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

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Nov 01, 2009

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.