Diarrhoea - Causes, Types, and Treatment

# AD ## Introduction Diarrhea is one of the most common diagnoses in clinical practice. It affects all age groups. Most of the deaths associated with diarrheal illness occur in the very young and the elderly populations, whose health may be put at risk from a moderate amount of dehydration. Accordin...

# AD ## Introduction Diarrhea is one of the most common diagnoses in clinical practice. It affects all age groups. Most of the deaths associated with diarrheal illness occur in the very young and the elderly populations, whose health may be put at risk from a moderate amount of dehydration. According to the World Health Organization, two million children die each year in developing countries from diarrhea. This makes diarrhea the second most serious killer of children under five, worldwide. Diarrhea can however in most cases be prevented or treated. Correct management of diarrhea could save the lives of up to 90% of children and many adults, who currently die from the effects of the disease. Acute diarrhea is caused by parasites, bacteria and viruses, the latter of which have been given significant attention in recent years. ## Diarrhoea ### Normal bowel frequency For most individuals, normal daily stool weight ranges between 100 and 200 grams. Normal bowel frequency ranges from 3 times a day to 3 times a week. ### Diarrhoea Diarrhoea is defined as an increase in daily stool weight above 200 grams. In clinical practice, the term is used to describe increased liquidity of the stools, usually associated with increased stool weight and frequency (more than 3 times per day). Pseudo-diarrhea or hyper-defecation represents increased frequency of defecation without an increase in stool weight above normal, as seen in irritable bowel syndrome or hyperthyroidism. ## Different types of diarrhoea Diarrhoea can be classified based on: - **Duration of the illness** - acute versus chronic - **Pathophysiological mechanisms** - osmotic versus secretory - **Severity** - less versus more - **Stool characteristics** - watery, fatty, or bloody In clinical practice, duration of the illness and stool characteristics are most useful in the evaluation and treatment of patients with Diarrhoea. ## Acute diarrhoea Acute diarrhea is defined as a diarrheal illness lasting for less than 4 weeks. If the illness persists for more than 4 weeks, it is considered chronic diarrhoea. ## Causes of Acute Diarrhoea The most common causes of acute diarrhoea are: - Infectious agents- viruses, bacteria and parasites [Infectious Diarrhoea] - Food poisoning- preformed toxins - Medications - Inflammatory or ischemic bowel disease - Fecal impaction - Recent ingestion of poorly absorbable sugars e.g., lactulose ## There are 4 mechanisms of diarrhea: ### 1. Osmotic Diarrhoea This type of diarrhoea is due to the presence of an unabsorbable or poorly absorbable solute that exerts an osmotic pressure effect across the intestinal mucosa, resulting in excessive water output. Because the diarrhea is caused by the solute, it tends to stop during fasting. Causes of osmotic diarrhoea include disaccharidase deficiency (lactose intolerance), malabsorption, poorly absorbed sugars (lactulose, sorbitol, mannitol), laxatives (magnesium, sodium citrate, sodium phosphate), and magnesium-containing antacids. ### 2. Secretory Diarrhoea In this type of diarrhoea there is abnormal ion transport across the intestinal epithelial cells, which results in increased secretion, decreased absorption, or both. As the diarrhoea is not related to intestinal contents, it typically does not stop with fasting. A classic example of acute secretory diarrhea is cholera, but it is also seen in infections like enterotoxigenic *E. coli*. ### 3. Altered Motility Abnormal motility (increased/decreased) can cause diarrhoea by the following mechanisms: ### 4. Exudative Diarrhoea Extensive injury of the small bowel or colon mucosa may result in fluid and protein loss into the intestinal lumen and ensuring diarrhoea. Exudation is rarely the only mechanism accounting for diarrhoea. Causes of exudative diarrhoea include invasive bacterial infections (*Shigella*, *Salmonella*) and inflammatory bowel disease. It is important to note that more than one mechanism may coexist. For example, in infectious and inflammatory conditions, malabsorption leading to osmotic diarrhoea and active secretion can coexist. ## Diarrhoea and the enteric nervous system The pathophysiological mechanisms underlying the fluid losses seen in different types of diarrhea have been debated for decades. The dominating hypothesis up to the 1970s was that most diarrheas, including the infectious, were caused by motility disturbances. However, during the last three decades it has been become increasingly evident that disturbances in the epithelial transport are often one of the major causes of intestinal fluid loss, although motility may contribute, at least in some types of diarrhoea. Studies on conscious neonatal mice with rotavirus diarrhoea showed that nerve blockers decreased diarrhoea. Subsequent studies *in vitro* confirmed that neurotransmitter blockers inhibit fluid secretion in the intestine. Opiates have been known to inhibit intestinal fluid and electrolyte secretion as well as gut motility. The endogenous opiates, enkephalins, are found in enteric nerves as neurotransmitters. Studies demonstrated that these enkephalins reduce fluid secretion in the gut. Inhibitors of the enzymes encephalinases, which degrade the enkephalins, cause a build up of the enkephalins and enhance their action. In line with this the enkephalinase inhibitor racecadotril has been shown to attenuate acute diarrhea in children and adults. Salazar-Lindo et al. have recently shown in a clinical trail that racecadotril markedly inhibited stool output in young Peruvian children with rotavirus diarrhoea. ## Enkephalins Enkephalins are of two types: leu-enkephalin and met-enkephalin. Enkephalins occur in the brain and spinal cord and also in the gastrointestinal tract. They have potent opiate-like effects and probably serve as neurotransmitters. ## Role of Enkephalinase Enkephalinase is a cell membrane peptidase enzyme located in various tissues, notably the epithelium of the small intestine. This enzyme contributes both to the digestion of exogenous peptides and to the breakdown of endogenous peptides such as enkephalins, neurokinin and substance P. ## Symptoms and signs of diarrhoea Patients with diarrhoea, present with various clinical features depending on the underlying cause. Diarrhoea due to small-intestinal disease is typically high-volume, watery, and often associated with malabsorption and dehydration is frequent. Diarrhoea due to colonic involvement is more often associated with frequent small-volume stools, with the presence of blood and a sensation of urgency. Patients with acute infectious diarrhoea typically present with nausea, vomiting, abdominal pain, fever, and frequent stools, which may be watery, malabsorptive or bloody depending on the specific pathogen. In general, small-intestinal pathogens are noninvasive, and ileocolonic pathogens are more likely to be invasive. Giardiasis may be associated with mild steatorrhea, gaseousness and bloating. ## Treatment for diarrhoea The principal components of the treatment of acute diarrhoea are fluid and electrolyte replacement, dietary modifications and drug therapy. ### Rehydration If patients are otherwise healthy and do not have dehydration, adequate fluid intake can be achieved with soft drinks, fruit juice, broth, soup and salted biscuits. In those with excessive fluid losses and dehydration, more aggressive measures like intravenous fluids or oral rehydration therapy with isotonic, electrolyte solutions containing glucose or starch should be given. ### Antidiarrheal Agents These can be very useful in amelioration of symptoms and include opioid derivatives like loperamide, diphenoxylate-atropine and tincture of opium. Bismuth subsalicylate is another useful agent, but it is contraindicated in HIV-infected patients since it may cause bismuth encephalopathy. The antimotility agents should not be used in febrile dysentery patients (e.g., those infected by *Shigella*), as these agents may prolong the disease. ### Antimicrobial Therapy Because the majority of patients have mild, self-limited disease due to viruses or noninvasive bacteria, empiric treatment of all patients is not warranted. Empiric treatment is indicated in those patients with suspected invasive bacterial infection, traveler's diarrhoea, or immunosuppression. ## Composition | Brand | Composition | |:--------|:-------------| | AD capsule | Each capsule contains: Racecadotril | 100mg | |AD sachet | Each sachet contains: Racecadotril | 10mg | Racecadotril is a lipophilic diesterified prodrug of the enkephalinase inhibitor thiorphan. It is the first and only enkephalinase inhibitor in its class. ## Mode of action of Racecadotril In peripheral tissues, orally administered racecadotril is rapidly hydrolyzed to the more potent enkephalinase inhibitor thiorphan. Within these tissues, membrane-bound enkephalinase enzymes degrade endogenous opioids (enkephalins). Thiorphan (racecadotril) is thought to inhibit enkephalinase. By inhibiting this enzyme, thiorphan (racecadotril) prevents the inactivation of endogenous enkephalins and prolongs their physiological action. The enkephalins act as neurotransmitters in the gastrointestinal tract by activating ä-opiate receptors and thus reducing the level of cyclic AMP. The result is reduced secretion of water and electrolytes into the intestinal lumen without any detectable effect on intestinal motility. Racecadotril has antisecretory actions only when hypersecretion is present and not in the basal state. ## Indications - Acute diarrhea including rotavirus diarrhoea in children and adults - Choleric and non-choleric diarrhoea - Chronic HIV-associated diarrhoea in adults ## Dosage ### ADULTS: **Day 1:** Treatment should be started with a single capsule of 100mg, administered immediately followed by 1 capsule 3 times a day. **Day 2 onwards:** 1 capsule 3 times a day until the first normal stool returns or to a maximum of 7 days. The treatment may be continued for 2-4 weeks in HIV-positive patients with chronic diarrhoea. ### CHILDREN [aged 2 months to 2 years] with severe diarrhoea: **Day 1:** The usual daily dose is decided according to the body weight on the basis of 1.5 mg/kg per dose, given immediately and then three more doses divided in the day. **Day 2 onwards:** 1.5mg/kg [per dose] three times daily. The powder should be swallowed as it is. It can also be taken along with food, or poured into a glass or a bottle of water, which should be shaken well and the entire mixture is to be swallowed immediately. **ELDERLY:** It is not necessary to adjust the dose in the elderly. ## Contraindications Racecadotril is contraindicated in patients with known hypersensitivity to any of the ingredients of the formulation. ## Precautions ### Pregnancy: Sufficient data is not available for humans regarding the use of Racecadotril during pregnancy and should not be used during pregnancy even though the potential benefits compensate the risks. ### Nursing: Sufficient data is not available for humans regarding the use of Racecadotril during lactation. ## Adverse effects Nausea, vomiting, constipation, dizziness and migraine were rarely reported. ## Comparison vs. Loperamide | Feature | Racecadotril | Loperamide | |:-------|:-------------|:-----------| | Mechanism of action | Antisecretory agent | Antimotility agent | | Treatment Regimen: | | | | (1) Adults | 100-300mg Three times daily | | | | 4mg initially, followed by: 2mg after each stool, maximum 16mg daily | | (2) Children | 1.5mg/kg Three times daily | | | | 4-8 years: 1mg 3-4 times daily for up to 3 days 9-12 years: 2mg 4 times daily for up to 5 days | | (3) Adverse effects | Can be given to children as young as 2 months of age Nausea, thirst, vertigo, headache, vomiting | | | | <4 years not recommended Abdominal cramps, dizziness, drowsiness, skin reactions, paralytic ileus, abdominal bloating | | (4) Frequency of post-treatment constipation | 8-37% | 31-58% | # Digestive Tract System ## Function of Digestive Tract System Food is masticated in the mouth by teeth & mixed with saliva from the salivary gland. The food (bolus) then travels through the esophagus to the stomach. The muscular ring, Upper Oesophageal Sphincter, allow the swallowed food in, and closes it to keep air out, moves the food in a sequence of muscular contractions called peristalsis. The Lower Esophageal Sphincter (LES) passes the food and closes it to prevent gastric reflux. All the sphincters located in the digestive tract help the digested food to move in one direction. The first stage of protein digestion takes part in the stomach. Rest of the digestion takes part in the duodenum. Absorption of digested food takes place in the small intestine. Water is reabsorbed in the large intestine to give the stool its consistency. Metabolism takes place in the liver, the largest gland in the body. ## Structure and Function of Stomach Stomach is a J shaped dilated portion of the alimentary canal situated in the epigastric, umbilical & hypochondriac regions of the abdominal cavity. The function of the Gastro Intestinal Tract is ruled and coordinated by the enteric nervous system (ENS). The lower part of the stomach is called the pyloric part. The opening through which food passes from this part into the intestine is called the pyloric orifice of antrum or pylorus. The rounded upper part of the stomach is known as the fundus. The opening of the oesophagus into the stomach is known as cardiac orifice. The middle or main part of the stomach is called the body. The left border of the stomach forms a large curve called the greater curvature. The right border from the entrance of esophagus to the pylorus is much shorter and is known as lesser curvature. At the distal end of the pyloric antrum there is a sphincter which guards the opening between the stomach and duodenum. This is known as pyloric sphincter. The four layers of tissue which form the stomach are from outside in as follows : - Peritoneum - Muscle Layer - The submucous layer - The mucous membrane Muscle coat of stomach consist of three layers of smooth muscle fibres. The outer layer has longitudinal fibres, the middle layer has circular fibres and the inner layer, oblique fibres. This layer consists of loose connective tissue with some elastic fibres. Within this layer there are blood vessels and nerves, lymph vessels & varying amount of lymphoid tissue. The mucous membrane of the stomach is covered with nonciliated columnar epithelium many cells of which secrete mucus, it is continuous with the cells of gastric glands. The gastric glands are innumerable simple or branched tubular glands in the mucous membrane. ## The cells of the gastric glands are : - Chief cells of the neck which secrete mucin. - Chief cells of the body which secrete pepsin. - Parietal or oxyntic cells which produce hydrochloric acid. The digestive juice secreted by the gastric glands is called gastric juice. It contains - Hydrochloric acid, Pepsin, Rennin, Lipase, Intrinsic factor and Mucus ## Functions of different components of gastric juice. - **Hydrochloric acid** - Pure gastric juice contains from 0.4 to 0.5 percent of hydrochloric acid. It helps pepsin to hydrolyse protein to the stage of proteoses & peptones. It acidifies food and converts pepsinogen into active enzyme pepsin, kills harmful microorganisms. - **Pepsin** - is an enzyme which in the presence of acid breaks down the protein into proteoses & peptones. - **Mucus** - prevents mechanical injury to stomach wall by lubricating contents. It also prevents chemical injury by acting as a barrier between stomach wall & contents of gastric juice. - **Rennin** - This enzyme clots or curdles milk. It changes caesinogen into casein & is present in gastric juice of infants. - **Lipase** - Gastric lipase is a very weak enzyme and it digests fatty materials, such as egg yolk, cream that are in the form of fine emulsions. The main digestion of fats, however takes place in intestines. - **Intrinsic factor** - is necessary for the absorption of Vitamin B₁₂ Strong emotional stimuli frequently increases the interdigestive or fasting juice to 50 ml or more of highly peptic and highly acidic type per hour. This increases of secretion during the presence of emotional stimuli is believed to be one of the factors in the development of peptic ulcers. ## The phases of secretion of gastric juice are:- - Cephalic phase - Gastric phase - Intestinal phase In Cephalic phase the flow of juice occurs before food reaches stomach. This is due to reflex stimulation of vagus (parasympathetic) nerve. It is initiated by the sight, smell or taste of food. ## Gastric phase When stimulated by the presence of food the stomach produces a hormone called gastrin. This hormone stimulates the glands in the wall of stomach to produce more gastric juice. In this way the secretion of digestive juice is continued after the completion of the meal & the end of the cephalic phase. When the partially digested contents of the stomach reach the small intestine a hormone called enterogastrone is produced which slows down the secretion of gastric juice and reduces gastric motility. By slowing the emptying rate of the stomach, the contents of the duodenum become more thoroughly mixed with bile and pancreatic juice. This phase of the gastric secretion is more marked when the meal has had high fat content. ## From inside, the gastrointestinal tract is lined by mucous membrane (mucosa) - The mucous membrane of the mouth to oesophagus is multilayered and is known as stratified squamous epithelium, while the lining of the stomach and intestines is simply columnar with abundance of mucous secreting cells. - Immediately beneath the epithelium there is structureless connective tissue known as Membrane Propria, followed by another layer called Lamina Propria. - A deeper stratum of connective tissue is known as submucosa. ## Parietal Cells Parietal cells are one of the large peripheral cells of the mucous membrane of the stomach that secrete hydrochloric acid. The parietal cell has three receptors : - Acetylcholine receptor - Histamine receptor (H₂-receptor), and - Gastrin receptor ## Gastric Hormones ### Acetylcholine Acetylcholine binds to cholinergic-receptors and stimulates parietal cells directly to secrete HCl. Acetylcholine also stimulates parietal cells indirectly by stimulating ECL cells (Enterochromafin-like cells or mast cells) to release histamine. ### Histamine Histamine is released by the Enterochromafin-like cells (ECL cells). Histamine binds to the H₂-receptor of the parietal cells to stimulate acid secretion. Histamine release is stimulated by gastrin and acetylcholine. ### Gastrin When there is food in the stomach, the G-cells release gastrin. Gastrin binds to the gastrin receptor in the parietal cell & stimulates it to produce HCl. Gastrin also stimulates ECL cells to produce more histamine. ## Basal acid secretion: Even if there is no stimulation, a certain amount of acid is secreted. This is called basal acid secretion. Basal acid production occurs in a circadian pattern, with highest level occurring in the night and lowest levels during the morning hours. ## Control of Acid Secretion As discussed earlier, Parietal cells bear receptors for three stimulators of acid secretion: - Acetylcholine (muscarinic type receptor) - Gastrin - Histamine (H₂ receptor) Histamine from enterochromafin-like cells may well be the primary modulator, but the magnitude of the stimulus appears to be a result of a synergistic interaction of signals of each type. Additionally, pharmacologic antagonists of each of these molecules can block acid secretion. Histamine's effect on the parietal cell is to activate adenylate cyclase, leading to elevation of intracellular cyclic AMP concentrations and activation of protein kinase A (PKA). One effect of PKA activation is phosphorylation of cytoskeletal proteins involved in transport of the H+/K+ ATPase from cytoplasm to plasma membrane. Binding of acetylcholine and gastrin both result in elevation of intracellular calcium concentrations. ## Acid Related Disorders - Gastro Esophageal Reflux Disorder (GERD) - Laryngeopharyngeal reflux disease (LPRD) - Peptic Ulcers - Gastritis - Functional Dyspepsia ## Drug Therapy for suppressing secretion of gastric acid Stomach & Duodenal ulcers can be treated with several types of medications. ### 1. Antacids Neutralises the acid present in the stomach. Although they provide immediate symptomatic relief, rebound hyperacidity and tolerance is common. E.g. Digene, Policrol, Gelusil ### 2. Cytoprotectors Mucosal protective agents to shield the stomach's mucous lining from the damage due to acid, but do not inhibit the release of acid. ### 3. H₂ Receptor Antagonists Despite some unresolved questions, it is clear that histamine is one of the primary regulators of acid secretion. The parietal cell receptor for histamine is of the H₂ type, and antihistamines that engage H₁ receptors have no effect on acid secretion. Evidence of histamine's role in acid secretion is strongly supported by finding that H₂ receptor antagonists are quite effective in inhibiting acid secretion. Four primary H₂ antagonists have been developed and found clinical utility : - Cimetidine - Ranitidine (Zinetac, Histac, Aciloc, etc.) - Famotidine (Topcid, Famonite, Famtac, etc.) - Nizatidine ### 4. Proton Pump Inhibitors Acid secretion is absolutely dependent on function of the H+/K+ ATPase or proton pump located in the cannilicular membrane of the parietal cell. Several drugs have been developed that non-competitively bind and inactivate the ATPase, resulting in strong inhibition of acid secretion. - Omeprazole, - Pantoprazole - Esomeprazole, - Rabeprazole ## PANTIN - Pantoprazole is the only PPI that binds to cysteine 822, which is buried in the transport domain of the proton pump and is inaccessible to glutathione or dithioreitol (which reverse the acid inhibition). Therefore, Pantoprazole exhibits longer duration of action than other PPIs. - Pantoprazole 40mg O.D. is superior to Ranitidine 300mg O.D. in inhibiting gastric acid secretion. - Pantoprazole 40mg is significantly more effective than Omeprazole 20mg in elevating daytime and 24 hours intragastric pH. - Pantoprazole is the safest PPI having minimal changes of drug interactions. Pantoprazole weakly inhibits cytochrome P450 compared to Omeprazole which strongly inhibits cytochrome P450 (2-to 6-fold stronger) ## 1. Favourable pharmacokinetic profile of Pantoprazole versus other PPIs | Characteristic | Pantoprazole | Omeprazole | Lansoprazole | Rabeprazole | |:-------|:-------------|:-----------|:-------------|:-----------| | Bioavailability (%) | 77 | 30-40 | 80-85 | 52 | | T_max (hrs) | 1.1-3.1 | 0.5-3.5 | 1.7 | 1.0-2.0 | | T_1/2 (hrs) | 1.0-1.9 | 0.5-1.0 | 1.3-1.7 | 1.0-2.0 | | Protein Binding (%) | 98 | 95 | 97 | 96 | ## 2. Drug Interactions of Pantoprazole versus other PPIs | Drug | Pantoprazole | Omeprazole | Lansoprazole | |:-------|:-------------|:-----------|:-------------| | Clarithromycin | Unknown | Omeprazole gastric mucous concentration of Clarithromycin and Clarithromycin inhibits Cytochrome P450 metabolism of Omeprazole | None | | Carbamazepine | None | metabolism | Unknown | | Diazepam | None | metabolism | None | | Ketoconazole | None | absorption | absorption | | Methotrexate | Unknown | renal secretion | Unknown | | Phenytoin | None | metabolism | None | | Warfarin | None | metabolism | None | | Theophylline | None | None | ↑ metabolism | ## Composition | Brand | Composition | |:-------|:-------------| | PANTIN 40 | Each enteric coated tablet contains Pantoprazole | 40mg | | PANTIN I.V. | Each vial contains Pantoprazole (Lyophilized powder) | 40mg | ## Description The above ingredient in PANTIN enteric-coated tablets is a susbtituted benzimidazole, a compound that inhibits gastric acid secretion. ## PHARMACODYNAMICS ### Mechanism of Action Pantoprazole is a proton pump inhibitor (PPI) that suppresses the final step in gastric acid production by forming a covalent bond to two sites of the H⁺ / K⁺ ATPase enzyme system at the secretory surface of the gastric parietal cell. This effect is dose- related and leads to inhibition of both basal and stimulated gastric acid secretion irrespective of the stimulus. The binding to the H⁺ / K⁺ ATPase results in a duration of antisecretory effect that persists longer than 24 hours. ### Antisecretory Activity Under maximal acid stimulatory conditions using pentagastrin, a dose- dependent decrease in gastric acid output occurs after a single dose of oral (20-80mg) or a single dose of intravenous (20-120mg) pantoprazole in healthy volunteers. pantoprazole given once daily results in increasing inhibition of gastric acid secretion. Acid secretion had returned to normal within a week after the last dose of pantoprazole; there was no evidence of rebound hypersecretion. ## PHARMACOKINETICS PANTIN is an enteric- coated tablet so that absorption of pantoprazole begins only after the tablet leaves the stomach. Peak serum concentration (C_max) and area under the serum concentration time curve (AUC) increase in a manner proprotional to oral and intravenous doses from 10mg to 80mg. Pantoprazole does not accumulate and its pharmacokinetics are unaltered with multiple daily dosing. Following oral or intravenous administration, the serum concentration of pantoprazole declines biexponentially with a terminal elimination half-life of approximately one hour. ### Absorption: The absorption of pantoprazole is rapid, with a C_max of 2.5 µg/mL that occurs approximately 2.5 hours after single or multiple oral 40mg doses. Pantoprazole is well absorbed; it undergoes little first-pass metabolism resulting in an absolute bioavailability of approximately 77%. Pantoprazole absorption is not affected by concomitant adminstration of antacids. Pantoprazole may be taken without regard to timing of meals. ## Distribution: The apparent volume of distribution of pantoprazole is approximately 11.0-23.6L, distributing mainly in extracellular fluid. The serum protein binding of pantoprazole is about 98%, primarily to albumin. ## Metabolism: Pantoprazole is extensively metabolized in the liver through the cytochrome P450 (CYP) system. Pantoprazole metabolism is independent of the route of administration (intravenous or oral). Pantoprazole bypass the Phase I metabolism in the liver by Cytocrome P450. ## Elimination: Approxiamtely 71% of the dose was excreted in the urine with 18% excreted in the faeces through biliary excretion. There was no renal excretion of unchanged pantoprazole. ## Special Populations ### Geriatric No dosage adjustment is recommended based on age. ### Paediatric The pharmacokinetics of pantoprazole have not been investigated in patients < 18 years of age. ### Renal impairment No dosage adjustment is necessary in patients with renal impairment or in patients undergoing hemodialysis. ### Hepatic impairment In patients with mild to severe hepatic impairment, maximum pantoprazole concentrations increased only slightly (1.5-fold) relative to healthy subjects. ## Drug Interaction Pantoprazole is metabolized through the cytochrome P450 system (Phase II). Therefore no dosage adjustment is needed with concomitant use of the following: theophylline, antipyrine, caffeine, carbamazepine, diazepam, diclofenac, digoxin, ethanol, glyburide, an oral contraceptive, metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. There was also no interaction with concomitantly administered antacids. ## Indication: - Peri-operative prophylaxis - Acute Peptic Ulcer - Stress ulcer prophylaxis ## Composition | Brand | Composition | |:-------|:-------------| | PANTIN-D | Each capsule contains Pantaprazole sodium enteric coated pellets Domperidone SR pellets (Immediate release 10mg and sustained release 20mg) | 20mg | 30mg | ## Pantoprazole (refer PANTIN notes) ## Domperidone ## PHARMACODYNAMICS ### Mechanism of Action: Domperidone is a dopamine D2 receptor antagonist with antiemetic properties similar to those of metoclopramide and certain neuroleptic medicines. Unlike these medicines, however, domperidone acts peripherally and does not readily cross the blood-brain barrier. It seldom causes extrapyramidal side effects. Its antiemetic effect may be due to a combination of peripheral (gastrokinetic) effects and antagonism of central dopamine receptors in the chemoreceptor trigger zone (CTZ) which lies in the area postrema and is regarded as being outside the blood-brain barrier. Studies have shown oral domperidone to increase the duration of antral and duodenal contractions, to increase the gastric emptying of liquids and semi-solids in healthy subjects and in patients in whom it was delayed and to increase lower oesophageal sphincter pressure in healthy subjects. Domperidone has no effect on gastric secretion. ## PHARMACOKINETICS ### Absorption: Domeridone is rapidly absorbed following oral administration with peak plasma concentrations occurrig at approximately 10 and 30 minutes, respectively. Bioavailability of oral domperidone is 13% to 17%. ## Metabolism: Oral domperidone does not appear to accumulate or induce its own metabolism: a peak plasma level after 90 minutes of 21 ng/mL after two weeks oral administration of 30 mg per day was almost the same as that of 18 ng/mL after the first dose. Domperidone undergoes rapid and extensive hepatic metabolism primarily by cytochrome P-450 involved in the N-dealkylation of domperidone, whereas CYP3A4, CYP1A2 and CYP2E1 are involved in domperidone aromatic hydroxylation. ## Distribution Domperidone is 91% to 93% bound to plasma proteins. Studies have shown wide tissue distribution with low brain concentration. Small amounts of medicine cross the placenta in rats and the medicine is excreated in the breast milk of this species. ## Elimination: Urinary and faecal excretion amounts to 31 and 66%, respectively, of the oral dose. The proportion of the medicine excreted unchanged is small (10% of faecal excretion and approximately 1% of urinary excretion). The plasma half-life after a single oral dose is 7-9 hours in healthy subjects but is prolonged in patients with severe renal insufficiency. ## INDICATIONS - Symptomatic treatment of the dyspeptic symptom complex which is often associated with delayed gastric emptying or gastro-oesophageal reflux and oesophagitis: epigastric sense of fullness, feeling of abdominal distension, upper abdominal pain, flatulence, heartburn. ## DOSAGE AND ADMINISTRATION Domperidone should be taken 15-30 minutes before meals and, if necessary, before retiring. Adult dose for gastrokinetic action: 10 mg three to four times daily. If necessary this dose may be doubled after weeks if an adequate therapeutic response is not attained. For acute and subacute conditions (e.g. nausea and vomiting): 20 mg three to four times daily. Use in Renal Impairment (see Warnings and Precautions) ## CONTRAINDICATIONS Domperidone should not be used whenever stimulation of gastrointestinal motility might be dangerous such as in the presence of gastrointestinal haemorrhage, mechanical obstruction or perforation. Domperidone is also contraindicated in patients with known intolerance to domperidone, and in patients with prolactinoma (a prolactin releasing pituitary tumour). ## ADVERSE EFFECTS The most frequent reactions are those related to elevated prolactin levels including breast tenderness, galactorrhoea, gynaecomastic and amenorrohea. These effects are dose-related and gradually resolve after lowering the dose or discontinuing treatment. Other rarely reported adverse reactions include headache, diarrhoea, dizziness, mild and transient abdominal cramps, dry mouth and drowsiness. Rare allergic reactions, such as rash and urticaria, have also been reported. ## PANTIN-D : RATIONALE OF THE COMBINATION Pantoprazole in PANTIN-D is a potent and precise PPI and Domperidone in PANTIN-D is a proven gastrokinetic. PANTIN-D has a three-pronged attack, which stabilizes gastric acidity, restores LES dysfunction and corrects gastric emptying. Therefore, in GASTRITIS, PANTIN-D is the RIGHT COMBINATION, RIGHT DOSE. # Gastrointestinal Motility ## PANTIN-L Gl motility refers to peristalsis, the smooth muscle contractions that propel digestive contents along the Gl tract. Peristaltic motor activity of the gut is an essential activity for digestion and absorption of nutrients to sustain life. These rhythms are critical during and after meals to maximize contact of nutrients with villous surface area for absorption. Motility is controlled by the enteric nervous system (ENS), or “gut brain”, a network of over 100 million neurons embedded in the lining of the Gl tract. Although the ENS is influenced by the central brain, it functions independently as a branch of the autonomic nervous system. The neurons within the ENS communicate using many of the neurotransmitters found in the brain; however, their local roles in the Gl tract are to regulate smooth muscle activity. The most important regulators of digestive motility are Serotonin, Acetylcholine & Dopamine. Dopamine decreases the Acetylcholine level while Serotonin increases Acetylcholine level, therefore dopaminergic and serotonergic activity balances the gut motility. Dopamine is a biogenic amine synthesized in various areas of the central and peripheral nervous system. Dopamine acts as a chemical messenger who affects brain process that control movement, emotional response and ability to experience pleasure and pain. Dopamine, while acting through specific dopaminergic receptors, inhibits lower esophageal sphincter (LES) pressure and gastroduodenal motility observed from the esophagus to the colon. Serotonin is a multifarious neurotransmitter, with many functions. Excess amounts of serotonin cause relaxation and sedation. Chemical name of serotonin is 5-hydroxytryptamine (5-HT). Serotonin is found to have a positive effect in the motor functions of the Gl tract. Over 95% of the body's total serotonin is generated by the Gl tract, where it coordinates motility by binding to serotonin type 4 (5 HT) receptors. Once activated, these receptors stimulate the release of acetylcholine into neuromuscular junctions, resulting in coordinated peristalsis, vascular tone and secretion. Serotonin dysfunction is involved in the pathophysiology of a number of functional Gl disorders, such as Chronic Constipation, Irritable Bowel Syndrome, Diabetic Gastroparesis, Functional Dyspepsia and GERD. 5-HTP supports coordinated motility of the upper and lower Gl tract, in part by supporting 5-HT₄ activity. In the Gl system dopamine delays gastric emptying & esophageal motility as it inhibits acetylcholine. Although functional Gl disorders are not life-threatening diseases, but they are important because the patients with them have a poor quality of life. Symptoms associated with these disorders are often bothersome and prevent those affected from leading full and productive lives. ## Upper-Gut Motility Disorders ### 1. Functional Dyspepsia: Dyspepsia is a group of symptoms of the epigastric region including bloating, fullness, early satiety, nausea, belching, vomiting, acid reflux and hyperacidity Dyspepsia can be caused by stress, spicy food & conditions which aggravate excess acid secretion etc. It is clear that dyspepsia and functional dyspepsia in particular are common conditions globally, affecting most populations, regardless of location. Risk factors for functional dyspepsia have been shown to include females and underlying psychological disturbances, whilst environmental/lifestyle habits such as poor socio-economic status, smoking, increased caffeine intake and ingestion of non-steroidal anti-inflammatory drugs appear to be more relevant to uninvestigated dyspepsia. ### 2. GERD: #### Gastro-Esophageal Reflux Disease (GERD) GERD is defined as chronic symptom or mucosal damage produced by the abnormal reflux of gastric contents into the esophagus. Reflux esophagitis refers to a subgroup of GERD patients with histopathologically demonstrated characteristic changes in the esophageal mucosa. #### Nonerosive reflux disease Also knows as endoscopy-negative reflux disease, refers to patients with typical GERD symptoms caused by intraesophageal acid that do not have visible mucosal injury at endoscopy. On the other hand, functional heartburn is defined as episodic retrosternal burning without evidence of increased esophageal acid exposure or other structural esophageal etiology. #### Treatment: The various agents currently used for treatment of GERD include Mucoprotective substances, Antacids, H₂ Blockers, Pro