Drugs for Treating Gastrointestinal Diseases

46
Drugs for Treating Gastrointestinal Diseases


Mark G. Papich


Antiemetic Drugs


Neurotransmitters Involved in Vomiting


Several neurotransmitters are important for stimulating vomiting (Table 46.1) and successful therapy involves blocking one or more of the receptors for these neurotransmitters. There are differences between dogs and cats with respect to the importance of various receptors, and there are also differences between dogs, cats, and people. Dogs respond readily to administration of apomorphine, which is an agonist for dopamine. Cats vomit more readily from stimulation of α2-adrenergic receptors than dogs, and respond more consistently to administration of the α2-adrenergic agonists xylazine or dexmedetomidine. Histamine seems to be a more important neurotransmitter in the chemoreceptor trigger zone (CRTZ) in people than dogs or cats. These differences and overlapping effects of neurotransmitters can be confusing, but some generalities can be made, as follows.



  • In the emetic (vomiting), histamine (H1), acetylcholine (muscarinic M1), serotonin (5-HT3), dopamine (DA2), and neurokinin (NK-1) all play some role, although the importance may vary among species.
  • In the CRTZ, dopamine, serotonin, and acetylcholine (muscarinic) all play a role. Histamine has uncertain importance in dogs and cats. Drugs that block dopamine can be effective antiemetics from stimulation of the CRTZ in most animals.
  • In the vestibular apparatus (motion sickness) acetylcholine (muscarinic receptor) and histamine (H1) are important. Serotonin and adrenergic receptors also may play a role. Anticholinergic drugs (e.g., scopolamine) and antihistaminic drugs (e.g., diphenhydramine) can produce an antimotion sickness, antiemetic effect in people, but are less effective in dogs. Some of this may be caused by pharmacokinetic differences.
  • Afferents from the gastrointestinal (GI) system may mediate vomiting. Cancer drugs (e.g., cisplatin) injure the GI tract and release serotonin (5-HT3). Cancer drugs also may stimulate the CRTZ directly.
  • Neurokinin (substance P, NK-1) is a more recently described neurotransmitter that stimulates vomiting from several sources. NK-1 receptors are found in the emetic center and the CRTZ, but the most important are those receptors in the emetic center. Drugs described as NK-1 receptor blockers (e.g., maropitant, aprepitant) block vomiting from several sources, but seem to be less effective for alleviating nausea.

Table 46.1 Neurotransmitters important in vomiting













Dopamine, type 2 (DA2)
Histamine (H1)
Serotonin type 3 (5-HT3)
Acetylcholine, muscarinic type 1 (M1)
Substance P, neurokinin (NK-1)

Phenothiazine Tranquilizers


Dopamine is one of the neurotransmitters in the emetic center and CRTZ for stimulating vomiting at the DA2 receptor. Phenothiazine tranquilizers such as chlorpromazine (Thorazine®), prochlorperazine (Compazine®), promethazine, and acepromazine antagonize stimulation from dopamine in the CNS (Table 46.2). In addition to the antidopamine effects, these drugs can block alpha-adrenergic receptors (α1) in the emetic center. Some phenothiazines also block the histaminic and muscarinic (M1) receptors. Because of this broad action, and ability to inhibit vomiting from a variety of stimuli, this group of drugs has been called “broad-spectrum” antiemetics. Their side effects may limit clinical use in some patients. These side effects include sedation, altered involuntary motor activity (extrapyramidal signs), and peripheral α-adrenergic receptor blockade (vasodilation). Metoclopramide (discussed in section Metoclopramide (Reglan®)) also has antiemetic effects through its action on the DA2 receptor.


Table 46.2 Antiemetic drugs and doses





























































Antihistamines
diphenhydramine (Benadryl®) 2–4 mg/kg, IM, PO, q8–12h
dimenhydrinate (Dramamine®) 4–8 mg/kg, PO, q8–12h
promethazine (Phenergan®) 0.2–0.4 mg/kg, PO, IM, q8h
Phenothiazines
chlorpromazine (Thorazine®) 0.5 mg/kg, IM, PO, q6–8h
prochlorperazine (Compazine®) 0.1–0.5 mg/kg, IM, q6–8h
Acepromazine 0.1 mg/kg, IM, PO, q12h
triflupromazine (Vesprin®) 0.1–0.3 mg/kg, IM, PO, q8–12h
trifluperazine (Stelazine®) 0.03 mg/kg, IM, q12h
triethylperazine (Torecan®) 0.13–0.2 mg/kg, IM, q8–12h
metoclopramide (Reglan®) 0.1–0.3 mg/kg, IM, PO, q12h
Anticholinergic drugs
Atropine 0.02–0.04 mg/kg, IM, SC, q8–12h
methscopolamine (Pamine®) 0.3–1.0 mg/kg, PO, q8h
isopropamide (Darbid®) 0.2–1.0 mg/kg, PO, q12h
Antiserotonin drugs
ondansetron (Zofran®)

0.5–1.0 mg/kg, IV or oral 30 min prior to administration of cancer drugs


For vomiting from other causes, 0.1–0.2 mg/kg slow IV injection and repeated every 6–12h to control vomiting

NK-1 Receptor blockers
Aprepitant (Emend®, human drug) 1 mg/kg PO, q24h.
Maropitant (Cerenia®) 1 mg/kg SC, q24h, 2 mg/kg oral q24h, or 8 mg/kg oral (for prevention of motion sickness)

Antimuscarinic Drugs


Drugs that block muscarinic receptors (muscarinic M1 receptor) include atropine, scopolamine, aminopentamide (Centrine®), and isopropamide (isopropamide is combined with prochlorperazine in Darbazine®) (Table 46.2). These drugs decrease vomiting from various causes, including vomiting caused by vestibular stimulation (motion sickness) and stimulation of the CRTZ. In people, scopolamine has been one of the most effective agents for treating motion sickness (Transderm-Scop®), but it is less effective in dogs and cats. The adverse effects of anticholinergic drugs include xerostomia, decreased stomach emptying, ileus, urine retention, and constipation. These drugs are not practical for many of the causes of vomiting that are encountered in veterinary medicine. The adverse effects, including potential for ileus, can lead to other complications. These agents should be used cautiously in patients with glaucoma because there is a risk of increased intraocular pressure. Scopolamine has produced excitement in animals, particularly cats.


Antihistaminic Drugs


The histamine H1 and H2 receptor is involved in trans- mission of vomiting. Antihistamine drugs are discussed further in Chapter 19. Histaminic nerve transmission stimulates vomiting from the CRTZ and vestibular apparatus. This pathway does not appear to be important for cats, and is less important in dogs than in people. Antihistamines also can produce antimuscarinic (atropine-like) effects as well. Some of the phenothiazine drugs also act on histamine receptors and there is some crossover between these drug groups. Antihistamine drugs administered to control vomiting have included diphenhydramine (Benadryl®), dimenhydrinate (Dramamine®), promethazine (Phenergan®, a phenothiazine with antihistamine effects), and cyclizine, (Marezine®) (Table 46.2 ). Dimenhydrinate and diphenhydramine contain the same drug. Dimenhydrinate contains 54% diphenhydramine and 46% 8-chlorotheophylline. Theophylline is added to the human formulation to decrease the drowsiness from the antihistamine component. In dogs there was greater oral absorption of diphenhydramine when administered as dimenhydrinate than from diphenhydramine alone.


There are few published data on pharmacokinetics of antihistamine drugs in dogs or cats. Diphenhydramine oral absorption was only 8% in dogs and was highly variable. Oral absorption was better when administered as dimenhydrinate (23%) and had a half-life of 11.6 hours, but was highly variable. The half-life of diphenhydramine injection is only 2 hours in dogs. For other antihistamines, the perceived lack of efficacy of antihistamines that has been reported may be caused by poor oral bioavailability, rather than lack of effect at the receptor.


Adverse Effects


The antihistamines are relatively safe drugs. The most significant side effect of therapy is sedation, but this usually is not undesirable in most patients being treated for vomiting. Sedation occurs because the H1 receptor regulates sleep–wake cycles. The ethanolamines (diphenhydramine and dimenhydrinate) have the greatest sedative effects. Paradoxically, some of the antihistamines have caused excitement in cats.


Metoclopramide (Reglan®)


Metoclopramide has antiemetic effects via three mechanisms: (i) metoclopramide (at low doses) inhibits dopaminergic (DA2) transmission in the CNS, similar to phenothiazines; (ii) metoclopramide has peripheral effects on the GI tract that increase emptying of the stomach and upper duodenum; (iii) metoclopramide (at high doses) inhibits serotonin (5-HT3) receptors. 5-HT3 stimulates vomiting in dogs and cats either in the CRTZ or vagal afferent neurons. Metoclopramide is a broad-spectrum antiemetic that has been popular in small animal medicine, particularly for animals that vomit because of drug therapy (e.g., cancer drugs) or gastrointestinal disease. However, for control of vomiting caused by cancer drugs the results have often been disappointing (Fukui et al., 1992). This drug is also discussed later in the section on prokinetic agents.


Pharmacokinetics


There is large variability in the pharmacokinetics of metoclopramide in dogs. The half-life in dogs has ranged from about 100 to 190 minutes; the systemic availability of an oral dose is only about 50%. The dose administered to dogs and cats is based in extrapolation and empirical use rather than pharmacokinetic studies.


Adverse Effects


Metoclopramide is a dopamine antagonist and at high dosages it can produce adverse reactions that are similar to those caused by phenothiazine drugs. Adverse CNS effects from metoclopramide include excitement and behavior changes. To produce adequate antiemetic effects from blocking 5-HT receptors, high doses may be needed, which increase the risk of extrapyramidal CNS effects attributed to central dopamine (DA2) antagonism.


The increase in GI motility may produce some abdominal discomfort. Because metoclopramide stimulates upper GI motility, it should not be administered if there is an obstruction. Metoclopramide produces transient endocrine changes, including an increase in prolactin, but the significance of this effect in dogs and cats has not been determined.


Serotonin Antagonists


The pharmacology of serotonin and the antagonists are covered in more detail in Chapter 19. Specific serotonin antagonists include ondansetron (Zofran), granisetron (Kytril), palonosetron (Aloxi), and dolasetron (Anzemet). New drugs in development include tropisetron and azasetron. Of these, ondansetron (Zofran®) is the best known to veterinarians of the specific serotonin (5-HT3) inhibitors.


Ondansetron has been used to treat vomiting associated with cancer chemotherapy as well as nausea and vomiting caused by gastroenteritis, pancreatitis, and inflammatory bowel disease. In cats, the oral absorption was 32% from oral administration and 75% from subcutaneous administration. The half-life in cats was 1.8 hours from IV administration, 1.2 hours from oral administration, and more prolonged (3.2 hours) from subcutaneous administration. In dogs, it is much less bioavailable (<10%) after oral administration and shorter half-life of 30 minutes, raising questions about the clinical effectiveness of ondansetron in dogs.


The doses used for ondansetron are 0.5–1.0 mg/kg, IV or oral 30 minutes prior to administration of cancer drugs. For other diseases it has been administered at a dose of 0.1–0.2 mg/kg to dogs and cats and increased to 0.5 mg/kg if necessary, and given as often as every 12 hours. Because of concerns regarding oral absorption in dogs to obtain full effects, it should be administered intravenously. Other serotonin antagonists used for antiemetic therapy include granisetron, ondansetron, dolasetron, azasetron, and tropisetron.


As discussed in Section Metoclopramide (Reglan®), metoclopramide at high doses of 1–3 mg/kg can act as a serotonin antagonist and have been used as an IV infusion during cancer chemotherapy to decrease vomiting; but adverse effects are more likely at these high doses.


Glucocorticoids


Glucocorticoids such as dexamethasone have antiemetic properties, possibly by inhibiting prostaglandin synthesis. These drugs are used sometimes in addition to other drugs for decreasing vomiting, particularly when it is caused by cancer chemotherapy. Glucocorticoids are covered in more detail in Chapter 29.


Cannabinoids


Cannabinoids have been used in people who have not responded to any other antiemetic drugs (e.g., patients that are receiving anticancer drugs). The availability of medical marijuana and prescription forms of cannabinoids have increase the interest in the use in veterinary medicine. They have also been used to increase the appetite in human patients with terminal disease, cancer, and AIDS. Except for anecdotal accounts, the use has not been reported in veterinary patients. These agents have been used occasionally by some veterinarians to increase the appetite in cats, but these effects have been untested in clinical studies.


There are approximately 100 cannabinoids in the cannabis plant, but delta-9 tetrahydrocannabinol (Δ9-THC) is believed to be the most pharmacologically active. There are two important cannabinoid receptors: CB1 and CB2. The CB2 receptor is almost entirely peripheral and responsible for antiinflammatory and antinociceptive effects. The CB1 receptor is located centrally and is responsible for antinausea, psychoactive effects, appetite stimulation, and other central nervous system properties (Vemuri and Makriyannis, 2015). The effect on nausea and vomiting may occur from binding to the CB1 cannabinoid receptor in the emetic center.


The active ingredient in many cannabinoid products is Δ9-THC. Δ9−THC is a partial agonist for CB1 and CB2. Synthetic marijuana (THC) is available as a prescription drug (dronabinol) for antiemetic therapy; it is marketed as Marinol®. Cannabinoids are relatively well tolerated in people, but side effects include drowsiness, dizziness, ataxia, and disorientation. Withdrawal signs may occur after abrupt discontinuation following repeated doses. For dronabinol, the oral absorption is good, but bioavailability is low due to high first-pass effects. The volume of distribution is very high.


Suggested doses for dronabinol (Marinol®) in animals (but untested in clinical trials) are 5 mg/m2, and increased as needed up to 15 mg/m2 for antiemetic administration prior to chemotherapy. For appetite stimulation in animals, doses start at 2.5 mg before meals. It is available as 2.5, 5, and 10-mg capsules.


NK-1 Receptor Antagonists


The neurotransmitter neurokinin-1 (NK-1, also known as substance P) has several functions that include regulating vascular tone and permeability, mucus production and bronchial tone in the respiratory tract, heart rate, and some activity in the central nervous system. The effects on the emetic center led to the development of a new class of antiemetics to antagonize this receptor. The first one approved for use in people for cancer chemotherapy-induced vomiting was aprepitant (Emend®), which was the first substance P/neurokinin-1 (NK-1) receptor antagonist (Dando and Perry, 2004). The use of NK-1 receptor antagonists such as aprepitant in dogs was primarily experimental until the approval of a specific veterinary drug, maropitant citrate (Cerenia®) (Wu et al., 2004; Watson et al., 1995; Huskey et al., 2004; Fukuda et al., 1999; de la Puente-Redondo et al., 2007a; Vail et al., 2007). This agent was approved for use in dogs in 2007, and later approved for cats in 2012. It is available as a 10 mg/ml injection to be administered 1 mg/kg once daily SC for up to 5 days, or a tablet 16, 24, 60, or 160 mg to be administered at a dose of 2 mg/kg per day, PO, for up to 5 days. The tablet can also be used to prevent vomiting caused by motion sickness (vestibulitis) at a dose of 8 mg/kg for up to 2 days. The dosing interval can also be extended to 14 days without significant accumulation as described below in Section Pharmacokinetic. The original approval for dogs and cats restricted injection of maropitant to the SC route. However, some patients may have a painful reaction to SC injection (discussed in Section Adverse Effects). Subsequently, the sponsor obtained FDA approval for intravenous route of administration in dogs and cats to prevent vomiting associated with anesthesia and medical procedures.


The efficacy of maropitant is attributed to its central site of action. It blocks neurokinin-1 (NK-1) receptors in the area of the brain called the nucleus tractus solitarius – the site known as the emetic center. Input into the emetic center may come from different sources: gastrointestinal tract, higher brain centers, CRTZ, and vestibular apparatus (motion sickness). These inputs also utilize a variety of neurotransmitters: dopamine, histamine, acetylcholine, and serotonin. Traditionally, to block emesis from these stimuli, multiple drugs may be needed: antihistamines, antidopamine drugs (e.g., metoclopramide), dopamine antagonists (e.g., phenothiazines), and serotonin antagonists (e.g., ondansetron). Because NK-1 inhibitors – such as maropitant – block input from multiple sources regardless of the input they are considered broad spectrum in action.


Pharmacokinetics


Maropitant is extensively metabolized by the liver and there is little clearance by the kidney; therefore, no dose adjustments are needed in patients with compromised kidney function. There are primarily two canine isoforms involved with metabolism: CYP2D15 and CYP3A1 (Benchaoui et al., 2007a). Absorption from SC administration is rapid and complete (91% absorption), but oral absorption is limited by the first-pass metabolic effects (24% at 2 mg/kg and 37% at 8 mg/kg) (Benchaoui et al., 2007a). The half-life is 7.75 hours and 4–5.5 hours after SC and oral administration, respectively. However, the effects persist for at least 24 hours after a dose, presumably because of binding to the CNS NK-1 receptor that maintains the drug at the site of action. Penetration across the blood–brain barrier has been demonstrated (de la Puente-Redondo, 2007c), which is necessary for activity in the emetic center.


After repeated administration for 14 days, the half-life was 9.22 hours (mean) and 22 hours after doses of 2 mg/kg and 8 mg/kg, respectively (Lesman et al., 2013). In early label warnings there was a concern about accumulation of maropitant after administration consecutively for more than 5 days. However, follow-up pharmacokinetic studies examined administration of maropitant to dogs at a dose of 2 and 8 mg/kg for 14 consecutive days and steady state was achieved after four doses for once-daily 2 mg/kg and after eight doses for daily 8 mg/kg administration. The explanation for this lack of significant accumulation caused by saturation is that even though saturation of the CYP2D15 occurs at the label dosages causing nonlinear pharmacokinetics, at higher concentrations, the CYP3A12 becomes the primary metabolizing enzyme and linear pharmacokinetics are re-established (Lesman et al., 2013). Therefore, there was not significant accumulation used at the low dose of 2 mg/kg or the high dose of 8 mg/kg for 14 days.


Maropitant in Dogs


Maropitant is an effective antiemetic for a variety of stimuli, including cisplatin (chemotherapy)-induced vomiting, pancreatitis, enteritis, copper sulfate and apomorphine-induced vomiting, motion sickness, and ipecac-induced vomiting. In clinical and research trials, maropitant has been effective to treat and prevent chemotherapy-induced vomiting in dogs (Vail et al., 2007; de la Puente-Redondo, 2007a; Benchaoui et al., 2007b) and a wide range of stimuli such as viral disease, food and toxin ingestion, enteropathy, and other diseases (de la Puente-Redondo et al., 2007b). It was more effective than metoclopramide in this trial.


Maropitant has been effective in dogs that were prone to vomiting because of opiate premedication (Lorenzutti et al., 2016; Kraus, 2013, 2014a; Koh et al., 2014; Claude et al., 2014). In these trials, it inhibited vomiting caused by morphine and hydromorphone. The dose in these studies (1 mg/kg, SC or 2 mg/kg oral) was more effective if administered prior to the anesthesia medication (30–60 minutes for injection or 2 hours for oral). In some of the studies in dogs (Kraus, 2014b; Lorenzutti et al., 2016; Benchaoui et al., 2007a) maropitant was effective for reducing vomiting, but less effective for relieving nausea. This observation may indicate that maropitant is highly effective at the vomiting center to decrease emesis, but less effective for preventing the feelings of nausea.


Maropitant in Cats


Maropitant (Cerenia) was approved by the FDA for use in cats in 2012. The antiemetic effects have been demonstrated in both clinical and research cats (Hickman et al., 2009). Oral absorption is higher than dogs (50%) and the long half-life in cats (13–17 hours) is suitable for once-daily administration. It has been tolerated at doses of 0.5–5 mg/kg SC every day for 15 doses. The recommended dose for cats is 1 mg/kg for vomiting caused by motion sickness, and other causes that stimulate the vomiting center.


In addition to the uses listed above, maropitant was effective for reducing the incidence of vomiting associated with dexmedetomidine and morphine (Martin-Flores et al., 2016). However, as observed in the canine studies described above, it was more effective for reducing vomiting than for reducing nausea. In a study in cats with chronic kidney disease, maropitant prevented vomiting in these cats, but did not improve appetite or weight gain (Quimby et al., 2015). Therefore, as observed in some studies with dogs, maropitant may be effective for preventing vomiting, but may not prevent nausea to a similar degree.


Adverse Effects


Compared to other antiemetic drugs, maropitant has had a good safety profile. There are NK-1, -2, and -3 receptors throughout the body. Maropitant has little binding affinity to NK receptors, other than NK-1; it also does not bind to other CNS receptors such as GABA, opiate, adrenergic, serotonin, histamine, muscarinic, or dopamine receptors. Although NK-1 receptors are involved in a large number of other physiological and behavioral responses, at doses used for antiemesis in dogs, there were no adverse effects associated with these other functions.


One of the adverse effects reported is pain or a stinging response when injected subcutaneously (SC). This is caused by the irritant effect of the drug formulation when it dissociates at room temperature (Narishetty et al., 2009). Maropitant forms a molecular inclusion complex with a clodextrin in the formulation but, at refrigerated temperatures, the drug remains complexed within the cyclodextrin cavity. This complex provides higher drug solubility and improved injection-site tolerance. Entrapment of drugs in this cyclodextrin cavity prevents the direct contact of the drug with biological membranes by limiting the free drug concentration and thus reduces the injection related local irritation. This drug complex will remain intact and is less likely to cause pain from injection if refrigerated between uses.


Other Uses


Because NK-1 is also involved in transmission of pain, there has been interest in using these antagonists for analgesia. In dogs, administration of maropitant (1 mg/kg IV, followed by continuous intravenous infusion, CRI) has decreased anesthetic requirements in dogs undergoing abdominal surgery (Boscan et al., 2011). Maropitant was shown in an uncontrolled study to decreasing coughing in dogs with chronic bronchitis. Although it decreased the severity and frequency of coughing, it had no effect on airway inflammation (Grobman and Reinero, 2016). It is presumed that the antitussive effect is through a central effect on NK-1 receptors in the cough center.


Mirtazapine (Remeron)


Mirtazapine is used more often as an appetite stimulant – especially in cats – but it also has antiemetic properties and is briefly discussed here and also included in Chapter 18, along with other appetite-stimulating drugs for cats. Mirtazapine is used as an antidepressant medication in people and is used to treat mood disorders. Its mechanism of action is unknown but it may enhance central noradrenergic and serotonergic activity. In animals it has appetite-stimulating and antinausea properties. These effects are attributed to the 5-HT3 antagonist properties; therefore, it may share similar effects as antiserotonin medications discussed in Section Serotonin Antagonists.


Clinical Use


Mirtazapine has been studied more in cats than in dogs (Quimby and Lunn, 2013). These studies in cats demonstrated that it is an effective appetite stimulant. The dose is usually 1.88 mg per cat oral. At high doses it produces adverse effects that include vocalization and increased restlessness. In cats it has a half-life of approximately 10 hours, which allows for once-daily dosing. In cats with chronic kidney disease – for which appetite stimulation often is desired – clearance is slower and the half-life increases to 15 hours, which indicates that an every-other-day dosing schedule should be used in cats with kidney disease to avoid accumulation (Quimby et al., 2011). Mirtazapine is available as 7.5-mg tablets, but also is available in 15, 30, and 45-mg sizes. The formulation that some veterinarians prefer is a rapidly disintegrating oral tablet that dissolves easily in an animal’s mouth (15, 30, and 45 mg).


Gastrointestinal Prokinetic Drugs


Prokinetic drugs increase gastrointestinal motility (Washabau and Hall, 1997). They are used in dogs, cats, horses, and occasionally ruminants to stimulate gastric emptying, rumen motility, or to increase intestinal motility (Whitehead et al., 2016). Intestinal motility is sometimes decreased after intestinal disease or surgery and can lead to ileus. Some of these drugs are intended to restore normal motility to facilitate recovery.


Metoclopramide (Reglan®, Maxeran®)


Metoclopramide has multiple actions. It is a dopamine (DA2) antagonist, serotonin (5-HT4) agonist and serotonin (5-HT3) antagonist. Among the proposed mechanisms of metoclopramide is an increase in the release of acetylcholine in the GI tract, possibly via a prejunctional mechanism. It also may increase motility of gastric smooth muscle by increasing sensitivity of the cholinergic response. Since it also is a dopamine antagonist, it may antagonize dopamine’s (DA2) inhibitory action on GI motility.


Metoclopramide increases gastric emptying, increases the tone of the esophageal sphincter, and stimulates motility of the duodenum. It has less effect on distal segments of the intestine. Metoclopramide acts centrally to inhibit DA2, which produces the antiemetic effects discussed in Section Antiemetic Drugs. In people, metoclopramide also has been used to treat hiccups and lactation deficiency.


Adverse effects from metoclopramide can include excitement (seen in horses, for example), anxiety, and involuntary muscle movements. There are also endocrine effects: There is a transient increase in prolactin and aldosterone. Since some breast cancers are prolactin-dependent, there has been some concern about the carcinogenicity of this drug in women.


Use in Small Animals


In dogs metoclopramide has been used as an antiemetic more commonly than other drugs. Although it has been used to promote GI motility as well, this effect is less established than previously thought (Whitehead et al., 2016). For example, it is of little benefit to increase stomach emptying in disorders of gastroparesis or chronic regurgitation. It also has been used to stimulate normal upper motility following surgery (e.g., corrective surgery for gastric dilatation), but one study showed that metoclopramide did not change gastric motor activity to promote gastric emptying in dogs with gastric dilatation volvulus (Hall et al., 1996). In another study, it reduced, but did not prevent gastroesophageal reflux in anesthetized dogs at a dose of 1 mg/kg (Wilson et al., 2006). Doses are in the range of 0.25 to 0.5 mg/kg, q 8–12 h, but they have been increased to 1–2 mg/kg.


Use in Horses


Some equine surgeons have used infusions of metoclopramide (0.125–0.25 mg/kg/h) added to IV fluids to reduce postoperative ileus in horses (Gerring and Hunt, 1986). It may stimulate small intestine – but not large bowel – motility, but this has little benefit for horses with intestinal ileus (Sojka et al., 1988). Undesirable side effects in horses have been common, and include behavioral changes and abdominal pain. Since this drug transiently increases prolactin secretion, there has been interest in using this drug for treating agalactia in animals, but efficacy has not been determined. Domperidone is preferred for this effect (see Section Domperidone (Motilium, Equidone)).


Use in Ruminants


The clinical use of metoclopramide in large animals has not been as common as in small animals. Metoclopramide has little usefulness in cattle, although it may increase the motility of the rumen in cattle and sheep. It has been used successfully in some cattle with functional pyloric stenosis (Braun et al., 1990), but was not effective in calves (0.1 mg/kg IM). At doses higher than 0.1 mg/kg in calves it caused severe neurological side effects (Wittek and Constable, 2005).


Domperidone (Motilium, Equidone)


Domperidone is a dopamine-2 receptor (DA2) antagonist. It may also have α1-receptor antagonist and serotonin (5-HT2) antagonist effects. It has been available as a 10-mg tablet outside the USA as a human prokinetic drug but not allowed for human use in the USA because of cardiac toxicity. Its mechanism of action and GI prokinetic effects are similar to metoclopramide, but its efficacy has not been very impressive in animals and thus a clinical use has not been recommended (Whitehead et al., 2016). A difference between metoclopramide and domperidone is that the latter does not cross the blood–brain barrier. Therefore, adverse CNS effects are not as much of a problem compared to metoclopramide in horses. It may have antiemetic properties, but only if the stimulus for vomiting affects the CRTZ. It is capable of reaching the area postrema of the brain because this area is not protected by the blood–brain barrier. An additional effect is to stimulate lactation (see Section Use in Horses).


Use in Small Animals


The use is not reported, but it will produce a prokinetic effect in dogs at a dose of 0.05–0.1 mg/kg (2–5 mg/animal).


Use in Horses


Domperidone has been investigated for use in horses to treat fescue toxicity and agalactia. Fescue toxicosis is caused by a fungus that produces a toxin that induces reproductive toxicity in horses. The action of domperidone to increase lactation is through the stimulation of prolactin. It is approved by the FDA as an equine formulation of domperidone (Equidone oral gel, 11%). The approved dose is 1.1 mg/kg once daily starting 10–15 days prior to the anticipated foaling date. Treatment may be continued for up to 5 days after foaling if mares are not producing adequate milk. (This dose is equivalent to 5 ml per 500 kg – 5 ml per horse – daily, PO of the 11% oral gel.) Do not administer with stomach antacids such as omeprazole, cimetidine, or antacids.


The prokinetic effects in horses are not very impressive. At an IV dose of 0.2 mg/kg it was effective at restoring motility in horses with ileus, but this drug is not available in an injectable formulation. The oral absorption in horses is only 1.2–1.5%. Oral administration of 1.1 mg/kg (the approved dose) had no effect on GI function in horses but at 5 mg/kg it increased stomach emptying (Nieto et al., 2013).


Another use of domperidone is to increase digital laminar microvascular blood flow in horses. This effect is presumed to be via the action as an antagonist on vascular α2-adrenergic receptors. It was shown to increase laminar microvascular blood flow in normal horses (1.1 and 5.5 mg/kg oral), but has not been evaluated clinically for treatment of laminitis (Castro et al., 2010).


Cisapride


In July 2000, cisapride (formerly called Propulsid®) was removed from the market because of serious cardiac adverse events, and some deaths in people, secondary to cardiac arrhythmias. The drug sponsor has no plans to market this drug to veterinarians, but there is continued interest among veterinarians and it is still available via compounding pharmacists. Until other new replacement drugs become available, such as prucalopride or mosapride, veterinarians will rely on compounded formulations or consider alternative drugs.


The reviews on cisapride by Washabau and Hall (1995) and Van Nueten and Schuurkes (1992) describe the details of its mechanism of action and clinical effects. Cisapride has greater prokinetic effects in comparison to the other drugs discussed thus far. Its mechanism is believed to be as an agonist for the 5-hydroxytryptamine (5-HT4) receptor on myenteric neurons (5-HT4 ordinarily stimulates cholinergic transmission in the myenteric neurons). (Serotonin and antagonists/agonists are covered in more detail in Chapter 19.) Cisapride may also be an antagonist for the 5-HT3 receptor. Via these mechanisms – or independently – cisapride may enhance release of acetylcholine at the myenteric plexus. There is evidence that, in cats, cisapride directly stimulates smooth muscle motility via an unknown noncholinergic mechanism (Washabau and Summarco, 1996). Cisapride increases the motility of the stomach, increases stomach emptying, and increases motility of the small intestine and colon. It accelerates the transit of contents in the bowel and intestines. Because of the 5-HT3 antagonist properties, it also has some antiemetic effects. Other drugs with a similar mechanism of action have been investigated, but are not in clinical use. One such drug is mosapride. Like cisapride, mosapride is also a 5-HT4 agonist and has been approved in some countries for treating upper gastrointestinal motility disorders in dogs (Chae et al., 2015). It has been studied in experimental horses and demonstrated to increase motility of the small intestine and cecum at a dose of 1.5–2 mg/kg PO (Sasaki et al., 2005).


Pharmacokinetics


Oral absorption is variable because of extensive metabolism. The oral absorption in dogs and cats ranges from 30 to 60%. In horses, rectal absorption has been attempted, but the amount absorbed systemically is negligible (Cook et al., 1997).


Elimination half-life is variable, but ranges from an average of approximately 5 hours in dogs and cats to a much faster rate in large animals, 2 hours or less in horses and ruminants. The volume of distribution is high in small animals (>4 l/kg) and approximately 1.5 l/kg in large animals.


Use in Dogs


In dogs at a dose of 0.1 mg/kg (range 0.08–1.25 mg/kg) orally, it stimulates smooth muscle of the stomach, small intestine, and colon, with a duration of effect of about 3 hours. Routine clinical doses have ranged from 0.1 to 0.5 mg/kg every 8–12 hours.


Although cisapride has been used by some veterinarians for treatment of megaesophagus in dogs, the response is usually poor. The canine esophagus is striated muscle, with no smooth muscle to directly respond to the medication. Clinical use in dogs has included treatment for gastroesophageal reflux, delayed gastric emptying, and small bowel motility disorders. Compared to metoclopramide, cisapride is more effective for increasing lower esophageal sphincter tone in dogs, which is helpful for preventing reflux esophagitis (Kempf et al., 2014).


Use in Cats


Experiments have demonstrated that cisapride causes stimulation of the entire GI tract in cats. Of particular interest is the effect of cisapride on colonic smooth muscle. Cisapride will stimulate this motility and has been used for treating chronic constipation. By contrast, metoclopramide has no effect on colonic smooth muscle. The dose of cisapride in cats is approximately 2.5 mg per cat, two or three times daily. Doses as high as 1 mg/kg every 8 hours, or 1.5 mg/kg every 12 hours have been recommended by some investigators (LeGrange et al., 1997).


Use in Horses


In horses cisapride increases the motility of the left dorsal colon and improves ileocecocolonic junction coordination. In contrast to metoclopramide, cisapride has fewer side effects at doses needed to affect the GI tract and greater effects on the jejunum and colon than metoclopramide. Many investigators believe that it has a place in the postoperative management of horses that have undergone abdominal surgery. One dose tested to be effective was 0.1 mg/kg, IV. At this dose, the effects appear to persist for approximately 2 hours. Oral administration is usually not possible in these horses because of gastric reflux and absorption after oral administration in a horse with gastric reflux probably is questionable.


Availability of Formulations


The previously available tablet was a 10-mg tablet from Janssen Pharmaceutica. Although cisapride is insoluble in most aqueous solutions, solubility is possible in acidic solutions. An IV form may be created by preparing a 4 mg/ml solution in tartaric acid by a reputable compounding pharmacist. The preparation of this formulation was described in the publication by Cook et al. (1997). To prepare this solution, 40 mg of cisapride is combined with 1 ml of 0.4 M tartaric acid. After the cisapride is dissolved, dilute with water to obtain a total volume of 10 ml. Oral formulations for cats have been prepared from the bulk powder administered in a capsule, via a suspension in a flavored vehicle or dissolved in cod liver oil.


Side Effects and Interactions


Adverse effects have not been reported in animals; however, abdominal discomfort has been observed when animals received high doses. In safety studies, dogs have tolerated high doses (40 mg/kg) for prolonged periods without problems.


In people, high plasma concentrations have caused cardiac arrhythmias. The arrhythmias are caused by prolonged QT intervals, presumably from blockade of potassium channels. This can lead to serious arrhythmias and has been responsible for deaths in people. These reactions have not been reported for animals. Nevertheless, one should be cautious about combining cisapride with drugs such as itraconazole and ketoconazole that may increase plasma concentrations by interfering with metabolism.


Bethanechol (Urecholine)


Many of the formulations of bethanechol have been discontinued and are no longer marketed. Some generic forms may still remain and veterinarians have also obtained it through compounding pharmacies. This drug is a cholinergic agonist that has been used to nonspecifically stimulate smooth muscle. It binds to muscarinic receptors and initiates GI smooth muscle contractions, but its actions are nonspecific. In contrast to cisapride or metoclopramide, bethanechol has a more pronounced effect on motility of the ileocecocolic region in cattle (0.7 mg/kg). In horses, bethanechol increases gastric emptying at a dose of 0.025 mg/kg IV (Ringger et al., 1996). One of its other uses has been to stimulate contraction of bladder smooth muscle in animals that have a failure to completely empty their urinary bladder when voiding. Adverse effects are common and include diarrhea and other consequences of cholinergic stimulation.


Neostigmine (Prostigmin)


Neostigmine inactivates the enzyme acetylcholinesterase, which results in inhibition of degradation of acetylcholine at the synapse. It prolongs the action of acetylcholine and may directly stimulate cholinergic receptors. It is short acting. In horses, its use is discouraged because it may actually decrease intestinal propulsive contractions, delay gastric emptying, and cause abdominal discomfort.


One of the other uses of neostigmine in animals is for the treatment of neuromuscular diseases such as myasthenia gravis. Its adverse effects are significant, and include diarrhea, salivation, respiratory difficulty, vomiting, and muscle twitching. (Usually, another anticholinesterase drug, pyridostigmine, is preferred for treating myasthenia gravis because it has fewer side effects.)


H2-Receptor Antagonists


H2-receptor blockers such as ranitidine and nizatidine have prokinetic effects on intestinal smooth muscle in animals. These drugs are discussed later in Section Drugs for Treatment of Gastrointestinal Ulcers in Animals.


Erythromycin


Erythromycin is a macrolide antibiotic ordinarily used to treat bacterial infections. Pharmacology of macrolides is discussed in Chapter 36. It has long been associated with vomiting and regurgitation in small animals as an adverse consequence of treatment. This effect is caused by stomach contraction and expulsion at high doses. However, at low doses it can produce a beneficial stimulation of GI motility. Not all macrolide antibiotics exhibit this property because it requires a unique chemical structure that not all drugs in this class possess. (Erythromycin has a 14 carbon structure, but other macrolides that are less effective – tylosin and tilmicosin – have a 16 carbon structure.)


Erythromycin stimulates GI motility via activation of motilin receptors, via release of endogenous motilin, or via cholinergic mechanisms in the upper GI tract (Hall and Washabau, 1997; Lester et al., 1998; Hawkyard and Koerner, 2007). Motilin is a 22 amino acid peptide released from endocrine cells of duodenal mucosa. It increases the motor contractions, the housekeeper wave, during the interdigestive period. Motility is stimulated specifically in the pyloric antrum or the smooth muscle cells of the proximal small intestine (Nouri and Constable, 2007; Nouri et al., 2008). Because most of the motilin receptors are on the stomach and proximal small intestine, there is a weak response to erythromycin in the distal GI tract. In people, erythromycin has been used to promote gastric motility and increase stomach emptying in patients with diabetic gastroparesis and used in conjunction with enteral feeding in critical care patients (Hawkyard and Koerner, 2007).


The effective dose is 1 mg/kg or less – much lower than the antibacterial dose. It was effective for stimulating motility in experimental horses (Ringger et al., 1996), but clinical responses to erythromycin in horses have been somewhat disappointing. One study showed that responses to erythromycin in horses that had undergone surgery were not as effective as the effects in healthy horses (Roussel et al., 2000). A dose of 8.8 mg/kg IM increased abomasal and rumen motility in calves (Nouri and Constable, 2007; Nouri et al., 2008; Wittek and Constable, 2005). The dose in small animals is also in the range of 0.5–1 mg/kg, but has not been tested for clinical efficacy (Whitehead et al., 2016). There is a concern that erythromycin may cause diarrhea in some horses through the effect on the normal bacterial flora of the intestine. An additional concern is that routine use may promote antibacterial resistance.


Lidocaine


Lidocaine is a well-known local anesthetic. (Local anesthetics are covered in more detail in Chapter 15, and with antiarrhythmics in Chapter 22.) It is used for local infiltration for minor surgical procedures and to treat cardiac arrhythmias. Intravenous infusions of lidocaine also improve intestinal motility in horses. Lidocaine has been used in horses postsurgically to reduce postoperative ileus. Postoperative ileus in horses is a widespread clinical problem that may be caused by (i) sympathetic stimulation, (ii) pain, or (iii) inflammation. These effects inhibit smooth muscle motility in the intestine and lidocaine may work by suppressing this transmission. Another view on the mechanism is that lidocaine does not have a direct prokinetic effect, but rather restores motility via other mechanisms (Cook and Bilkslager, 2008). These authors presented evidence that in horses lidocaine restores motility by inhibiting intestinal inflammation and reperfusion injury.


In one study (Malone et al., 2006), lidocaine administration to horses produced less reflux and shorter time of hospitalization. Infusions of lidocaine have decreased postoperative ileus either through a direct effect, or via suppression of painful stimuli. Doses in horses are 1.3 mg/kg loading dose (bolus), followed by 0.05 mg/kg/min IV infusion.


Adverse Effects


As with the other uses of lidocaine, systemic administration may produce adverse events. The most common in horses have been muscle fasciculations, ataxia, and seizures. If signs are observed, decrease rate of infusion.


Opiate Antagonists for Promoting Intestinal Motility


Opiates and their antagonists are discussed in Chapter 13. Activation of opiate µ receptors in the intestinal smooth muscle decreases propulsive motility. Expression of µ-opiate receptors have been found in the submucosal plexus, myenteric plexus, and longitudinal muscle of the ileum. Activating these receptors has been used to treat some forms of diarrhea (e.g., loperamide). Administration of opiate analgesics postoperatively (Boscan et al., 2006; Sojka et al., 1988) or increased levels of endogenous opioids (endorphins), stimulate these receptors to inhibit intestinal motility causing postoperative ileus (DeHaven-Hudkins et al., 2008). Therefore, postoperative ileus may be treated by blocking intestinal opiate receptors (µ receptors) (Hicks et al., 2004).


Selective peripheral opiate antagonists act as peripheral opioid antagonists, rather than central opioid antagonists. They do not produce a central effect because they are unable to cross the blood–brain barrier. Naloxone should not be used for this indication because it will cross the bloodbrain barrier to diminish the analgesic effect of opioids. Such agents include alvimopan, methylnaltrexone, and naloxegol.


Alvimopan (Entereg®) has advantages over methylnaltrexone with respect to potency and duration of activity (DeHaven-Hudkins et al., 2008; Taguchi et al., 2001). It is administered orally with low bioavailability (6%) and produces a local effect on the intestine to promote motility, without diminishing analgesic effect of opioids. It is a zwitterionic molecule and the high polarity restricts its diffusion across the blood–brain barrier. A dose of 3 mg orally to people, three times daily completely reversed the GI effects of morphine, without affecting analgesia. The typical dose is 12 mg (one capsule) administered orally prior to surgery, and continuing after surgery twice daily.


Methylnaltrexone (Relistor®) is available as a SC injection (0.15 mg/kg) administered once every 48 hours for postoperative ileus. Like alvimopan, it does not have systemic effects and will not interfere with analgesia. There has been limited use of methylnaltrexone in horses. At a dose of 0.75 mg/kg IV q 12 h for four days to horses inhibited morphine-induced intestinal effects (Boscan et al., 2006).


Naloxegol (Movantik®), in 12.5 and 25-mg tablets, is a pegylated opioid antagonist. It is used for oral treatment of opioid-induced constipation. It acts peripherally because pegylation of the molecule reduces the ability of naloxegol to cross the blood–brain barrier and makes it a substrate for the efflux transporter P-glycoprotein.


Drugs for Treatment of Gastrointestinal Ulcers in Animals


Histamine H2-receptor antagonists, sucralfate, proton pump inhibitors (omeprazole), and antacids remain the principal drugs used to manage gastrointestinal ulceration in small and large animals (Table 46.3 ; Figure 46.1). The medical management of ulcer diseases will not be covered in this section, but readers are referred to other references for this information (Merritt, 2003; Papich, 1993; Matz, 1995; Henderson and Webster, 2006a, 2006b; Feldman and Burton, 1990).


Table 46.3 Antiulcer drugs: clinical uses



















Gastritis
Gastric ulcers
Duodenal ulcers
Gastrointestinal ulcer prevention
Esophagitis
Mast cell tumors
Hypergastrinemic syndromes
Prevention and treatment of NSAID-induced ulcers
Diagram shows stomach antisecretory drugs action with markings for gastric parietal cell, gastrin, histamine, ACh, cimetidine, atropine, gastric mucosa, et cetera.

Figure 46.1 Action of stomach antisecretory drugs on various receptors that stimulate acid secretion. Action of H2-receptor antagonists (e.g., cimetidine) and proton pump inhibitors (omeprazole) are shown. Gastrin and acetylcholine (Ach) are Ca++-dependent pathways and the histamine H2 is a cAMP-mediated pathway. See text for details.


Because many of the ulcerative diseases encountered in veterinary medicine are induced by drugs that inhibit prostaglandin synthesis (nonsteroidal antiinflammatory drugs, NSAIDs), one should be familiar with the role of prostaglandins in the GI tract, how their synthesis is inhibited, and treatments used to maintain the protective effect of prostaglandins in the GI tract. Veterinarians also should be familiar with the normal physiological role of protective mucus layer in the stomach, the cytoprotective mechanisms, role of bicarbonate secretion, and the normal mechanisms that restore epithelial cells in the stomach and intestine. These factors were reviewed by Allen et al. (1993) several years ago, but are still relevant today. When these protective factors become disrupted or compromised, ulcers can occur in animals. Gastrointestinal ulcers are a major health problem in horses, pigs, dogs, cats, and zoo animals. Conditions that increase the risk of gastrointestinal ulceration are administration of ulcerogenic drugs (NSAIDs, corticosteroids, and stomach irritants), stress, disrupted mucosal blood supply, and inflammatory diseases.


Gastrointestinal ulceration is an important medical problem in horses, in which the prevalence in animals involved in showing and racing has been listed as 81–93%, and even as high as 100% in some studies. In Thoroughbreds and Standardbreds the prevalence is was 80–95%; and in show horses it may be as high as 58%. Factors such as stall confinement, intense exercise, diet (high energy concentration in diet), and racing stress may be contributing factors. Location of ulcers in horses is primarily in the squamous epithelium (nonglandular portion). Factors that contribute to ulcers are the intermittent feeding schedule and high stomach acidity. In sick foals, ulcers also are common. Factors that contribute to ulcers in foals are NSAIDs, stress, and sepsis.


Antacids


The common antacids are bases of either aluminum, magnesium, or calcium. Examples include aluminum hydroxide (Al(OH)3), magnesium hydroxide (Mg(OH)2), and calcium carbonate (CaCO3, e.g., Tums®). These drugs neutralize stomach acid through a simple reaction to form water and a neutral salt. They have no systemic effects. In addition to their acid-neutralizing ability, antacids may benefit patients by decreasing pepsin activity, binding to bile acids in the stomach, and stimulating local prostaglandin (e.g., PGE2) synthesis.


Formulations


These drugs are common and almost always available over-the-counter (OTC). Commonly available antacid preparations (e.g., Maalox®, Mylanta®, DiGel®) are combinations of magnesium hydroxide and aluminum hydroxide to optimize the buffering abilities of each compound. These combinations balance the adverse effects of constipation from aluminum hydroxide and the laxative effect from magnesium hydroxide. One of the common products is Gaviscon®, which is popular for reflux esophagitis (heartburn) in people. The regular strength tablets contain 80 mg aluminum hydroxide and 14.2 mg magnesium trisilicate. The oral liquid contains 95 mg aluminum hydroxide and 358 mg magnesium carbonate per 5 ml (mint flavor). The tablets must not be swallowed whole and should be chewed, which should be considered before using the tablets for pets.


Adverse Effects / Interactions


Adverse effects from antacids are rare because they are seldom administered long term. Additionally, antacids are not absorbed and therefore lack serious systemic effects. In animals with kidney disease, magnesium accumulation may be a problem. For example, Gaviscon® oral suspension contains 115 mg magnesium per 5 ml. Antacids will interfere with the oral absorption of other drugs (e.g., tetracyclines, fluoroquinolones, and digoxin), if administered concurrently. The magnesium component, like any divalent cation (Mg++) can chelate with fluoroquinolones or tetracyclines and inhibit oral absorption. If these drugs are used together, administer the antibiotic 2 hours prior to the antacid drug. Oral antacids also reduce stomach acid, which affects oral absorption of some medications, particularly oral azole antifungal drugs. This is discussed with the drug interactions for other acid-suppressing drugs in Section Drug Interactions with Proton Pump Inhibitors.


Dosing Recommendations


Dose recommendations vary and are not precisely determined for dogs and cats. Empirically, 5–10 ml six times daily for small animals is often cited, regardless of the animal’s size or product used. The frequency of administration is a significant disadvantage for administration to pets; therefore, if long-term acid suppression is needed for dogs or cats, other agents are used (see other drugs in Section Drugs for Treatment of Gastrointestinal Ulcers in Animals). Doses of 180 to 250 ml have been administered to adult horses, but only suppressed acidity for 45 min to 2 hours (Murray, 1997). A dose of 30–60 ml for calves and foals has been recommended. For the treatment of acid rumen, magnesium hydroxide has been administered orally at a dose of 225–440 grams per adult cow, or mineral oil at 4 liters per rumen. For the treatment of grain overload, antacids have been administered at a dose of 450 grams per rumen, repeated every 6–8 hours.


Histamine H2-Receptor Antagonists


These drugs include cimetidine (the first in this class), ranitidine, famotidine, and nizatidine. These drugs became extremely popular after the initial release in the 1980s, but the use has declined because of the more potent and longer-acting proton pump inhibitors (discussed in Section Proton Pump Inhibitors). Blockade of histamine H2 receptors inhibits gastric acidity that can be beneficial for ulcer healing in the stomach and duodenum. In animals the evidence for efficacy – based on data generated from controlled studies – is lacking. In studies that have measured stomach acidity, or compared results with proton pump inhibitors (e.g., omeprazole) the H2-receptor antagonists were less effective. Nevertheless, many veterinarians continue to administer cimetidine, ranitidine, and famotidine with the impression that they are beneficial for the treatment of gastric and duodenal ulceration, gastric erosions, esophageal reflux disease, and gastritis in animals. There are various drugs in this group. They vary in their potency (Table 46.4) and in their pharmacokinetics, but there is no evidence for differences in efficacy among the drugs.

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Feb 8, 2018 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Drugs for Treating Gastrointestinal Diseases

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