Pharmacology/Gastrointestinal tract

Many drugs discussed elsewhere in this collection have applications in the treatment of gastrointestinal diseases. M-cholinolytic agents inhibit the food-stimulated secretion of gastric acid and also affect intestinal smooth muscle; these drugs are useful in some forms of functional bowel disease. M-cholinomimetics stimulate smooth muscle and are used to promote gastrointestinal motility. Several other groups of medications are used almost exclusively in gastrointestinal disease; these are grouped and discussed below according to their therapeutic uses.

Drugs regulating appetite
These drugs are divided into drugs that increase and decrease appetite. Action is related with influence on the appetite control center (centers of hunger and satiation), located in hypothalamus.

Drugs that increase an appetite include bitters (amara). Bitters are the substances that possess strong bitter taste. Bitters irritate taste receptors of oral cavity and stomach mucosa that cause reflective increasing of gastric juice secretion and promote digestion. Bitters are used for the treatment of the atrophic gastritis, hypoacidity (lower than normal level of hydrochloric acid), and anorexia (aversion to food). Bitters are should be used for 15-30 minutes before meals. Agents include bitter (amara) tincture, tincture of wormwood (absinthium), etc. Some taste substances (e.g., mint, pepper, and mustard) also exhibit features of bitters. They contain ether oil that stimulates an appetite. Bitters will be prohibited during hyperacidity, ulcer disease of stomach. Cyproheptadine (peritol) is an antihistamine (H1) drug that stimulates the center of hunger in the CNS. It is used for the treatment of anorexia.

Appetite suppressants are sympathomimetic agents. They are phepranone (amphepramone), desopimon, and mazindol. These agents have pharmacological effects similar to those of phenamine, including CNS stimulation and elevation of blood pressure. It is believed that the main effect of these medications is decreasing of the appetite control center activity. Phepranon and desopimon (relatives of phenamine) are weaker than phenamine as appetite suppressants, but less stimulate CNS and cardiovascular system, seldom causing drug addiction. Appetite suppressants are indicated in the management of exogenous obesity for short-term use (a few weeks) in conjunction with a regimen of weight reduction based on caloric restriction, exercise, and behavior modification. Adverse effects include insomnia, tachycardia, increasing of blood pressure, sleeplessness, accustoming and drug addiction. They are contraindicated during hypertonia, disorders of cerebral blood circulating, thyrotoxicosis, diabetes mellitus, and epilepsy.

Substances stimulating and inhibiting secretive function of the stomach
Drugs that stimulate stomach juice secretion are the next: pepsin, natural gastric juice, abomin, and panzynorm (see chapter “Enzyme preparations and enzyme inhibitors”). They normalize secretion and motility of gastrointestinal tract and are indicated for replacement therapy of stomach upset such as achlorhydria (absence of hydrochloric acid in the gastric juice) or hypoacidity. Pentagastrin is a synthetic analog of the natural hormone, gastrin. Pentagastrin as well as gastrin stimulate the secretion of hydrochloric acid, pepsin, and increases GI motility. It is useful as a diagnostic test for achlorhydria and hypersecretion of stomach juice.

Drugs, decreasing the secretive function of stomach, include M-cholinolytics, ganglioblockers, and blockers of H2-histamine receptors, antacids, adsorbents, astringents, and local anesthetics. Gastric acid secretion is under the control of histamine, acetylcholine, and gastrin. The final common pathway is through the proton pump, H/K ATPase.

H2(histamine)-receptors antagonists, e.g., cimetidine, ranitidine, famotidine, and nizatidine blockade H2-receptors of stomach mucosa that leads to reduction in basal, food-stimulated, and nocturnal secretion of gastric acid. Many trials have demonstrated their effectiveness in promoting the healing of duodenal and gastric ulcers and preventing their recurrence. H2-antagonists are rapidly and well absorbed following oral administration. Food delays and may slightly decrease absorption of the drugs. For active ulcer, any H2-blocker can be given twice daily or once at bedtime. Reversible hematologic abnormalities have been a rare occurrence with all members of this class of drugs. Cimetidine may cause reversible gynecomastia. This has been reported only rarely with ranitidine and famotidine. Cimetidine also slows hepatic microsomal metabolism of some drugs, such as neodicumarin, euphylline, diazepam, and diphenine. Ranitidine appears to have less effect and famotidine and nizatidine no effect on hepatic drug metabolism.

Cholinoreceptor antagonists such as M-cholinolytics (e.g., atropine, pirenzepine) and ganglioblockers (e.g., pirilen, pentamine) decrease the influence of nervus vagus that results in lowering of gastric juice secretion. Ganglioblockers are now rarely used because they’re adverse effects. Pirenzepine, an antimuscarinic agent with activity relatively selective for gastric M1-receptors, is approved for ulcer therapy. It may causes the disorder of accommodation, dryness of mouth, but less frequent than others M-cholinolytics.

Omeprazole irreversibly inhibits the gastric parietal cell proton pump, (H/K ATPase). Inactivation of this enzyme system blocks the final step in the secretion of hydrochloric acid by these cells. The drug requires activation in the acid environment of the secretory canaliculus of the parietal cell, i.e., it is a prodrug. Omeprazole inhibits basal and stimulated gastric acid secretion. Omeprazole is a more potent inhibitor of such secretion than are H2-receptor antagonists. Although omeprazole has a short terminal plasma half-life, the drug has a long duration of action (about 3 days). Omeprazole increases plasma gastrin concentrations via a negative feedback mechanism resulting from decreased gastric acid secretion. Omeprazole is approved for the treatment of gastric and duodenal ulcers as well as for prevention of recurrence of duodenal ulcers. The initial dose is 20 mg once daily. Omeprazole is well-tolerated drug. However, increase in gastric carcinoid tumors has been observed during long-term omeprazole exposure in animals.

Gastric antacids are weak bases that react with gastric hydrochloric acid to form a salt and water. Their usefulness in peptic ulcer disease appears to lie in their ability to reduce gastric acidity. Antacid-induced increases in gastric pH inhibit the proteolytic action of pepsin. Some antacids, such as aluminum hydroxide, have astringent action. Most antacids in current use have as their principal constituent magnesium or aluminum hydroxide, alone or in combination, and occasionally in combination with sodium bicarbonate or a calcium salt.

Antacids include sodium bicarbonate, magnesium oxide, calcium carbonate, aluminum hydroxide, and a lot of complex drugs (e.g., almagel, maalox, phosphalugel, vicair, de-nol, etc). Sodium bicarbonate possesses the most quick but short period of action. During interaction with acid, carbon dioxide is formed, which stretches stomach and causes secondary wave of secretion. Absorbing into blood, sodium bicarbonate may causes systemic alkalosis. Magnesium oxide, aluminum hydroxide act slower, more durable, and more active than sodium bicarbonate. Magnesium oxide may cause purgative effect, however aluminum hydroxide may cause constipation. Calcium carbonate is slowly solubilized in the stomach. In high doses it may cause hypercalcemia and alkalosis.

There are many complex antacids. They are almagel (aluminum hydroxide and magnesium oxide), maalox (aluminum and magnesium hydroxide). These agents possess antacid, adsorptive, astringent, and envelop activities. Also agents that contain bismuth such as vicair (bismuth subnitrate, magnesium carbonate, sodium bicarbonate, and powder of frangula bark), de-nol (bismuth subcitrate) are well known. Bismuth salts have antacid and astringent effects. In addition, de-nol has mild activity against Helicobacter pylori that is associated with gastritis and peptic ulcer. Antacids are used as an adjunct to physical and emotional rest, other drugs for the relief of peptic ulcer pain and to promote the healing of peptic ulcers, hyperacid gastritis. Antacids also are used for the relief of dyspepsia, heartburn, and sour stomach.

Sucralfate is a gel (aluminum salt), which in acid surrounding forms glutinous and sticky substance, covering the ulcerous surface and protecting it from damages. Sucralfate is not absorbed.

A great meaning in treatment of gastritis and ulcer disease of stomach and duodenum is taken by gastric protectors – drugs that increase protection function of sputum and stableness of mucous layer (carbenoxolone, misoprostole). Carbenoxolone increases secretion of sputum, forming it more glutinous. It may cause retention of water in organism, hypertension. Misoprostole is a synthetic prostaglandin E1 that increase stability of gastric mucous, lower secretion of hydrochloric acid and fasten secretion of sputum. Now are widely used drugs, which promote stomach mucosa regeneration. To them are concerned solcoseril, vitamin U, anabolic steroids (retabolil, phenobolil, etc.), riboxin and methyluracil.

Emetic and anti-emetic drugs
Vomiting is a protective stomach reaction directed on its cleaning. Coordination of the complex motor activity of the stomach and abdominal musculature takes place in the vomiting center, which is located in the reticular formation in the medulla. The vomiting center receives input from the chemoreceptor trigger zone located on the floor of the fourth ventricle, the vestibular apparatus, and other areas.

Vomiting can be evoked for turning out irritate and toxic substances from the stomach. For that purpose apomorphine is used. It stimulates dopamine receptors of trigger zone. Apomorphine is characterized by short period of nausea. It is contraindicated during unconscious state, burns of esophagus and stomach by acid and alkaline. Sometimes it is used during treatment of alcoholism for forming of negative conditional reflex on alcohol. Nausea and vomiting may be manifestations of a wide variety of conditions, including pregnancy, motion sickness, gastrointestinal obstruction, peptic ulcer, drug toxicity, myocardial infarction, cancer chemotherapy, etc. So choosing of antiemetic drugs is determined by reasons, caused vomiting.

The major categories of antiemetic agents include H1-antihistamines, neuroleptics, M-cholinolytics, metoclopramide, and ondansetron. The antihistamines with good antiemetic activity (e.g., dimedrole diprazin) possess significant antimuscarinic and sedative effects (see chapter “Agents for the treatment of hypersensitivity”). It appears probable that both of these actions and the H1-blocking effect contribute to the antiemetic efficacy. They are particularly effective for the nausea and vomiting associated with motion sickness, perhaps because of specific depression of conduction in the vestibulocerebellar pathway. Anticholinergic agents, especially atropine, scopolamine (aeron), are also used to prevent motion sickness.

The neuroleptics block dopamine receptors in the trigger zone as well as other areas of the brain (see chapter “Neuroleptics”). Aminazine and galoperidol are often used as antiemetics. Extrapyramidal symptoms (parkinsonism) can be severe when large doses of neuroleptics are used. Thiethylperazine is a phenothiazine derivative (as aminazine). Agent is a strong antiemetic, however it causes mild extrapyramidal disorders. Metoclopramide promotes gastrointestinal motility. In addition to its M-cholinomimetic properties, metoclopramide is a potent dopamine antagonist. It does not increase gastric or pancreatic secretion. These drugs hasten esophageal clearance, raise lower esophageal sphincter pressure, accelerate gastric emptying, and shorten small intestine transit time. Metoclopramide's central dopamine antagonist effect is thought to be responsible for its significant antiemetic properties. Metoclopramide injection is indicated for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy, in postoperative period. Oral metoclopramide is indicated in adults for the symptomatic treatment of heartburn and reflux esophagitis, for correcting the slow gastric emptying. The most common side effects of metoclopramide are somnolence and nervousness. Parkinsonism has also been reported.

Ondansetron is a selective inhibitor of serotonin (5-HT3) receptors. The antiemetic activity of ondansetron appears to be mediated both centrally and peripherally via inhibition of 5-HT3 receptors. Ondansetron is used orally or intravenously for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy. Ondansetron appear to be more effective and better tolerated than the pharmacologically less selective metoclopramide and therefore may be preferred for the management of acute emetic effects in many patients.

Substances influencing on motility of intestine
They are divided into drugs, depressing intestine motility (antidiarrheal agents), and drugs, increasing intestine motility (laxatives).

Diarrhea is a symptom of many diseases (poisoning, infections, diseases of stomach and pancreas, etc.). For the diarrhea therapy it reason is necessary to confirm. If diarrhea is caused by infection process, antimicrobe agents must be taken. In the treatment of uncomplicated diarrhea that caused by modification of the intestinal flora by drugs (e.g., antibiotics) or during different diseases one can use chilac, biphidumbacterin, etc. These agents contain an acid-producing intestine bacterium (e.g., Lactobacillus acidophilus) or its extract prepared in a concentrated, dried, and viable culture for oral administration.

As drugs for symptomatic diarrhea therapy are used astringents, enveloping and adsorptive substances, which possess non-specific anti-inflammatory and protect intestine mucosa from irritate agents. M-cholinolytics, ganglioblockers, and spasmolytics of myotrope action (papaverine, no-spa, dibasole, etc.) decrease the tonus of smooth muscles of intestine wall that results in lowering of intestine motility. Loperamide is a synthetic piperidine-derivative antidiarrheal agent. Drug binds with opioid receptors of intestine (like morphine) and enhances contractions of intestinal circular musculature, thus increasing segmentation and retarding forward motion through the intestine. Loperamide is potent, specific, and long acting antidiarrheal agent. It has no analgesic activity. Loperamide is used in the control and symptomatic relief of acute nonspecific diarrhea and of chronic diarrhea associated with inflammatory bowel disease. Adverse effects of loperamide are constipation, dizziness, and nausea. Also it has M-cholinolytic activity.

Drugs that increase the motility of intestine include M- and M-, N-cholinomimetics (aceklidine, proserine, halantamine, etc.). These agents stimulate tonus of nervus vagus that leads to the activation of smooth muscles of intestine wall and intestine motility in general. Direct stimulating action on the intestine wall have purgatives.

Purgatives are the substances that fasten movement of intestinal content and promote defecation. In dependence of mechanism of action they are divided into next groups:

(1) drugs, acting basically on small intestine (castor oil);

(2) drugs, acting basically on large intestine (leaves of senna, bark of frangula, phenolphtalein, bisacodyl);

(3) drugs, acting on all parts of intestine (salt laxatives – magnesium sulfate);

(4) bulk laxatives (agar, methylcellulose, bran)

(5) stool softeners (mineral oil, vaselin).

Castor oil is hydrolyzed in the upper small intestine to ricinoleic acid, a local irritant that increases intestinal motility. The onset of action is prompt (2-6 hours) and continues until the compound is excreted via the colon. It is administered during acute constipation. Castor oil is contraindicated during poisoning by fat-dissolved substances.

Bark of frangula, leaves of senna contain emodin alkaloids that are liberated after absorption from the intestine and are excreted into the colon, where peristalsis is stimulated. Thus, their onset of activity is delayed for 6-10 hours. So, they are usually administrated in evening. These agents are used for the treatment of chronic constipation. Adverse effects include spasm of intestine, meteorism. Phenolphthalein and bisacodyl, which are synthetic drugs, are also potent colonic stimulants. They are absorbed in small intestine and excreted in large intestine, increasing it’s peristaltic.

Saline cathartics (magnesium sulfate) distend the bowel and stimulate its contractions. These nonabsorbable salts hold water in the intestine by osmotic force and cause distention. In result magnesium sulfate increases the motility of all intestine. Saline cathartics serve for removal of ingested toxin and as colonic lavage solutions, chiefly in preparation for radiological or endoscopic procedures. It has to be administrated with enough volume of warm water (1-2 glasses). Potent laxative effect develops after 2-4 hours. Magnesium sulfate is taken seldom because it impairs the absorption of nutritious substances in intestine.

'''Bulking laxatives. Agar and methylcellulose''' are swelling in the large intestine lumen that is associated with their enlargement. They distend the intestine and thereby stimulating its peristaltic activity. Bran (by-product of the milling of wheat, containing the indigestible cellulose) and other forms of vegetable fiber have the same effect. Bulking laxatives are taken for chronic constipation.

Stool softeners become emulsified with stool. They serve to soften stool and make passage easier. Examples are mineral oil, glycerin. They have weak laxative effect. Adverse effects include impairment of food digestion, uncontrolled defecation, and soil of clothes.

Purgatives are contraindicated during acute appendicitis and cholecystitis, peritonitis, mechanical impassability of intestines, pinched hernia, bleeding in GI tract, menorrhagia. They are to be carefully used during pregnancy due risk of abortion.

Hepatotropic drugs
Hepatotropic drugs consist of three groups. They are (1) bile-drive drugs, (2) hepatoprotectors, and (3) choleolytics.

Bile-drive drugs regulate the bile production and bile output. Lack of gall causes disorder of emulsion and absorption of lipids, fat-dissolved vitamins as well as development of putrid microflora in intestine and depression of its motility. Bile-drive drugs are divided into two main groups.

1. Drugs that stimulate bile production (cholesecretics). Drugs of resorptive type action, which activate hepatocytes. Also they irritate the intestine chemoreceptors that in reflective way promotes bile secretion. In addition, drugs including bile can act as substitutive agents. Cholesecretics are indicated during insufficiency of bile production. They will be contraindicated during acute and considerable lever defeats, obturating of bile ducts by gallstone, etc., because they form additive loading on liver and may increase jaundice.

1.1	drugs that contain bile: allohole (consist of bile, garlic and nettle extracts, and activated carbon), cholenzyn (bile, dry powder of cattle pancreas and intestine), etc.

1.2	drugs of plant origin: cholosas (syrupus of wild rose hips), corn oil, etc. 1.3	synthetic drugs: nicodin (nicotinamide + formaldehyde), cycvalone, etc.

2. Drugs promoting bile excretion into duodenum

2.1 drugs that increase tonus and motility of gallbladder, and accelerate its emptying (cholekinetics): cholecystokinine, pituitrine, magnesium sulfate, sorbit, etc. They are used for the hypotonia of gallbladder and bile ducts.

2.2 drugs that decrease tonus of bile ducts and Oddi’s sphincter (spasmolytics): atropine, platyphylline, papaverine, no-spa, etc.

They are used for removing of liver colic, Oddi’s sphincter spasm.

That classification is quite comparative, because drugs, stimulating the gall formation, at the same time increase its excretion. And drugs, increasing the gall excretion, promote gall formation. The most important factor during treating of liver and gall-ducts diseases, is the bettering of gall outflow, what deletes it’s stagnation and absorption to blood, lower risk of infection’s development in gall-ducts, and forming of gall-stones.

Hepatoprotectors are the drugs that increase the resistance of hepatocytes membrane, induce the hepatocytes enzymes, and promote restoration of liver function (synthesis of proteins, detoxication). As the rule, these drugs possess antioxidant properties. These features are possessed by legalon, essentiale. The last one includes essential (important) phospholipids, vitamins (B6, B12, PP, etc.). Hepatoprotectors are used for the treatment of hepatitis, cirrhosis.

Choleolytics are the drugs that cause desaturation of the bile by increasing the ratio of bile acids to cholesterol. The reduced cholesterol saturation allows for the gradual solubilization of cholesterol from gallstones, resulting in their eventual dissolution. Choleolytics are chenodeoxycholic acid (chenofalk, chenodiol) and ursodesoxycholic acid (ursofalk). Choleolytics are indicated for dissolution of cholesterol gallstones in selected patients with uncomplicated gallstone disease and functioning gallbladder.

Drugs influencing on outsecretive (exocrine) function of pancreas
They are divided into agents, which stimulate exocrine function of pancreas (bitters, acid hydrochlorici), agents for replacement therapy (pancreatin, panzynorm forte, festal, mezym forte), and agents, which inactivate pancreas enzymes. Uses of replacement therapy drugs are discussed in chapter “Enzyme preparations and enzyme inhibitors”. Agents, inhibiting pancreas enzymes are discussed below.

Enzymes of pancreas take part in destruction of proteins, fats and hydrocarbons. Usually in pancreas enzymes are present in nonactive (pre-enzyme) form, which is transformed to active form in the intestine lumen only. During acute pancreatitis, activation of enzymes especially proteolytic begins in gland tissues that lead to “self-destruction” of pancreas. Treatment of acute pancreatitis is directed on lowering of pancreatic secretion, using M-cholinolytics (atropine, etc.) and inactivation of proteolytic enzymes (tripsine and kallikrein) by using their inhibitors (contrycal, trasilol). Contrycal is obtained from cattle lung or pancreas tissues. Its activity is expressed in international unites (IU). Contrycal is injected intravenously droply. The most serious adverse effect of this agent is allergic reactions.