METHODOLOGICAL INSTRUCTION TO LESSON N 5 FOR STUDENTS
Theme: CLINICAL PHARMACOLOGY OF DRUGS FOR GASTROINTESTINAL DISORDERS
Aim: To acquaint with actions, pharmacokinetics, therapeutic uses, adverse effects, concomitant use of agents influencing on gastrointestinal tract, their clinical usage and complications.
Professional motivation:
Many drugs have applications in the treatment of gastrointestinal diseases. The treatment of II disease have been profoundly modified by recent development of medicine. Therapeutically, the H2 antihistamine preparations, with their potent antacid effects, have changed the management of peptic ulcer disease. The discovery of the role of Campylobacter pylori in bowel disease has led to advances in its treatment. hepatic and biliary disorders need specific therapy, such as hepatoprotectors, bile drugs, enzyme agents etc.
Basic Level. For learning this theme students have to review anatomical and physiological peculiarities of gastro-intestinal tract (departments of normal anatomy and normal physiology), pathogenesis and main symptom of gastrointestinal diseases (departments of pathologic physiology and therapy).
Students’ Independent Study program
Antiulcer agents
History: The most common causes of chronic peptic ulcer disease (PUD) in the
The discovery of the residence of Helicobacter pylori in areas of mucosal ulceration has drastically changed the approach to prevention, diagnosis, and treatment of PUD. Conventional therapy with acid-suppressive agents alone is effective in healing peptic ulcers, and continued low-dose maintenance therapy reduces recurrences to roughly 20% per year. However, the use of accepted antibiotic regimens for H. pylori eradication in H. pylori-positive patients eradicates the infection, heals the infection-related ulcer, and also decreases the incidence of ulcer-related complications. Therapy also reduces the risk of non-NSAID-related ulcer recurrence to 10% or less per year. Thus, current guidelines call for the use of eradication regimens in most H. pylori-positive patients with active ulcer. The role of using antibiotic eradication regimens for H. pylori infections in those patients with non-ulcer dyspepsia is controversial, although some experts believe eradication is of benefit. Eradication is not recommended for the asymptomatic patient under current guidelines. Depending on the antibiotic regimen chosen for active ulcers, concurrent anti-secretory therapy with either a proton-pump inhibitor (PPI) or H2-blocker is administered for ulcer healing. However, regimens using a PPI typically produce higher organism eradication rates than H2-blockers; PPIs also heal ulcers and decrease ulcer pain more rapidly.
The treatment of NSAID-induced GI ulceration involves the removal of the offending agent, when possible, and using standard curative therapies (e.g., PPIs or H2-blockers). If H. pylori infection is also present, it should be treated concurrently. Current recommendations state that prophylactic drug therapy is not necessary for all patients taking NSAIDs. Measures to prevent NSAID induced-ulceration should be instituted in patients at high-risk for GI complications (e.g., elderly age and chronic health condition requiring NSAID use). Misoprostol, PPIs, and H2-blockers have all been used for prophylaxis. The role of sucralfate is less clear, but many studies have claimed no protective benefit. The more selective NSAIDs (e.g., COX-2 inhibitors) are postulated to decrease the risk of GI ulceration in some patients, but ulceration and bleeding have still been reported. Long-term post-marketing surveillance should resolve whether the COX-2 inhibitors will decrease the incidence of GI complications related to NSAIDs.
Mechanism of Action: Antacids, such as magnesium hydroxide and calcium carbonate, temporarily neutralize stomach acid. Antacids do not reduce the secretion of stomach acid but, in the case of calcium carbonate, can actually stimulate acid secretion.
Antimuscarinic anticholinergics (such as propantheline), H2-blockers, and proton-pump inhibitors (PPIs) all reduce gastric secretions, albeit via distinct mechanisms. PPIs do not interfere with transmitters such as acetylcholine or histamine, but instead inhibit the gastric acid proton “pump.” Other antiulcer agents work at the mucosal surface. These drugs include sucralfate, which forms a protective covering by binding to exposed mucosal proteins, and misoprostol, a prostaglandin that enhances the production of gastric mucus and bicarbonate. Misoprostol also may exhibit an antisecretory effect.
Finally, antibiotics, such as amoxicillin, clarithromycin, tetracycline, and metronidazole, along with bismuth salts have been used in various combinations against H. pylori. Although these antiinfective agents are not known to possess any mucosal protective action other than their direct antibacterial effect, bismuth might exert multiple actions including a direct effect on H. pylori, stimulation of prostaglandin production, alteration of mucus production, and modulation of the immune response.
Distinguishing Features:Peptic ulcer disease: Magnesium hydroxide-aluminum hydroxide-based antacids are the most common types of antacids used to treat peptic ulcer disease, but there are others. Because of their short duration of action and because other agents are more effective, antacids are rarely used for treating acute peptic ulcer disease. However, antacids are commonly used for immediate relief of symptomatic complaints related to dyspepsia or pyrosis.
H2-blockers are similar in actions and adverse reactions. Cimetidine, however, is involved in many drug interactions related to inhibition of the hepatic oxidative microsomal P450 enzyme system. Interactions between theophylline and cimetidine, for example, are especially clinically significant. Famotidine, nizatidine, and ranitidine do not have the same ability to inhibit these CYP450 enzymes and are much less likely to interact with other medications. The H2-blockers do not have in vitro activity against Helicobacter pylori (H. Pylori) and cannot be used as single agents against the infection.
The proton-pump inhibitors (PPIs) lansoprazole, omeprazole, pantoprazole and rabeprazole are extremely potent; with antisecretory duration of action approaching 24 hours after a single dose. Higher intragastric pH values can be achieved with the PPIs than with H2-blockers. Rabeprazole may have the shortest duration of anti-secretory effect, but this does not appear to be a clinically significant feature. Significant in vitro activity against Helicobacter pylori (H. Pylori) has been demonstrated for all the PPIs. Omeprazole and lansoprazole might inhibit the hepatic metabolism of other drugs, but there is little documentation of interactions. Pantoprazole and rabeprazole do not appear to significantly inhibit hepatic cytochrome P450.
Suggested appropriate regimens for the treatment of Helicobacter pylori-associated ulcer disease have been recently revised. It is known that treatment with a single agent – whether that agent is an acid pump inhibitor or an antibiotic – is inadequate. The relapse rate after treatment with omeprazole alone is very high and resistance to metronidazole develops readily when metronidazole is used alone. To avoid the development of microbial resistance and to ensure adequate eradication rates, drug regimens containing one antibiotic are no longer recommended, even though they are FDA approved. The use of a PPI in combination with 2 antibiotics provides the highest H. pylori eradication rates currently. There are many alternative regimens that may be used in case of treatment failures or in tolerance.
Sucralfate was originally approved to treat acute duodenal ulcers and was subsequently approved for long-term maintenance therapy to prevent their recurrence. It is significantly superior to placebo, but slightly less effective than cimetidine. Unlike H2-blockers and PPIs, sucralfate does not relieve ulcer pain. It is also not effective for H. pylori and should not be used in combination regimens for this infection.
Misoprostol is not approved for treating duodenal ulcer, although data suggest misoprostol is superior to placebo for this condition. Although no studies directly comparing misoprostol to sucralfate in this setting are known, reports do exist of misoprostol success after failure of traditional H2-antagonist therapy with or without sucralfate. Nevertheless, some believe there is no reason to use misoprostol over conventional acid-suppressive therapy for active peptic ulcer disease. Misoprostol is not commonly used for the treatment of PUD.
Prevention and treatment of NSAID-induced ulceration and related complications:
Where possible, the NSAID should be discontinued when GI ulceration or another GI complication occurs. Misoprostol is considered the drug of choice for preventing NSAID-related ulcers and related GI events. The PPIs and H2-blockers appear to be effective at preventing and also treating NSAID-induced GI complications, but the PPIs may be preferred over H2-blockers based on a recent trial. At least one recent study has shown that the PPIs are as effective as misoprostol in healing NSAID-induced ulceration and that PPI therapy may be better tolerated.Some experts suggest that a PPI should be utilized for the treatment of an active NSAID-induced ulceration, and that combination treatment of a PPI with misoprostol should be reserved for refractory ulcers. There is no rational for combining a PPI with an H2-blocker.
Based on its pharmacologic actions, sucralfate has been studied for the prevention of NSAID-induced mucosal injury. In one comparison of misoprostol 200 µg PO four times per day to sucralfate
Adverse Reactions: Although anti-ulcer agents are all relatively well tolerated, several potential adverse reactions should be kept in mind.The most common side effects of antacids involve the GI tract. The GI effects are dose-related. Magnesium-containing antacids cause diarrhea; aluminum-containing antacids cause constipation. Calcium carbonate has been associated with acid rebound. Sodium bicarbonate can be absorbed systemically, causing metabolic alkalosis. Aluminum-containing antacids, when administered chronically in high doses, may cause hypophosphatemia. There is also evidence that aluminum-containing antacids may be problematic in hemodialysis patients. Magnesium-containing antacids should not be used in patients with significant renal impairment.
Most people tolerate the H2-blockers well. Side-effects are fairly infrequent; headache is the most common problem reported with oral use. All have been associated with bone marrow toxicity, although, in general, this toxicity is rare (i.e., 1 out of every 100,000 patients or less). Central nervous system reactions are idiosyncratic and are reported primarily in critically ill patients or the elderly receiving these drugs. Other rare side effects in this class may include hepatitis, pancreatitis, or hypersensitivity reactions. The weak anti-androgenic effects of cimetidine may lead to gynecomastia in men with 1 month of use, but the effect is typically reversible with drug discontinuation. Cimetidine can also inhibit the hepatic metabolism of many drugs.
The proton pump inhibitors (PPIs) are typically well tolerated. Side effects reported with short-term use are similar to those of the H2-blockers (e.g., headache, diarrhea, or constipation). Omeprazole, lansoprazole and pantoprazole, due to their ability to almost completely shut down acid secretion, have been associated with gastrointestinal infections, particularly in immunocompromised hosts. There was some concern that PPIs could increase the risk of developing gastric hyperplasia and carcinoma due to the fact that some patients develop hypergastrinemia with prolonged therapy. There does not appear to be any evidence of such increased risk, however, based on over 15 years of PPI use surveillance.
Misoprostol, because it is a prostaglandin, can cause severe exacerbation of inflammatory bowel disease. It has been shown that lower doses of misoprostol (e.g., 200 µg PO twice to three times per day) are as effective as the original dose of 200 µg
The most common side-effect of sucralfate is constipation. In critically-ill or long-term-care residents with nasogastric or other gastrointestinal feeding tubes, bezoar formation may occur with administration if tubes are not carefully flushed during and after medication administration. Sucralfate contains aluminum, and there is concern that hypophosphatemia may occur in patients on chronic sucralfate therapy. Patients with renal failure or those receiving dialysis can develop aluminum accumulation with sucralfate therapy, due to impaired aluminum excretion. The systemic burden of aluminum with chronic sucralfate therapy is similar to that present with the use of aluminum-containing antacids.
In general, the agents used to treat H. pylori are well-tolerated; up to 30% of patients, however, report minor side effects. When used in various combinations for H. pylori infection, the most commonly reported side effects are taste abnormalities (clarithromycin, metronidazole); diarrhea, abdominal pain, and nausea/vomiting. The incidence of side effects increases with the use of regimens containing bismuth preparations ( 50%). All of these medications may cause hypersensitivity in susceptible individuals. Antibiotics such as amoxicillin and tetracycline occasionally cause diarrhea, rash, or vaginitis. Metronidazole may invoke a disulfiram-type reaction in those patients who ingest a sufficient amount of ethanol-containing beverages or medicines, but this type of reaction is not frequent. Bismuth causes constipation and imparts a black color to the stool. In extremely high doses, bismuth subsalicylate can cause salicylate toxicity. Due to the potential for some of these medications to cause harm during pregnancy (e.g., tetracycline and metronidazole), regimens for H. pylori eradication are not for use in the pregnant patient. Additionally, some of these drugs are not recommended for use during lactation.
You should prepare for the practical class using the existing textbooks and lectures. Special attention should be paid to the following:
1. Mechanism of stimulative activity of sitters on appetite and bowel secretion. Uses of bitters.
2. Agent that can stimulate appetite (anorexogenic drugs), mechanism of action, use, side effects, contraindication.
3. Principle action, pharmacodymic and usage of agents that reduce gastric secretion.
4. Comparative characteristic and usage of antacids.
5. Agents of substitute therapy of gastric secretion insufficient.
6. Agents increasing gastric secretion.
7. Principles of combine usage of different drugs for gastritis, ulcer disease management.
8. Drugs’ characteristics that used for reduced pancreatic secretion treatment.
9. Characteristic, mechanism of action and usage of agent stimulate bale run out (cholikinetics).
10. Pharmacodynamic mechanism of action, use and toxicity of cholagogue drugs, stimulating the producing of bile.
11. Agent influencing on intestinal motility.
12. Vomiting and antiemetic remedies, mechanism of action, usage, side effects, contraindication.
13. Classification of laxative preparations mechanism of their action, use, contraindications.
Key words: bitter appetite, anorexogenic agents, gastric juice, hyperacidity, hypoacidity, gallbladders, gastriciulcer, cholestasis, bowel motility, liver, jaundice, pancreas, vomiting, laxative.
I. Tests and assignment for self-assessment
1. Write out the prescriptions to the following drugs in different medicinal forms: tincture Absinthii herb Centraurii, Phepranonum, Succus gastricus naturalis, Acidum hydrochloricum dilute, Atropini Sulfas, Magnesii oxydum, Aluminii hydroxydum, Denol, Natrii hydrocarbonas, Ranitidinum, Phamotidinum, Gastrocepinum, Plantaglucidum, herba Plantagims majoris, extractun and tincture Belladonae, Pavarerini hydrochoridum, Aceclydinum, Proserinum, Apamorphini hydrochloridum, Aethaperazinum, Scopolamini hydrochloridum, Metoclopramide, “Aeronum”, “Alcoholum” Cholosasum, Nicodinum, Cholagolunu, Magnessi sulfas, Oleum Ricini, Bisacodinum, Phenolphthaleinum, Isapheninum, Isamanum, Extractum Fraugulae, Folium Sennae, Senadexunum, Lopamidum, Nospanum.
2. Choose the correct answer/statement:
A. Which of the following substances has its major activity as a saline cathartic?
1) Sodium bicarbonate
2) Aluminium hydroxide
3) Magnesium sulfate
4) Calcium carbonate
5) All of above
A. In general, mechanisms of laxation include
1. adding bulk to the stool
2. increasing peristaltic activity
3. emulsifuing aqenons and fatty substances with stool
4. lubricating the passage of stool
5. all of the above
B. Drug which exerts anti-peptic effects through histamine-2 receptor antagonism:
1. Denol
2. Ranitidine
3. Omeprasole
4. Aluminium hydroxide
5. All of above
3. Real-life situation to be solved .
For treatment of heartburn patient regularly used some powder. After a week of drug using vomiting, nausea, abdomen pain, fibrillation, shallow and slow breathing. Biochemical examination show alkalosis. What drug used patient?
III. Answer to the self-assessment
1. A-3: B-5: C-2
2. Natrii hydrocarbonas
Visual aids and material tools
1. Charts
2. Drugs in different medicinal forms
Students’ practical Activities
Students must know: Pharmacodynamics and pharmacokinetic effects, uses and contraindications of different groups of drugs used for treatment of gastrointestinal diseases.
Students should be able to: make a choice of drugs used for management of gastrointestinal diseases in real life situation, write out the prescription for these drugs in different medicinal forms
I. Answer the following questions:
1. Why bile’s are prescribed 15-20 minutes before meal?
2. Why anorexogenic agents are prescribed in the morning?
3. What kinds of antacids do you know?
4. What inhibitor of proteolitic enzymes are used for acute pancreatitis treatment?
5. What are the contraindications for chologogue prescribing?
6. What drugs are used for bowel atonia management?
7. What neuroleptic has antiemetic action?
8. What saline cathartic aren’t prescribe for chronic constipation treatment?
II. Control task.
1. Write out a prescription, a property to pharmacological drug group, therapeutic usage of such drug: “Allocholum”, Magnesii sulfas, Aethaperazinum, Proserinum, Oleum Ricini, Nospanum, Atropini sulfas.
2. Choose the correct statement
1) Antacid, having a relativelly non-systemic effect include.
1. aluminium hydroxide
2. sodium bicarbonate
3. calcium carbonate
4. all of the above
5. 1 and 3
2) In esophagi’s, elevation of the head of the bed, abstinence from ethanol and tabacco, a frequent meal are all useful adjunctive therapeutic measures. Other useful therapy may include all of the following EXCEPT;
1. Omeprazole
2. Metoclopamide
3. Aluminium hydroxide
4. Cimetidine
5. Amitriptyline
3) Real-Life situation.
Patient suffers from choledocholithiasis used infusion of stigmata ulaydis (chologogue agent) every day. Soon, dull abdominal pain occurs and yellow skin tint appears. What is the reason of this state?
References: 1. B.G.Katzung. Clinical and Basic Pharmacology. – 1982.-P.773-779.
2.Ama drug evaluations. – Ed. V. – 1984 – P.1261-1339.
Adapted at the Chair sitting
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