Dr. Mahmoud H. Taleb 1 بسم الله الرحمن الرحيم Lecture 12 Pharmacotherapy of...

Dr. Mahmoud H. TalebDr. Mahmoud H. Taleb 11

الرحيم الرحمن الله الرحيم بسم الرحمن الله بسم

Lecture 12Lecture 12Pharmacotherapy of Acid-Peptic DisordersPharmacotherapy of Acid-Peptic Disorders


DEVELOPMENT OF ACID-PEPTIC DISEASEDEVELOPMENT OF ACID-PEPTIC DISEASE

Acid-peptic disease can affect various organs in Acid-peptic disease can affect various organs in the GI tract including the esophagus, stomach, the GI tract including the esophagus, stomach, and duo denum. Although a bacterium, and duo denum. Although a bacterium, H. pylori, H. pylori, has recently been shown to cause duodenal has recently been shown to cause duodenal ulcers and other types of acid-peptic disease, ulcers and other types of acid-peptic disease, gastric acid plays a major role in development gastric acid plays a major role in development of these problems, and suppression of acid of these problems, and suppression of acid production is an important element in their production is an important element in their therapy. Gastric acid production reflects three therapy. Gastric acid production reflects three stages of stimulation to the gastric parietal cell.stages of stimulation to the gastric parietal cell.


The general pharmacological approaches to The general pharmacological approaches to treating acid-peptic disorders are directed at the treating acid-peptic disorders are directed at the various steps in the physiology of acid various steps in the physiology of acid production. The main strat egies include:production. The main strat egies include:

(1) use of antacids to neutralize acid already (1) use of antacids to neutralize acid already secreted in the stomach;secreted in the stomach;

(2) interference with the production of acid by (2) interference with the production of acid by blocking the histamine H2-receptor (H2-receptor blocking the histamine H2-receptor (H2-receptor blockers), the muscarinic receptor (pirenzepine), blockers), the muscarinic receptor (pirenzepine), or the proton pump itself (omeprazole);or the proton pump itself (omeprazole);

(3) increase of mucosal defenses (prostaglandin (3) increase of mucosal defenses (prostaglandin analogs, sucralfate). analogs, sucralfate).

DRUGS FOR ACID PEPTIC DISEASE


Figure 28.3 Effects of acetylcholine, histamine, prostaglandin E2, and gastrin on gastric acid secretion by the parietal cells of stomach. Gs and Gi are membrane proteins that mediate the stimulatory or inhibitory effect of receptor coupling to adenylyl cyclase.


1- Antacids1- AntacidsAntacids, the original drug treatment for acid-peptic Antacids, the original drug treatment for acid-peptic

disease, are still widely used. Bicarbonate of soda disease, are still widely used. Bicarbonate of soda (sodium bicarbonate) is rarely used medically as an (sodium bicarbonate) is rarely used medically as an antacid, and sodium citrate has limited application, antacid, and sodium citrate has limited application, because they both can cause systemic alkalosis. The because they both can cause systemic alkalosis. The three categories of antacids in general use are those three categories of antacids in general use are those containing primarily calcium, magnesium, or aluminum containing primarily calcium, magnesium, or aluminum salts. Calcium-containing antacids usually contain salts. Calcium-containing antacids usually contain calcium carbonate. Magnesium hydroxide and calcium carbonate. Magnesium hydroxide and magnesium trisilicate are the major magnesium salts magnesium trisilicate are the major magnesium salts used, and aluminum hydroxide and aluminum phos phate used, and aluminum hydroxide and aluminum phos phate are the usual aluminum salts. The neutralizing chemical are the usual aluminum salts. The neutralizing chemical reaction with hydrochloric acid results in formation of reaction with hydrochloric acid results in formation of calcium, magnesium, or aluminum chloride and water. calcium, magnesium, or aluminum chloride and water. Antacids vary in their buffering capacity and side effects.Antacids vary in their buffering capacity and side effects.


Side effectsSide effectsAntacids containing mainly calcium salts may cause Antacids containing mainly calcium salts may cause

rebound acidity rebound acidity mediated by the increased intragastric mediated by the increased intragastric calcium concentration released from the antacid. The calcium concentration released from the antacid. The clinical importance of this phenomenon (socalled "acid clinical importance of this phenomenon (socalled "acid rebound. Chronic use of carbonate antacids together rebound. Chronic use of carbonate antacids together with large amounts of milk may also be associated with with large amounts of milk may also be associated with the the milk-alkali syndromemilk-alkali syndrome). The major problem with ant ). The major problem with ant acids containing mostly magnesium salts is acids containing mostly magnesium salts is diarrhea. diarrhea. Antacids containing exclusively aluminum hydroxide bind Antacids containing exclusively aluminum hydroxide bind phosphates in the intestinal tract. In some patients this is phosphates in the intestinal tract. In some patients this is useful for removing phosphate, but in other patients useful for removing phosphate, but in other patients hypophosphatemia may develop. Absorption of hypophosphatemia may develop. Absorption of aluminum may also be toxic.aluminum may also be toxic.


H2-BlockersH2-BlockersH2-blockers were developed specifically to be

competitive inhibitors of the histamine H2-receptor. They are examples of "designer drugs" and chemically they resemble histamine. The major drugs of this class currently in use are cimetidine, ranitidine, famotidine, and nizatidine . Typically all these drugs inhibit basal and nocturnal gastric acid secretion, as well as gastric acid secretion provoked by administration of histamine, acetylcholine, or (penta)gastrin. They also decrease pepsin production.


Ranitidine: Compared to cimetidine, ranitidine is longer acting and is five- to ten-

fold more potent. Ranitidine has minimal side effects and does not produce the

antiandrogenic or prolactin-stimulating effects of cimetidine. Unlike

cimetidine, it does not inhibit the mixed-function oxygenase system in the liver

and, thus, does not affect the concentrations of other drugs.

Famotidine: Famotidine is similar to ranitidine in its pharmacologic action, but it

is 20 to 50 times more potent than cimetidine, and 3 to 20 times more potent

than ranitidine.

Nizatidine: Nizatidine is similar to ranitidine in its pharmacologic action and

potency. In contrast to cimetidine, ranitidine, and famotidine, which are

metabolized by the liver, nizatidine is eliminated principally by the kidney.

Because little first-pass metabolism occurs with nizatidine, its bioavailability is

nearly 100 percent. No intravenous preparation is available.


Therapeutic uses1- H2-receptor blockers are very effective

treatment for reflux esophagitis and for duodenal and gastric ul cers

2- They can be used for prophylaxis against stress ulceration in acutely ill patients with head trauma or compromised respiration.

3- In high doses they are suitable for treat ment of Zollinger-Ellison syndrome (gastrinoma).

4- H2-receptor blockers are also prescribed to prevent gastrointestinal complications induced by long-term use of anti-inflammatory analgesics.


Side effectsSide effects

A problem with long-term cimetidine treatment is the high incidence of side effects.

1- Common side effects include elevated serum creatinine or aminotransferases during

treatment.

2- Central nervous system syn dromes occur: Confusion is the principal

problem, especially in the elderly, but it may also occur in children.

3- Cimetidine has an antiandrogen effect due to displacement of

dihydrotestosterone from androgen binding sites. This competitive inhibition

is re flected by increased basal level of serum testosterone. Impotence and

gynecomastia have developed in some adult male patients. Cimetidine may

cause increased serum prolactin, although only after a large bolus dose.

4- Drug interactionsBy contrast, ranitidine and famotidine have fewer side effects. Common side effects of ranitidine are relatively

trivial, including skin rash, headache, and dizziness. Ranitidine hardly penetrates into the cen tral nervous

system, and therefore side effects such as confusion are infrequent. Ranitidine does not appear to exert

antiandrogenic effects; reported fre quencies of gynecomastia or impotence are low. Fa motidine is relatively

free of side effects despite its high potency.


3- Antimuscarinic drug (Pirenzepine)3- Antimuscarinic drug (Pirenzepine)Classic anticholinergics such as atropine and propantheline are not used for Classic anticholinergics such as atropine and propantheline are not used for

gastric acid suppression because of their adverse side effects. Pirenzepine gastric acid suppression because of their adverse side effects. Pirenzepine is a complex tricyclic compound, chemi cally related to tricyclic is a complex tricyclic compound, chemi cally related to tricyclic antidepressants, which selec tively inhibits postganglionic M1 muscarinic antidepressants, which selec tively inhibits postganglionic M1 muscarinic receptors. It thus reduces both acid and pepsin secretion and can act receptors. It thus reduces both acid and pepsin secretion and can act synergistically with H2-blockers. Addi tionally, it may have mucosal synergistically with H2-blockers. Addi tionally, it may have mucosal protective properties.protective properties.

After oral administration, bioavailability is com paratively poor—only 25% of After oral administration, bioavailability is com paratively poor—only 25% of the drug is absorbed. Peak plasma concentrations are found approximately the drug is absorbed. Peak plasma concentrations are found approximately 4 hours after administration; little (12%) is protein-bound. The elimination 4 hours after administration; little (12%) is protein-bound. The elimination half-life is 11 hours. Most of the drug is excreted unchanged in the urine, half-life is 11 hours. Most of the drug is excreted unchanged in the urine, as there is little hepatic metabolism.as there is little hepatic metabolism.

Pirenzepine appears free of major side effects. Many patients develop some Pirenzepine appears free of major side effects. Many patients develop some degree of dry mouth. Intestinal motility, apart from gastric emptying, is not degree of dry mouth. Intestinal motility, apart from gastric emptying, is not affected. Pirenzepine is quite hydrophilic and does not cross the blood-affected. Pirenzepine is quite hydrophilic and does not cross the blood-brain barrier.brain barrier.

Pirenzepine can be used as effective treatment for peptic ulcer disease and Pirenzepine can be used as effective treatment for peptic ulcer disease and may have a role in prophylaxis against stress ulceration; however, actual may have a role in prophylaxis against stress ulceration; however, actual clinical use of this drug has been limited.clinical use of this drug has been limited.


4- Proton pump inhibitors4- Proton pump inhibitorsMechanism of actionMechanism of actionTheses substituted benzimidazole are important Theses substituted benzimidazole are important

because of their novel mode of action: they because of their novel mode of action: they block the proton pump, the (H+ + K+)-ATPase, block the proton pump, the (H+ + K+)-ATPase, on the parietal cell membrane. They are on the parietal cell membrane. They are extremely potent, because in the highly acidic extremely potent, because in the highly acidic milieu around the proton pump these drugs milieu around the proton pump these drugs become protonated and undergoe molecular become protonated and undergoe molecular rearrangement to highly reactive derivatives that rearrangement to highly reactive derivatives that bind irreversibly to the ATPase. Thus These bind irreversibly to the ATPase. Thus These drugs effectively block both basal and stimulated drugs effectively block both basal and stimulated gastric acid secretion. gastric acid secretion.

PPIs are now available:Omeperazole, lansoprazole rabeprazole

pantoprazole and esomeprazole


Therapeutic usesTherapeutic usesPPIs are even more effective than the H2-PPIs are even more effective than the H2-

blockers for treating acid-peptic disease. blockers for treating acid-peptic disease. They are may be curative in cases of They are may be curative in cases of peptic ulcer disease that do not respond to peptic ulcer disease that do not respond to H2-blockers. In severe reflux esophagitis H2-blockers. In severe reflux esophagitis they has a success rate for healing they has a success rate for healing and for long-term treatment of pathologic hypersecretory conditions (for example, Zollinger-Ellison syndrome, in which a gastrin-producing tumor causes hypersecretion of HCl).


Adverse effectsAdverse effects

Omeprazole has potentially serious adverse side Omeprazole has potentially serious adverse side ef fects. It abolishes acid production so ef fects. It abolishes acid production so completely that serum gastrin levels rise. In completely that serum gastrin levels rise. In rodents enterochromaffin-like cell tumors and rodents enterochromaffin-like cell tumors and carcinoid tumors have devel oped. It is not known carcinoid tumors have devel oped. It is not known whether this drug is carcino genic in humans by a whether this drug is carcino genic in humans by a similar mechanism. Moreover, bacterial similar mechanism. Moreover, bacterial overgrowth may develop in the stomach in the overgrowth may develop in the stomach in the absence of acid. Bacterial metabolism of dietary absence of acid. Bacterial metabolism of dietary nitrites may then lead to production of nitrites may then lead to production of NN-nitroso -nitroso compounds that are carcinogenic. This risk is compounds that are carcinogenic. This risk is not limited to chronic omeprazole treatment; it not limited to chronic omeprazole treatment; it can theoretically occur with any effective long-can theoretically occur with any effective long-term antacid regimen. term antacid regimen.


5- Mucosal Protectors5- Mucosal ProtectorsDrugs that increase mucosal defenses, independently of Drugs that increase mucosal defenses, independently of

any effect on acid secretion, represent an im portant any effect on acid secretion, represent an im portant complement to treating acid-peptic disease by removing complement to treating acid-peptic disease by removing or neutralizing gastric acid. The major drugs that act as or neutralizing gastric acid. The major drugs that act as mucosal protectors are prostaglandin E analogs and mucosal protectors are prostaglandin E analogs and sucralfate. Prostaglandin E analogs (misoprostol, sucralfate. Prostaglandin E analogs (misoprostol, enprostil, arbaprostil) are used as mucosal protectors enprostil, arbaprostil) are used as mucosal protectors although it is evident that they have multiple actions. although it is evident that they have multiple actions. Several modes of action that result in "mucosal Several modes of action that result in "mucosal protection" are increased bicarbonate secretion, protection" are increased bicarbonate secretion, increased mucus secretion, in creased mucosal blood increased mucus secretion, in creased mucosal blood flow, and enhanced epithelial regeneration. With respect flow, and enhanced epithelial regeneration. With respect to inhibition of gastric acid production, prostaglandin to inhibition of gastric acid production, prostaglandin analogs bind to a specific receptor on the parietal cell analogs bind to a specific receptor on the parietal cell (not the histamine H2-receptor) and prevent activation of (not the histamine H2-receptor) and prevent activation of adenylyl cyclase by histamine They also inhibit release adenylyl cyclase by histamine They also inhibit release of gastrin by gastrin-producing cells.of gastrin by gastrin-producing cells.


Of the various prostaglandin analogs available, misoprostol is the only one in common use. It is absorbed rapidly

after oral administration, is highly (85%) protein-bound, undergoes some hepatic biotransformation, and is

mostly excreted via the kid neys. Its elimination half-life is 1.5 hours. Major side effects are diarrhea and intestinal cramps. It increases uterine contractility and may cause uterine bleeding or loss of pregnancy; this limits its use

in women of child-bearing potential. Although as effective as cimetidine for ulcer healing, misoprostol is less

effective than ranitidine and may provide little immediate symptomatic relief. The main indication for misoprostol is as prophylaxis against gastritis due to nonsteroidal anti-

inflammatory drugs.


Sucralfate is a complex basic salt of sucrose sulfate and aluminum hydroxide (Fig. 44-5), It poly merizes to form a paste (a viscous polyanionic gel with a strong negative charge) that adheres selec tively to ulcerated areas in the mucosa. Its mucosal protective effect may be due in part to enhanced local prostaglandin action as a result of increased mucosal cyclooxygenase activity and increased re lease of prostaglandins directly from the mucosa by mechanisms involving aluminum and/or epidermal growth factor. However, its other possible modes of action include:

(1) inactivating pepsin,(2) providing a physical barrier over the ulcerated area,(3) chang ing the composition of gastric mucus, and(4) in creasing bicarbonate output from the gastric mucosa

(by both prostaglandin-dependent and prostaglandin-independent mechanisms).


6- Agents Targeting H. pylori1- Colloidal bismuth subcitrate

2- Colloidal bismuth subsalicylate

3- Current regimens include a bismuth compound and one or more antibiotics, of which the most frequently used are a tetracycline, metronidazole, amoxicillin, and clarithromycin.


Drugs Used in the Treatment of Intestinal Drugs Used in the Treatment of Intestinal Motility DisordersMotility Disorders

DRUGS AFFECTING GASTROINTESTINAL MOTILITYDRUGS AFFECTING GASTROINTESTINAL MOTILITYPROKINETIC AGENTSPROKINETIC AGENTSMetoclopramide, domperidone, and cisaprideMetoclopramide, domperidone, and cisapride

Enteric nerve plexuses operate by release of acetylcholine. Enteric nerve plexuses operate by release of acetylcholine. Dopamine antagonizes their action. Thus a prokinetic drug Dopamine antagonizes their action. Thus a prokinetic drug may work by enhancing the cholinergic effect directly (i.e., as may work by enhancing the cholinergic effect directly (i.e., as a cholinergic agonist) or indirectly (either by enhanc ing a cholinergic agonist) or indirectly (either by enhanc ing acetylcholine release or by sensitizing the muscarinic acetylcholine release or by sensitizing the muscarinic receptors of the enteric smooth muscle so that the threshold for receptors of the enteric smooth muscle so that the threshold for acetylcholine action is lower), or by interfering with the action acetylcholine action is lower), or by interfering with the action of dopamine (i.e., as a dopamine antagonist). The overall of dopamine (i.e., as a dopamine antagonist). The overall outcome on smooth-muscle activity varies from species to outcome on smooth-muscle activity varies from species to species and may vary somewhat from one part to another of species and may vary somewhat from one part to another of the human GI tract.the human GI tract.


LAXATIVESLAXATIVES1- Laxatives That Increase Secretion1- Laxatives That Increase SecretionDanthron is a synthetic derivative that may be absorbed by the small intestine

and/or alter the function of this portion of the bowel. Cascara sagrada, in usual doses, is the mildest of the anthra quinone laxatives. It is effective in

about 8 hours and seldom causes colic. Senna is more active, is effective in about 6 hours, and usually causes some colic. Aloe is the most irritant and can stimulate other visceral smooth muscles including the uterus. It acts in

about 8-12 hours and usually causes considerable colic. Rhubarb is a relatively mild laxative that causes littlediscomfort.

These agents appear to work by inhibiting colonic mucosal (Na+ + K+)-ATPase, leading to accumula tion of salt and water in the lumen. At higher

doses they may stimulate colonic mysenteric nerve fibers.


Castor oilCastor oilRicinoleic acid acts rapidly on the small intestine and colon Ricinoleic acid acts rapidly on the small intestine and colon to increase the intraluminal fluid content. It inhibits to increase the intraluminal fluid content. It inhibits mucosal (Na++K+)-ATPase, thus de creasing the mucosal (Na++K+)-ATPase, thus de creasing the absorption of Na+ and of the actively cotransported solutes absorption of Na+ and of the actively cotransported solutes (sugars, amino acids, etc.). It increases intracellular cyclic (sugars, amino acids, etc.). It increases intracellular cyclic AMP, either as a re sponse to an increased synthesis of AMP, either as a re sponse to an increased synthesis of prostaglandin E2 that stimulates adenylyl cyclase activity prostaglandin E2 that stimulates adenylyl cyclase activity or by a competitive inhibition of soluble cAMP-or by a competitive inhibition of soluble cAMP-phosphodiesterase activity, or both. It damages enterocytes phosphodiesterase activity, or both. It damages enterocytes directly. On electron microscopy, disintegration of mi cro directly. On electron microscopy, disintegration of mi cro villi and damaged villus tips have been observedvilli and damaged villus tips have been observed..


BisacodylBisacodylThis agent (Dulcolax) is chemically similar to phe nolphthalein. It is an effective This agent (Dulcolax) is chemically similar to phe nolphthalein. It is an effective

laxative, acting 6-8 hours after oral administration. It is active only after laxative, acting 6-8 hours after oral administration. It is active only after deacetylation, absorption from the small intestine, and excretion in the bile. deacetylation, absorption from the small intestine, and excretion in the bile. When given in a rectal suppository, it is effective in 20-60 minutes. Like When given in a rectal suppository, it is effective in 20-60 minutes. Like phenolphthalein, it has no laxative effect after bile duct ligation.phenolphthalein, it has no laxative effect after bile duct ligation.

The mechanism of action of these drugs is essentially similar to that of ricinoleic The mechanism of action of these drugs is essentially similar to that of ricinoleic acid.acid.

(1) Both drugs inhibit (Na++K+)-ATPase.(1) Both drugs inhibit (Na++K+)-ATPase.(2) Bisacodyl increases adenylyl cyclase activity and intracellular cyclic AMP. (2) Bisacodyl increases adenylyl cyclase activity and intracellular cyclic AMP.

This direct effect is controversial in the case of phe nolphthalein.This direct effect is controversial in the case of phe nolphthalein.(3) Both compounds increase the syn thesis and release of PGE2, resulting in (3) Both compounds increase the syn thesis and release of PGE2, resulting in

an indirect increase in cyclic AMP. The role of PGE2 in the laxative effects an indirect increase in cyclic AMP. The role of PGE2 in the laxative effects of phenolphthalein and bisacodyl ex plains the reduction of their laxative of phenolphthalein and bisacodyl ex plains the reduction of their laxative effect after pretreatment with indomethacin.effect after pretreatment with indomethacin.

(4) They may dam age intestinal mucosa and increase permeability.(4) They may dam age intestinal mucosa and increase permeability.(5) Bisacodyl has also been shown to cause a two- to threefold rise in K+ efflux (5) Bisacodyl has also been shown to cause a two- to threefold rise in K+ efflux

across the colonic mucosa. It has been proposed that this effect depends on across the colonic mucosa. It has been proposed that this effect depends on raised levels of intracellular Ca2+, and it probably reflects an increase in raised levels of intracellular Ca2+, and it probably reflects an increase in mucosal K+ permeability. There is evidence that both cyclic AMP and Ca2+ mucosal K+ permeability. There is evidence that both cyclic AMP and Ca2+ may have a role in modulation of mucosal border Kmay have a role in modulation of mucosal border K++ permeability. permeability.


Dioctyl Sodium Sulfosuccinate (DSS)Dioctyl Sodium Sulfosuccinate (DSS)

This compound (Colace) was developed for use as a synthetic wetting This compound (Colace) was developed for use as a synthetic wetting agent—as a stool softener; this action is attributed to its ability to agent—as a stool softener; this action is attributed to its ability to decrease surface tension and thus increase exposure of the stool decrease surface tension and thus increase exposure of the stool sur face to luminal water, resulting in fecal hydration. More recent sur face to luminal water, resulting in fecal hydration. More recent studies have shown that DSS also acts through an increase in studies have shown that DSS also acts through an increase in intraluminal water by mecha nisms similar to those described for intraluminal water by mecha nisms similar to those described for ricinoleic acid (inhibition of (Na++K+)-ATPase, increase in cyclic ricinoleic acid (inhibition of (Na++K+)-ATPase, increase in cyclic AMP, and cellular damage).AMP, and cellular damage).


Laxatives That Decrease Water Absorption Laxatives That Decrease Water Absorption (Emollient Cathartics): Liquid Petrolatum(Emollient Cathartics): Liquid Petrolatum

Hydrophilic Colloids, Bulk-Forming Hydrophilic Colloids, Bulk-Forming LaxativesLaxatives

This group includes both natural and semisynthetic This group includes both natural and semisynthetic polysaccharides and cellulose derivatives that dis solve polysaccharides and cellulose derivatives that dis solve or swell in water, forming a viscous solution or emollient or swell in water, forming a viscous solution or emollient gel. These gelatinous masses, of greatly increased bulk gel. These gelatinous masses, of greatly increased bulk when moistened with water, exert a mildly laxative when moistened with water, exert a mildly laxative action. action.

Agar, psyllium (plantago), methylcellulose, Agar, psyllium (plantago), methylcellulose, and and sodium sodium carboxymethylcellulose carboxymethylcellulose are examples of hydrophilic are examples of hydrophilic cellulose derivatives.cellulose derivatives.


Laxatives that Increase OsmolarityLaxatives that Increase OsmolarityMagnesium saltsMagnesium saltsfunction or prolonged retention of the saline solution in the intestine.function or prolonged retention of the saline solution in the intestine.LactuloseLactulose (4-β-galactoside-(1,4) -D-fructose) (4-β-galactoside-(1,4) -D-fructose)This disaccharide is resistant to hydrolysis by the small-intestinal This disaccharide is resistant to hydrolysis by the small-intestinal

disaccharidases. It has an osmotic effect in the small bowel, drawing water disaccharidases. It has an osmotic effect in the small bowel, drawing water into the intestinal lumen. Thus, a large volume of fluid enters the colon. into the intestinal lumen. Thus, a large volume of fluid enters the colon. Once in the large intestine, lactulose is acted upon by the endogenous flora Once in the large intestine, lactulose is acted upon by the endogenous flora of the colon with the production of lactic acid and of short-chain, volatile fatty of the colon with the production of lactic acid and of short-chain, volatile fatty acids. As these acids have a low lipid solubility, their colonic absorption is acids. As these acids have a low lipid solubility, their colonic absorption is very limited; therefore, they also have an osmotic effect. Like lactic acid, very limited; therefore, they also have an osmotic effect. Like lactic acid, they increase colonic mucosal secretion.they increase colonic mucosal secretion.


Side Effects of LaxativesSide Effects of LaxativesCathartic colon syndromeCathartic colon syndromeThis is a frequent cause of diarrhea, abdominal, pain, and cramps. In radiographs the This is a frequent cause of diarrhea, abdominal, pain, and cramps. In radiographs the

colon appears di lated, hypomotile, with few or absent haustral margins; sometimes colon appears di lated, hypomotile, with few or absent haustral margins; sometimes areas of pseudostricture are ob served. Morphologically, there is mucosal inflamma areas of pseudostricture are ob served. Morphologically, there is mucosal inflamma tion, hypertrophy of the muscularis mucosae, thin ning or atrophy of outer muscle tion, hypertrophy of the muscularis mucosae, thin ning or atrophy of outer muscle layers, and damage to submucosal and myenteric plexuses.layers, and damage to submucosal and myenteric plexuses.

HypokalemiaHypokalemiaThe loss of Na+ and water in stools results in a reduction of plasma volume, The loss of Na+ and water in stools results in a reduction of plasma volume,

stimulation of the renin-angiotensin system, and increased serum levels of stimulation of the renin-angiotensin system, and increased serum levels of aldosterone. In the colon and kidney, aldosterone increases the reabsorption of Na+ aldosterone. In the colon and kidney, aldosterone increases the reabsorption of Na+ in exchange for K+ that is then lost in stools and urine, respectively. Abnormal in exchange for K+ that is then lost in stools and urine, respectively. Abnormal release of insulin and carbohydrate intol erance may occur as a consequence of release of insulin and carbohydrate intol erance may occur as a consequence of hypokalemia.hypokalemia.

MalabsorptionMalabsorptionChronic and continuous use of laxatives can lead to malabsorption of xylose and other Chronic and continuous use of laxatives can lead to malabsorption of xylose and other

carbohydrates, fat, fat-soluble vitamins, and calcium and thus to the production of carbohydrates, fat, fat-soluble vitamins, and calcium and thus to the production of osteomalacia.osteomalacia.

Increased loss of proteins through the intestineIncreased loss of proteins through the intestine..


ANTIDIARRHEALSANTIDIARRHEALSDiphenoxylateDiphenoxylate acts as an agonist at opioid re ceptors at two locations in the GI acts as an agonist at opioid re ceptors at two locations in the GI

tract:tract:Diphenoxylate is well absorbed after oral admin istration but does not cross the Diphenoxylate is well absorbed after oral admin istration but does not cross the

blood-brain barrier as easily as most opioids do and therefore is relatively blood-brain barrier as easily as most opioids do and therefore is relatively selective for peripheral opioid receptors. selective for peripheral opioid receptors.

LoperamideLoperamide has largely replaced diphenoxylate as the drug of choice. It is has largely replaced diphenoxylate as the drug of choice. It is effective, nonhabituating, and safe. It is similar chemically to both effective, nonhabituating, and safe. It is similar chemically to both diphenoxylate and haloperidol Loperarnide has high affinity for both diphenoxylate and haloperidol Loperarnide has high affinity for both peripheral and central opioid receptors but enters the brain even less peripheral and central opioid receptors but enters the brain even less readily than diphenoxylate, Loperarnide is two to three times more potent readily than diphenoxylate, Loperarnide is two to three times more potent than diphenoxylate, and its action is more rapid in onset and more than diphenoxylate, and its action is more rapid in onset and more prolonged. It has no analgesic effects. It has not been reported to have prolonged. It has no analgesic effects. It has not been reported to have central nervous system or cardiovascular effects. Side effects are un central nervous system or cardiovascular effects. Side effects are un common but include dizziness, dry mouth, and fa tigue.common but include dizziness, dry mouth, and fa tigue.

Dr. Mahmoud H. Taleb 1 بسم الله الرحمن الرحيم Lecture 12 Pharmacotherapy of...

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