs stimulate parasympathetic activity or make the GI tissues more sensitive to parasympathetic activity.

• Metoclopramide (INN) (pronounced /ˌmɛtəˈkloʊprəmaɪd/ or /ˌmɛtəˈklɒprəmaɪd) is an antiemetic and gastroprokinetic agent. Thus it is primarily used to treat nausea and vomiting, and to facilitate gastric emptying in patients with gastroparesis

Clinical use

• Metoclopramide is commonly used to treat nausea and vomiting (emesis) associated with conditions including: emetogenic drugs, uraemia, radiation sickness, malignancy, labor, and infection. It is also used by itself or in combination with paracetamol (acetaminophen) (paracetamol/metoclopramide available in the UK as Paramax) or aspirin (MigraMax) for the relief of migraine.

• It is considered ineffective in postoperative nausea and vomiting (PONV) at standard doses, and ineffective for motion sickness. In nausea and vomiting associated with cancer chemotherapy, it has been superseded by the more effective 5-HT3 antagonists (e.g. ondansetron).

anti-diarrheal drug

• An anti-diarrheal drug is any medication which provides symptomatic relief for diarrhea.

Types• Electrolyte solutions are used to replace lost fluids and solutions are used to replace lost fluids and

salts in acute cases. in acute cases. • Bulking agents like like methylcellulose, , guar gum or plant or plant fibre

((bran, , sterculia, , etc.) are used for diarrhea in functional , , etc.) are used for diarrhea in functional bowel disease and to control bowel disease and to control ileostomy output. output.

• Absorbents absorb toxic substances that cause infective absorb toxic substances that cause infective diarrhea, methylcellulose is an absorbent as well. diarrhea, methylcellulose is an absorbent as well.

• Opioids' classical use besides pain relief is as an anti-' classical use besides pain relief is as an anti-diarrheal drug. Opioids have diarrheal drug. Opioids have agonist actions on the actions on the intestinal opioid receptors, which when activated cause intestinal opioid receptors, which when activated cause constipation. Drugs such as . Drugs such as morphine or or codeine can be can be used to relieve diarrhea this way. A notable opioid for the used to relieve diarrhea this way. A notable opioid for the purpose of relief of diarrhea is purpose of relief of diarrhea is Loperamide which only is an which only is an agonist of the agonist of the μ opioid receptors in the large intestine and in the large intestine and does not have opioid affects in the does not have opioid affects in the central nervous system as it doesn't cross the as it doesn't cross the blood brain barrier in significant in significant amounts. This enables loperamide it to be used to the amounts. This enables loperamide it to be used to the same benefit as other opioid drugs but without the CNS same benefit as other opioid drugs but without the CNS side effects or potential for abuse. side effects or potential for abuse.

Emetics

• An emetic, such as syrup of ipecac, is a substance that induces vomiting when administered orally or by injection. An emetic is used medically where a substance has been ingested and must be expelled from the body immediately (for this reason, many toxic and easily digestible products such as rat poison contain an emetic). Inducing vomiting can remove the substance before it is absorbed into the body. Ipecac abuse can cause detrimental health effects.

• Copper sulfate was also used in the past as an emetic. It is now considered too toxic for this use.

Antiemetics

• An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side-effects of some opioid analgesics and chemotherapy directed against cancer.

• Antiemetics act by inhibiting the receptor sites associated with emesis. Hence, anticholinergics, antihistamines, dopamine antagonists, serotonin antagonists, and cannabinoids are used as anti-emetics.

““Only as high as I Only as high as I reach can I grow, reach can I grow,

only as far as I only as far as I seek can I go, seek can I go,

only as deep as I only as deep as I look can I see, look can I see,

only as much as I only as much as I dream can I be.”dream can I be.”Thank you for a wonderful summer…Aim High Thank you for a wonderful summer…Aim High

Batch 2011…Batch 2011…