Prokinetics: it's a moving story! (Proceedings)

Gastrointestinal (GI) prokinetic drugs stimulate smooth muscle contractions to enhance gastric emptying and transit of the small and large intestines. They are useful in the treatment of motility disorders in humans and animals because they induce coordinated motility patterns.

In human medicine, prokinetic drugs are used for the pharmacological treatment of several GI motility disorders such as gastroesophageal reflux disease, diabetic gastroparesis, delayed gastric emptying in critically ill patients, functional dyspepsia, constipation-dependent irritable bowel syndrome, idiopathic chronic constipation and postoperative ileus. In recent years however, withdrawal from the US market of two new prokinetic drugs has created a therapeutic challenge for the practitioner since it is increasingly recognized that the presently available "traditional" prokinetic drugs have major limitations.

In veterinary medicine, there is presently no prokinetic drug labeled for use in companion animals. Hence, the availability of these promotility drugs for use in veterinary patients is entirely dependent on the approval of their usage in human medicine. The most common GI motility disorders identified in companion animals are delayed transit disorders involving the esophagus (hypomotility, megaesophagus), stomach (delayed gastric emptying), small intestine (postoperative ileus) and colon (constipation and megacolon). These pathophysiological conditions of the GIT may benefit from the administration of prokinetic agents. However, it is important to remember that even though these medical conditions are commonly diagnosed (for which pharmacological treatment is warranted), adequate double-blinded, controlled, randomized, prospective studies have not been conducted in dogs or cats for any of the available prokinetic drugs.

In order to understand the specific mechanisms of action of the different prokinetic drugs, it is important to briefly review the physiology of the GIT. Roles of the GIT include immunologic interactions, digestive processes, modulation of sensation, and coordination of motility and secretion. The pathophysiology of functional GI disorders is thought to arise mainly from disturbances in sensation, motility and/or secretion. Receptors modulating these functions are prime pharmacological targets for the development of agonist or antagonist agents of prokinetic activity.

Objectives

1. Provide the practitioner with a brief review of GI physiology with emphasis on the Enteric Nervous System (ENS) and its important neuromodulating substances.

2. Provide the practitioner with an understanding of the different mechanisms of action underlying prokinetic action of available drugs.

3. Provide the practitioner with pharmacokinetic data that have clinical implications in the use of prokinetic drugs in dogs and cats.

4. Provide the practitioner with specific clinical uses of available prokinetic drugs.

5. Identify the adverse side effects and potential drug interactions associated with the administration of specific prokinetic drugs.

6. Provide the practitioner with an insight on future prokinetic drug development.

Important GI physiological points

1. Gastrointestinal functions are regulated by fine tuned extrinsic (parasympathetic and sympathetic fibers) and intrinsic (ENS) systems that are under complex neurohormonal control.

2. The ENS (also called "mini-brain") is a large and highly organized collection of neurons located in the walls of the GIT that includes the myenteric plexus (Auerbach's plexus) and the submucous plexus (Meissner's plexus).

3. Important identified neuromodulator substances involved in GI motility are either excitatory or inhibitory. Receptors for acetylcholine (ACh), serotonin (5-HT) and peptides (substance P, ghrelin, motilin, guanylate cyclase C, octreotide, CCK) are excitatory whereas NE (norepinephrine), dopamine, nitric oxide (NO), vasoactive intestinal peptide (VIP) and endorphins are inhibitory.

Important GI pathophysiological points

1. The most common GI motility disorders identified in companion animals involving the esophagus are hypomotility, megaesophagus, lower esophageal sphincter disorders.

2. The most common GI motility disorder identified in companion animals involving the stomach is delayed gastric emptying (functional obstruction/gastroparesis).

3. The most common GI motility disorders identified in companion animals involving the small intestine is postoperative ileus.

4. The most common GI motility disorders identified in companion animals involving the colon are chronic constipation and megacolon.

5. Most common etiological factors decreasing GI motility are autoimmune (myasthenia gravis), neuronal (trauma, dysautonomia), hormonal (hypothyroidism, hypoadrenocorticism, diabetes), inflammatory (bacterial, viral), iatrogenic (surgery, drugs), traumatic and congenital.

General mechanisms of action

Current pharmacologic targets for prokinetic action include cholinergic, dopaminergic and serotonergic receptors, motilin, opioid and H2 receptors, and chloride channels (Table 1).

Table 1. Current pharmacological targets for prokinetic action

Important pharmacologic points

1. Most of what we know is derived from in vivo and in vitro studies conducted in rodents and dogs as animal models for humans, as well as several clinical studies (Phase II to IV) conducted in human patients

2. In general, because of their pharmacological action, prokinetic drugs may affect the absorption of other oral medications and they are contraindicated in the presence of GI obstruction.

3. Metoclopramide has a short half-life hence it must be given often and has a variable oral bioavailability.

4. Metoclopramide is contraindicated in epileptic patients (extrapyramidal reactions and frequency/severity of seizure may increase) or with head injury (increase ICP).

5. The substituted benzamides, metoclopramide and cisapride, are mainly metabolized by the liver and may interact with other drugs.

6. Cisapride should not be given concomitantly with antifungal agents or macrolide antibiotics. These combinations may result in potentially fatal ventricular arrhythmias.

7. Erythromycin inhibits CYP450 and PgP transport (great potential for drug interactions).

8. Erythromycin increases gastric emptying rate in dogs, but large chunks may enter the small intestine and be inadequately digested.

9. Erythromycin may have decreased efficacy with long-term use. The combination of erythromycin and metoclopramide has shown to be beneficial and may be associated with less tachyphylaxis.

10. Ranitidine may increase the risk of side effects associated with metoclopramide when administered concomitantly.

Important therapeutic points (Table 2)

Critically ill/hospitalized veterinary patients are prone to impaired GI motility as they are often administered drugs that decrease GI motility (opioids, anticholinergics, calcium channel blockers, proton pump inhibitors, sedatives, cimetidine), have high levels of circulating catecholamines, may have head trauma or sepsis, have decrease activity or have undergone invasive surgery. These patients may benefit from the administration of prokinetic drugs as they may potentially shorten the hospital stay.

Table 2. Common gastrointestinal motility disorders and potential for the use of prokinetic drugs in dogs and cats

Additional details

Vomiting

Vomiting is complex and best described as a reflex act that is initiated by stimulation of the emetic center located in the medulla oblongata of the brain. Activation of the emetic center is initiated through neural central or peripheral stimulation (afferent vagal, sympathetic, vestibular and cerebrocortical pathways) and indirectly through humoral stimulation by activation of the chemoreceptor trigger zone (CRTZ) located outside of the BBB. Vomiting can arise from a variety of disorders (physiological or medical) or iatrogenically with the administration of certain drugs (e.g. cisplatin, xylazine, apomorphine, syrup of ipecac).

Important receptors involved in the vomiting process include 5-HT3, D2, M1, H1 and NK1 strategically located in the cerebellum, solitary tract nucleus, CRTZ and/or stomach. These receptors are pharmacodynamic targets for antiemetic agents. Metoclopramide possesses antiemetic properties due to its antidopaminergic effect on D2 receptors at the CRTZ, and antihistamines block the H1 receptor at the inner ear/cerebellum against motion sickness. Recently, several new antiemetic drugs have emerged in response to the increase use of chemotherapeutic agents in human as well as in veterinary patients. Antagonists of 5-HT3 such as ondansetron, granisetron and alosetron are efficient at preventing chemotherapy-induced vomiting. Most recently, a NK1 receptor antagonist, maropitant, has been approved by the FDA for the prevention of acute vomiting and the prevention of emesis due to motion sickness. However, with the exception of metoclopramide, none of these drugs have demonstrated prokinetic abilities, and may in fact, cause a decrease in GI propulsive motility.

Novel pharmacodynamic targets for prokinetic action

Prokinetic agents represent a significant unmet medical need and remain an active area of research for the pharmaceutical industry. New drugs are presently being investigated with the intent of providing targeted therapeutic strategies to address specific motor abnormalities of the GIT while ensuring safe pharmacological profiles. Novel targets include the motilin (agents without antibacterial activity), ghrelin, guanylate cyclase C (GC-C), 5-HT4/5-HT3, mu (µ), cholecystokinin (CCK1) and Neurokinin Type 1 (NK1) receptors, as well as chloride (ClC-C) channels and nitric oxide synthase (NOS). Lubiprostone and prucolapride offer some promise in the treatment of constipation, however, there are presently no clinical/pharmacokinetic studies conducted in dogs and cats using this PGE1 analog and highly selective 5-HT4 receptor antagonist respectively.

Summary

Prokinetic drugs are a useful treatment tool for a variety of GI motility disorders however, since there are no drugs of this class approved for use in companion animals, veterinarians are dependent on their availability for human patients. Metoclopramide remains the most common prokinetic drug used in veterinary medicine however it has its limitations. Since cisapride and tegaserod have been removed from the market by the FDA, the treatment of constipation has become a challenge for veterinarians. As our understanding of GIT motility disorders and the implication of different transmitter substances increases, it is hoped that novel prokinetic drugs will offer more targeted therapeutic action and safe pharmacological profiles.

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