Prokinetic agents are medications that enhance coordinated gastrointestinal motility and transit of content in the gastrointestinal tract, mainly by amplifying and coordinating the gastrointestinal muscular contractions. In addition to dietary therapy, prokinetic therapy should be considered as a means to improve gastric emptying and symptoms of gastroparesis, balancing benefits and risks of treatment. In the United States, metoclopramide remains the first-line prokinetic therapy, because it is the only approved medication for gastroparesis. Newer agents are being developed for the management of gastroparesis. This article provides detailed information about prokinetic agents for the treatment of gastroparesis.
Key points
- •
Prokinetic agents are medications that enhance coordinated gastrointestinal motility and transit of content in the gastrointestinal tract, mainly by amplifying and coordinating the gastrointestinal muscular contractions.
- •
Prokinetic therapy should be considered as a means to improve gastric emptying and symptoms of gastroparesis.
- •
Metoclopramide remains the first-line prokinetic therapy, because it is the only approved medication for gastroparesis in the United States.
- •
Other medications for gastroparesis should be used by balancing benefits and risks of treatment.
- •
There are newer agents being developed for the management of gastroparesis targeting different pathways: 5-hydroxytryptamine type 4 (receptor agonists), new motilin receptors agonists, and ghrelin agonists.
Introduction
Gastroparesis is defined as objectively delayed gastric emptying in the absence of mechanical obstruction and in the presence of upper gastrointestinal symptoms including early satiety, postprandial fullness, nausea, vomiting, bloating, and upper abdominal pain. The most common causes of gastroparesis are diabetes mellitus, postsurgical, and idiopathic; less common causes are iatrogenic, extrinsic neuronal (such as parkinsonism and paraneoplastic disease), and infiltrative disorders (such as scleroderma). The management of gastroparesis is based on dietary therapy; restoration of fluid and electrolyte balance; nutritional support; treating the underlying cause, such as optimization of glycemic control in diabetics; and stimulation of gastric emptying ( Fig. 1 ).
This article discusses in detail the prokinetic agents available or under evaluation for the treatment of gastroparesis.
Introduction
Gastroparesis is defined as objectively delayed gastric emptying in the absence of mechanical obstruction and in the presence of upper gastrointestinal symptoms including early satiety, postprandial fullness, nausea, vomiting, bloating, and upper abdominal pain. The most common causes of gastroparesis are diabetes mellitus, postsurgical, and idiopathic; less common causes are iatrogenic, extrinsic neuronal (such as parkinsonism and paraneoplastic disease), and infiltrative disorders (such as scleroderma). The management of gastroparesis is based on dietary therapy; restoration of fluid and electrolyte balance; nutritional support; treating the underlying cause, such as optimization of glycemic control in diabetics; and stimulation of gastric emptying ( Fig. 1 ).
This article discusses in detail the prokinetic agents available or under evaluation for the treatment of gastroparesis.
Prokinetics: definitions and classifications
Prokinetic agents are medications that enhance coordinated gastrointestinal motility and transit of content in the gastrointestinal tract, mainly by amplifying and coordinating the gastrointestinal muscular contraction. Prokinetics enhance coordination among the segments of the gut, which is necessary for propulsion of luminal contents. Prokinetics may be either selective to certain areas of the gastrointestinal tract or more generalized, and this reflects the distribution of the receptor targets of the different compounds.
Acetylcholine (Ach), released from primary motor neurons in the myenteric plexus, is the principal excitatory transmitter mediating muscle contractility; other excitatory transmitters are the tachykinins (such as substance P), motilin, and ghrelin. To date, most of the clinically useful prokinetic agents act upstream of Ach, at receptor sites on the motor neuron, or on neurons or nonneuronal cells that synapse with cholinergic neurons. Prokinetic agents are pharmacologically and chemically diverse; they release excitatory neurotransmitters at the nerve-muscle junction without interfering with the normal physiologic patterns and rhythms of motility.
The gastric prokinetics (their main effect is to enhance gastric contractility) include dopamine receptor antagonists, motilin receptor agonists, serotonin (5-hydroxytryptamine [5-HT] type 4 [5-HT 4 ]) receptor agonists, cholinesterase inhibitors, and ghrelin agonists. This article categorizes medications as approved or under evaluation.
Prokinetics in management guidelines for gastroparesis
The American College of Gastroenterology (ACG) guidelines, published in 2013, documented the evidence for the pharmacologic management of gastroparesis and used the GRADE (Grades of Recommendation Assessment, Development and Evaluation) system to evaluate the strength of the recommendations (strong, moderate, or weak if the desirable effects on an intervention clearly outweigh the undesirable effects, and as conditional if there is uncertainty) and the overall quality of evidence (high, moderate, low, or very low).
The most recently published guidelines for the pharmacologic management of gastroparesis are shown in Box 1 .
- •
In addition to dietary therapy, prokinetic therapy should be considered to improve gastric emptying and gastroparesis symptoms, taking into account benefits and risks of treatment (strong recommendation, moderate level of evidence).
- •
Metoclopramide is the first line of prokinetic therapy and should be administered at the lowest effective dose in a liquid formulation to facilitate absorption. The risk of tardive dyskinesia has been estimated to be less than 1%. Patients should be instructed to discontinue therapy if they develop side effects including involuntary movements (moderate recommendation, moderate level of evidence).
- •
For patients unable to use metoclopramide, domperidone can be prescribed with investigational new drug clearance from the US Food and Drug Administration and has been shown to be as effective as metoclopramide in reducing symptoms without the propensity for causing central nervous system side effects; given the propensity of domperidone to prolong corrected QT interval on electrocardiogram, a baseline electrocardiogram is recommended and treatment withheld if the corrected QT is greater than 470 milliseconds in men and greater than 450 milliseconds in women. Follow-up electrocardiogram on treatment with domperidone is also advised (moderate recommendation, moderate level of evidence).
- •
Erythromycin improves gastric emptying and symptoms from delayed gastric emptying. Administration of intravenous erythromycin should be considered when intravenous prokinetic therapy is needed in hospitalized patients. Oral treatment with erythromycin also improves gastric emptying. However, the long-term effectiveness of oral therapy is limited by tachyphylaxis (strong recommendation, moderate level of evidence).
- •
Treatment with antiemetic agents should be given for improvement of associated nausea and vomiting, but does not result in improved gastric emptying (conditional recommendation, moderate level of evidence).
- •
Tricyclic antidepressants can be considered for refractory nausea and vomiting in gastroparesis, but do not result in improved gastric emptying and may potentially retard gastric emptying (conditional recommendation, low level of evidence).
Approved medications (including off-label use)
Dopamine Receptor Antagonists
There are 2 dopamine receptor antagonists available for the management of gastroparesis: metoclopramide and domperidone. Metoclopramide should be the first-line treatment and is the only medication approved by the US Food and Drug Administration (FDA) for the indication of gastroparesis, with recommended use for less than 12 weeks. Domperidone can be prescribed through the FDA’s Expanded Access to Investigational Drugs program. Both agents are dopamine2 (D2) receptor antagonists. Dopamine inhibits the release of Ach, thus decreasing gastric and proximal small bowel motility. A D2 antagonist reverses the inhibitory effects of endogenous dopamine.
Metoclopramide
Chemistry and pharmacokinetics
Metoclopramide, or 4-amino-5-chloro- N -(2-(diethylamino)ethyl)-2-methoxybenzamide, is a substituted benzamide derivative, with a chemical structure similar to procainamide, but without antiarrhythmic effects. Metoclopramide is metabolized mainly by CYP2D6 and to a lesser extent by the CYP3A4 and CYP1A3 ; up to 30% of the drug is excreted unchanged in the urine.
Mechanism of action
Metoclopramide has dual activity as a D2 receptor antagonist and a 5-HT 4 agonist, decreasing effects of dopamine and thereby stimulating the cholinergic receptors. This effect promotes the release of Ach, which increases lower esophageal sphincter and gastric tone, increases intragastric pressure, improves antroduodenal coordination, and accelerates gastric emptying. The dual effects on gastric contractility and the centrally mediated antiemetic effect are considered responsible for the improved symptoms of gastroparesis ( Fig. 2 ). The antiemetic effect is mainly mediated from inhibition of D2 and 5-HT 3 receptors within the nausea or vomiting centers in the brainstem, especially the chemoreceptor trigger zone and the area postrema.
Pharmacodynamics and clinical pharmacology
The effect of metoclopramide on gastric emptying has been shown in short-term (less than 4 weeks) studies ( Table 1 ). Metoclopramide significantly increased gastric motor activity in patients with gastroparesis, often triggering an intense burst of motor activity in the stomach. Metoclopramide improved gastric emptying by 56% in patients with gastroparesis compared with 37% in the placebo group. These short-term studies showed generally poor correlation of acceleration of gastric emptying with symptom improvement.
| Reference # | Design | #, Cause | Dose | Duration | Results |
|---|---|---|---|---|---|
| DB, PC, XO, RCT | 10 DG | 10 mg QID | 3 wk/arm | Improved symptoms and vomiting; ∼60% acceleration in GE liquid 150-kcal meal | |
| DB, PC, PG, RCT | 28: 5 DM, 4 PSG, 19 IG | 10 mg QID | 3 wk | Improved symptoms by 29% | |
| PC, RCT | 18 DG | 10 mg QID | 3 wk | Improved symptom score by 29%, improved GE by 25% | |
| DB, PC, XO, RCT | 13 DG with GE accelerated by metoclopramide | 10 mg QID | 3 wk/arm | Improved symptoms with mean reduction of 52.6% | |
| DB, RCT, domperidone controlled | 45 DG | 10 mg QID | 4 wk | Improved symptoms by 39%; similar efficacy with domperidone, which had fewer AEs | |
| DB, XO, erythromycin- control RCT | 13 DG | 10 mg TID | 3 wk/arm | Both treatments accelerated GE compared with baseline and improved symptoms score | |
| Open | 1 DG | 15 mg QID | 6 mo | Improved symptoms, GE liquids, antral contraction frequency | |
| Open | 10 GI symptomatic (N,V) type 1 DM; 6 asymptomatic T1DM, 18 controls | 10 mg once | acute | Improved GE solids |
Formulations
Metoclopramide is available in multiple formulations: oral, orally disintegrating sublingual, intranasal, subcutaneous injections, and intravenous. The last 3 formulations have the advantage of bypassing the first-pass elimination in the liver and are ideal in patients with limited absorption caused by recurrent vomiting.
Dosing
The current guidelines recommend starting with liquid formulation at 5 mg orally, 30 minutes before meals and at bedtime. If needed, the doses can be increased to 10 mg, up to 4 times per day, but it is recommended to avoid doses higher than 40 mg daily to avoid side effects.
Adverse effects
Metoclopramide is associated with reversible or irreversible side effects, and the FDA has placed a Black Box warning on the use of metoclopramide ( http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm149533.htm ). Metoclopramide’s central nervous system (CNS) side effects are secondary to easy crossing of the blood-brain barrier and are observed in up to 30% of patients. Thus the most common side effects are related to the dopaminergic effects on the CNS. The reversible side effects, which resolve once the drug is discontinued, are mainly drowsiness, fatigue, lethargy, hyperprolactinemia, and worsening depression.
The extrapyramidal reactions associated with metoclopramide are acute dystonic reactions, such as facial spasms, torticollis, oculogyric crisis, trismus, abdominal rigidity, or spasm of the entire body; these effects usually are reversible. The irreversible and most concerning side effect is tardive dyskinesia, which typically occurs at doses higher than 40 mg daily. The overall frequency of all extrapyramidal side effects associated with metoclopramide is 0.2%. Treatment recommendations and careful monitoring are described by Rao and Camilleri.
In addition, metoclopramide may increase the half-life of other drugs metabolized by CYP2D6. Hence, the use of metoclopramide in combination with other neuroleptic drugs, such as haloperidol, thioridazine, chlorpromazine, perphenazine, and risperidone, can increase the risk of extrapyramidal symptoms. Polymorphisms in CYP2D6 , KCNH2 , and HTR4 genes were associated with side effects, whereas polymorphisms in KCNH2 and ADRA1D genes were associated with clinical response.
Domperidone
Chemistry and pharmacokinetics
Domperidone is a D2 receptor antagonist with similar efficacy to metoclopramide as an antiemetic and prokinetic. However, domperidone has poor penetration of the blood-brain barrier with limited to no CNS side effects. Domperidone structure is based on butyrophenones, and the drug has a low oral bioavailability (15%) that can be further decreased by increasing gastric pH. Domperidone has high affinity for gastrointestinal tissue, and high concentrations of the drug are found in the esophagus, stomach, and small intestine after oral administration. Approximately 90% of domperidone is bound to plasma proteins. It has a half-life of 7.5 hours, is mainly metabolized by the liver, and 32% of the drug is excreted in the urine.
Mechanism of action
Domperidone increases the amplitude of esophageal motor function and antroduodenal contractions, coordinates peristalsis across the pylorus, and accelerates gastric emptying. The effect of domperidone on gastric emptying has been shown in short-term studies ( Table 2 ).
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
