Reglan

Reglan (metoclopramide)

Pharmacology

Pharmacology: Metoclopramide, a benzamide, is an antiemetic agent. The mechanism of action of metoclopramide involves potent antidopaminergic activity in the chemoreceptor trigger zone. In addition, metoclopramide possesses prokinetic properties. While the prokinetic effects of metoclopramide are not well established, antidopaminergic activity as well as possible sensitization to acetylcholine may be involved. The prokinetic effects of metoclopramide do not depend on intact vagal innervation. The net result is stimulation of upper gastrointestinal motility, decreased pyloric sphincter tone, accelerated gastric emptying, and decreased intestinal transit time. Metoclopramide is indicated for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy and surgery. In addition, metoclopramide is indicated for the treatment of gastroesophageal reflux disease and gastroparesis as well as to aid in intubation of the small intestine and in radiologic examination of the upper gastrointestinal tract. Metoclopramide has also shown efficacy in the treatment of migraine headaches and intractable hiccups. However, these used have not been approved by the FDA and further studies are needed before this drug can be recommended for use for these indications.

Warnings

Metoclopramide is considered contraindicated in patients with a gastrointestinal hemorrhage, mechanical bowel obstruction, bowel perforation, or other disorder in which an increase in gastrointestinal motility could be harmful. Metoclopramide is considered contraindicated in patients with pheochromocytoma. Hypertensive crisis, possibly due to catecholamine release, has been associated with the administration of metoclopramide in these patients. Metoclopramide is considered contraindicated in patients with a seizure disorder or taking other medications which cause extrapyramidal side effects as metoclopramide may increase the incidence and severity of seizures or extrapyramidal symptoms in these patients. Neuroleptic malignant syndrome (NMS), a potentially fatal symptom complex, has been reported with the use of metoclopramide. The clinical manifestations of NMS include altered consciousness, diaphoresis, cardiac arrhythmias, hyperthermia, irregular pulse or blood pressure, muscle rigidity, and tachycardia. Tardive dyskinesia, a syndrome characterized by potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with metoclopramide. The syndrome can develop after brief treatment periods at low doses; in this type of scenario, symptoms are more likely to be reversed. Symptoms of mental depression, from mild to severe, including suicidal ideation and suicide have been reported with the use of metoclopramide. In patients with a prior history of depression, metoclopramide should be used only if the expected benefits outweigh the potential risks. Parkinsonian-like symptoms have been reported to occur within the first 6 months after the start of metoclopramide treatment, and in some situations after longer periods. In patients with a diagnosis of Parkinson's disease, metoclopramide should be used with caution. Acute dystonic reactions (extrapyramidal symptoms (SPS)) have been reported to occur more frequently in pediatric, and adult patients younger than 30 years of age, as early as 24 to 48 hours after initiation of treatment with metoclopramide. Caution should be exercised when administering metoclopramide IV to patients diagnosed with hypertension since there is a release of catecholamines associated with this route of administration. Because there is a transient increase in plasma aldosterone after metoclopramide administration, patients diagnosed with cirrhosis or congestive heart failure may be at risk of developing fluid retention and volume overload. If this occurs, the drug should be discontinued.

Pregnancy

Metoclopramide has been assigned to pregnancy category B by the FDA. Animal studies have failed to reveal evidence of fetal harm. There are no controlled data in human pregnancy. However, metoclopramide has been used during pregnancy for its antiemetic and gastric prokinetic effects. Metoclopramide is only recommended for use during pregnancy when benefit outweighs risk.Metoclopramide rapidly crosses the placenta near term. Fetal plasma concentrations are approximately 60% to 70% of maternal serum concentrations. While administration of metoclopramide at term is associated with significant increases in maternal serum prolactin levels, no changes were noted in cord arterial or venous plasma prolactin levels. In addition, metoclopramide does not affect maternal plasma TSH or estradiol levels. A case of acute porphyria in a female patient treated for hyperemesis gravidarum with metoclopramide in the 10th, 12th, and 18th week of pregnancy is reported in the literature. A normal infant was delivered at term. Data on the safety and efficacy of metoclopramide during pregnancy are primarily limited to the last trimester. More data are needed to evaluate safety in the first and second trimesters. Until then, the use of metoclopramide should typically be limited to the management of severe nausea and vomiting in the last trimester and to decrease gastric emptying time in the prevention of Mendelson's syndrome during labor and delivery.

Lactation

Metoclopramide is excreted into human milk. The American Academy of Pediatrics considers metoclopramide use during lactation to be of concern, citing the potent nervous system effects of the drug. The manufacturer recommends caution.In one study involving 23 women, metoclopramide milk concentrations ranged from 20 to 157 ng/ml following the oral administration of metoclopramide 10 mg three times a day for two weeks. Milk concentrations were consistently higher than corresponding serum concentrations. The estimated maximum exposure of the infant ranged from 6 to 24 µg/kg/day in the early puerperium and from 1 to 13 µg/kg/day in the late puerperium. Metoclopramide was detected in the serum of only one infant. In four of seven infants studied, plasma prolactin levels were elevated during maternal metoclopramide treatment compared to prolactin levels of control infants. Plasma thyrotropin concentrations in the infants were unaffected. In another study, infant serum prolactin, TSH, and free thyroxine concentrations were unaffected by maternal metoclopramide therapy (10 mg three times a day for 3 weeks).

Side effects

Nervous system side effects have been commonly reported and include drowsiness, fatigue, restlessness, and lassitude in approximately 10% of patients. Drowsiness may occur in up to 70% of cancer patients treated with high-dose (1 to 2 mg/kg/dose) metoclopramide. Tardive dyskinesia, dystonia, pseudo-parkinsonism, and the neuroleptic malignant syndrome have also been reported. In addition, cases of akathisia have been reported. Seizures and hallucinations are reported rarely.

Tardive dyskinesia involves involuntary, dyskinetic, repetitive movements and may be more common in elderly women. Tardive dyskinesia may be irreversible and is related to both the duration of therapy and the total amount of drug consumed. Frequent discontinuation and resumption of therapy may predispose patients to the development of tardive dyskinesia. Dystonias frequently involve tongue protrusions, muscle rigidity, torticollis, and opisthotonos. Dystonias usually resolve after metoclopramide discontinuation, but may require antihistamine and antiparkinsonian therapy if symptoms are severe or if respiration is compromised. Treatment of dystonic reactions and extrapyramidal effects, in addition to general supportive measures, may include judicious use of one or more of the following: benztropine, trihexyphenidyl, biperiden, or diphenhydramine. Hyperthermia, altered consciousness, autonomic dysfunction, and muscle rigidity are the hallmarks of the neuroleptic malignant syndrome. The neuroleptic malignant syndrome is associated with a case fatality rate of about 20%. Immediate discontinuation of metoclopramide therapy, consideration of dantrolene administration, as well as intensive monitoring and supportive care are indicated. Drug-induced parkinsonian symptoms due to metoclopramide may be misdiagnosed and inappropriately treated with dopaminergic agents. Parkinsonian-like symptoms have occurred, more commonly within the first 6 months from the start of therapy with metoclopramide, but occasionally after longer periods. Caution should be exercised when diagnosing movement disorders in patients currently being treated with metoclopramide. Additionally, metoclopramide should be avoided in patients with confirmed Parkinson's disease.

Endocrine side effects have included galactorrhea, amenorrhea, gynecomastia, and impotence secondary to hyperprolactinemia. In addition, metoclopramide may cause a transient increase in circulating aldosterone levels and subsequently cause edema.

Psychiatric side effects have included depression, anxiety, mania, and insomnia.

Depression may occur in patients without prior history of depression or other psychiatric illness and may be severe. Suicidal ideation may be present. Several reports suggest that dose reduction may alleviate depressive symptomatology. In addition, reintroduction of metoclopramide with slow titration of the dose upwards to a therapeutic level has been successful in some patients.

Cardiovascular side effects have included hypertension, hypotension, supraventricular tachycardia, and bradycardia. In addition, metoclopramide is associated with hypertensive crisis in patients with pheochromocytoma and has been implicated in a case of congestive heart failure.

It is postulated that metoclopramide may indirectly cause release of catecholamines from tumors in pheochromocytoma patients. Hypertensive crisis may ensue. The use of metoclopramide is considered contraindicated in patients with pheochromocytoma. Hypertensive crisis has been documented in the absence of pheochromocytoma as well. The manufacturer recommends cautious use of metoclopramide in patients with essential hypertension.

Hematologic side effects have been reported rarely and include leukopenia, neutropenia, and agranulocytosis. Methemoglobinemia has also been reported with metoclopramide use in adults, but may be more common in infants who are treated with high doses.

Hepatic side effects have included rare reports of elevations in liver function tests and jaundice. A case of arteriovenous shunting and cholestasis in conjunction with hepatic hemangiomatosis has been reported.

A 22 year old female, treated with metoclopramide 10 to 15 mg per day for 7 to 8 months for abdominal pain, developed hepatic hemangiomatosis with arteriovenous shunting and cholestasis. Hyperprolactinemia, galactorrhea, amenorrhea, and virilization were also noted on initial presentation. The patient was placed on a waiting list for liver transplantation. However, complete, albeit slow, resolution occurred following discontinuation of metoclopramide.

Genitourinary side effects have included urinary frequency, incontinence, and urinary retention.

Hypersensitivity side effects have included rash, urticaria, bronchospasm, angioneurotic edema, and glossal or laryngoedemal reactions.

Gastrointestinal side effects have included nausea and diarrhea.

Respiratory side effects have been reported rarely. A case of metoclopramide-induced bronchospasm is reported in the literature.

Other side effects have included porphyria, visual disturbances, local pain during intravenous injection, and transient flushing during high-dose infusion.