Portage Pharmacology Module 7- Gastroenterology

Emollient

(also known as "stool softeners" and "lubricant laxatives") Mechanism of Action: - Stool softeners work by lowering the surface tension of the GI fluids so that more water and fat are absorbed into the stool and the intestines. - Lubricant laxatives work by the fecal material and intestinal wall and preventing the absorption of water from the intestines. This water then works to soften and expand the stool. This promotes bowel distention and peristalsis leading to a bowel movement. Uses: Acute and Chronic constipation, fecal impaction Adverse Events: Decreased absorption of vitamins, electrolyte imbalance Drug Interactions: Mineral oil can decrease the absorption of fat-soluble vitamins (A, D, E, And K) Example Drugs: Docusate salts, mineral oil

Adsorbents

(are typically used in milder cases of diarrhea.) Mechanism of Action: Act by coating the wall of the GI tract. They bind the causative substance to their adsorbent surface for elimination from the body. Adverse Events: Bismuth subsalicylate can cause increased bleeding, constipation, dark stools, confusion, ringing in ears, and metallic taste. Drug Interactions: These drugs are known to decrease the effectiveness of other drugs by decreasing their absorption. Examples include digoxin and hypoglycemic drugs. Warfarin effects increase leading to increased risk of bleeds. Example Drug: Activated charcoal, bismuth subsalicylate, and cholestyramine

antiemetics

- Medications used for the treatment of nausea and vomiting - work within different sites of the vomiting pathway. For this reason, they can often be combined, and the overall effect can be greater. (1) Anticholinergics, (2) Antihistamines, (3) Antidopaminergics, (4) Neurokinin antagonists, (5) Prokinetics, (6) Serotonin blockers.

Probiotics

- are used in patients that have antibiotic induced diarrhea. Mechanism of Action: They work by replenishing bacteria that may have been destroyed by antibiotics. This helps restore the normal flora and suppresses the growth of diarrhea causing bacteria. No known adverse events or drug interactions. Example Drug: lactobacillus acidophilus

treatment of constipation

- should be individualized based on the person's age, the duration, and severity of the constipation, and potential contributing factors. - one of the most important considerations is often the onset of action. (time to bowel movement) Laxatives: - If used too long or too often, can cause laxative dependence, damage to the bowel, or new intestinal problems. - 5 types: (1) Bulk Forming (only class safe for long term use) (2) Emollient (3) Hyperosmotic (4) Saline (5) Stimulant.

Antimotility drugs

- typically used in more severe cases of diarrhea. - Anticholinergic or Opiates

Peristalsis

- wavelike movements of the intestines in which circular contraction and relaxation of the muscle propel the contents toward the rectum - Upon reaching the colon, water and minerals are removed from the contents. The remaining waste product is then compressed into feces for elimination through the rectum

Common causes of constipation

1. Adverse drug event Ex: analgesics, anti-cholinergics, iron, aluminum and calcium antacids, opiates, calcium channel blocker's 2. Lifestyle Ex: diet: poor fluid intake and/or low fiber, excessive calcium. Physical inactivity. Physiological factors: anxiety, stress 3. Metabolic and Endocrine Disorders Ex: diabetes, hypothyroidism, pregnancy, hypercalcemia (high calcium), hypokalemia (low potassium) 4. Neurogenic Disorders Ex: neuropathy, multiple sclerosis, spinal cord lesions, Parkinson's disease, stroke

three major stimulators that affect the release of gastric juices

Acetylcholine (ACh), gastrin, and histamine.

laxative onset action summary

Bisacodyl: - Trade name: Ducolax - Laxative Category: stimulant - Common Dosage forms: oral tablet, suppository - onset of action: Oral: 6 to 12 hours. Rectal: 15 to 60 minutes Docusate sodium: - Trade name: Colase - Laxative Category: stool softener/emollient - Common Dosage forms: oral capsule - onset of action: one to three days Glycerine: - Trade name: Fleet - Laxative Category: hyper osmotic - Common Dosage forms: suppository - onset of action: rectal only: 16 to 36 minutes Lactulose: - Trade name: Enulose - Laxative Category: hyper osmotic - Common Dosage forms: oral liquid - onset of action: 24 hours Magnesium citrate/sulfate: - Trade name: Generic only, epsom salts - Laxative Category: Saline - Common Dosage forms: oral liquid - onset of action: 0.5 to 3 hours Methylcellulose: - Trade name: Citrucel - Laxative Category: bulk forming - Common Dosage forms: powder to be mixed into water - onset of action: 12 to 24 hours Mineral oil: - Trade name: Fleet mineral oil - Laxative Category: emollient - Common Dosage forms: oral oil, rectal enema - onset of action: 6 to 8 hours Polyethylene glycol: - Trade name: Miralax , Go-Lytely - Laxative Category: hyper osmotic laxative - Common Dosage forms: oral powder to be mixed with water/4 L solution to be taken prior to procedure - onset of action: one hour Psyllium: - Trade name: Metamucil - Laxative Category: bulk forming - Common Dosage forms: powder to be mixed with water - onset of action: 12 to 24 hours Senna: - Trade name: Senokot - Laxative Category: stimulant - Common Dosage forms: oral tablet or liquid - onset of action: 6 to 24 hours

Linaclotide (Linzess)

Class: Peptide guanylate cyclase-C agonist Mechanism of Action: Not entirely understood. It is thought to work by increasing fluid secretion and GI motility. Use: IBS with constipation and chronic idiopathic (of unknown cause) constipation. Adverse Events: Diarrhea, abdominal pain, and flatulence Drug Interactions: No known drug interactions

Alosetron (Lotronex)

Class: Selective serotonin receptor antagonist Mechanism of Action: By blocking the serotonin receptors in the intestines resulting in a slowing of the movement of stool. Use: Severe Chronic diarrhea predominant IBS for women who have failed conventional treatment. If the response is inadequate after 4 weeks, the medication should be discontinued. Adverse Events: Constipation, abdominal discomfort, and pain, nausea, infrequent but serious ischemic colitis (if this occurs drug must be discontinued). Drug Interactions: When taken with fluvoxamine (antipsychotic) alosetron levels increased.

GERD treatment

Depending on the severity of the disease, the recommended treatment may differ. In mild-moderate GERD, the H2 antagonists are a great option. They have a longer duration of action than alternatives such as an OTC antacid and provide good relief. However, in severe GERD or in cases where there is ulcerative damage, PPIs are considered first line therapy. Lifestyle modifications are a critical part of the management of peptic ulcers and GERD. Recommendations include smoking cessation, avoiding caffeine and alcohol, as well as reducing stress. If possible, NSAIDs should be avoided. If the patient is overweight, weight loss can help. If the patient has symptoms at night, it is recommended to elevate their bed.

release of gastric juices:

First, the ingestion of food stimulates ACh to bind to its target receptors, stimulating the release of pepsin, gastrin, histamine, and HCl from chief cells, G cells, enterochromaffin like (ECL) cells, and parietal cells respectively. Gastrin then binds to its target receptors on ECL and parietal cells which stimulates the release of more histamine and more HCl. The histamine then binds to the H2 receptors on the parietal cells which, in turn, increases the amount of HCl or gastric acid released.

summary chart of the H2 receptor antagonists and the PPIs.

H2 antagonists: Cimetidine - Trade Name: Tagamet - Uses: Duodenal/Gastric, Ulcers, GERD - Special Considerations: available OTC, antacids delay absorption, limited use due to drug interactions Famotidine - Trade Name: Pepcid - Uses: Duodenal/Gastric, Ulcers, GERD - Special Considerations: available OTC Nizatidine - Trade Name: Axid - Uses: Duodenal/Gastric, Ulcers, GERD - Special Considerations: available OTC Ranitidine - Trade Name: Zantac - Uses: Duodenal/Gastric, Ulcers, GERD - Special Considerations: available OTC, antacids delay absorption PPIs: Omeprazole - Trade Name: Prilosec - Uses: Duodenal (short term)/Gastric, Ulcers, GERD - Special Considerations: available OTC, Interacts w/ clarithromyacin (increased concentrations of both drugs by unknown mechanism), increases levels of select anti seizure meds, may decrease effect of Plavix (anticlotting med) Lansoprazole - Trade Name: Prevacid - Uses: Duodenal Ulcer, GERD - Special Considerations: available OTC Esomeprazole - Trade Name: Nexium - Uses: GERD - Special Considerations: Newly available OTC (2014) Pantoprazole - Trade Name: Protonix - Uses: GERD - Special Considerations: Prescription only Dexlansoprazole - Trade Name: Dexilant - Uses: GERD - Special Considerations: Prescription only Rabeprazole - Trade Name: Aciphex - Uses: Duodenal (short term)/Gastric, Ulcers, GERD - Special Considerations: Prescription only

Peptic Ulcers treatment

If the patient has a peptic ulcer that is caused by H. Pylori, they will need to be treated with antibiotics. - The recommended antibiotics to treat H. pylori include amoxicillin, tetracycline, metronidazole, and clarithromycin. - The purpose of the Pepto-Bismol is that bismuth is thought to disrupt the bacterial cell wall and prevent further binding to the mucosa. Treatment typically lasts for 8 weeks leading to the eradication of the bacteria. triple therapy: two antibiotics in combination with bismuth salts (Pepto-Bismol or Kaopectate), quadruple therapy: When a proton pump inhibitor (PPI) is added to the regimen If the ulcer was not caused by H. Pylori, treatment does not involve antibiotics but rather anti-secretory drugs. - Anti-secretory drugs are defined as drugs that inhibit the secretion of digestive enzymes, hormones, or acids. Such drugs include H2 receptor antagonists, prostaglandins, and proton pump inhibitors. Treatment should last 4-8 weeks. Prostaglandins are only useful in the treatment or prevention of NSAID-induced ulcers. Prostaglandins inhibit histamine which counteracts the NSAIDs inhibition of prostaglandin synthesis. There is only one synthetic prostaglandin available, misoprostol. It is limited in its use, primarily being used for patients at high risk of developing an ulcer that must be on an NSAID for a limited time. Misoprostol has not been shown to be effective at preventing ulcers in patients on chronic NSAID therapy. Misoprostol is also known to cause uterine contractions and is, therefore, contraindicated in pregnancy due to the risk of miscarriage.

Opiates

Mechanism of Action: Work by acting on smooth muscle cells in the GI tract inhibiting motility and excessive GI propulsion. This results in a decrease in the number of stools and their water content. Adverse Events: Drowsiness, dizziness, lethargy, constipation, nausea/vomiting, low blood pressure, urinary retention, respiratory depression. Drug Interactions: Additive CNS depressant effects when co-administered with alcohol, opioids, sedative-hypnotics, antipsychotics, or skeletal muscle relaxants. Example Drug: Diphenoxylate with atropine (Lomotil), loperamide (Imodium A-D)

Anticholinergic

Mechanism of Action: Work by slowing peristalsis by reducing the contractions and smooth muscle tone in the GI tract. They also work by drying gastric secretions. Adverse Events: Urinary retention, impotence, headache, dizziness, anxiety, drowsiness, drop in heart rate, drop in blood pressure, dry skin, and blurred vision. Drug Interactions: Antacids decrease their effect. Example Drug: Atropine, hyoscyamine

Neurokinin antagonists

Mechanism of Action: Inhibit substance-P neurokinin receptors. Use: Nausea and vomiting associated with chemotherapy Adverse Events: Decrease in blood pressure and heart rate, fatigue, dizziness, diarrhea, and abdominal pain. Drug Interactions: Has been shown to induce the metabolism of warfarin, thus lowering the concentration. Neurokinin antagonists can also increase the concentration of corticosteroids (dexamethasone and methylprednisolone) and anti-anxiety medications (triazolam, alprazolam, and midazolam). They can also reduce the effectiveness of oral contraceptives. Example Antiemetic: Aprepitant, fosaprepitant

Prokinetics

Mechanism of Action: These drugs work in two ways; primarily they work by stimulating peristalsis through ACh receptors in the GI tract. This increases stomach emptying into the small intestines. Secondly, they also block dopamine receptors in the CTZ. Use: Delayed gastric emptying, GERD, nausea, and vomiting. Adverse Events: Decreased blood pressure, increased heart rate, sedation, fatigue, restlessness, dry mouth, and diarrhea. Drug Interactions: Can cause CNS depression when taken with alcohol. Anticholinergics and analgesics can also block the motility effect of metoclopramide. Example Antiemetic: Metoclopramide

Anticholinergics

Mechanism of Action: They act by binding to and blocking vestibular nuclei receptors deep within the brain. When ACh is blocked from these receptors, the nausea inducing signals are prevented from reaching the CTZ. The drying effects of anticholinergics help to dry GI secretions and reduce smooth muscle spasms which can also have a positive impact on reducing the symptoms of nausea and vomiting. Use: Motion sickness, Nausea/Vomiting Adverse Events: Dizziness, drowsiness, disorientation, increased heart rate, blurred vision, dry mouth, difficulty with urination, and constipation. Drug Interactions: Additive drying effects when given with antihistamines. Example Antiemetic: Scopolamine

Antihistamines (specifically H1 receptors)

Mechanism of Action: They bind to and block H1 receptors which prevents ACh from binding to the receptors in the vestibular nuclei. This mechanism gives them potent anticholinergic activity. Use: Motion Sickness, nonproductive cough, sedation, rhinitis, allergies, nausea/vomiting. Adverse Events: Dizziness, drowsiness, confusion, blurred vision, dry mouth, and difficulty with urination. Drug Interactions: Additive CNS depressant effects are seen when given with opioids, hypnotics, some antidepressants, and alcohol. Example Antiemetic: Dimenhydrinate, diphenhydramine, meclizine

Antacids

Mechanism of Action: They work by neutralizing the gastric acidity by reacting with HCl to form water and salts. Antacids are typically taken orally in a tablet or liquid formulation. They are known to have a quick onset of action but a short duration of action, making them a good choice for mild symptoms but not appropriate for maintenance or more severe disease. Uses: Antacids are often used for mild symptoms of heartburn or to treat breakthrough symptoms in patients already on one of the maintenance therapies above. Antacids are available OTC and most contain Magnesium, Aluminum, or Calcium ions. Adverse Events: Most adverse events are related to the ion component of the antacid. For example, magnesium containing antacids are known to cause diarrhea. Aluminum and calcium containing antacids can cause constipation. However, such side effects are only seen with chronic use. Drug Interactions: Antacids alter the absorption of some drugs. For example, oral tetracyclines may be inhibited by antacids. Example Antacids: Aluminum hydroxide; magnesium hydroxide (Gaviscon, Maalox), Magnesium hydroxide (Milk of magnesia), and Calcium carbonate (Tums)

Hyperosmotic

Mechanism of Action: Work by increasing fecal water content which causes distention and peristalsis and ultimately a bowel movement. Uses: Chronic constipation, bowel prep for surgical procedures Adverse Events: Abdominal bloating, rectal irritation, electrolyte imbalance Drug Interactions: Can cause increased CNS depression when combined with barbiturates, opioids, or antipsychotics. Oral antibiotics can decrease the effects of lactulose. Example Drugs: Polyethylene glycol, lactulose, sorbitol, and glycerin.

Saline

Mechanism of Action: Work by increasing osmotic pressure in the small intestines. This inhibits water absorption and increases both water and electrolyte secretions from the bowel wall. This causes watery stool. The increase distention promotes peristalsis and evacuation. Uses: Constipation, bowel prep for surgical procedures Adverse Events: Magnesium toxicity, electrolyte imbalances, cramping, diarrhea, increased thirst Drug Interactions: No major drug interactions Example Drugs: Magnesium hydroxide, magnesium sulfate, or magnesium citrate

Stimulant

Mechanism of Action: Work by stimulating the nerve within the intestine which causes peristalsis. They also increase bulk and soften stool. Uses: Acute constipation, bowel prep for surgical procedures. Adverse Events: Nutrient malabsorption, gastric irritation, electrolyte imbalance, discolored urine, rectal irritation. Drug Interactions: Antibiotic, digoxin, salicylates and oral anticoagulant absorption is decreased. Example Drugs: Senna and bisacodyl

Bulk-Forming

Mechanism of Action: Work similar to natural fiber. They absorb water into the intestines which increases bulk and distends the bowel to initiate activity, thus promoting a bowel movement. Use: Acute and chronic constipation, IBS Adverse Events: Fluid disturbances, electrolyte imbalance, gas, esophageal blockage Drug Interactions: Can decrease the absorption of antibiotics, digoxin, tetracyclines, and warfarin. Example Drugs: Psyllium, methylcellulose

Drug Therapy: H2 receptor antagonists

Mechanism of action: Work by competitively inhibiting the interaction of histamine with H2 receptors within the GI mucosa. This blockade significantly reduces the secretion of acid and pepsin from the stomach. Uses: Recommended for the short-term use (up to 8 weeks) of benign gastric ulcers and duodenal ulcers, GERD, stress ulcers and gastric irritation in patients that need to remain on NSAIDs. Adverse Events: Headache or constipation. Cimetidine specifically has been associated with reversible CNS effects such as confusion and disorientation, usually in critically ill patients. Drug Interactions: Cimetidine has been reported to increase the drug levels of many medications by altering metabolism. Select examples include calcium channel blockers, beta blockers, sulfonylureas, and theophylline. Famotidine and nizatidine have no effect on the metabolic pathway and are therefore preferred. They do not appear to interact with food and therefore can be taken at mealtime. Example Drugs: Cimetidine, ranitidine, famotidine, and nizatidine

two gastrointestinal disorders that can range from mild, self-limiting symptoms to extremely unpleasant symptoms leading to more serious problems

Nausea and vomiting

Pathophysiology of peptic ulcers

The cause of peptic ulcers is not always the same. The majority of GI ulcers are caused by the bacterium Helicobacter Pylori (H. Pylori). The bacterium is believed to enter the body through contaminated food or water. Reacting to the bacteria, an inflammatory response is initiated, which is often associated with an increase in stomach acid secretions. The long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) is also closely related to the incidence of peptic ulcers. NSAIDs block prostaglandins which play a role in inhibiting gastric acid secretion. In both cases, the resulting increase in stomach acid secretions places a strain on the inner lining of the stomach until an ulcer (break or tear) appears.

Antidopaminergic:

These drugs were historically used for the antipsychotic effects but were also shown to prevent nausea and vomiting. Mechanism of Action: Block dopamine receptors in the CTZ of the brain. Use: Psychotic disorders, intractable hiccups, and nausea/vomiting Adverse Events: Orthostatic hypotension, increased heart rate, extrapyramidal symptoms (examples include: slurred speech, tremor, muscle contractions, rigidity, and muscle slowness), blurred vision, dry eyes, urinary retention, and dry mouth. Drug Interactions: Additive CNS depressant effect when given with opioids, hypnotics, some antidepressants, and alcohol. Example Antiemetic: Prochlorperazine, promethazine

Constipation

a condition where the frequency of defecation occurs less often than usual, or the consistency of the feces makes it difficult to defecate. - symptom, not a disease. - It is a disorder of movement through the colon.

IBS (Irritable Bowel Syndrome)

a functional disorder of the colon associated with abdominal pain, cramping, bloating, diarrhea and/or constipation. - Patients often cope with IBS by avoiding irritating foods and/or taking OTC laxatives and antidiarrheals. - IBS is more commonly seen in women than in men. - Besides self-treatment with OTC medications, there are two prescription medications indicated specifically for IBS: (1) alosetron (2) linaclotide. It is important to note that these medications should be reserved for patients where conventional therapy has failed. They are not to be used first line.

Heartburn (acid indigestion)

a painful burning feeling behind the sternum that occurs when stomach acid backs up into the esophagus.

five main neurotransmitters involved in the vomiting process

acetylcholine (ACh) dopamine histamine (H1) serotonin (5-HT3) substance P (Neurokinin 1).

Diarrhea

an abnormal looseness of the stool or watery stool, which may be accompanied by a change in stool volume or frequency. - can be acute (lasting less than 14 days) or chronic (lasting longer 30 days) in nature. - Acute diarrhea is often self-limiting and resolves without complications. - Chronic diarrhea, however, can result in large quantities of water and electrolytes being lost, leading to dehydration and electrolyte imbalances. Pathophysiology/causes: - microorganisms can invade the GI tract and cause inflammation and irritation. This, in turn, causes the bowel to increase motility as a means of eliminating the microorganism. Treatment, in this case, is often centered around treating the infection. - A second common cause of diarrhea is a side effect of another drug therapy the patient may be taking. When this is the case, it is recommended to reduce or discontinue the causative drug if possible. - The third cause to consider is diarrhea associated with other medical problems. Examples include anemia, cancer, diabetes, nerve damage, IBS, and Crohn's disease. In these instances, antidiarrheal drugs are typically the treatment of choice. Drug Therapy Treatment: - antidiarrheal drugs. They are divided into different groups based on how they exert their effect: (1) adsorbents (2) antimotility (anticholinergic and opiates) (3) probiotics

vomiting center

area of the brain that is involved in stimulating the physiologic events that lead to nausea and vomiting.

chemoreceptor trigger zone (CTZ)

area of the brain that is involved in the sensation of nausea and the action of vomiting - controls vomiting center/process - The CTZ sends neurotransmitters to the vomiting center which then alerts the brain of nauseating substances that need to be expelled from the body

Symptoms of GERD

go beyond occasional heartburn. In GERD, heartburn is part of an ongoing problem, often occurring after meals and upon lying down. In severe cases, there can even be blood loss from chronic injury to the esophagus.

Pathophysiology of GERD

involves the lower esophageal sphincter (LES) or valve at the bottom of the esophagus going into the stomach. This valve loosens such that the gastric acid is able to go back up (reflux) into the esophagus.

organs of the upper gastrointestinal tract

mouth, pharynx, esophagus, stomach, and duodenum - work in conjunction to first digest food and then absorb the nutrients obtained from the digested food.

Serotonin blockers

newest class to treat nausea and vomiting. They have played a major role in treating nausea and vomiting associated with cancer chemotherapy and radiation therapy. Mechanism of Action: They work by blocking the serotonin receptors in the GI tract, CTZ and vomiting center. There are many subtypes of serotonin receptors throughout the body. The subtype involved in nausea and vomiting is the 5-hydroxytryptamine (5-HT3) receptor. Use: Nausea and vomiting associated with chemotherapy and postoperative nausea and vomiting. It is also commonly used to treat nausea associated with pregnancy. It is pregnancy category B. However, there is some concern regarding cleft palate development in the fetus when used in the first trimester. Adverse Events: Headache, diarrhea, bronchospasm Drug Interactions: No major drug interactions. Example Antiemetic: ondansetron, granisetron, dolasetron, and palonosetron.

Peptic ulcers

open sores in the mucous membranes of the mucosal lining of the stomach or duodenum.

Symptoms of a peptic ulcer

pain, nausea, and loss of appetite. The pain is typically described as a dull, gnawing, burning sensation similar to heartburn. Interestingly, if the ulcer is in the duodenum, food often relieves the pain, whereas if the ulcer is in the stomach, food often worsens the pain.

stomach and the upper part of the small intestines

release hormones and enzymes that help in this process.

HCl

released by parietal cells located in the stomach. Due to its acidic nature, HCl aids in the breakdown of food entering the stomach

GERD

stands for gastrointestinal esophageal reflux disease and is characterized primarily by the presence of heartburn.

PPIs

superior in their effectiveness in acid reduction and ulcer healing compared to H2 receptor antagonists. Mechanism of action: The exchange of hydrogen and potassium via the ATPase exchange is essential to the production of HCl. PPIs work by inhibiting this exchange, therefore, preventing the formation of acid. Uses: First line along with antibiotics to treat H. Pylori related ulcers, benign gastric ulcers, active duodenal ulcers, and GERD. They promote better healing over H2 blockers and therefore are the drug of choice for healing ulcers. Adverse Events: Headache, abdominal pain, diarrhea, nausea, and constipation. New concerns have arisen that long-term use could lead to the development of osteoporosis. Overprescription of PPIs could lead to an increase in GI infections because of the reduction of normal acid-mediated microbial protection. Drug Interactions: Omeprazole can increase levels of warfarin and some seizure medications (diazepam, phenytoin). It can also affect the absorption of drugs that require an acidic environment such as iron. Omeprazole has also been shown to decrease the antiplatelet effects of clopidogrel. Lansoprazole, pantoprazole, and rabeprazole have no clinically relevant drug interactions. Example Drugs: Omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, and rabeprazole.

Emesis (vomiting)

the forcible emptying or expulsion of gastric and occasionally intestinal contents through the mouth.

Pepsin

the primary digestive enzyme found in the stomach. Pepsin is responsible for the catabolism (breaking down) of proteins into polypeptides.

Nausea

the sensation often leading to the urge to vomit.

When food enters the body,

the stomach is triggered to begin releasing gastric juices such as hydrochloric acid (HCl) and an enzyme called pepsin.