Handbook of Clinical Neurology, Vol. 120 (3rd series) Neurologic Aspects of Systemic Disease Part II Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 43

Commonly used gastrointestinal drugs ANNU AGGARWAL AND MOHIT BHATT* Center for Brain and Nervous System, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Mumbai, India

INTRODUCTION Commonly used gastrointestinal drugs, including antiemetics, motility modifying drugs, and drugs for acidrelated disorders (Table 43.1), are extensively prescribed in various outpatient clinics, emergency departments, and intensive care units (Karamanolis and Tack, 2006; Herbert and Holzer, 2008). While, as a group, these drugs are generally considered safe across all age groups and many are available as over-the-counter preparations (Parikh and Howden, 2010), some of these drugs can occasionally lead to serious cardiovascular and neurologic complications (Pasricha et al., 2006). Table 43.2 lists a range of neurologic complications that have been reported following use of these gastrointestinal drugs. For instance, acute neurotoxicities including transient akathisias, oculogyric crises, delirium, seizures, strokes can develop after use of certain gastrointestinal medications (described in more detail below), while disabling and pervasive tardive syndromes are described following long-term, and often unsupervised, use of phenothiazines, metoclopramide, and other drugs. In rare instances, some of the antiemetics can precipitate lifethreatening extrapyramidal reactions, neuroleptic malignant syndrome, or serotonin syndrome. At the extreme, concerns over the cardiovascular toxicity of drugs such as cisapride or tegaserod have been grave enough to lead to their withdrawal from many world markets. However, most often the symptoms of neurotoxicity are innocuous (as in akathisias and various tardive dyskinesias), not readily reported by patients or attributed to a gastrointestinal medication, and the offending drug is continued (Miller and Jankovic, 1989). In this chapter we review the mode of action of the commonly used gastrointestinal drugs as well as the spectrum and mechanism of their neurotoxicity,

(Tables 43.1 and 43.2). This information should help a clinician weigh the benefits of prescribing the particular gastrointestinal drug against the associated risk of adverse effects, and recognise symptoms of neurotoxicity if they occur.

ANTIEMETICS Nausea and vomiting are triggered by stimulation of the medullary chemoreceptor trigger zone located outside the blood–brain barrier, the medullary central pattern generator, and the limbic forebrain regions (Hesketh, 2008). Development of antiemetics has paralleled understanding of neurotransmitters and neuroreceptors responsible for emesis. Early research on antiemetics focused on dopamine 2 (D2) receptor antagonists (phenothiazines, substituted benzamides, and butyrophenones). A recent advance in antiemetic therapy has been the elucidation of the key role of serotonin and tachykinins in stimulating emesis through central and peripheral receptors and development of selective serotonin 3 (5-HT3) receptor antagonists and selective neurokinin 1 (NK1) receptor antagonists (Roila and Fatigoni, 2006; Herrstedt and Dombernowsky, 2007; Hesketh, 2008; Feyer and Jordan, 2011). Since the introduction of cisplatin, a highly emetogenic chemotherapeutic agent, in the late 1970s, the main clinical drive to develop potent antiemetics has been to help prevent or abolish chemotherapy-induced nausea and vomiting (CINV) (Herrstedt, 2008). Currently, the therapeutic usefulness of an antiemetic is classified as high or low (Hesketh, 2008) based on their ability to prevent CINV (Roila and Fatigoni, 2006; Herrstedt and Dombernowsky, 2007; Hesketh, 2008; Feyer and Jordan, 2011).

*Correspondence to: Dr. Mohit Bhatt, Center for Brain and Nervous System, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Four Bungalows, Andheri West, Mumbai 400053, India. Tel: þ91-986-704-0404, E-mail: [email protected]

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Table 43.1

Table 43.2

Commonly used gastrointestinal drugs

Potential neurologic adverse effects associated with various commonly used gastrointestinal drugs#

Antiemetics

Promotility drugs

Laxatives

Antimotility agents Drugs for acidrelated disorders

Phenothiazines, e.g., chlorpromazine, prochlorperazine, promethazine Substituted benzamides – metoclopramide Butyrophenones – domperidone, droperidol Sertons, e.g., ondansetron, granisetron, tropisetron, dolasetron, palonosetron Neurokinin (NK1) receptor antagonists, e.g., aprepitant and fosaprepitant Substituted benzamides – metoclopramide Butyrophenones – domperidone, droperidol Cisapride Mosapride Renzapride Tegaserod Levosulpiride Stimulant laxatives, e.g., bisacodyl, sodium picosulfate Osmotic laxatives, e.g. (magnesium salts) Bismuth salts Dronobinol Selective H2 blockers, e.g., cimetidine, ranitidine, famotidine, nizatidine Proton pump inhibitors (PPI), e.g., omeprazole, esomeprazole, lansoprazole, pantoprazole, tenatoprazole, rabeprazole

Phenothiazines Antipsychotics, phenothiazines (for example, chlorpromazine, prochlorperazine, promethazine) were the first effective antiemetics. They acted by blocking central D2 receptors. Their antiemetic doses were limited by hypotension, restlessness, and sedation. At tolerable doses phenothiazines had a low therapeutic usefulness as antiemetics and extrapyramidal reactions and depression were a serious concern (Bateman et al., 1989; Weiden et al., 1987; Burke et al., 1989). Over the last three decades the availability of newer antiemetics with safer adverse effect profile (like selective serotonin 3 (5-HT3) receptor antagonists and selective neurokinin 1 (NK1) receptor antagonists) has helped curtail the use of phenothiazines as antiemetics.

Metoclopramide Metoclopramide is a benzamide derivative of procaine that was developed in 1964 to equal the antiemetic

Headache Dizziness Extrapyramidal syndromes Acute

Chronic

Mood disorders

Encephalopathy Seizures Cataplexy Syncopy Strokes Hyperthermic syndromes

Akathisias Dystonia including oculogyric crisis, oromandibular dystonia, retrocollis, opisthotonus posturing, dysphagia,* respiratory spasm,* status dystonicus* Tremor Myoclonus Drug induced parkinsonism Akathisias Tardive dyskinesias* Tardive dystonia Myoclonus Anxiety Psychosis Depression

Neuroleptic malignant syndrome* Serotonin syndrome*

#

Neurologic adverse effects associated with a particular gastrointestinal drug are detailed in the text. *Potentially life-threatening neurotoxicities.

properties of phenothiazines. Like phenothiazines, metoclopramide is a selective D2 receptor blocker, but unlike phenothiazines it has only a weak antipsychotic effect (Schulze-Delrieu, 1981). Additionally, metoclopramide has a partial 5-HT4 receptor agonist activity that enhances release of acetylcholine in the myenteric plexus and is responsible for its gastrointestinal prokinetic action. Metoclopramide is equipotent to chlorpromazine in preventing vomiting, at one-tenth of chlorpromazine doses (Harrington et al., 1983; Ganzini et al., 1993). In high doses, metoclopramide can prevent cisplatin-induced vomiting from antagonism of 5-HT3 receptors (Gralla et al., 1981; Schulze-Delrieu, 1981; Karamanolis and Tack, 2006). Metoclopramide was initially approved for use in diagnostic radiology to facilitate duodenal intubation and barium studies of upper gastrointestinal tract in patients with delayed gastric emptying. Later its use was extended to treat nausea and vomiting, diabetic gastroparesis, refractory gastroesophageal reflux and postoperative ileus. Over time, metoclopramide found application in a range of disorders including nonmigrainous headaches,

COMMONLY USED GASTROINTESTINAL DRUGS 635 Tourette’s syndrome, hiccups, neurogenic bladder, orthomarkets in 2000, following reports of its cardiotoxicity, static hypotension, anorexia nervosa, and select cases led to a surge of metoclopramide use as a prokinetic and of amenorrhea (Schulze-Delrieu, 1981; Tisdale, 1981; an increase in the incidence of metoclopramide-induced Harrington et al., 1983; Miller and Jankovic, 1989; TD (Shaffer et al., 2004; Kenney et al., 2008). Currently, Ellis et al., 1993). Currently, metoclopramide is used metoclopramide accounts for a third of all reported extensively as a prokinetic and to lesser extent as an DIMDs (Pasricha et al., 2006). antiemetic agent. TD are characterized by involuntary, repetitive moveMetoclopramide use can lead to extrapyramidal ments typically involving the oromandibular muscles symptoms (movement disorders or parkinsonism) that and axial muscles, including lip puckering, pursing develop acutely (within minutes or days) to more pervaand smacking, facial grimacing, tongue protrusion, sive disorders that develop after high doses or long-term rapid eye movements or blinking, and choreiform use. The extrapyramidal symptoms comprise acute movements of the limbs. The movements may be akathisia, dystonia, oculogyric crisis, tremor, and parkinaccompanied by tremor, dystonia, or parkinsonism. sonism, to tardive syndromes such as tardive dyskinesias, Metoclopramide-induced TD have been reported to dystonia, tremor or myoclonus, and rarely catalepsy lead to life-threatening dyspnea and dysphagia (Samie (Costall and Naylor, 1973; Miller and Jankovic, 1989; et al., 1987). High cumulative doses and long duraSethi, 2004). Mixed movement disorders may occur and tion of treatment are the major risk factors for may be accompanied by behavioral changes such as metoclopramide-induced TD. Elderly women and those restlessness, anxiety, or frank psychosis. The manufacwith a family history of DIMD and diabetes (Miller and turer’s package inserts (http://dailymed.nlm.nih.gov/daiJankovic, 1989; Sewell and Jeste, 1992; Ganzini et al., lymed) warn of extrapyramidal reactions in 1:500 1993) are vulnerable to metoclopramide-induced TD. patients treated with metoclopramide, but reviews of case In 2009, the US Food and Drug Administration (FDA) series suggest a higher figure (1–15%) (Miller and issued a black box warning for metoclopramide, advisJancovic, 1989; Parkman et al., 2004; Pasricha et al., ing that the drug use be restricted to recommended doses 2006). A prospective study of physician-reported and for not more than 12 weeks. It warned that chronic drug-induced dyskinesias-dystonia estimated the inciuse of metoclopramide therapy should be avoided in all dence of metoclopramide-induced dyskinesias-dystonia but rare cases where the benefits were believed to outto be 1/213 new prescriptions (Bateman et al., 1989). weigh the risks (http://dailymed.nlm.nih.gov/dailymed). Miller and Jankovic (1989) identified 131 patients with In a minority of patients TD can abate or resolve after drug-induced movement disorders (DIMD) from a discontinuing metoclopramide but in 71% of patients database of 3000 patients seen over 12 years, of whom or more TD are persistent despite drug withdrawal 16 (12.2%) had metoclopramide-induced DIMD. The aver(Grimes, 1981; Grimes et al., 1982a, b; Sewell and Jeste, age duration of metoclopramide use prior to DIMD onset 1992; Tarsy and Indorf, 2002). Currently there is no was 12 months (range 1 day to 4 years). Interestingly, the known treatment for TD (Samie et al., 1987; Miller drug was continued for 6 months after developing DIMD, and Jancovic, 1989; Sethi, 2004). TD developing after indicating either failure to diagnose DIMD or failure to discontinuation of long-term metoclopramide is also attribute the DIMD to metoclopramide. described (Lavy et al., 1978). Tardive dyskinesias (TD) are persistent and often Acute dystonic reactions including retrocollis, oculoirreversible involuntary movements that occur following gyric crisis, trismus, facial grimacing, dysarthria, dysphaprolonged neuroleptic therapy (Sethi, 2004). TD is the gia, and opisthotonus spasms are observed in commonest of the metoclopramide-induced movement approximately 1% of patients receiving metoclopramide disorders. In an epidemiologic study in the UK a review (Robinson, 1973). Dystonic spasms are often painful of 15.9 million metoclopramide prescriptions from 1967 and frightening. The resultant disability may vary from to 1982 identified 455 patients with TD (Bateman et al., a slight neck discomfort from cervical dystonia to 1985). Ganzini et al. (1993) examined 51 patients prepotentially life-threatening status dystonicus, dysphagia, scribed metoclopramide over a 4 month period at a respiratory distress, or respiratory arrest. Acute rhabdoveterans hospital medical outpatient clinic with an agemyolysis and myoglobinuria are known to occur (Mark and gender-matched control population for DIMD. and Newton-John, 1988; Mastaglia and Argov, 2007). The authors found relative risk of TD to be 1.67 in the The dystonic reactions commence within minutes to metoclopramide group. A retrospective analysis of 434 hours of drug administration and are often self-remitting, patients followed up for TD at a movement disorder or resolve within minutes of anticholinergic or dopamine clinic revealed that metoclopramide was responsible agonist treatment (Bhatt et al., 2004). Dystonia may for 39.4% of cases, and was the second most common be accompanied by acute parkinsonism, dyskinesia, astermedicine to induce TD following haloperidol (Kenney ixis, and myoclonus (Grimes et al., 1982b; Lu and Chu, et al., 2008). Withdrawal of cisapride from the US 1988; Miller and Jankovic, 1989).

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Children, young adults, and men are susceptible to developing acute dystonia following normal recommended doses of metoclopramide (Casteels-Van Daele et al., 1970; Robinson, 1973; Reid, 1977; Grimes et al., 1982b; Ganzini et al., 1993; Sethi, 2004). Acute dystonic reactions are also reported following metoclopramide overdose or accidental injection (Sills and Glass, 1978; Kerr, 1996). Metoclopramide doses need to be reduced in patients with renal failure (Bateman and Gokal, 1980; Grimes et al., 1982b). A familial tendency towards metoclopramide-induced dystonia is described (Gatrad and Gatrad, 1979; Miller and Jankovic, 1989; Guala et al., 1992). Poorly functioning or nonfunctioning CYP2D6 alleles, which slow metoclopramide metabolism, are reported in some familial cases of metoclopramide-induced dystonia (Van der Padt et al., 2006). Re-exposure to metoclopramide can cause recurrent dystonic reactions and the drug is best avoided if an extrapyramidal reaction has occurred. Rarely, recurrent dystonic reactions such as oculogyric crisis develop despite complete withdrawal of metoclopramide (Sethi, 2004; Schneider et al., 2009). Metoclopramide-induced parkinsonism or worsening of idiopathic Parkinson disease usually develops in the first 3 months of therapy and resolves within months of discontinuation of the drug. Symptoms persisting for a year after drug withdrawal are described (Miller and Jankovic, 1989). Compared to idiopathic Parkinson disease, patients with drug-induced parkinsonism are younger and have a symmetrical tremor (Indo and Ando, 1982; Yamamoto et al., 1987; Miller and Jankovic, 1989; Bondon-Guitton et al., 2011). People at the extremes of the age spectrum, children and the elderly, are at risk of metoclopramide-induced parkinsonism (Andrejak et al., 1990; Perez-Lloret et al., 2010). Akathisia, or motor restlessness, relieved by movements such as pacing, body rocking, crossing and uncrossing of legs, foot tapping, folding and unfolding of arms, or hand rubbing, is observed in association with metoclopramide use. Acute-onset akathisia is reported following intravenous metoclopramide use. Rapid infusions are associated with earlier onset and more severe akathisia (Parlak et al., 2005). Oral metoclopramide use reaching high peak plasma concentrations (over 100 ng/dL) can also lead to akathisia (Bateman et al., 1978), lasting for days after drug cessation (Poortinga et al., 2001). Acute akathisia was observed generally within the first 3 months of metoclopramide therapy (Lang, 1988). Acute onset akathisia is often selfremitting but may be associated with considerable anxiety, feelings of impending doom, and agitation, leading to refusal of treatment or surgery, violence, and even attempted suicide (Drake and Ehrlich, 1985; Caldwell et al., 1987; Sachdev and Kruk, 1994; Chow et al., 1997;

LaGorio et al., 1998). Tardive akathisia has been observed years after metoclopramide exposure (Burke et al., 1989). High-amplitude resting and postural tremor following chronic metoclopramide use has been reported (Stacy and Jankovic, 1992; Tarsy and Indorf, 2002). Reversible palatopharyngeal tremor with parkinsonism was observed in a woman following oral metoclopramide for 3 weeks (Nampiaparampil and Oruc, 2006). Metoclopramide-induced depression can develop after a few doses or after more protracted use (Anfinson, 2002).

Domperidone Domperidone is a peripheral D2 receptor antagonist and is used as a prokinetic and antiemetic of low therapeutic efficacy. It is the preferred drug to counteract levodopainduced vomiting and constipation in patients with Parkinson disease as in recommended doses domperidone does not block central dopamine receptors (Critchley et al., 1985). There are isolated reports of domperidone-induced akathisia, parkinsonism, depression, and tardive dyskinesias (Franckx and Noel, 1984; Biasini and Alberti, 1985; Leeser and Bateman, 1985; Steinherz et al., 1986; Bondon-Guitton et al., 2011), usually in the context of high doses. Psychosis following domperidone withdrawal after chronic use is described (Roy-Desruisseaux et al., 2011). Overdosage can lead to seizures (Weaving et al., 1984).

Setrons (5-hydroxytryptamine 3 (5-HT3) receptor antagonists, serotonin 3 receptor antagonist) Setrons are antiemetics that selectively block peripheral and central 5-HT3 receptors. Ondansetron and granisetron were the first setrons marketed in 1990s, followed by introduction of tropisetron, dolasetron, and finally the second generation setron, palonosetron, in 2003. Ramosetron and azasetron are currently available only in Japan. The available setrons have high therapeutic usefulness, and can prevent cisplatin-induced nausea and vomiting. The first generation setrons are interchangeable at equivalent doses. The drugs are safe, with the commonest adverse effects being constipation, transient elevation of hepatic aminotransferases, mild headache, and lightheadedness. Extrapyramidal reactions are rare (Kovac, 2003; Feyer and Jordan, 2011). Dramatic acute extrapyramidal syndromes have been observed following intravenous ondansetron. These complex involuntary movements variably include multifocal myoclonus, jerky “seizure-like” movements, tremor, involuntary eye blinking, eye deviation, facial grimacing, tongue protrusion, oromandibular dystonia, generalized dystonia, or opisthotonus spasms (Dobrow

COMMONLY USED GASTROINTESTINAL DRUGS et al., 1991; Tolan et al., 1999; Duncan et al., 2001; Ritter et al., 2003; Sprung et al., 2003; Spiegel et al., 2005; Kumar and Hu, 2009). The movements are focal or generalized, and occasionally voluntarily suppressible for short periods of time. Associated confusion, agitation, pyramidal signs, and hemodynamic instability are described (Ritter et al., 2003). Involuntary movements have also been described following use of oral ondansetron for several days (Lee et al., 2010) or overdosage (Sprung et al., 2003). Dose reduction has been shown to prevent the extrapyramidal reaction (Sprung et al., 2003). Benzodiazepines, diphenhydramine, or procyclidine (Stonell, 1998; Ritter et al., 2003; Sprung et al., 2003; Kumar and Hu, 2009) have helped ameliorate these extrapyramidal symptoms. Ondansetron has no direct effect on dopamine receptors. It is postulated that an overlap of central serotonergic and central dopaminergic systems is responsible for the observed extrapyramidal reaction to ondansetron. This hypothesis is supported by animal studies and benefit of ondansetron in levodopa-induced psychosis and dyskinesias in patients with Parkinson’s disease (Ritter et al., 2003; Sprung et al., 2003; Kumar and Hu, 2009). In a 2 year retrospective analysis of 1521 inpatients who received ondansetron for nausea and vomiting, Singh et al. (2009) identified three patients who developed brief generalized tonic-clonic seizures after intravenous ondansetron. Clinical seizures have also been reported following intravenous ondansetron use with other epileptogenic drugs (Sargent et al., 1993; Sharma and Raina, 2001). However, in the absence of electroencephalographic evidence of seizure, some authors have suggested that the “seizure-like” movements may be involuntary movements of extrapyramidal origin (Kanarek et al., 1992; Sprung et al., 2003; Singh et al., 2009). As yet no extrapyramidal reaction has been reported following granisetron or dolasetron, though crossreactivity with ondansetron is described (Lee et al., 1993; Sorbe et al., 1994). There are isolated reports of palonosetron-induced seizures (Zambelli et al., 2009).

Neurokinin receptor antagonists Aprepitant and its prodrug fosaprepitant are nonpeptide molecules that cross the blood–brain barrier and inhibit both peripheral and central receptors of substance P (neurokinin 1 (NK1) receptors). The drugs were initially developed as potential analgesics and antidepressants and later found to have a beneficial antiemetic effect. Both aprepitant and fosaprepitant are highly efficacious antiemetics and have emerged as the first-line antiemetics for controlling CINV. They are well tolerated and are not known to have any serious neurologic

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adverse effects (Feyer and Jordan, 2011). Aprepitant is metabolized by P450 (CYP) 3A4 and when coadministered with ifosfamide may aggravate ifosfamideinduced encephalopathy (Aapro and Walko, 2010).

DRUGS AFFECTING GASTROINTESTINAL MOTILITY Gastrointestinal motility is regulated by a complex interaction of the enteric nervous system, interstitial cells of Cajal (gastrointestinal pacemakers), smooth muscle cells (effectors of gastrointestinal motility), mucosal neuroendocrine cells, and the autonomic nervous system. Various neuroendocrine mediators including serotonin, dopamine, acetylcholine, motilin, cholecystokinin, and catecholamines help regulate gastrointestinal motility (Grundy et al., 2006; Herbert and Holzer, 2008).

Promotility drugs These accelerate gastric emptying and colonic transit and are used for treating symptoms associated with gastroparesis, functional dyspepsia, or constipation. Currently, metoclopramide is the most widely used gastrointestinal prokinetic. Development of newer prokinetics has been modeled to stimulate the prokinetic properties of metoclopramide without its extrapyramidal adverse effects. Cisapride is a serotonin 5-HT4 receptor agonist and 5-HT3 receptor antagonist that increases gastrointestinal motility by augmenting cholinergic transmission through the myenteric plexus. In 2000, cisapride was withdrawn from the North American and most European markets because of concerns about its potential to induce serious cardiac arrhythmias. Cisapride interferes with the pore-forming subunits of hERG (human Ether-a-go-go-Related Gene) K þ channels, delaying the ventricular repolarization and prolonging the QTc interval on ECG. Cisapride associated cardiotoxicity is enhanced when cisapride coadministered with drugs that inhibit the CYP3A4 enzyme and slow its metabolism (Karamanolis and Tack, 2006; Toga et al., 2007). Cisapride is available in some markets as a prokinetic for infants and young children (Raschetti et al., 2001; Vandenplas et al., 2001). Neurotoxicity from cisapride use is rare. Cisaprideinduced chorea in an 8-month-old boy (Lucena et al., 1998) and torticollis, dystonia, and myoclonus during infancy (Dieckmann et al., 1996) are described. Cisapride has been associated with persistent akathisia in a 3-yearold child from neonatal life. The movements resolved 2 months after discontinuation of the drug. The authors postulated that children are prone to neurotoxicity because of poorly developed blood–brain barrier

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and CYP3A4 enzymes (Elzinga-Huttenga et al., 2006). Dystonia, orofacial dyskinesias, and aggravation of parkinsonism following cisapride use in adults is reported (Naito and Kuzuhara, 1994). Renzapride and mosapride are benzapride derivatives, partial 5-HT4 receptor agonists, and 5-HT3 receptor antagonists. They are less efficacious than cisapride but have a good cardiac safety profile (with little or no action on hERG K þ channels). Renzapride has application in constipation-dominant irritable bowel syndrome while mosapride is used for upper gastrointestinal motility disorders (Karamanolis and Tack, 2006; Toga et al., 2007). Neurotoxicity has not been described as yet. Tegaserod is a partial 5-HT4 receptor agonist and 5-HT2b receptor antagonist. Antagonism of the 5-HT2b receptor results in decreased prokinetic efficacy. Postmarketing surveys have shown an increased risk of cardiovascular events (unstable angina, myocardial infarction, and stroke) and death with tegaserod use compared to placebo, leading to tegaserod withdrawal from the US and other markets. However, tegaserod is used in some regions for chronic constipation and constipation-dominant irritable bowel syndrome in women (Pasricha, 2007; Herbert and Holzer, 2008). Levosulpiride is a benzamide derivative, a selective D2 receptor inhibitor, 5-HT4 and partial 5-HT3 receptor stimulator. It is as effective as cisapride, but more effective than metoclopramide and domperidone, in increasing gastric and small intestinal motility (Rossi and Forgione, 1995; Karamanolis and Tack, 2006). Over the past decade there has been a considerable increase in levosulpiride prescriptions, especially in Asia and Europe. In South Korea, levosulpiride prescriptions were almost double of metoclopramide prescriptions (Shin et al., 2009). Extrapyramidal reactions have been reported following levosulpiride use and may be related to its ability to cross the blood–brain barrier (Rossi and Forgione, 1995; Kim et al., 2003; Karamanolis and Tack, 2006; Baik et al., 2008). In a movement disorder clinic in South Korea, 91 of 132 patients diagnosed with DIMD between 2002 and 2008 developed DIMD secondary to levosulpiride use. A majority of patients were elderly. Parkinsonism (n ¼ 85) was the commonest DIMD followed by TD (restricted to the orolingual region) (n ¼ 9) and isolated tremor (n ¼ 3). Levosulpiride was administered for period ranging from a few days to a few weeks (up to 3 years) prior to development of DIMD. Parkinsonism was reversible in 51.9% of patients within months of drug withdrawal. Three of the nine patients with TD and all three patients with isolated tremor recovered after levosulpiride withdrawal (Shin et al., 2009).

Antimotility and antidiarrheal agents Bismuth salts have been used for dyspepsia, peptic ulcer disease, colitis, and parasitic infections for many centuries. In 1970s, there was a series of reports of a potentially fatal myoclonic encephalopathy following use of bismuth salts (Ford et al., 2008). In France, 1000 cases of encephalopathy with 72 deaths were reported within a short period leading to the withdrawal of bismuth. The encephalopathy was characterized by a subacute confusional state, visual and auditory hallucinations, generalized tremulousness, myoclonic jerks, and gait problems. The encephalopathy was associated with high serum and CSF levels of bismuth and periodic complexes on EEG (Morrow, 1973; Burns et al., 1974; Escourelle et al., 1977; Supino-Viterbo et al., 1977; Tillman et al., 1996). Autopsy showed bismuth deposits in the brain, primarily in the gray matter, perivenular lymphocytic infiltration, and intracytoplasmic lipofuscin accumulation. Bismuth withdrawal led to remission. Recently there has been a renewed interest in using bismuth salts in smaller doses and for short periods for Helicobacter pylori eradication (Tillman et al., 1996; Ford et al., 2008). Dronabinol is a nonselective cannabinoid receptor agonist and is used to delay gastric emptying. Neurologic adverse events are uncommon and include headaches, dry mouth, lightheadedness and vasovagal syncopes, and poor concentration (Herbert and Holzer, 2008).

LAXATIVES Stimulant (bisacodyl, sodium picosulfate) and osmotic (magnesium salts) laxatives are safe and free from major adverse effects but can cause electrolyte disturbances (Herbert and Holzer, 2008).

DRUGS FOR ACID-RELATED DISORDERS Selective histamine 2 (H2) blockers (cimetidine, ranitidine, famotidine, nizatidine) and proton pump inhibitors (omeprazole, esomeprazole, lansoprazole, pantoprazole, tenatoprazole, rabeprazole) are widely used to treat acid-related diseases and functional gastrointestinal disorders (Lewis, 1991; Howden and Tytgat, 1996). As a class, both H2 blockers and proton pump inhibitors are safe with very few adverse effects other than diarrhea, headache, and dizziness, even on long-term use (Parikh and Howden, 2010). In fact, pooled data analysis suggested that incidence of adverse effects following ranitidine and famotidine use was no more than seen following placebo use (Lewis, 1991; Howden and Tytgat, 1996). A concern with the use of H2 blockers and proton pump inhibitors is inhibition of cytochrome 450 and the prolongation of the half-life of drugs with low

COMMONLY USED GASTROINTESTINAL DRUGS therapeutic index (such as warfarin, phenytoin, tacrolimus, ciclosporin, theophylline, and others). However, clinically relevant drug-to-drug interactions are not observed on chronic outpatient use of H2 blockers or proton pump inhibitors and these drugs are freely available as over-the-counter medications (Parikh and Howden, 2010). Long-term proton pump inhibitor treatment can lead to hypomagnesemia-induced seizure (Cundy and Dissnayake, 2008). Cimetidine (Edmonds et al., 1979; Flind and Rowley-Jones, 1979; Sharpe and Burland, 1980; Cerra et al., 1982; Handler et al., 1982), ranitidine (Bories et al., 1980; Hughes et al., 1983; Davis, 1984; Silverstone, 1984), famotidine (Henann et al., 1988; Catalano et al., 1996; Rodgers and Brengel, 1998; Yuan et al., 2001) and nizatidine (Galynker and Tendler, 1997; Bhanji and Margolese, 2004) induced mental confusion is described in elderly inpatients with coexistent liver or renal failure, or drug overdose. The confusion may be variable, associated with seizures, and visual hallucinations, cerebellar signs, and mild extrapyramidal features are reported. Symptoms remit with dose reduction or drug withdrawal. Dystonia is reported following acute use of cimetidine (Peiris and Peckler, 2001), acute and long-term use of ranitidine (Wilson et al., 1997), and overdosage of nizatidine (Bhanji and Margolese, 2004). Ranitidine-induced acute hemiballismus and dyskinesias are described (Fouddah et al., 2001; Elzinga-Huttenga et al., 2006). There are isolated reports of cimetidine-induced parkinsonism (Leo et al., 1995), myopathy, and motor neuropathy (Feest and Read, 1980; Walls et al., 1980). Further, both H2 blockers and proton pump inhibitors can theoretically impair neuromuscular transmission (Kounenis et al., 1994).

CENTRAL HYPERTHERMIA SYNDROMES AND GASTROINTESTINAL DRUGS Antiemetic use is associated with two life-threatening hyperthermic syndromes; the neuroleptic malignant syndrome (NMS) and the serotonin syndrome. NMS is characterized by hyperthermia, muscle rigidity, fluctuating sensorium, and autonomic instability. It is caused by abrupt central dopamine blockade and has been associated with prochlorperazine, promethazine, metoclopramide, and droperidol use. Dehydration and concomitant lithium therapy are risk factors. The syndrome can be rapidly fatal from rhabdomyolysis and multiorgan failure. Treatment involves withdrawal of the offending drug, hydration, benzodiazepines, dantrolene (muscle relaxants), dopamine agonists and supportive care (Guze´ and Baxter, 1985; Fisher and Davis, 2002).

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Serotonin syndrome results from a hyperserotonergic state following therapeutic drug use or inadvertent drugto-drug interactions. Manifestations of the serotonin syndrome range from mild akathisia and tachycardia to severe tremulousness, myoclonus, rigidity, sustained clonus, delirium, autonomic instability, hyperthermia, and cardiovascular shock. Metoclopramide and the setrons have been implicated in causing serotonin syndrome. Their use with serotonin reuptake inhibitors, antidepressants, lithium, triptans, opioid analgesics, valproate, linezolid, and other proserotonergic drugs can heighten the symptoms. Treatment involves withdrawal of the offending drug(s), hydration, benzodiazepines, HT2a antagonists, control of hyperthermia and autonomic dysfunction, and supportive care (Fisher and Davis, 2002; Boyer and Shannon, 2005; George et al., 2008; Patel et al., 2011).

CONCLUSION Antiemetic therapy has evolved from the use of dopamine blockers like the phenothiazines with the potential for serious extrapyramidal reactions to selective serotonin and neurokinin receptor inhibitors that are more potent than the phenothiazines (D2 blockers) and have a better safety profile. While metoclopramide remains the most extensively used prokinetic in most parts of the world, newer prokinetic agents with better adverse effect profiles are under development and review. Postmarketing surveys have been critical in identifying serious adverse effects such as the cardiotoxicity of cisapride, cardiovascular events following tegaserod use, and risk of tardive dyskinesias following long-term use of metoclopramide or levosulpiride. Epidemiologic studies have also helped in defining the spectrum of drug-induced neurotoxicity and at-risk populations. For instance, young men are susceptible to metoclopramide-induced acute dystonic reactions while the elderly are more vulnerable to suffering tardive dyskinesias (Bhatt et al., 2004). The commonly used gastrointestinal drugs, comprising antiemetics, promotility drugs and drugs to treat acidrelated disorders, are used to treat disorders that can lead to morbidity but are not fatal (Parikh and Howden, 2010). Therefore, the benefits of their use should be evaluated taking into account possible adverse effects, even if these are uncommon. As far as possible, drugs such as metoclopramide and others that can lead to tardive dyskinesias should be used for as short a time as possible, with close clinical monitoring and patient education.

ACKNOWLEDGEMENT The authors would like to thank Dr. Amruta Ravan for help with manuscript assembly and proofreading.

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