Drugs Affecting Gastroinestinal System and Nutrition
Drugs
for Gastric and Duodenal Ulcers
In
the area of a gastric or duodenal peptic ulcer, the mucosa has been attacked
by
digestive juices to such an extent as to expose the subjacent connective tissue
layer
(submucosa).
This
self-digestion occurs when the
equilibrium between the
corrosive hydrochloric acid and acid-neutralizing mucus, which forms a protective cover on the mucosal surface, is shifted in favor of
hydrochloric acid. Mucosal
damage can be promoted by Helicobacter
pylori bacteria that colonize the gastric mucus. Drugs are employed with the following therapeutic aims: (1) to relieve pain; (2) to accelerate healing; and
(3) to prevent ulcer
recurrence. Herapeutic approaches are threefold: (a) to
reduce aggressive
forces by lowering H+ output; (b) to increase protective forces by means of mucoprotectants; and (c)
to
eradicate Helicobacter
pylori.
I.
Drugs for Lowering Acid Concentration
Ia.
Acid neutralization. H+-binding groups such as CO3 2–, HCO3 – or OH–, together with their counter ions, are
contained in antacid
drugs. Neutralization
reactions
occurring after intake of CaCO3 and NaHCO3, respectively, are shown in (A) at left. With nonabsorbable antacids, the counter ion is
dissolved in the acidic
gastric juice in the process of neutralization. Upon mixture with the alkaline ncreatic secretion in the duodenum, it is largely precipitated again by basic groups, e.g., as CaCO3
or
AlPO4, and excreted in
feces. Therefore, systemic absorption of counter ions or basic residues is minor. In the presence of renal insufficiency, however,
absorption of even small
amounts may cause an increase in plasma levels of counter
ions
(e.g., magnesium intoxication with paralysis and cardiac disturbances). Recipitation in the gut lumen is responsible for other side effects, such as reduced absorption of other drugs due to their adsorption to the surface of
precipitated antacid or,
phosphate depletion of the body with excessive intake of Al(OH)3. Na+ ions remain in solution even in the presence of HCO3 –-rich pancreatic secretions and are subject to absorption, like HCO3 –. Because of the uptake of Na+, use of NaHCO3 must be avoided in
conditions requiring
restriction of NaCl intake, such as hypertension, cardiac failure, and edema. Since food has a buffering effect, antacids are taken between meals (e.g., 1 and 3 h after meals and at
bedtime). Nonabsorbable
antacids are preferred. Because Mg(OH)2 produces a laxative effect (cause: osmotic action, release of cholecystokinin by Mg2+, or both) and Al(OH)3 produces
constipation (cause:
astringent action of Al3+), these two antacids are frequently used in combination.
Antacids are cleared from the
empty stomach in about 30 minutes and vary in the extent to which they are
absorbed. Antacids that contain aluminum, calcium, or magnesium are less
completely absorbed than are those that contain NaHCO3. In persons
with normal renal function, the modest accumulations of Al3+ and Mg2+
do not pose a problem; with renal insufficiency, however, absorbed Al3+
can contribute to osteoporosis, encephalopathy, and proximal myopathy. About
15% of orally administered Ca2+ is absorbed, causing a transient
hypercalcemia. Although not a problem in normal patients, the hypercalcemia
from as little as 3 to 4 g per day can be problematic in patients with uremia.
Absorption of unneutralized NaHCO3 will cause alkalosis. Neutralized
antacids also may cause alkalosis by permitting the absorption of endogenous
NaHCO3 spared by the addition of exogenous neutralizing equivalents
into the gastrointestinal tract. These disturbances of acid-base balance by
antacids usually are transient and clinically insignificant in persons with
normal renal function. In the past, when large doses of NaHCO3
and/or CaCO3 were commonly administered with milk or cream for the
management of peptic ulcer, the milk-alkali
syndrome occurred frequently. This syndrome results from large
quantities of Ca2+ and absorbable alkali; effects consist of
hypercalcemia, reduced secretion of parathyroid hormone, retention of
phosphate, precipitation of Ca2+ salts in the kidney, and renal
insufficiency. Therapeutic regimens emphasizing the use of dairy products
seldom are employed in current practice. By altering gastric and urinary pH, antacids
may alter rates of dissolution and absorption, the bioavailability, and renal
elimination of a number of drugs. Al3+ and Mg2+ compounds
also are notable for their propensity to adsorb drugs and to form insoluble
complexes that are not absorbed. Unless bioavailability also is affected,
altered rates of absorption have little clinical significance when drugs are
given chronically in multiple doses. In general, it is prudent to avoid
concurrent administration of antacids and drugs intended for systemic
absorption. Most interactions can be avoided by taking antacids 2 hours before
or after ingestion of other drugs.
Ib.
Inhibitors of acid production. Acting on their respective receptors, the transmitter acetylcholine, the
hormone gastrin, and
histamine released intramucosally
stimulate
the parietal cells of the gastric mucosa to increase output of HCl. Histamine comes from
enterochromaffin- like (ECL) cells; its release is stimulated by the vagus nerve (via M1 receptors) and hormonally by gastrin. The effects of acetylcholine and
histamine can be abolished
by orally applied antagonists that reach parietal cells via
the
blood. The
cholinoceptor antagonist pirenzepine, unlike atropine, prefers holinoceptors of the M1 type, does not penetrate into the CNS, and thus
produces fewer
atropine-like side effects The cholinoceptors on parietal cells probably belong to the M3 subtype. Hence, pirenzepine may act by
blocking M1 receptors on
ECL cells or submucosal neurons. Histamine
receptors on parietal cells belong to the H2 type and are blocked by H2-antihistamines.
Four different H2-receptor antagonists
(H2RAs) are currently on the market in the United States: cimetidine (TAGAMET), ranitidine (ZANTAC), famotidine (PEPCID), and nizatidine (AXID). Their different
chemical structures do not alter the drugs' clinical efficacies as much as they
determine interactions with other drugs and change the side-effect profiles. H2RAs
inhibit acid production by reversibly competing with histamine for binding to H2
receptors on the basolateral membrane of parietal cells.
The most prominent effects of
H2RAs are on basal acid secretion; less profound but still
significant is suppression of stimulated (feeding, gastrin, hypoglycemia, or
vagal stimulation) acid production. These agents thus are particularly
effective in suppressing nocturnal acid secretion, which reflects mainly basal
parietal cell activity. This fact has clinical relevance in that the most important
determinant of duodenal ulcer healing is the level of nocturnal acidity. In
addition, some patients with reflux esophagitis who are being treated with PPIs
may continue to produce acid at night (so-called nocturnal acid breakthrough)
and could benefit from the addition of an H2RAs at night.
Figure 6
H2RAs are absorbed rapidly
after oral administration, with peak serum concentrations reached within 1-3
hours. Unlike PPIs, only a small percentage of H2RAs is
protein-bound. Small amounts of these drugs undergo metabolism in the liver.
Both metabolized and unmetabolized products are excreted by the kidney by both
filtration and renal tubular secretion. It is important to reduce doses of H2RAs
in patients with renal and in advanced liver disease. All
four H2RAs are available in dosage forms for oral administration;
intravenous and intramuscular preparations of cimetidine, ranitidine, and
famotidine also are available. Therapeutic levels are achieved quickly after
intravenous dosing and are maintained for several hours (4 to 5 hours for
cimetidine, 6 to 8 hours for ranitidine, and 10 to 12 hours for famotidine). In
clinical practice, these drugs can be given in intermittent boluses or by
continuous infusion. The overall incidence of adverse
effects of H2-receptor antagonists is low (<3%). Side effects
usually are minor and include diarrhea, headache, drowsiness, fatigue, muscular
pain, and constipation. Less-common side effects include those affecting the
CNS (confusion, delirium, hallucinations, slurred speech, and headaches), which
occur primarily with intravenous administration of the drugs. Gynecomastia in
men and galactorrhea in women may occur due to the binding of cimetidine to
androgen receptors and inhibition of the cytochrome P450-catalyzed
hydroxylation of estradiol. H2RAs
have been associated with thrombocytopenia. H2-receptor antagonists
cross the placenta and are excreted in breast milk. Although no major
teratogenic risk has been associated with these agents, caution is nevertheless
warranted when they are used in pregnancy. All agents that inhibit gastric acid
secretion may alter the rate of absorption and subsequent bioavailability of
the H2RAs. Drug interactions with H2RAs
can be expected mainly with cimetidine, and these are an important factor in
the preferential use of other H2-receptor antagonists. Cimetidine
inhibits cytochrome P450 more so than do the other agents in this class and can
thereby alter the metabolism and increase the levels of drugs that are
substrates for the cytochrome P450 system.
Because histamine plays a pivotal role in the activation of parietal cells,
H2-antihistamines also diminish responsivity to other stimulants, e.g., gastrin (in gas- trin-producing pancreatic tumors,
Zollinger-Ellison syndrome). Cimetidine, the first H2-antihistamine used
therapeutically, only rarely produces side effects (CNS disturbances such as confusion; endocrine effects in the male, such as gynecomastia, decreased libido,
impotence). Unlike cimetidine,
its newer and more potent
congeners, ranitidine, nizatidine, and famotidine, do not
interfere with the hepatic
biotransformation of other drugs. Omeprazole can
cause maximal inhibition of
HCl secretion. Given orally in gastric juice-resistant capsules, it reaches parietal cells via the
blood. In the acidic
milieu of the mucosa, an active metabolite is formed and binds covalently to the ATP-driven proton pump (H+/K+ ATPase) that transports H+ in
exchange for K+ into the
gastric juice. Lansoprazole and pantoprazole produce
analogous
effects. The proton pump inhibitors are first-line drugs for the treatment
of
gastroesophageal reflux disease.
Proton Pump Inhibitors The most
effective suppressors of gastric acid secretion are the gastric H+,K+-ATPase
(proton pump) inhibitors. Current proton pump inhibitors (PPIs) on the market
include: omeprazole (PRILOSEC),
lansoprazole (PREVACID), rabeprazole (ACIPHEX), and pantoprazole (PROTONIX). They
arepyridylmethylsulfinyl benzimidazoles with different substitutions on the
pyridine or the benzimidazole groups. PPIs are "prodrugs," requiring
activation in an acid environment. These agents enter the parietal cells from
the blood stream and accumulate in the acidic secretory canaliculi of the parietal
cell, where they are activated by a proton-catalyzed process that results in
the formation of a thiophilic sulfenamide or sulfenic acid. This activated form
reacts by covalent binding with the sulfhydryl group of cysteines from the
extracellular domain of the H+,K+-ATPase. Binding to
cysteine 813, in particular, is essential for inhibition of acid production,
which is irreversible for that pump molecule. PPIs have profound effects
on acid production. When given in a sufficient dose, the daily production of
acid can be diminished by more than 95%.
Secretion of acid resumes only after new molecules of the pump are
inserted into the luminal membrane.PPIs are unstable at a low pH. The oral
dosage forms ("delayed release") are supplied as enteric-coated
granules encapsulated in a gelatin shell (omeprazole and lansoprazole) or as
enteric-coated tablets (pantoprazole and rabeprazole). The granules dissolve
only at an alkaline pH, thus preventing degradation of the drugs by acid in the
esophagus and stomach. PPIs are rapidly absorbed, highly protein bound, and
extensively metabolized in the liver by the cytochrome P450 system
(particularly CYP2C19 and CYP3A4). Their sulfated metabolites are excreted in
the urine or feces. Their plasma half-lives are about 1 to 2 hours, but their
durations of action are much longer. Chronic renal failure and liver cirrhosis
do not appear to lead to drug accumulation with once-a-day dosing of the drugs.
Hepatic disease reduces the clearance of lansoprazole substantially, and dose
reduction should be considered in patients with severe hepatic disease. The
requirement for acid to activate these drugs within the parietal cells has
several important consequences. The drugs should be taken with or before a
meal, since food will stimulate acid production by parietal cells; conversely,
coadministration of other acid-suppressing agents such as H2-receptor
antagonists may diminish the efficacy of proton pump inhibitors. Since not all
pumps or all parietal cells are functional at the same time, it takes several
doses of the drugs to result in maximal suppression of acid secretion. With
once-a-day dosing, steady-state inhibition, affecting about 70% of pumps, may
take 2 to 5 days. Since the binding of
the drugs' active metabolites to the pump is irreversible, inhibition of acid
production will last for 24 to 48 hours or more, until new enzyme is
synthesized. The duration of action of these drugs, therefore, is not directly
related to their plasma half-lives.
PPIs inhibit the activity of some hepatic cytochrome P450 enzymes and
therefore may decrease the clearance of benzodiazepines, warfarin, phenytoin,
and many other drugs. PPIs usually cause
few adverse effects (<3%); nausea, abdominal pain, constipation, flatulence,
and diarrhea are the most common side effects. Subacute myopathy, arthralgias,
headaches, and skin rashes also have been reported.
Chronic treatment with PPI’s decreases the absorption of vitamin B12,
but insufficient data exist to demonstrate whether or not this leads to a
clinically relevant deficiency. Hypergastrinemia (>500 ng/liter) occurs in
approximately 5% to 10% of long-term PPI users. Gastrin is a trophic factor for
epithelial cells, and there is a theoretical concern that elevations in gastrin
can promote the growth of different kinds of tumors in the gastrointestinal
tract. In rats undergoing long-term administration of proton pump inhibitors,
there has been development of enterochromaffin-like cell hyperplasia and
gastric carcinoid tumors secondary to sustained hypergastrinemia; this has
raised concerns about the possibility of similar complications in human beings.
There are conflicting data on the risk and clinical implications of
enterochromaffin-like cell hyperplasia in patients on long-term proton pump
inhibitor therapy. These drugs now have a track record of more than 15 years of
use worldwide, and no major new issues regarding safety have emerged. PPI’s have not been
associated with a major teratogenic risk when used during the first trimester
of pregnancy; caution, however, is still warranted.
II.
Protective Drugs Sucralfate (A) contains numerous aluminum hydroxide residues. However, it is not an antacid because it fails to
lower the overall
acidity of gastric juice. After oral intake, sucralfate molecules undergo cross-linking in gastric juice,
forming a paste that
adheres to mucosal defects and exposed deeper layers. Here sucralfate intercepts H+. Protected from acid, and also from pepsin, trypsin, and
bile acids, the
mucosal defect can heal more rapidly. Sucralfate is taken on an empty
stomach
(1 h before meals and at bedtime). It is well tolerated; however, released Al3+ ions can cause constipation.
In the presence of acid-induced damage,
pepsin-mediated hydrolysis of mucosal proteins contributes to mucosal erosion
and ulcerations. This process can be inhibited by sulfated polysaccharides. Sucralfate (CARAFATE) consists of the
octasulfate of sucrose to which aluminum hydroxide has been added. In an acid
environment (pH < 4), it undergoes extensive cross-linking and
polymerization to produce a viscous, sticky gel that adheres strongly to
epithelial cells and even more strongly to ulcer craters for as long as 6 hours
after a single dose. In addition to inhibition
of hydrolysis of mucosal proteins by pepsin, sucralfate may have additional
cytoprotective effects, including stimulation of local production of
prostaglandin and epidermal growth factor. Sucralfate also binds bile salts,
accounting for its use in some patients with esophagitis or gastritis in whom
reflux of bile is thought by some to play a role in pathogenesis. The role of
sucralfate in the treatment of acid-peptic disease clearly has diminished in
recent years. It still may be useful in the prophylaxis of stress ulcers, where
its use may be associated with a lower incidence of nosocomial pneumonia
compared to acid-suppressing therapy with its tendency to promote gastric
bacterial colonization. Since it is activated by acid, it is
recommended that sucralfate be taken on an empty stomach one hour before meals
rather than after; the use of antacids within 30 minutes of a dose of
sucralfate should be avoided.
Figure 8
The most commonly reported
side effect is constipation (2%). Small amounts of aluminum can be absorbed
with the use of sucralfate, and special attention needs to be given to patients
with renal failure, who are at risk for aluminum overload. Aluminum-containing
antacids should not be used with sucralfate in patients with renal failure.
Since sucralfate forms a viscous layer in the stomach, it may inhibit
absorption of other drugs and change their bioavailability. These include
phenytoin, digoxin, cimetidine, ketoconazole, and fluoroquinolone antibiotics.
It is therefore recommended that sucralfate be taken at least 2 hours after the
intake of other drugs.
Misoprostol
(B) is a
semisynthetic prostaglandin
derivative with greater stability than natural prostaglandin, permitting absorption after oral administration. Like locally released prostaglandins, it promotes mucus production and inhibits acid secretion.
Additional systemic effects
(frequent diarrhea; risk of precipitating contractions of the gravid uterus) significantly restrict its therapeutic utility.
Prostaglandins PGE2 and PGI2, the
major prostaglandins synthesized by gastric mucosa, inhibit acid production by
binding to the EP3 receptor on parietal cells. Prostaglandin binding to the receptor results
in inhibition of adenylyl cyclase and decreased levels of intracellular cyclic
AMP. PGE also can prevent gastric injury
by its so-called cytoprotective effects, which include stimulation of secretion
of mucin and bicarbonate and improvement in mucosal blood flow; however, acid
suppression appears to be its more critical effect. Since NSAIDs inhibit prostaglandin formation,
the synthetic prostaglandins provide a rational approach to reducing
NSAID-related mucosal damage. Misoprostol
(15-deoxy-16-hydroxy-16-methyl-PGE1; CYTOTEC) is a synthetic analog
of prostaglandin E1 with an additional methyl ester group at C1
(resulting in an increase in potency and in the duration of the antisecretory
effect) and a switch of the hydroxy group from C15 to C16 along with an
additional methyl group (resulting in improved activity and duration of action).
The degree of inhibition of gastric acid secretion by misoprostol is directly
related to dose; oral doses of 100 to 200 ug produce significant inhibition of
basal acid secretion (decreased by 85% to 95%) or food-stimulated acid
secretion (decreased by 75% to 85%). Misoprostol is rapidly
absorbed and undergoes extensive and rapid first-pass metabolism
(deesterification) to form misoprostol acid (the free acid), the principal and
active metabolite of the drug. Some of this conversion may in fact occur in the
parietal cells. After a single dose, inhibition of acid production can be seen
within 30 minutes, peaks at 60 to 90 minutes, and lasts for up to 3 hours. Food
and antacids decrease the rate of absorption of misoprostol, resulting in
delayed and decreased peak plasma concentrations of misoprostol acid. The
elimination half-life of the free acid, which is excreted mainly in the urine,
is about 20 to 40 minutes.
Carbenoxolone
(B) is a derivative of glycyrrhetinic acid, which occurs
in
the sap of licorice root
(succus liquiritiae). Carbenoxolone stimulates mucus production. At the same time, it has a mineralocorticoid-like action (due to
inhibition of
11-β-hydroxysteroid dehydrogenase) that promotes renal reabsorption of NaCl and water. It may, therefore, exacerbate hypertension, congestive heart failure, or edemas.
It is
obsolete.
u Helicobacter
pylori
III.
Eradication of Helicobacter pylori C. This microorganism plays an important
role
in the pathogenesis of chronic gastritis and peptic ulcer disease. The combination of antibacterial drugs and omeprazole has proven
effective. In case of
intolerance to amoxicillin or clarithromycin, metronidazole can be used as a substitute. Colloidal bismuth compounds are also effective; however, the
problem of heavy-metal
exposure compromises their long-term use.
NSAID-Related Ulcers
Chronic
NSAID users have a 2% to 4% risk of developing a symptomatic ulcer,
gastrointestinal bleeding, or even perforation.
Ulcer healing despite continued NSAID use is possible with the use of
acid-suppressant agents, usually at higher doses and for a considerably longer
duration than with standard regimens (e.g.,
8 weeks or longer). Again, PPIs are superior to H2RAs and
misoprostol in promoting healing of active ulcers (80% to 90% healing rates
compared to 60% to 75%) as well as in preventing recurrence (while on NSAIDs)
of both gastric ulcers (5% to 13% versus
10% to 16% recurrence rates) and duodenal ulcers (0.5% to 3% versus 4% to 10% recurrence rate).
Zollinger-Ellison Syndrome
Patients
with this syndrome develop gastrinomas that drive the secretion of large
amounts of acid. This can lead to severe gastroduodenal ulceration and other
consequences of the uncontrolled hyperchlorhydria. Proton pump inhibitors are
clearly the drugs of choice and are usually given at twice the dosage for
routine ulcers, with the goal of therapy being to reduce acid secretion in the
range of 1 to 10 mmol/hour.
Laxatives
Laxatives
promote and facilitate bowel evacuation by acting locally to stimulate intestinal peristalsis, to soften
bowel contents, or
both.
1.
Bulk laxatives. Distention
of the intestinal wall
by bowel contents stimulates propulsive movements of the gut musculature (peristalsis). Activation of intramural mechanoreceptors induces a neurally mediated ascending reflex
contraction (red in A)
and descending relaxation (blue) whereby the intraluminal bolus is moved in the anal direction.
Hydrophilic
colloids or bulk gels (B) comprise insoluble and nonabsorbable carbohydrate substances that expand on taking up water in the bowel. Vegetable fibers in the diet act in this manner. They consist of the
indigestible plant cell walls
containing homoglycans that are resistant to digestive enzymes, e.g., cellulose (1_4β-linked
glucose molecules vs. 1_4α glucoside bond in starch). Bran, a grain milling waste product, and linseed (flaxseed) are both rich in cellulose. Other hydrophilic colloids
derive from the seeds
of Plantago species or karaya gum. Ingestion of hydrophilic gels for the prophylaxis of constipation usually entails a low risk of side
effects. However, with
low fluid intake in combination with a pathological bowel
stenosis,
mucilaginous viscous material could cause bowel occlusion (ileus).
Osmotically
active laxatives (C) are soluble but nonabsorbable particles that retain water in the bowel by
virtue of their osmotic
action. The osmotic pressure (particle concentration) of bowel contents always corresponds to that of the extracellular space. The
intestinal mucosa is unable
to maintain a higher or lower
osmotic pressure of the luminal contents. Therefore, absorption of molecules (e.g., glucose, NaCl)
occurs isoosmotically,
i.e., solute molecules are followed by a corresponding amount of water.
Conversely,
water remains in the bowel when molecules cannot be absorbed. With Epsom and Glauber’s salts (MgSO4 and Na2SO4, respectively), the SO4 2– anion is nonabsorbable and retains cations to maintain
electroneutrality. Mg2+ ions are also believed to promote release from the duodenal mucosa of cholecystokinin/pancreozymin, a polypeptide that also stimulates
peristalsis. These so-called
saline cathartics elicit a watery bowel discharge 1–3 h after administration (preferably in
isotonic solution). They
are used to purge the bowel (e.g., before bowel surgery) or to hasten the elimination of ingested
poisons. Glauber’s salt
(high Na+ content) is contraindicated in hypertension, congestive eart failure, and edema. Epsom salt is contraindicated in renal
failure (risk of Mg2+
intoxication). Osmotic laxative
effects are also produced by the polyhydric alcohols,mannitol and sorbitol, which
unlike glucose cannot be
transported through the intestinal mucosa, as well as by the nonhydrolyzable disaccharide, lactulose. Fermentation of lactulose by colon
bacteria results in
acidification of bowel contents and microfloral damage. Lactulose
is
used in hepatic failure in order to prevent bacterial production of ammonia and its subsequent absorption (absorbable NH3 _ nonabsorbable NH4 +), so as to forestall hepatic coma.
2.
Irritant laxatives—purgatives cathartics. Laxatives in this group exert an irritant action on the enteric
mucosa (A). Consequently, less fluid is absorbed han is secreted. The increased
filling of the bowel
promotes peristalsis; excitation of sensory nerve endings elicits enteral hypermotility. According to the site of irritation, one distinguishes
the small bowel
irritant castor oil from the large bowel irritants anthraquinone and diphenolmethane derivatives.
Misuse
of laxatives. It is
a widely held belief that
at least one bowel movement per day is essential for health; yet three bowel evacuations per week are quite normal. The desire for frequent bowel emptying probably stems from the time-honored, albeit
mistaken, notion that absorption of
colon contents is
harmful. Thus, purging has long been part of standard therapeutic practice. Nowadays, it is known that intoxication from intestinal
substances is impossible as
long as the liver functions normally. Nonetheless, purgatives continue to be sold as remedies to “cleanse the blood” or to rid the
body of “corrupt
humors.” There can be no
objection to the ingestion of bulk substances for the purpose of supplementing low-residue “modern diets.” However, use of irritant purgatives or cathartics is not
without hazards.
Specifically, there is a risk of laxative dependence, i.e., the inability to do without them. Chronic intake of
irritant purgatives
disrupts the water and electrolyte balance of the body and can
thus cause
symptoms of illness (e.g., cardiac arrhythmias secondary to hypokalemia). Causes of purgative dependence (B). The defecation reflex is triggered when the sigmoid colon and rectum are filled. A natural defecation empties
the large bowel up
to and including the descending colon. The interval between natural stool evacuations depends on the speed with which these colon
segments are refilled. A
large bowel irritant purgative clears out the entire colon. Accordingly, a longer period is needed
until
the next natural defecation can occur. Fearing constipation, the user becomes impatient and again resorts to the laxative, which then produces the desired effect as a result of
emptying out the upper
colonic segments. Therefore, a “compensatory pause” following cessation of laxative use must not give cause for concern (1).In the colon,
semifluid material entering from the small bowel is thickened by absorption of water and salts (from about 1000 to 150 mL/d). If,
due to the action of
an irritant purgative, the colon empties prematurely, an enteral loss of NaCl, KCl and water will be incurred. To forestall depletion of NaCl and water, the body responds with an increased release of aldosterone,
which stimulates their reabsorption in the kidney.
The
action of aldosterone is, however, associated with increased renal excretion of KCl. The enteral and renal K+ loss add up to a K+
depletion of the body,
evidenced by a fall in serum K+ concentration (hypokalemia). This condition is accompanied by
a
reduction in intestinal peristalsis (bowel atonia). The affected individual infers “constipation,” again partakes
of the purgative, and the vicious circle is closed (2).
Chologenic
diarrhea results
when bile acids fail
to be absorbed in the ileum (e.g., after ileal resection) and enter the colon, where they cause enhanced secretion of electrolytes and water, leading to the discharge of fluid
stools.
2.a
Small Bowel Irritant Purgative, Ricinoleic Acid
Castor
oil comes from Ricinus
communis (castor plants; Fig: sprig, panicle, seed); it is obtained from the first coldpressing of the seed (shown in natural size). Oral administration of 10–30
mL
of castor oil is
followed within 0.5 to 3 h by discharge of a watery stool. Ricinoleic acid, but not the oil itself, is
active. It arises as a
result of the regular processes involved in fat digestion: the duodenal mucosa releases the enterohormone cholecystokinin/pancreozymin into the blood. The hormone elicits
contraction of the
gallbladder and discharge of bile acids via the bile duct, as well as release of lipase from the pancreas
(intestinal peristalsis is
also stimulated). Because
of
its massive effect, castor oil is hardly suitable for the treatment of ordinary constipation. It can be employed
after oral ingestion
of a toxin in order to hasten
elimination
and to reduce absorption of toxin from the gut. Castor oil is not indicated after the ingestion of lipophilic toxins likely to depend on bile acids for their absorption.
2.b
Large Bowel Irritant Purgatives
Anthraquinone
derivatives are of plant origin. They occur in the
leaves (folia
sennae) or fruits (fructus
sennae) of the senna
plant, the bark of Rhamnus frangulae and Rh. purshiana, (cortex frangulae, cascara sagrada), the roots of rhubarb (rhizoma rhei), or the
leaf extract from Aloe species.
The structural
features of anthraquinone derivatives are illustrated by the prototype structure. Among other substituents, the
anthraquinone nucleus contains
hydroxyl groups, one of which
is bound to a sugar (glucose, rhamnose). Following ingestion of galenical preparations or of the anthraquinone glycosides, discharge
of
soft stool occurs after
a latency of 6 to 8 h. The anthraquinone glycosides themselves are inactive but are converted by
colon
bacteria to the active free aglycones.
Diphenolmethane
derivatives were
developed from phenolphthalein, an accidentally discovered laxative, use of which had been noted to result in rare but severe allergic reactions. Bisacodyl and sodium picosulfate are
converted by gut bacteria
into the active colonirritant principle. Given by the enteral route, bisacodyl is subject to hydrolysis of acetyl residues, absorption,
conjugation in liver to
glucuronic acid (or also to sulfate), and biliary secretion into the duodenum. Oral administration is followed after approx. 6 to 8 h by discharge of soft formed stool. When given
by
suppository, bisacodyl produces its effect within 1 h.
Indications
for colon-irritant purgatives are the prevention of straining at stool following surgery, myocardial
infarction, or stroke; and
provision of relief in painful diseases of the anus, e.g., fissure, hemorrhoids. Purgatives must not be given in abdominal complaints of unclear origin.
3.
Lubricant laxatives. Liquid
paraffin (paraffinum
subliquidum) is
almost nonabsorbable and makes feces softer and more easily passed. It interferes with
the
absorption of fat-soluble vitamins by trapping them. The few absorbedparaffin particles may
induce formation of foreign-body granulomas in enteric lymph nodes (paraffinomas). Aspiration into the bronchial tract can result
in lipoid pneumonia.
Because of these adverse effects, its use is not advisable.
Antidiarrheal
Agents
Causes
of diarrhea (in
red): Many bacteria (e.g., Vibrio cholerae) secrete toxins
that
inhibit the ability of mucosal enterocytes to absorb NaCl and water and, at the same time, stimulate mucosal
secretory activity.
Bacteria
or viruses that
invade the gut wall
cause inflammation characterized by increased fluid secretion into the lumen. The enteric
musculature reacts with
increased peristalsis. The aims of antidiarrheal therapy are to prevent: (1) dehydration and electrolyte depletion; and (2)
excessively high stool
frequency. Different therapeutic approaches (in green) listed are variously suited for these
purposes. Adsorbent powders are nonabsorbable materials with a large surface area. These bind diverse substances,
including toxins,
permitting them to be inactivated and eliminated. Medicinal charcoal possesses a particularly large surface because of the preserved cell structures. The recommended effective antidiarrheal dose is in the range of 4–8 g. Other adsorbents are kaolin
(hydrated aluminum
silicate) and chalk.
Oral
rehydration solution (g/L
of
boiled water: NaCl 3.5,
glucose 20, NaHCO3 2.5, KCl
1.5). Oral administration of glucose-containing salt solutions enables fluids to be absorbed because toxins do not impair the cotransport
of
Na+ and glucose (as well
as of H2O) through the
mucosal epithelium. In this manner, although frequent discharge of stool is not prevented, dehydration is successfully corrected.
Opioids.
Activation of opioid
receptors in the enteric nerve plexus resultsin
inhibition of propulsive motor activity and enhancement of segmentation activity. This antidiarrheal effect
was formerly induced
by application of opium tincture (paregoric) containing morphine. Because of the CNS effects (sedation, respiratory depression, physical dependence), derivatives with
peripheral actions have been
developed. Whereas diphenoxylate
can still produce clear CNS effects, loperamide does not affect brain functions at normal
dosage. Loperamide is,
therefore, the opioid
antidiarrheal
of first choice. The prolonged contact time of intestinal contents and mucosa may also improve absorption of fluid. With overdosage, there is a hazard of ileus. It is
contraindicated in infants below age 2 y.
Antibacterial
drugs. Use of these agents (e.g., cotrimoxazole) is only rational when bacteria are the cause of diarrhea. This is rarely the
case. It should be
kept in mind that antibiotics also damage the intestinal flora which, in turn, can give rise to diarrhea. Astringents such as tannic acid (home remedy: black tea) or metal
salts
precipitate
surface proteins and are thought to help seal the mucosal epithelium. Protein denaturation must not include cellular proteins, for this would mean cell death. Although astringents induce constipation, a therapeutic
effect in diarrhea is doubtful. Demulcents, e.g.,
pectin (home remedy: grated
apples) are carbohydrates
that
expand on absorbing water. They improve the consistency of bowel contents; beyond that they are devoid of any favorable effect.
Drugs
for Dissolving Gallstones (A)