Cachexia

Cachexia is an involuntary state characterized by loss of more than 5% of body weight. In humans it occurs over a defined period, generally of 2 to 6 months. Ultimately, it is a condition of starvation characterized by depletion of body mass, particularly muscle, but to a lesser degree, adipose tissue.¹² Cachexia develops in 50% of human patients with cancer, contributing to substantially shortened survival times. Cachexia also is a manifestation of other chronic diseases, including (in humans), acquired immune-deficiency syndrome (AIDS), heart failure, rheumatoid arthritis, Crohn’s disease, chronic obstructive pulmonary disease, and chronic renal disease.¹² It appears to be a cytokine-driven process, with key components including anorexia and a state of hypercatabolism. The principle cytokines appear to include TNF-alpha, interleukins 1 and 6, and interferon-γ Of these, TNF-alpha is presumed to stimulate mechanisms that lead to severe cachexia.¹² Muscle wasting may reflect inhibition of myogenic differentiation; an energy sink may result from increased concentrations of mitochondrial uncoupling proteins. Lipoproteinase activity is inhibited by TNF-alpha. Interleukins contribute to CNS-mediated anorexia and decreased albumin synthesis in the liver. Megestrol acetate is the only treatment approved by the Food and Drug Administration for cancer or AIDS-related cachexia syndromes in humans.¹² Other less commonly used drugs are glucocorticoids, anabolic steroids, antiseratonergic drugs, dronabinol, and prokinetic drugs.

Megestrol is a synthetic derivative of progesterone.¹² As such, megestrol acetate targets cachexia by directly and indirectly stimulating appetite and antagonizing the catabolic metabolic effects of cytokines. As with other steroidal hormones, the effects of megestrol (and progesterone) involve passive diffusion into the cell and binding to specific intracellular progesterone receptors A or B (PR-A or -B) and heat shock proteins. The drugs move into the nucleus, bind to progesterone response elements on target genes, and influence transcription through inhibition (PR-A) or stimulation (PR-B) of other steroid response elements. Although the majority of progesterone effects are genomic, nongenomic actions also occur. Metabolic effects of progesterone include increased basal insulin concentration and increased response to carbohydrate load; increased lipoprotein lipase with altered fat deposition, plasma lipid, and lipoprotein concentrations; and modulation of body temperature.¹² In humans and animal models of cancer, megestrol stimulates appetite, increases caloric intake, induces a sense of well-being, and causes weight gain, particularly of fat. Fat is the preferred weight gain because it provides more kilocalories per gram than proteins or carbohydrate and helps stabilize body temperatures.¹² Megestrol decreases the effects, sometimes by inhibiting formation of TNF-alpha, interleukin-1 (IL-1), and interleukin-6 (IL-6). Centrally, megestrol appears to modulate neurotransmitters responsible for appetite regulation such as NPY, which in turn stimulates the release of other mediators. Megestrol may also stabilize declining concentrations of β-endorphins in the cerebrospinal fluid.

Effects of megestrol are dose and (particularly for fat gain) duration dependent. Initial weight gain requires high concentrations (>300 ng/mL) for more than 40% of a 24-hour dosing interval. In humans this requires administration of the tablet four times daily. Megestrol acetate is used rather than other progestationals, which must be given parenterally.¹² Bioavailabilty of megestrol acetate is variable, being greater with the oral solution compared to the tablet. With tablets, peak concentrations may vary 6 fold; variability is much less with the oral solution. Disposition is complex. Hepatic metabolism is necessary to free the steroid from acetate, with the steroids subsequently conjugated with glucuronic acid before elimination. Elimination also varies, with half-lives that range from 13 to 105 hours. In humans, a single daily dose of the suspension (800 mg) achieves peak concentrations between 1500 and 3000 ng/mL. Not surprisingly, the oral solution is associated with a much higher rate of response compared with the tablet. A micronized (nanocrystal) preparation is currently under investigation for human use.

Limited information is available regarding use of megestrol acetate in animals. The disposition of megestrol acetate has been described in Beagles as part of the preclinical assessment in humans. Four preparations were studied for 72 hours after administration of 10 mg/kg (by oral gavage) either in the fasted or the fed (high-fat meal) state. The preparations included two different nanocrystal oral solutions and two commercially available oral suspensions (Par Pharmaceutical and Bristol-Myers). After the high-fat meal, peak concentrations (1600 to 2200 ng/mL) and area under the curve (AUC) were higher with the nanocrystal oral suspensions compared with the commercially available oral suspensions (both approximating 300 ng/mL). Although the elimination half-life was not reported, the disappearance half-life of megestrol appeared to be between 10 and 20 hours.¹²

Megestrol acetate appears to be better tolerated in humans compared with animals. The primary adverse events in humans are thromobembolic, reflecting increased thrombin receptors in smooth muscles. Venous distention and capacitance increase, contributing to reduced blood flow and stasis. Addison’s disease and glucose intolerance are sporadically reported, reflecting its intrinsic corticosteroid activities.¹²

Anecdotally, megesterol acetate has been effective in dogs to treat chemotherapy-induced nausea and inappetence. However, in humans a prospective randomized controlled clinical trial in cachectic human cancer patients compared the efficacy of an anabolic steroid (fluoxymesterone [10 mg, 0.142 mg/k] twice daily), megestrol acetate tablets (800 mg [11.4 mg/kg] once daily), and a glucocorticoid (dexamethasone, 0.75 mg [0.01 mg/kg] four times daily) as appetite stimulants. Of the three, the anabolic steroid was least (significantly) and megestrol (nonsignificantly) most clinically effective. Glucocorticoids usually were discontinued because of side effects, although megestrol acetate was associated with the most thromboembolic events.¹³

The Vomiting Reflex

Emesis is a complex protective reflex that is not well developed in all species but does occur in both dogs and cats.^16-18 Although several afferent pathways may be responsible for initiating emesis, all signals are coordinated by the emetic center. Located in the lateral reticular formation in the mid brainstem, the emetic center is in close proximity to the nucleus tractus solitarius of the vagus nerve and the chemoreceptor trigger zone (CTZ), the latter of which is located adjacent to the area postrema in the bottom of the lateral ventricle. The latter coordinates vomiting associated with blood-borne chemicals (Figures 19-2 and 19-3). The emetic center coordinates vomiting associated with afferent peripheral and central (neural) signals. Among the signals coordinating vomiting is the tachykinin neuropeptid, ≥substance P. Drugs that cause or ameliorate vomiting generally do so by modifying afferent or efferent neurotransmitters responsible for transmission of the signal from various afferent sites. The emetic center is protected by the blood–brain barrier, whereas the CTZ is not; therefore, the CTZ is able to monitor the presence of emetics in the blood or cerebrospinal fluid. However, drug penetrability to each site varies, affecting both drug safety and efficacy.^16-20

Figure 19-2 Sites that mediate the emetic reflex. The secondary neurotransmitters at each site are in parentheses. Stimuli that mediate emesis at each site are listed below the neurotransmitter. CNS, Central nervous system; CTZ, chemoreceptor trigger zone; CSF, cerebrospinal fluid; LES, lower esophageal sphincter.

Figure 19-3 Antiemetic drugs effective at each site of the emetic reflex. CTZ, Chemoreceptor trigger zone.

Several sites in the vomiting reflex are targeted by drugs. Ideally, drugs that target the emetic center would be characterized by the broadest spectrum and potentially the best efficacy. Historically, because such drugs must be able to penetrate the blood–brain barrier, they tend to be characterized by increased risk of side effects. This risk is minimized if the drug targets a mediator whose effects are limited to the vomiting center only. In addition to integration of the emetic reflex, impulses integrated by the center include afferent signals from higher centers such as the cerebral cortex and limbic system. For example, psychogenic vomiting, or vomiting induced by visual and olfactory stimuli, originates in the cerebral cortex, whereas head injuries and increased intracranial pressure initiate emesis by way of the limbic pathways. The solitarius nucleus contains receptors for enkephalin, histamine, serotonin (5-HT3), and acetylcholine (ACh). ACh is a major afferent neurotransmitter in the higher centers, with histamine acting as a secondary transmitter by way of H₁ receptors.¹⁹ However, substance P, a member of the tachykinin family of neuropeptides, has recently been identified as a key neurotransmitter associated with emesis in higher centers, including the emetic center.²¹ Substance P targets neurokinin (NK₁) receptors located throughout the emetic center (as reviewed by Wu²⁰), including the nucleus tractus solitarius, the area postrema, and the dorsal motor nucleus of the vagus.²² The emetic center also involves cannabinoid receptors (also located in the CTZ), although their role is not clear.

Blood-borne chemical compounds stimulate the CTZ.^17,19 Examples include circulating toxins associated with disease (uremia, pyometra, liver disease, endotoxemia), radiation sickness, and drugs (e.g., opioids, cardiac glycosides, anticancer chemotherapeutic agents). Signals in the CTZ are mediated by dopaminergic (D₂)¹⁹ and serotonergic (5-hydroxytryptamine; 5-HT₃) receptors²³ and neurokinin receptors. Histamine by way of H₁ receptors acts as a secondary neurotransmitter at the CTZ. Neurokinin receptors in humans are responsible for the delayed phase of vomiting associated with cisplatin anticancer chemotherapy. Alpha-2 receptors associated with the area postrema also induce emesis in dogs, cats, and other species.^24-26 The CTZ also is rich in opioid receptors. The safety of CTZ-active drugs may be increased by selectively targeting the subreceptor types for each neurotransmitter.

Emetic impulses originating from the semicircular canals of the vestibular apparatus are transmitted by the eighth cranial nerve to the vestibular nuclei and then by way of the CTZ and the uvula and nodulus of the cerebellum to the emetic center. This pathway, mediated by histaminergic (subtype H₁) receptors, is responsible for eliciting the emesis that accompanies motion sickness and labyrinthitis.²⁷

Peripheral impulses cause emesis that arises from stimulation of the pharynx and fauces; the signals are transmitted by afferent nerves in the ninth cranial nerve to the emetic center. Other peripheral afferent pathways include those arising from stimulation (i.e., irritation or distention) of various visceral organs and tissues. Impulses may be carried by sympathetic or vagal afferents from the heart, stomach, duodenum, small intestine, liver, gallbladder, peritoneum, kidneys, ureter, urinary bladder, and uterus. ACh is the primary neurotransmitter mediating the afferent limb of the emesis reflex from peripheral causes. Muscarinic receptors initiate the impulse that travels to the emetic center by way of the vagus nerve.

Efferent signals that stimulate the emetic reflex travel back to the stomach by the tenth cranial (vagus) nerve. ACh also acts as the primary efferent neurotransmitter in the vagus and in the smooth muscle of the stomach. In the stomach, dopamine receptors (D2) appear to inhibit gastric motility, during nausea and vomiting. In addition, dopamine receptors contribute to reflexes that allow relaxation of the upper stomach and delayed gastric emptying associated with gastric distention caused by food.²⁴ Finally, serotonin (by way of 5-HT₃ receptors) contributes afferent pathways from the stomach and small intestine.²⁴

Emetics

Clinically, emesis is pharmacologically induced to empty the anterior portion of the digestive tract. Indications include preparation for induction of general anesthesia in animals that may have food in the stomach (e.g., use of hydromorphone) or treatment of ingested, noncorrosive poisons.

Antiemetics

Antiemetics control emesis by either a central or a peripheral action (see Figures 19-2 and 19-3). Both actions depend on and can be correlated with blockade of neurotransmission at receptor sites.^27,28 Centrally acting antiemetics block impulses at higher centers and at the emetic center and include muscarinic anticholinergics and drugs that target neurokinin receptors; antidopaminergics and antiserotonergics, which block dopaminergic receptors at the CTZ; and antihistaminergics, which primarily block H₁ receptors at the vestibular apparatus but secondarily at multiple central centers. Antiemetic agents possess either a limited or a broad effect, depending on which signals and centers are inhibited.

Centrally Acting Antiemetics

Vomiting center

Maropitant (Cerenia) is a neurokinin (NK₁) receptor antagonist that blocks the actions of substance P in the area postrema and nucleus solatarius; Aprepitant is a human drug in the same classused as rescue anti-emetic therapy in cancer patients nonresponsive to 5HT₃–dexamethasone combinations.²⁹ Approved as an oral or subcutaneous preparation for dogs for the prevention of acute vomiting and motion sickness, maropitant has proved efficacious in the control of vomiting associated with many central and peripheral causes (Table 19-2).

Table 19-2 Antiemetic Drug–Receptor Interactions

In dogs bioavailability is greater after subcutaneous (91%) compared with oral (24%) administration, probably because of first-pass metabolism (PI). Relevant pharmacokinetic parameters include C_max (ng/mL) of 92 and 81 ng/mL at 0.75 and 2 hours, respectively, after administration of 1 mg/kg subcutaneously and 2 mg/kg orally, respectively. It is highly (99.5%) bound to plasma proteins. Maropitant is metabolized in dogs by CYP2D15 and CYP3A12. Elimination half-life in dogs approximates 9 hours after subcutaneous administration and 4 to 5 hours after oral administration. However, saturation of drug-metabolizing enzymes (probably CYP2D15) results in nonproportional increases in drug concentrations as the dose is increased up to 16 mg/kg orally; proportionality returns at 20 to 50 mg/kg orally. The injectable product remains potent for 28 days when prepared and stored according to labeled directions (amber vial at room temperature). Pain on injection may be common. Side effects delineated on the package insert include bone marrow hypoplasia in puppies younger than 11 (but not greater than 15) weeks of age.

KEY POINT 19-7

As a neurokinin antagonist, the specificity of maropitant results in safe and effective control of motion sickness and vomiting associated with both central and peripheral causes of vomiting.

Maropitant kinetics have been described in the cat after single subcutaneous and oral dosing and multiple subcutaneous dosing.²² The drug was well tolerated in cats (n = 6) during 15 days of subcutaneous administration at doses ranging from 0.5 to 5 mg/kg; one cat developed tremors at the 5 mg/kg dose. No changes occurred in clinical laboratory tests. Plasma maropitant concentrations increased proportionately with dose. After single intravenous dosing, the volume of distribution of maropitant in cats was 6.2 L/kg. Maximum drug concentration after oral and subcutaneous administration of 1 mg/kg in cats were 156 ng/mL and 269 ng/mL (with 50% coefficient of variabilility), respectively. The elimination half-life in cats was 13 to 17 hours; oral bioavailability varied from 50% to 117%. A dose of 1 mg/kg administered intravenously, orally, or subcutaneously prevented emesis induced by xylazine (0.44 mg/kg intramuscularly) and experimentally induced motion sickness.

Maropitant was approved for use in animals in Europe before the United States. It has proved effective for control of vomiting associated with drugs such as cisplatin, apomorphine, and morphine derivatives. Maropitant has been compared with metoclopramide (0.33 mg/kg every 8 hours subcutaneously in study one, 0.5 to 1 mg/kg/day in study two) in two multicenter, prospective, randomized, positively controlled clinical trials.³⁰ Dogs (n = 64 in study one, 77 in study two) were at least 8 weeks of age and had been vomiting for at least 24 hours. Maropitant as studied at 1 mg/kg once daily subcutaneously in study one, and 0.5 to 1 mg/kg subcutaneously in study two with oral dosing of either maropitant or metoclopramide continued in study two until vomiting stopped or for up to 5 days. Vomiting caused by toxin ingestion or in patients with clinical signs indicating the need for acute surgical treatment were excluded. Causes of vomiting were multiple, including metabolic disorders, neoplasia, drug-induced reactions, food intolerance, and parvovirus. In both studies, maropitant was associated with a greater antiemetic response (discontinuation of vomiting) compared with metoclopramide.³¹

The comparative efficacy and safety of maropitant have been recently described for dogs on the basis of manufacturer-sponsored studies. It was compared (1 mg/kg) to placebo, metoclopramide (0.5 mg/kg subcutaneously), chlorpromazine (0.5 mg/kg subcutaneously), or ondansetron (0.5 mg/kg intravenously) in prevention of apomorphine-induced (0.1 mg/kg intravenously) vomiting. Efficacy in controlling vomiting either central or peripheral in origin was superior to that of chlorpromazine or metoclopramide but did not differ from ondansetron.³² Both safety and efficacy for prevention of emesis associated with motion sickness were assessed in dogs (n = 198) 16 weeks or older. Dogs received approximately 8 mg/kg orally. Data were collected from 26 different clinics in two different crossover randomized, placebo-controlled double-blinded trials with a 14-day washout period between trials. Vomiting was prevented in 86% or 77% of dogs dosed at 2 or 10 hours before a 60-minute car ride. No adverse events were described.

Vestibular Apparatus

Vomiting caused by motion sickness or inner ear disease is mediated by the vestibular apparatus (see Table 19-2). Motion sickness in dogs and cats can be controlled for several (8 to 12) hours by administration of antihistamines such as cyclizine hydrochloride, meclizine hydrochloride, or diphenhydramine hydrochloride (Figure 19-4; see also Figure 19-3). Effects may reflect, in part, sedative effects. In addition to direct effects on neural pathways arising in the vestibular apparatus, actions may also be independent of antihistaminic effects. These may include anticholinergic effects. Those drugs able to penetrate the blood–brain barrier may thus have effects at the vomiting center but generally only at higher doses. Drowsiness and xerostomia (dry mouth) are typical side effects that occur with use of this group of drugs in humans. Although phenothiazine antiemetics may be used to treat motion sickness (e.g., acepromazine), efficacy may reflect sedative rather than direct effects. Centrally active maropitant is approved for use in dogs to treat motion sickness (see preceding discussion) and has been used successfully in cats as well.

Figure 19-4 Chemical structures of selected gastrointestinal drugs.

Pathophysiology of Gastrointestinal Ulceration

Physiology of Gastric Acid Secretion

Gastric acid secretion occurs in four phases. The first three phases—referred to as cephalic, gastric, and intestinal—are stimulated by food and mediated by gastrin, which is the most potent secretagogue.⁴⁸ Secretion is persistent during these phases, and gastric pH progressively decreases as nutrients traverse the GI tract. Gastrin secretion is inhibited as gastric pH declines to 3.5 and is completely inhibited at a pH of 1.5, to begin again only when pH approximates 3 to 3.5. The fourth phase of gastric acid secretion is basal and occurs in the absence of external stimuli. The amount of basal secretion varies among animals. In humans basal secretion follows a circadian rhythm, reaching a peak at midnight and a nadir at 7 am.⁴⁹ As a model for the study of antisecretory drugs, information can be found regarding basal and responsive gastric acid secretion in dogs.^50,51

In fasted Beagle dogs (n = 8), gastric pH (collected by stomach tube) fluctuated from 2.7 to 8.3. Basal pH tended to be 7.0; treatment with a placebo (500 mg lactose) reduced pH almost the same magnitude as pentagastrin (3 and 2, respectively) at 1-2 hrs post treatment.50

Gastric acid secretion at the cellular level involves the generation and subsequent secretion of hydrogen ions by the parietal (oxyntic) cells of the gastric mucosa. Responses are controlled through chemical signals interacting with corresponding receptors located on the basolateral membrane of parietal cells. Central and peripheral signals stimulating gastric acid secretion include endocrine (gastrin: CCK), paracrine (histamine: H₂), and neuronal (ACh: M₃) (Figure 19-5).⁴⁹ In addition to its direct effects, acetycholine indirectly increases release of gastrin from G cells and histamine from enterochromaffin cells. Of the mediators increasing gastric acid secretion, gastrin is the most potent, although its effects are mediated indirectly through stimulation of histamine receptors, particularly on enterochromaffin cells.⁴⁸ Somatostatin, which inhibits gastric acid secretion, is released from D cells when gastric pH is less than 3. In humans the effects of Helicobacter spp. may reflect, in part, the ability of these organisms to decrease D cells. The hydrogen ion pump, located at the apical membrane and associated with the smooth endoplasmic reticulum, is unique in that it is a hydrogen–potassium ATPase exchange system. Three distinct pathways are capable of stimulating gastric acid. Each acts through chemical mediators that in turn interact with receptors on the parietal cell membrane.⁴⁹ H₂ receptors are linked to adenylyl cyclase and cyclic AMP.⁴⁸ Of these, the ACh pathway appears to be less important in small animals.

Figure 19-5 Receptor interactions that mediate gastric acid secretion by the parietal cell include acetylcholine with muscarinic receptors and histamine with H₂ receptors. Gastrin may interact with either receptor. Receptor stimulation activates the K⁺, H⁺-ATPase pump and exchange of potassium for hydrogen into the lumen. Prostaglandin E₁ (PGE) modulates gastric acid secretion by inhibiting cyclic adenosine monophosphate (cAMP). ATP, Adenosine triphosphate.

KEY POINT 19-12

Prevention and treatment of gastrointestinal ulceration focuses on prevention of hydrochloric acid secretion and promotion of cytoprotection.

Intracellular messengers mediating gastric acid secretion vary with the receptor stimulated. Histamine increases cAMP production, which subsequently activates the adenylyl cyclase cAMP-dependent protein kinases. Gastrin and muscarinic stimulation by cholinergic drugs increased cytosolic calcium, through inositol phosphate pathways. Both pathways activate an H+, K+-ATPase proton pump that exchanges hydrogen and potassium across the parietal cell membrane. Prostaglandins of the E series serve to modulate these effects, inhibiting gastric acid secretion by blocking cAMP production through EP3 receptors, also on parietal cells.^48,49 The impact of opioid receptors on gastric acid secretion is discussed with drugs targeting intestinal secretion.

Mucosal Defenses

The primary mucosal defense of the esophagus reflects increased lower esophageal sphincter tone. Defenses of the GI mucosa require sufficient mucosal blood flow and act to prevent or repair GI ulceration (Figure 19-6).^52-54 These include (1) secretion of bicarbonate into the lumen and neutralization of hydrochloric acid in the lumen; (2) secretion of a thick, insoluble, alkaline mucus that traps and neutralizes inward-moving hydrogen ions and protects against macromolecules such as pepsin; (3) a gastric epithelial barrier composed of active phospholipids, a lipoprotein cell membrane, and tight junctional complexes, all of which prevent hydrogen ion back diffusion; (4) mucosal blood flow, which first provides nutrients and oxygen to mucosal cells and second removes hydrogen ions that have penetrated the gastric barrier; (5) rapid replication of mucosal epithelial cells; and (6) production of cytoprotective agents. Many of these effects reflect local secretion of prostaglandin E₂ and I₂, important defense mechanisms. They modulate hydrochloric acid secretion, increase bicarbonate and mucus production, and enhance mucosal blood flow and epithelialization.^55,56 Sulfhydryls also produced locally may act as scavengers of oxygen and other tissue-damaging radicals.⁵⁷

Figure 19-6 Protective mechanisms mediated by prostaglandin E against gastroduodenal ulceration provide targets for drug therapy. Bicarbonate secretion acts to neutralize gastric acid; mucus protects against hydrochloric and bile acids. The rapid turnover of epithelial cells is paramount for rapid healing if damage occurs. Mucosal blood flow not only provides critical oxygen and nutrients necessary for epithelialization but also removes H⁺ ions that have penetrated the protective barrier. Other protective factors include mechanisms to control gastric hydrochloric acid secretion and the production of protective factors that scavenge mediators capable of cell damage.

Cytoprotective Drugs

Sucralfate

Sucralfate (see Figure 19-4) is an orally administered disaccharide (octasulfate of sucrose) aluminum hydroxide product that binds to and protects damaged epithelial cells from acid, bile, and pepsin activity.^96-99 In the acid environment of the stomach, sucrose is freed from aluminum hydroxide, cross-polymerizes, and binds to exposed (damaged) anions of GI epithelial cell membranes (Figure 19-7).¹⁰⁰ The maximum protective effects of sucralfate depend on an acid environment (pH <4) for activation; therefore it should be administered at least 30 minutes before antacids¹⁰⁰ and on an empty stomach, 1 hour before feeding.⁴⁸ Binding occurs in the base of ulcer craters and is greater in duodenal than in gastric ulcers. Sucralfate also binds to and inactivates bile acids, thus promoting its use in biliary disorders, and inhibits pepsin-mediated hydrolysis of mucosal proteins.¹⁰¹ In addition to binding and protection of cells, the polymerized sucrose prevents exudation of protein and electrolytes into the gastric lumen. Effects of sucralfate may last up to 6 hours, supporting a four-times-daily dosing regimen.⁴⁸ The amount of aluminum hydroxide released from sucralfate may not effectively neutralize gastric acidity, although this may be controversial.¹⁰² Sucralfate appears to stimulate production of local mediators that protect the gastric mucosa. These include prostaglandins^99,101,103 sulfhydryl ions or other oxygen radical scavengers, and epidermal growth factor.¹⁰⁴ Sucralfate effects on epidermal growth factor cause its accumulation in ulcerated lesions.^99,105 Sucralfate also increases mucosal blood flow either by inducing local nitric oxide or prostaglandin production¹⁰⁶ or by directly stimulating mucosal angiogenesis.¹⁰⁷

Figure 19-7 An endoscopic view of sucralfate bound to damaged gastrointestinal epithelium. Binding not only protects the damaged epithelium from further damage but also prevents loss of critical nutrients and fluids.

KEY POINT 19-23

In addition to its mechanical protection, sucralfate also increases local prostaglandin protection and promotes angiogenesis and epithelialization.

Drug interactions with sucralfate are limited to local effects. Sucralfate binds to a number of drugs, with the prototypic example being cimetidine. Because cimetidine also increases gastric pH (thus potentially reducing activation of sucralfate), these two drugs probably should be alternated (i.e., administer sucralfate 1 to 2 hours before cimetidine) in patients receiving both drugs. In addition to direct binding to drugs, sucralfate may influence drug absorption through formation of a thick mucus layer. Thus, in general, other drugs should be administered at least 2 hours before sucralfate.

Sucralfate is minimally absorbed after oral administration and is associated with few, if any, side effects. Sucralfate is recognized to be the safest drug available for treatment of gastroduodenal ulcers.¹⁰¹ Constipation occurs in up to 2% of humans. Currently, sucralfate is recommended for treatment of gastroduodenal erosion ulceration, regardless of the cause. Its prophylactic use is also recommended for illnesses associated with ulceration such as renal or liver disease, mastocytosis, and IBDs for which prolonged use of antiprostaglandin is indicated. However, sucralfate does not prevent the formation of the ulcer; rather, it protects damaged tissue once it occurs. Sucralfate appears beneficial prophylactically for stress-induced ulcers but is less effective prophylactically in patients receiving NSAID therapy.¹⁰⁰ Sucralfate is effective for treatment of acid-induced esophagitis,¹⁰⁸ although antisecretory drugs such as omeprazole or H₂-receptor antagonists are probably superior.⁴⁸ In critical patients at risk for nosocomial pneumonia, sucralfate may be preferred to antisecretory drugs such that increased gastric pH might be prevented.⁴⁸ Sucralfate has been administered rectally (in humans) for treatment of rectal ulcerative disease.

Normal Physiology

The GI tract functions to ensure the metabolic survival of the host and in doing so sorts ingested materials as to nutritional, toxic, or pathologic status. To accomplish its activities, the alimentary tract has its own enteric neurologic system (ENS) composed of vagal and sympathetic nerves (Figure 19-8). The network communicates through a large variety of chemicals, including neurotransmitters and neuropeptides. Primary signals include ACh, the tachykinins (substance P, neurokinin A), nitric oxide, adenosine triphosphate (ATP), vasoactive intestinal polypeptide, opioid peptides, neuropeptide Y, and 5-hydroxytryptamine.¹⁰⁹ Circuits of the ENS include intrinsic primary afferent neurons; interneruons; and either excitatory or inhibitory neurons that innervate effector motor, secretomotor, or vasodilator neurons. Additionally, the ENS integrates with the CNS, forming a brain–gut axis. The interactions of the integrated signals are complex and often not well characterized and thus are difficult to correct in the face of dysfunction, whether induced by disease or drugs.

Figure 19-8 The integrated neurologic systems of the intestinal tract. See text for details. Metoclopramide antagonizes dopamine receptors, which antagonize release of acetylcholine. Cisapride is an agonist of 5-HT₄ receptors, which are excitatory in the enteric nervous system. Erythromycin acts as an agonist at excitatory motilin receptors. Ach, Acetylcholine, NO, nitric oxide; VIP, vasoactive intestinal peptide.

Regulation of electrical and mechanical, activities of GI smooth muscle is a complex but ordered activity involving hormonal, myogenic, and neurogenic factors and sensory, relay and effector functions.²⁴ Integration occurs at the level of the CNS at both spinal and supraspinal levels¹¹⁰ and locally through the ENS, including intrinsic and interneuronal nerves and ganglia are located between the longitudinal and smooth muscles and at least 10 different classes of receptors located on the smooth muscle cell. Intrinsic innervation includes the Auerbach (or myenteric) plexus, which forms a neural sympathetic and parasympathetic network connecting longitudinal and circular smooth muscle and the secondary Meissner (or submucosal) plexus, which parasympathetically innervates circular muscle. Both systems are secretory and motor in effect, although the Meissner plexuses predominantly modify mucosal absorption and secretion. Coordination of inhibitory and excitatory muscle movements results in two primary movements: mixing and aboral propulsion of liquefied contents. Mixing reflects rhythmic segmentations caused by simple nonprogressive contractions of circular muscle. Electrical activity for propulsion occurs initially as a “slow waves” whose crest is followed by “spike potentials.” Slow waves keep the membrane potential in a constant state of fluctuation, with the frequency of contraction waves ranging between 10 to 20 times per minute, being fastest in the small intestine. Slow waves coordinate synchronous muscle contraction by releasing neurotransmitters from the myenteric plexus such that smooth muscle fibers are “primed” to respond to the spike potential that follows. Gap junctions between circular and longitudinal fibers ensure that electrical stimuli (i.e., depolarization) spread outward in a circular fashion such that an entire ring of circular smooth muscle contracts in a coordinated fashion (Figure 19-9).

Figure 19-9 The sequelae of smooth muscle contraction in the intestines vary with the type of muscle. Longitudinal muscle contraction shortens the gastrointestinal tract; peristalsis thus forces expulsion of luminal contents. Contraction of circulatory muscle causes segmentation or resistance to outflow. This effect predominates with opioids. Anticholinergic drugs impair both types of muscle activity.

Peristalsis is the major propulsive movement, occurring principally in the esophagus and intestines, involving both longitudinal and circular smooth muscles and reflecting signals originating in the myenteric plexus without being influenced by signals peripheral to the ENS. Peristalsis reflects an ascending excitatory reflex of circular smooth muscle causing contraction on the oral side of a bolus, with ACh and substance P as the primary interneuronal mediators, and a descending inhibitory aboral reflex that causes relaxation, with nitric oxide, vasoactive intestinal peptide, and ATP as mediators.²⁴ Luminal contents follow the net pressure gradient. Contraction of longitudinal smooth muscle in the descending (aboral) phase and relaxation in the ascending oral phase facilitates peristaltic movements and aboral movement of intestinal contents.¹¹¹ Although peristaltic activity is mainly propulsive, it also ensures mixing and successful absorption. Wilson and coworkers review the physiology of the gastroesophageal sphincter.¹¹² Relaxation is mediated by noncholinergic and nonadrenergic signals. Absorption of luminal contents is facilitated as intestinal luminal contents are impeded by narrowing of the intestinal luminal diameter.

Receptors and Signals

Most smooth muscle activity ultimately reflects response to ACh through cholinergic receptors. However, activity of cholinergic receptors is modulated by a variety of other receptors (see Figure 19-8). Muscarinic (M₂) receptors regulate phasic bowel movements during fasting. Several types of muscarinic receptors have been identified pharmacologically (M_1-4) in the GI tract. Of these, M₁ or M₃ receptors interact with G protein and mobilize intracellular calcium; M₂ and M_41`receptors inhibit adenylyl cyclase and regulate ion channels. M₁ receptors present in the myenteric plexus may inhibit motility by way of gabaminergic mechanisms. M₂ receptors, located presynaptically and postsynaptically, mediate presynaptic inhibition of ACh release. M₃ receptors appear to be located on smooth muscle cells, and although less abundant than M₂ by a ratio of 4:1, they are more important because they increase intracellular calcium.^24,110

A number of other receptor types influence GI motility. Adrenergic receptors, including α₁, and α₂ postsynaptically and α₂, presynaptically regulate ACh release from the myenteric plexus. Generally, cholinergic neurons stimulate and adrenergic neurons inhibit gastric motility. Both H₁ and H₂ receptors have been identified in the GI tract. They are located both prejunctionally, where they control ACh release, and postjunctionally. Stimulation of H₁ receptors induces, whereas H₂-receptors inhibit, smooth muscle contraction.¹¹³ The role of dopamine and serotonin in gastric motility is complex and not well elucidated. Among the effects of dopamine are reduction in esophageal sphincter and intragastric pressures. Dopamine, by way of D₂ receptors, inhibits smooth muscle of the stomach, duodenum, and colon and has been implicated as a mediator of receptive relaxation in dogs (see Figure 19-8).^24,34 Dopamine exerts its inhibitory effect through inhibition of ACh at myenteric motorneurons.³⁴

Over 90% of serotonin in the body is located in the GI tract, indicating its importance in this system. The majority of serotonin is produced by enterochromaffin cells that rapidly release serotonin in response to a variety of mechanical or chemical stimuli. Its effects generally are stimulatory by way of 5-HT₃ and 5-HT₄ receptors and inhibitory by way of 5-HT_1P receptors. The result is a peristaltic reflex, mediated by 5-HT_1P and 5-HT₄ receptors at the myenteric plexuses and 5-HT₃ receptors at extrinsic vagal and spinal sensory neurons.²⁴ Serotonin often exerts its effects through secondary chemicals. For example, the inhibitory effects of 5-HT_1P receptors reflect release of nitric oxide, which reduces muscle tone, whereas the stimulatory effects of 5-HT₄ receptors reflect enhanced ACh release. However, the effects of 5-HT₄ receptor stimulation appear to vary with species and origin. In the guinea pig ileum, effects are stimulatory, but in human and canine colons, 5-HT₄ receptor stimulation causes relaxation of smooth muscle.¹¹⁴ In the dog, 5-HT₄ receptors appear to mediate relaxation in gastric cholinergic neurons where gastric contraction facilitates gastric emptying, and jejunal and ileal mucosa and circular colonic smooth muscle cells, where activation appears to cause relaxation. Conflicting studies may reflect the different roles that 5-HT₄ receptors have in stimulating contraction and peristalsis: a positive effect may occur with mucosal stimulation but not luminal distention.¹¹⁴ 5-HT₄ receptors appear to be potent secretagogues in most species, again with effects variable among species and location. These differences among species and tissues suggest that extrapolation of therapeutic indications and doses should be based on scientific studies in the target species. The effects of serotonin are ameliorated, in part, by reuptake. However, uptake can be inhibited by CNS-active serotonin reuptake inhibitors, although the sequelae may cause diarrhea.

Other sites are targeted by motility-modifying drugs. Activation of the noncholinergic, nonadrenergic inhibitory neurons results in bowel relaxation.¹¹³ Prostanoids and specifically prostaglandin E (PgE) receptors have been identified in the gastric fundus and ileum. PgE receptors may modulate motility from the esophagus to the colon.¹¹³ Generally, PgE inhibits mechanical activity of circular smooth muscle, whereas prostaglandins of the D and F series are stimulatory. At high doses, PgE stimulates peristaltic activity, although this may represent mechanical response to excess watery fluid in the intestinal lumen stimulated by PgE.¹¹³ Motilin is a peptide hormone located in M and enterochromaffin cells of the GI tract. Motilin appears to enhance and potentially induce phase III activity.

Smooth muscle activity in the large bowel varies from that in the small bowel. In the small bowel, slow waves generally occur continuously and propagate aborally. In the colon slow waves are sometimes absent, and propagation may be variable.¹¹⁰

Prokinetic Drugs

Prokinetics enhance the transit of intraluminal contents.³⁴ The mechanisms of action of these drugs are varied and are not completely understood. Their effects on intestinal functions generally reflect either promotion of an agonist, such as ACh by muscarinic drugs, or inhibition of an inhibitory signal, such as dopamine (see Figure 19-8).³⁴ Organ-specific and species-specific differences complicate our comprehension of these drugs.³⁴

Cholinergics

Clinically, the use of cholinergics is limited by their tendency to cause systemic effects. Bethanechol is an ester derivative of choline that acts as a cholinergic agonist almost exclusively at muscarinic (M₂) receptors.¹¹³ Bethanechol will enhance the amplitude of contractions throughout the GI tract, including the lower esophageal sphincter (Figure 19-10; see also Figure 19-8).^34,113 Its effects on the coordination of small intestinal contraction may be minimal, however, and thus it is often not considered to be a prokinetic agent.³⁴ Adverse effects reflect direct enhanced parasympathomimetic stimulation and include abdominal cramps, diarrhea, salivation, and bradycardia.³⁴

Figure 19-10 The sites of actions of two clinically useful prokinetic drugs. In vivo, at standard doses, metoclopramide’s actions are limited to the lower esophagus (feline more than canine), stomach, and upper duodenum, where it physiologically antagonizes vomiting. Cisapride appears to increase motility throughout the gastrointestinal tract.

Metoclopramide

Metoclopramide is a lipid-soluble derivative of para-aminobenzoic acid. It is structurally related to procainamide, a cardiac antiarrhythmic (see Figure 19-4).³⁴ In addition to its central antidopaminergic (antiemetic) effects, metoclopramide acts peripherally as both an antidopaminergic and as a direct and indirect stimulator of cholinergic receptors.^34,35

The effect of metoclopramide on canine gastromotility was described as early as 1969.¹¹⁵ Compared with saline, metoclopramide decreased transit time and volume but did not affect flow of intestinal contents. Clinically, its effects appear to be limited to the upper intestinal tract (see Figure 19-10).^{35,37,116,117} The peripheral effects of metoclopramide apparently reflect enhanced release of ACh from intrinsic cholinergic neurons. These effects are completely inhibited by pretreatment with anticholinergics such as atropine.^34,37,118 The peripheral effects, however, appear to be mediated by effects on other (noncholinergic) local neurotransmitters, particularly dopamine. Serotonin receptors also may play a role.³⁴ The prokinetic activity of metoclopramide reflects muscarinic activity, D₂ receptor antagonist activity, and 5-HT₄ receptor agonist activity.³⁴ Because of its effects on the stomach, metoclopramide physiologically antagonizes emesis by increasing the tone in the lower esophageal sphincter, increasing the force and frequency of gastric antral contractions (gastrokinetic effect), relaxing the pyloric sphincter, and promoting peristalsis in the duodenum and jejunum, resulting in accelerated gastric emptying and upper intestinal transit.³⁵

Metoclopramide is well absorbed orally but undergoes significant first-pass metabolism with a bioavailability in the 50% to 70% range. Tissue distribution is rapid, and excretion is both renal and hepatic. Because the plasma half-life in the dog is only 90 minutes, metoclopramide has a short duration of action.³⁵ Dose-dependent CNS side effects include nervousness, restlessness, listlessness, depression, and disorientation.^34,35,119 Extrapyramidal antidopaminergic effects include tremors and motor restlessness. Tremors in cats, particularly after intravenous administration, are not unusual. Gynecomastia caused by enhanced release of prolactin has been reported in humans.³⁴ GI disorders may also be observed, with constipation being common with long-term use.

Metoclopramide has a demonstrated impact on the oral bioavailability of several drugs, with the effect varying with the drug. For example, co-administration with the oral hypoglycemic agent ciglitazone decreased C_max by 16% and AUC 8%,¹²⁰ but co-administration with cephalexin increased cephalexin C_max by 21% and AUC by 36%.¹²¹ It is not clear if the latter effect reflected increased gastric emptying or interference with intestinal transport proteins. As an antiemetic, the main indications for metoclopramide include severe and intractable emesis caused by chemotherapy or other blood-borne toxins as well as nausea and vomiting associated with delayed gastric emptying, gastroesophageal reflux, reflux gastritis, and peptic ulceration. As a prokinetic, metoclopramide is indicated for treatment of a variety of gastric motility disorders, including gastric dilation, volvulus, postoperative ileus, gastric ulceration, and idiopathic gastroparesis.³⁷ Metoclopramide is contraindicated in GI obstruction or perforation, potentially in epilepsy, and for patients receiving neuroleptics. Because of their anticholinergic effects, atropine and the opioid analgesics antagonize the action of metoclopramide.

Domperidone

Domperidone is a dopamine antagonist whose prokinetic properties are similar to those of metoclopramide.¹²² However, unlike metaclopramide, it has no cholinergic activity and is not inhibited by atropine. Domperidone does not cross the blood–brain barrier as readily as metoclopramide. Like metoclopramide, however, domperidone can affect central dopamine receptors and thus modulate temperature control, prolactin secretion, and activity at the CTZ.³⁴ Extrapyramidal side effects are rare. Domperidone acts peripherally to coordinate antroduodenal contractions. Its peripheral effects accelerate small intestinal transit, but colonic activity is apparently unaffected.¹¹⁹

Cisapride

Cisapride has the broadest spectrum of action of the prokinetic agents.¹²³ It causes dose-dependent increased activity at all GI sites, including the esophagus, stomach, jejunum, ileum, small intestine, and colon³⁴ (see Figure 19-10). Because 75% of the feline esophagus is skeletal muscle, esophageal prokinetic effects are likely to be less in cats than in dogs. The prokinetic actions of cisapride appear to reflect indirect stimulation of cholinergic nerves. Serotonin appears to mediate this effect through 5-HT₄ receptors (see Figure 19-8). Stimulation of colonic contractions reflects 5-HT_2a. Because secretion is not enhanced, stimulation probably occurs at the level of the myenteric plexus.³⁴

Well absorbed after oral administration, cisapride undergoes first-pass metabolism, with oral bioavailability in humans being 50%. Metabolites are apparently inactive. Volume of distribution is large (2.4 L/kg) in humans, and elimination half-life is 10 hours. Cisapride kinetics have been reported in the cat.¹²⁴ Oral administration is characterized by 30% bioavailability, and the elimination half-life approximates 5 hours. A dose of 1 mg/kg every 8 hours or 1.5 mg/kg every 12 hours is recommended on the basis of these data. Elimination may be prolonged in the presence of liver disease.¹²³ Indications for use of cisapride are similar to those for metoclopramide (excluding dopaminergic effects). Indications in humans include any disorder associated with impaired gastric emptying as well as gastroesophageal reflux. Unlike metacolopramide, cisapride does not interact with central dopamine receptors, and its use is not associated with extrapyramidal side effects.¹¹³ However, stimulation of 5-HT₄ receptors by cisapride (and other drugs) causes blockade of the rapid component of potassium influx through the delayed rectifier potassium channel. Prolongation of the QT interval results in torsades de pointes and the potential for sudden cardiac death. Subsequently, cisapride has been withdrawn from the human-medicine market, mandating the need for compounding for veterinary use. Myocardial side effects have not been reported in peer-reviewed literature but have been reported anecdotally. Further, in vitro studies have revealed a similar effect in the canine myocardium. The risk is greater when cisapride is combined with other drugs that inhibit the cytochrome P450 enzyme responsible for cisapride metabolism in humans (e.g., clarithromycin, itraconazole).¹²⁵

Miscellaneous and Pending Prokinetic Drugs

Erythromycin stimulates GI motility at low doses not associated with antimicrobial effects (0.5-1 mg/kg every 8 hours). Its effects appear to mimic those of motilin (see Figure 19-8). Lower esophageal sphincter pressure will be increased. However, contraction in the stomach is not coordinated and may result in “dumping” of food from the stomach into the intestines before maceration is complete. Increased small bowel motility has led to its clinical use in humans with small bowel dysmotilities, but clinical use has not been reported in animals. Doses greater than 3 mg/kg may actually cause spastic contractions and cramps. The prokinetic effects of erythromycin may be responsible, in part, for GI disturbances that occur in up to 50% of patients receiving this drug. However, tolerance develops rapidly, probably because of downregulation of motilin receptors. Other macrolides will also stimulate motility to variable degrees.

Among the H₂- receptor antagonists, ranitidine and nizatidine inhibit anticholinesterase activity and thus are prokinetic at antisecretory doses.¹²⁶ Comparison between cisapride and ranitidine, an H₂-receptor antagonist, for the treatment of gastroesophageal reflux reveals both to be effective.¹²⁷ Nizatidine was demonstrated to have prokinetic effects similar to those of cisapride owing to noncompetitive inhibition of ACh at a level comparable to that of neostigmine.¹²⁸

Misoprostol, a PgE analog, also is associated with prokinetic properties in the colons of dogs and cats. At least two prokinetic agents have been in various stages of approval in human medicine: prucalopride (R093877; Janssen Pharmaceutical) and tegaserod. Both are potent, partial agonists of 5-HT₄ receptors. Prucalopride (benzamide) is void of activity at other serotonin receptors or cholinesterase enzyme activity. Although pharmacokinetics have not been reported in dogs, prucalopride causes a dose-dependent (0.01-0.16 mg/kg [dog]) increase in gastric emptying and increased giant migrating contractions with defecation in dogs (0.02-1.25 mg/kg) or cats (0.64 mg/kg).¹²⁹ Fecal consistency does not appear to be affected. In contrast to prucalopride, tegaserod is a nonbenzamide. In addition to effects at 5-HT₄ receptors, it acts as a weak agonist at 5-HT_1D receptors. Like prucalopride, tegaserod acts as a prokinetic in the canine colon, with effects apparent within 1 hour of an intravenous dose (0.03-0.3 mg/kg). Prokinesis also appears to occur in the intestine on the basis of normalization of transit time in opioid-induced bowel dysfunction in dogs (3-6 mg/kg orally). Because the colonic effects of tegaserod do not appear to be dose dependent, prokinetic effects in the colon may reflect an alternative mechanism of action. The impact of tegaserod on the canine stomach or in the cat have yet to be described. Tegaserod was approved for human use in the United States in 2002 (Zelnorm).

Physiology, Pathophysiology, and Motility

The primary clinical sign reflecting intestinal disease is diarrhea; accordingly, drugs targeting the intestinal tract frequently are intended to control diarrhea. Drug therapy for diarrhea tends to be nonspecific, preferably targets the underlying disease rather than the GI tract, but occasionally might target the physiologic (rather than pathologic) cause of diarrhea. Diarrheas can be classified as inflammatory or infectious, osmotic (including malabsorption), and secretory. The goal of antidiarrheal therapy generally is to reduce the discomfort and inconvenience of frequent bowel movements and, when indicated, to replace fluids or electrolytes lost with diarrhea. Rehydration followed by oral replacement therapy often is the preferred treatment for diarrheas associated with infectious agents.¹³³ Suitable solutions contain K⁺, HCO⁺, Na⁺, and glucose in sufficient quantities to replace stool losses.¹³³ Substantial evidence exists linking GI secretion with GI motility, with increased motility usually being accompanied by increased fluid and electrolyte secretion.¹³⁴ The physiology of intestinal motility was previously discussed.

Absorption and Secretion

Increased amounts of fecal water reflect either diminished absorption or a net secretion (accumulation) of fluid into the lumen of the intestine. In all diarrheal states, increased fecal water loss is associated with an overall secretion of electrolytes and water in selected segments of the GI tract. The absorptive capacity of the alimentary canal is overwhelmed distal to the site of secretion. Sodium-absorbing cells are present predominantly on the villi, and chloride-secreting cells are located primarily in the crypts.

Absorption in the small intestine occurs by passive sodium absorption across the luminal membrane and by active secretion of sodium across the basolateral membrane. Water follows the osmotic draw of sodium into the lateral intracellular space. The electrochemical gradient caused by sodium movement facilitates chloride diffusion into the cell.¹³³ A specific brush border carrier for NaCl co-transport accomplishes absorption. Nutrients such as glucose and other organic solutes, however, facilitate solvent drag of water and electrolytes as they enter cells.¹³³ Secretion in crypt cells of the intestinal epithelium is initiated by intracellular signaling (cAMP) or calcium. Increased chloride conductance into the lumen results in sodium recycling, first through the lateral intercellular space and second into the lumen. Although NaCl co-transport can be inhibited, NaCl movement can still occur as a result of solvent drag (i.e., that mediated by nutrients).¹³³

Increased intestinal cell cyclic adenosine monophosphate, cyclic guanosine monophosphate, and Ca²⁺ (through calmodulin) all diminish sodium absorption and increase chloride secretion, with a net efflux of water into the lumen. Cholera enterotoxin is the best-known intestinal secretagogue,¹³³ but several hormones, including vasoactive intestinal peptide, gastric inhibitory peptide, CCK, secretin, glucagon, and PGE₁, and infectious agents (e.g., Escherichia coli, Staphylococcus spp.) are associated with net fluid accumulation.¹³³ Several laxative agents such as bile acids and ricinoleic acid may act through this mechanism. The exact role of intestinal motility in the alteration of fluid and electrolyte movement and the role of mucosal permeability or mucosal damage in the genesis of fluid accumulation within the gut lumen remain unclear.

Modulators of Intestinal Motility and Secretions

Drugs

Diphenoxylate hydrochloride is a meperidine derivative used specifically to control diarrhea. It is often administered in combination with atropine-like compounds, whose bitter taste and drying effect on salivary secretions are added as a deterrent to substance abuse. The actions of diphenoxylate largely depend on a direct peripheral effect on the GI wall. Because diphenoxylate can penetrate the blood–brain barrier, systemic opiate effects may occur. The potential for drug abuse has led to its designation as a Schedule V drug. The use of opioids in cats is generally reasonable, as long as accommodation is made for the increased sensitivity that appears to characterizes their response.

Loperamide hydrochloride, a butyramide derivative, is an orally active and effective antidiarrheal agent used for symptomatic control of acute and chronic nonspecific diarrhea. Unlike diphenoxylate, systemic opiate agonist effects do not appear to occur after oral administration of loperamide, and there are few side effects. Although loperamide has some structural similarities to diphenoxylate, it does not cross the blood–brain barrier, and it differs both qualitatively and quantitatively from diphenoxylate and difenoxin in its pharmacologic actions.¹³⁸ Intestinal transit time and intestinal luminal capacity increase after treatment with loperamide.¹¹³

Emollient Laxatives

The emollient laxatives (lubricant laxatives, mechanical laxatives, fecal softeners) act unchanged. They are not absorbed to any appreciable extent and simply soften and lubricate the fecal mass, which in turn facilitates expulsion. Although not always reliable, particularly in the ruminant, they are used in all species.

Mineral oil (liquid paraffin) is a commonly used lubricant laxative. It is bland and generally safe, but chronic administration may impair absorption of fat-soluble vitamins, other nutrients, and co-administered therapeutic agents. Decreased irritability of the intestinal mucosa may develop with protracted use and, paradoxically, cause chronic constipation. White or yellow soft paraffins are used most commonly for small animals as lubricant laxatives (e.g., feline hairballs). Several anionic surfactants are employed as fecal softeners. Examples include docusate sodium, previously called dioctyl sodium sulfosuccinate and dioctyl calcium sulfosuccinate.

Simple Bulk Laxatives

The simple bulk laxatives are hydrophilic and not digested. As such, they adsorb water and swell, forming an emollient gel. Increased volume or bulk causes distention and reflex contraction, leading to peristaltic activity. Feces remain soft and hydrated. Methylcellulose, carboxymethylcellulose sodium, and plantago seed (psyllium seed) are examples of simple bulk purgatives. Wheat bran, prunes, and other fruits also belong in this group. In addition to their bulk action, celluloses and hemicelluloses will be fermented in the hind gut by bacteria to produce volatile fatty acids and other products that exert an osmotic effect, which enhances their laxative action. Meteorism and a very fluid stool often result from the use of simple bulk laxatives.

Osmotic Cathartics

Osmotic cathartics (saline purgatives) consist of salts or compounds that are either partially and slowly absorbed or not absorbed. Water is osmotically retained or attracted into the intestinal lumen, although enhanced mucosal secretion of fluid may also occur. Drinking water must be freely available, and use is contraindicated with dehydration. Effects are realized in monogastric animals generally in 3 to 12 hours. Magnesium salts are frequently used as saline purgatives. Magnesium ions also cause release of CCK, which increases peristaltic activity. Magnesium sulfate (Epsom salts), isotonic in a 6% solution, magnesium hydroxide, magnesium oxide (milk of magnesia), and magnesium citrate are the magnesium salts most commonly employed. The solutions need not be hypertonic to produce an effect. About 20% of the magnesium ions are absorbed when magnesium sulfate is dosed orally, and if purgation does not occur, additional amounts of magnesium may be absorbed with subsequent depression of the excitable tissues in the body. This is more likely to occur if renal function is impaired. Salts such as sodium sulfate (Glauber’s salt), sodium phosphate, potassium sodium tartrate (Rochelle salt), and even large quantities of sodium chloride are effective saline purgatives. Saline purgatives are often combined with polyethylene glycol (PEG) for whole bowel irrigation implemented for bowel preparation before lower bowel procedures such as surgery or colonoscopy.The safety and efficacy of sodium phosphate has been described in healthy dogs (n = 8) when used to prepare for colonoscopy. Orogastric sodium phosphate (1 mL/kg in 2 mL/kg water followed by 2 mL/kg) was less effective as a preparatory agent compared with PEG (66 mL/kg) and bisacodyl (10 mg/dog; dog weight not provided). Most (five of eight) dogs receiving sodium phosphate vomited during or after administration. In contrast, dogs receiving PEG tended to regurgitate. Sodium phosphate enemas were associated with transient hyperphosphatemia and hypocalcemia that were not considered clinically relevant in these normal dogs. Other electrolyte concentrations statistically varied but remained within normal limits. The protocols for colonoscopy preparation included 20 mL/kg warm water enemas; treatments were repeated at 4 hours and enemas at 24 hours (before procedures). Enemas may have contributed to vomiting because of distention. Dogs receiving PEG were also pretreated (20 minutes) with metoclopramide (0.3 mg/kg subcutaneously). The authors concluded that sodium phosphate enemas should not be considered as preparative agents for colonoscopy.¹⁴⁸

The sugar alcohols mannitol and sorbitol will also induce an osmotic catharsis, as will the synthetic disaccharide lactulose, which is not digested in the small intestine because no specific enteric enzyme is present. It passes to the large intestine, where saccharolytic microflora ferment lactulose to produce acetic, lactic, and other organic acids, which in turn lower the pH of the colonic content and exert an osmotic effect. Water is attracted, the fecal mass softens, and colonic peristalsis ensues. Lactulose is used for chronic constipation and treatment of hepatic encephalopathy. Acidification of the contents of the large intestine favors a greater formation of the ionized and thus nonabsorbable ammonium ion rather than the readily absorbable ammonia molecule, which requires detoxification in the liver by the urea cycle. Hyperammonemia is thus decreased. Absorption of other toxic amines from the hind gut is also reduced by acidification of the contents. Some meteorism may be evident after administration of lactulose. Lactitol is an alternative osmotic cathartic. It is less sweet than lactulose and may be better tolerated.

Irritant Cathartics

Contact or irritant purgatives were thought to stimulate the mucosal lining of the GI tract and thereby initiate local myenteric reflexes that would enhance intestinal transit. However, they also activate secretion. Irritant cathartics act either directly or indirectly, depending on whether the compound must be metabolized to its active product. Some purgatives are so highly irritating that they may cause severe colic and superpurgation.

Several bland vegetable oils act as irritant purgatives. Their action is based on hydrolysis by pancreatic lipase in the small intestine and subsequent formation of sodium and potassium salts of the released fatty acids, which act as irritant soaps. They differ in potency depending on the oil used. Castor oil produces highly irritant ricinoleates; raw linseed oil leads to formation of less irritant linoleates; and olive oil leads to rather mild oliveates. The response to castor oil is prompt, and evacuation of the whole intestinal tract occurs, leading to an almost complete emptying. Moist bulky feeds are necessary after purgation with castor oil. It is used mainly in nonruminants and often employed in calves and foals. The effect occurs in 4 to 8 hours in small animals.

The diphenylmethane cathartics appear to have a greater effect on the large intestine. Their precise mechanism of action is unclear. An effect is usually seen within 6 to 8 hours, and excessive catharsis may occur with overdosage. Bisacodyl also is a diphenylmethane cathartic that inhibits glucose absorption and Na⁺, K⁺ ATP activity, as well as altering motor activity of the visceral smooth muscle. Only about 5% of any dose of bisacodyl is absorbed. This agent is used both orally and by enema.

Enemas

Introduction of solutions or suppositories into the rectum to initiate the defecation reflex is a useful and simple method to correct or prevent constipation. Many preparations have successfully served as enemas, including soapy water (soft anionic soap), isotonic or hypertonic sodium chloride solutions, sorbitol, glycerol, surfactants such as sodium lauryl sulfoacetate, mineral oil, and olive oil. Enema preparations that contain phosphate should not be used indiscriminately because they can precipitate potentially fatal hyperphosphatemia, hypocalcemia, and hypernatremia in cats¹⁴⁹ or debilitated animals.

Digestive Enzymes

Pancreatic extracts that stimulate pancreatic exocrine secretions are of therapeutic benefit in cases of chronic pancreatitis and pancreatic hypoplasia, in which glandular function is diminished or destroyed. Pancreatin (Panteric, Stamyl, Viokase) obtained from hog pancreas is the major ingredient of most commercial pancreatic enzyme preparations. Enteric-coated preparations to prevent destruction of pepsin in the stomach are generally thought to be better than noncoated preparations. In a few instances, enteric-coated preparations are the most effective in dogs with pancreatic insufficiency; they are added to food and must be provided with each meal. Dosage is adjusted to obtain a normal stool. Simultaneous administration of nonsystemic alkalinizing agents to maintain an optimal pH range for enzyme activity has not proved successful clinically. However, the administration of cimetidine about half an hour before dosing with pancreatic extract does limit gastric inactivation of the enzymes. Proper dietary control is also essential for the successful management of animals suffering from pancreatic insufficiency. Premixing in food does not appear to be necessary for efficacy of these products.

Bile acids and their salts promote absorption of long-chain fatty acids and fat-soluble vitamins. They also act as choleretics (discussed previously). Examples include dehydrocholic acid (Decholin) and chenodiol (previously called chenodeoxycholic acid).

Diastases are amylolytic enzymes obtained from malt and Aspergillus oryzae and are used for replacement of pancreatic α-amylase and to control flatulence caused by gas produced from soluble carbohydrates by bacterial flora.

Antiflatulence Drugs

Simethicone is an inert over-the-counter mixture of siloxane polymers stabilized with silicon dioxide.²⁴ It acts as an antifoaming agent by covering bubbles with a thin layer that facilitates bubble collapse. Reduction in foam may reduce gas volume, although therapeutic efficacy is not clear.²⁴

Product Definitions

The term probiotic was originally coined in 1965 to refer to substances secreted by one microorganism that stimulate the growth of another.¹⁵⁰ The term has been modified at least five times and continues to vary with the author. Most recent modifications are intended to encompass nondairy products (e.g., plant-based products), recognizing the importance of organism load to ensure a therapeutic effect; to allow for transient, rather than prolonged, effects that would otherwise require transplantation (implying colonization), and to allow for multiple and diverse benefits, including those manifested beyond the GI tract.¹⁵⁰ Perhaps the easiest working definition of probiotics is that offered by the World Health Organization: live microorganisms that, when administered in adequate amounts, confer a health benefit on the host.¹⁵⁰

In contrast to probiotics, prebiotics are nondigestible food ingredients (e.g., dietary fiber) that beneficially affect the bacterial population. They differ from other fermentable carbohydrates in that they interact with selective microorganisms.¹⁵¹ They presumably are most beneficial to those microbes targeted for their therapeutic benefit, thus shifting the composition of the intestinal microbiota toward the beneficial organisms. Examples include fructooligosaccharides, inulin, transgalactosylated oligosaccharides, and soybean oligosaccharides that selectively promote the growth of bifidobacteria. Metabonomics is the scientific discipline that studies compounds formed from prebiotics. Synbiotics contain both prebiotics and probiotics, with the prefix syn implying a synergistic effect of the prebiotic on the probiotic portion of the combination products. To be a symbiotic, the prebiotic portion should have demonstrated positive effects on the specific probiotic component of the combination product.¹⁵⁰ Some products sold as probiotics are actually the fermentation products produced by target microbe; presumably, the products are those imparting the therapeutic benefits of the microbes.

Normal Microbiota

Probiotics as Therapeutic Agents

The science behind the use of probiotics is profoundly complicated by the unknown nature of the normal microbiota; the variables that influence it, including diets, diseases, and other patient factors such as breed, age, or gender; a lack of understanding of the pathophysiology of targeted disease; and issues regarding the quality of the products. Further hampering our understanding are the studies themselves. A variety of in vitro and in vivo models have been used (as reviewed by de Vrese and Schrezenmeir¹⁶⁰ and Lenoir-Wijnkoop and coworkers¹⁵¹), but poor scientific design mars the credibility of many.

KEY POINT 19-35

Evidence for the beneficial effects of probiotics will be difficult to establish because of the impact of multiple (including unknown) variables on response.

In humans probiotics have been demonstrated to have an impact on a large number of potential health problems (Table 19-4).¹⁵¹ Although the data were drawn from humans, a review of those indications relevant to dogs and cats is reasonable; this discussion is limited to those indications for which sufficient evidence exists to support potential to probable therapeutic benefit. This review summarizes human reviews of well-designed clinical trials.^151,161,162

Table 19-4 Examples of Probiotic Indications for Treatment of (Human) Disease¹⁶¹

Gingival disease

Theoretically, probiotic microbes able to adhere to dental tissues occupy spaces that otherwise would be occupied by pathogens. For example, dairy products containing Lactobacillus or Bifidobaceriumorganisms might compete with cariogenic microbes such as salivary Streptococcus mutans or others. Several clinical trials have demonstrated a reduction in the number of dental caries in humans who ingest probiotics containing Lactobacillus.¹⁵¹

Antibiotic-induced diarrhea

Diarrhea as a side effect of selected commonly used antibiotics may reflect colonic overgrowth of Clostridium difficile or other organisms. Strategies for treatment (discontinuation of the inciting antibiotic, immediate retreatment with a new antibiotic) are not always successful, and one of the most commonly selected antibiotic in humans (oral vancomycin) to treat overgrowth of Clostridium organisms tends to be associated with adverse events. Although other antibiotics may be as effective as vancomycin, use of probiotics is a reasonable approach.

Based on a review of 10 clinical trials in close to 2000 children ranging in age from less than 1 year up to 18 years of age, probiotics were beneficial in the prevention of pediatric antibiotic-associated diarrhea.¹⁶² Probiotic strains that showed the most promise included Lactobacillus GG, Lactobacillus sporogenes, and Saccharomyces boulardii when 5 to 40 billion colony-forming units were administered daily. Other organisms studied included members of Lactobacillus spp., Bifidobacterium spp., Streptococcus spp., and S. boulardii alone or in combination, including other treatments that might prevent antibiotic-associated diarrhea. The impact of age (e.g., infants versus older children) or duration of antibiotic therapy could not be assessed. Probiotics tended to be well tolerated after 2 to 12 weeks of therapy. Although the review concluded that routine treatment of probiotics for the prevention of pediatric antibiotic-associated diarrhea could not yet be recommended, further studies are warranted.

Infectious diarrhea

Probiotics also appear to be beneficial when used as an adjunct to rehydration fluids in the treatment of acute, infectious diarrhea in adults and children, although further research is indicated to determine the most effective probiotic and dosing regimen. In contrast, the use of probiotics as an adjunct to antibiotic therapy for C. difficile colitis could not be supported by a review of relevant clinical trials. However, the number of studies was small.

Liver disease

A review of clinical trials studying the use of probiotics for treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis found insufficient evidence to support or refute treatment. However, the use of probiotics and synbiotics to support liver function or treat liver disease has been reviewed by Lenoir-Wijnkoop and coworkers¹⁵¹ and is discussed with regard to the management of liver disease.

Hyperlipidemia

Several species of Lactobacillus may bind to cholesterol in the presence of bile acids and low redox potential.¹⁶¹

Inflammatory bowel disease

Because of the complex relationship between the intestinal microbiota and the immune response, the use of probiotics as adjunct therapy for treatment of IBD is reasonable.¹⁶³ Probiotics have been used successfully to reduce Helicobacter pylori colonization in humans; severity of mucosal inflammation also is reduced in a mouse model. Clinical trials investigating the efficacy of probiotics in the treatment of H. pylori often are conflicting, ranging from ineffective as sole therapy to effective if used in conjunction with standard therapy antimicrobial and antiulcer therapy. One study in humans (n = 138) found that equal numbers of Lactobacillus acidophilus, Lactobacillus bulgaricus, Streptococcus thermophilus, and Bifidobacterium lactis (total of 10⁹ organisms/mL) combined with quadruple therapy (amoxicillin, metronidazole, bismuth subcitrate, and omeprazole) eradicated infection in 85% of humans compared with 71% receiving quadruple therapy alone (as reviewed by Lenoir-Wijnkoop and coworkers¹⁵¹).

Probiotic therapy with conventional therapy does not appear to provide any benefit compared with conventional therapy alone in patients with mild to moderate ulcerative colitis. Although limited evidence suggests that probiotics may reduce clinical signs, support was not sufficient for recommendations. Likewise, evidence was not sufficient to support a role for probiotics in the treatment of Crohn’s disease.

Probiotics do not appear to be effective for prevention of allergic diseases or food hypersensitivity in pediatric patients.

Urinary tract infection

The use of probiotics in the treatment of urinary tract infections in human patients was reviewed by Lenoir-Wijnkoop.¹⁵¹ GI bacteria are a major source of urinary tract infections. As in animals, those causing UTI in humans are predominantly caused by uropathogenic E. coli, gram-negative organisms, and Enterococcus faecalis. In general, Lactobacillus sp. is the most common probiotic recommended for treatment of UTI. However, selected species are likely to emerge as more effective than others. A meta-analysis of 25 studies in human medicine found probiotics (lactobacilli) to be of benefit in treatment of bacterial vaginosis. However, a clear benefit could not be demonstrated for UTI (five studies); conclusions were difficult to draw because of limitations, including differences in study design and limited sample size.^163a

Oxalate urolithiasis

The use of probiotics in the treatment of renal oxalate stones in human patients was reviewed by Lenoir-Wijnkoop and coworkers.¹⁵¹ The absence of O. formigenes from fecal microbiota increases the risk of kidney stones. Both animal and human studies have documented that O. formigenes is able to become established in the GI tract, and establishment reduces urinary oxalate concentration. At least two studies have demonstrated a potential benefit of probiotics containing O. formigenes in the prevention or treatment of oxalate crystalluria.^164,165 Weese and coworkers¹⁶⁶ demonstrated that fecal samples containing lactic acid bacteria and several bacteria isolated from dogs or cats degraded oxalate in vitro. The addition of selected prebiotics (e.g., guar gum) increased the degradation.¹⁶⁶

Allergic diseases

The use of probiotics in the treatment of allergic diseases (including atopic allergic disease and asthma in human patients) was reviewed by Lenoir-Wijnkoop and coworkers.¹⁵¹ The rationale for efficacy reflects the immunomodulatory effects of probiotics. Based on clinical trials in humans, response has been limited to younger patients with severe disease. Similarly, probiotics have had only a limited, if any, effect on allergic rhinitis and asthma in humans.

Nosocomial infections

A meta-analysis examined the impact of probiotics on the prevention and treatment of nosocomial C. difficile–associated diarrhea and hospital-associated pneumonia in humans.¹⁶⁷ Although the prevention of antibiotic-induced diarrhea was a recognized beneficial effect, no evidence was found to support the theory that probiotics prevent nosocomial infection; clinical trials were recommended.

Irritable bowel syndrome

A meta-analysis¹⁶⁸ identified the limitations of drawing conclusions given differences in study design, including organisms, doses, and the definition of irritable bowel syndrome (IBS). Clinical efficacy was reported in several studies, with improvement manifested as decreased bloating, gas, and pain. Lactobacillus spp. and Bifidobacterium were targeted treatments.

Prebiotics (as opposed to probiotics) also have been associated with therapeutic benefits in humans with effects extending beyond local (GI) sites. The list is not much different than that for probiotics. Those conditions for which scientific evidence supports the potential use of prebiotics include allergies, immunomodulation (gut-associated lymphoid tissue as well as cellular Th1/Th2 ratio) that improves resistance to infections, constipation, irritable bowl syndrome, mineral metabolism (particularly strengthening of bone), prevention of cancer, and treatment of H. pylori infections. In addition, prebiotics have been scientifically associated with weight loss, presumably as a result of increased satiety mediated through GI suppression of ghrelin. Feed conversion efficiency has been described in food production animals. Interestingly, fermentation of prebiotics purportedly increases bacterial biomass in which nitrogen is fixed, thus decreasing the ammonia load in patients with hepatic encephalopathy.

Scientific data regarding the use of biotherapeutics in dogs and cats are slowly emerging. The use of prebiotics and probiotics in dogs has been reviewed by Rastall.¹⁵⁴ L. acidophilus DSM 13241 fed (2 × 10⁹ colony-forming units daily per dog) in 15 healthy dogs decreased the number of culturable Clostridum spp. and was associated with an increase in indices indicative of immunomodulation (increased serum IgG and monocytes and decreased plasma nitric oxide). Prebiotics that have been studied¹⁵⁴ include lactosucrose and fructooligosaccharides. In their report, the authors noted that most prebiotics are enzymatically synthesized and that the technology can be modified such that enzymes are obtained from the target microbe, thus yielding highly specific probiotics.

Feeding 1.5 g lactusucrose daily for 2 weeks to healthy dogs (n = 8) increased bifidobacteria and decreased Clostridium spp. In another study, Bifidobacterium and Lactobacillus organisms also increased, and Clostridium and Enterobacteriaceae organisms decreased in cats receiving 0.75 g daily. A decrease in toxin levels and odor also was described for both dogs and cats. Fructooligosaccharides fed at a rate of 4 g/day to adult health dogs (n = 20) increased Bifidobacterium and Lactobacillus organisms and decreased Clostridium spp. Although both lactate and butyrate increased, ammonia, dimethylsulfide, and hydrogen sulfide also increased. Fructooligosaccharides at a rate of 0.75% in the diet of healthy adult cats for 2 weeks decrease Clostridium spp. and E. coli. Rastall¹⁵⁴ also described the formulation of a symbiotic containing Lactobacillus organisms cultured from one dog, following the tradition of probiotics being based on microbes isolated from the target species. Among the isolates cultured, Lactobacillus mucosae, L. acidophilus, and Lactobacillus reuteri were subjected to prebiotic carbohydrates. Baillon and coworkers¹⁶⁹ prospectively studied the viability of L. acidophilus added to a dry dog food at a concentration of 10(9) colony-forming units. Dogs (n = 15) were fed control and treated diet for 2 weeks each. Supplementation of the diet resulted in fecal recovery of organisms during but not after feeding of the treated diet, indicating colonization had occurred. The number of clostridial organisms was decreased.

Probiotics might comprise wild-type microbes associated with natural microbiota or genetically mutated forms of otherwise pathogenic but normal microbiota. Different strains of probiotic bacteria are presumed to impart differential effects, with variability representing habitat preferences of the microbe, specific capabilities of the microorganism, and differential enzymes. The number of colony-forming units ingested as probiotics is minor compared with the normal microbiota.¹⁵¹ However, they travel through regions of the GI tract that are sparsely populated and therefore may transiently become the dominant microbe, potentially muting pathogens as a result of competitive exclusion. Rinkinen and coworkers¹⁷⁰ demonstrated the ability of lactic acid bacteria to competitively inhibit adhesion of selected canine pathogens (including C. perfringens) in vivo using isolated canine jejunal mucosa. However, Enterococcus faecium actually facilitated adhesion and colonization of Campylobacter jejuni, supporting the need for controlled clinical trials before assumptions are made regarding the impact of probiotics.

Probiotics and related compounds are not approved drugs and undergo no premarket approval with regard to efficacy, safety, or quality. Data, if available, represent efforts of the manufacturer or the scientific community. Consumer Laboratories (www.consumerlab.com) reviewed issues specifically related to quality assurance of a probiotic product. Many of these factors should be addressed on the label, including the following:

1. All types of bacteria or yeast, including genus and species, should be listed, with their correct spelling. The number of colony-forming units should also be included on the label. The number must be sufficient to allow adequate dosing in reasonable volumes. Generally 1 to 10 billion (10⁹ to 10¹⁰) colony-forming units are recommended (in humans) per day.

2. Viability of organisms, which may decrease during time that elapses from manufacture to purchase because of exposure to heat, moisture, and oxygen.

3. The presence of contaminating (potentially pathogenic) organisms including E. coli, Salmonella spp., Staphylococcus aureus, and Pseudomonas aeruginosa (according to Food and Drug Administration requirements).

4. The extent of enteric protection of selected organisms, including L. bulgaricus, S. thermophilus, and Leuconostoc and Lactococcus spp., varies (Table 19-4). Organisms that generally do not need protection include most Lactobacillus, Bifidobacterium, and Streptococcus organisms or organisms present as spores, including Bacillus and some Lactobacillus spp.

KEY POINT 19-36

Because probiotics and related compounds are not approved products, they undergo no premarket approval with regard to efficacy, safety, or quality; extra care should be taken to find a high-quality product.

Consumer Laboratories might also be solicited to identify superior products. Of 27 products (23 human, 4 pet) reviewed by Consumer Laboratories (as reviewed by the author January 2010), 10 (9 human, 1 pet) failed to contain the labeled amount of microbes and 5(2 human, 3 pet) failed to provide at least 10⁹ colony-forming units per serving (although dogs and cats may require less than 1 billion). Marked variability was found in the dose delivered among pet products. No product failed as a result of microbial contamination (with mold). Weese and coworkers¹⁶⁶ also examined the quality of probiotics, including eight veterinary products. The contents of only two of thirteen products matched labeled descriptions, with five veterinary products not providing specific content information. Some products did not contain all labeled products while some products contained additional bacteria, some of which were potentially pathogenic. Organisms in several products were not viable. These studies emphasize the importance of selecting a probiotic that meets the standards of quality assurance reviews.