The P-I-E-N-O Parkinsn's List Drug Database
metoclopramide / ReglanTM , MaxolonTM , PraminTM
ANTIVOMITING:
Antiemitic: HIGH RISK
Description: Metoclopramide enhances GI motility and is an effective antinauseant. It is chemically related to procainamide and the generic name is derived from the chemical name "methoxychloroprocainamide". Metoclopramide, however, does not possess local anesthetic or antiarrhythmic properties. It was originally developed to treat nausea during pregnancy but is also extremely useful in the treatment of chemotherapy-induced nausea and vomiting. It also is effective in treating diabetic gastroparesis. Finally, metoclopramide facilitates intubation of the small bowel during radiologic examination. Metoclopramide was originally approved by the FDA in 1979. Phase III investigation of an intranasal dosage form for the treatment of chemotherapy-induced emesis has been completed. A NDA is expected to be filed by early 1995.
Mechanism of action: Metoclopramide's mechanism of action is complex. Unlike bethanechol, metoclopramide enhances gastric motility without stimulating gastric secretions. Peripherally, metoclopramide augments cholinergic activity either by causing release of acetylcholine from postganglionic nerve endings or by sensitizing muscarinic receptors on smooth muscle. Vagotomy does not inhibit metoclopramide effects on the GI tract as much as pretreatment with atropine does. Further confounding the issue is the fact that high doses of metoclopramide depress mechanical activity of GI smooth muscle, while low doses stimulate it. Effects on the resting tone of the lower esophageal sphincter combined with increased gastric emptying reduce gastroesophageal reflux, although this benefit is greater during the day than at night. The net effect of metoclopramide is a remarkable coordination of gastric and duodenal motility.
Centrally, metoclopramide blocks dopaminergic receptors, specifically, the DA subtype, in the chemoreceptor trigger zone as do other clinically useful antinauseants such as prochlorperazine. Unlike the phenothiazines, however, metoclopramide does not possess antipsychotic or tranquilizing activity. Metoclopramide also appears to be less sedating than other central dopamine antagonists. Metoclopramide effectively antagonizes the actions of apomorphine, a known central dopamine agonist. Antiemetic effects of metoclopramide are mainly the result of central dopamine antagonism and increased gastric motility, however, metoclopramide also possesses weak 5-HTA (e.g., serotonin type 3) receptor antagonism. Discovery of this minor action of metoclopramide lead to the development of potent 5-HTA antagonists such as ondansetron and granisetron. Central dopaminergic blockade produces antiemesis but also sedation and extrapyramidal effects. Inhibition of dopamine receptors in the pituitary and hypothalamus increases prolactin secretion, which can produce other adverse effects. Metoclopramide also acts on adrenal tissue to increase secretion of aldosterone.
Pharmacokinetics: Metoclopramide is administered orally and parenterally; an intranasal dosage form is under investigation. In the absence of gastroparesis, metoclopramide is rapidly absorbed from the GI tract. Peak plasma levels are generally achieved within 2 hours after oral dosing. Bioavailability is approximately 80% ñ 15.5%. Onset of action is 1-3 minutes after IV injection, 10-15 minutes after IM injection, and 30-60 minutes after oral dosing. Metoclopramide is distributed into breast milk, and it crosses the blood-brain barrier and the placenta. Metoclopramide is only weakly bound to plasma protein (about 30%).
Metoclopramide appears to undergo minimal metabolism but is conjugated with sulphuric acid or glucuronic acid. It is unknown if the major metabolite 2-[(4-amino-5-chloro-2-methoxybenzoyl)amino]acetic acid has any activity. Plasma concentrations decline in a biphasic manner, with a half-life of about 5 minutes in the initial phase and 2.5-6 hours in the terminal phase. Half-life is prolonged in patients with renal insufficiency. Within 72 hours, about 85% of an oral dose is excreted in the urine as unchanged drug (20%) or as the glucuronide or sulfate in patients with normal renal function. About 5% of an oral dose is excreted in the feces via the bile.
CONTRAINDICATIONS/PRECAUTIONS: Metoclopramide stimulates smooth muscle in the GI tract. It is contraindicated in patients with GI obstruction and GI perforation. It should be used cautiously in patients with GI bleeding for similar reasons, but metoclopramide has been used to empty the stomach of blood prior to endoscopy.
Metoclopramide is contraindicated in patients with pheochromocytoma because it can stimulate the release of catecholamines, possibly leading to a hypertensive crisis. Caution also is recommended in patients with existing hypertension.
Various CNS reactions can occur with metoclopramide, depending on the dose used (see Adverse Reactions). Metoclopramide should be administered cautiously to patients with a preexisting seizure disorder or parkinsonism. Children and adolescents are more likely to experience extrapyramidal effects. It is recommended that use in pediatrics be restricted to intubation of the small intestine. Metoclopramide should be used cautiously in patients requiring mental acuity; high-dose therapy causes drowsiness in 70% of patients. The occurrence of CNS depression also indicates cautious use in patients with a history of major depression.
Since metoclopramide is structurally related to procainamide, metoclopramide should be used cautiously in patients with a known procainamide hypersensitivity.
Metoclopramide should be used with caution in patients with renal disease, such as renal failure or renal impairment, due to possible accumulation and toxicity. Reduced doses are recommended for patients with low creatinine clearance.
Metoclopramide increases prolactin secretion and should be used with caution in patients with breast carcinoma.
Metoclopramide is classified as pregnancy category B. Although teratogenicity and/or fetotoxicity have not been observed, this drug should be used during pregnancy only if necessary.
Metoclopramide is distributed into breast milk and should be avoided during breast-feeding, if possible.
Some preparations contain sodium metabisulfite and should be used with caution in patients with a known sulfite hypersensitivity or in patients with asthma because bronchospasm can occur.
DRUG INTERACTIONS: Concurrent use of ethanol can increase the CNS depressant effects of metoclopramide. Combined use of metoclopramide and other CNS depressants can increase possible sedation.
Metoclopramide can increase the rate or extent of absorption of other drugs because of accelerated gastric emptying. Drugs that can be affected include acetaminophen, aspirin, diazepam, levodopa, lithium, and tetracycline.
Drugs with antimuscarinic anticholinergic activity can antagonize the stimulatory effects of metoclopramide on the GI tract. These drugs include antispasmodic anticholinergics such as atropine, dicyclomine, and propantheline; certain HA-blockers; opiate agonists; and certain tricyclic antidepressants.
Although data are limited, oral metoclopramide has been shown to increase the mean bioavailability of oral cyclosporine by roughly 30%. Until more data are available, cyclosporine serum concentrations should be monitored carefully if metoclopramide is added.
Because metoclopramide causes release of catecholamines in patients with essential hypertension, it should be administered cautiously to patients receiving MAOIs.
Metoclopramide is a central dopamine antagonist. Antagonism can occur if it is used concurrently with drugs that augment dopamine activity such as bromocriptine, pergolide, and levodopa.
If metoclopramide is used with other drugs that antagonize dopamine receptors, additive effects can occur such as extrapyramidal effects or dystonic effects. Other central dopamine antagonists include phenothiazines, thioxanthenes, amoxapine, droperidol, haloperidol, loxapine, and metyrosine.
Metoclopramide has been implicated in prolonging neuromuscular blockade from succinylcholine. Patient receiving metoclopramide and succinylcholine should be monitored for this effect. Succinylcholine doses may need to be reduced.
Because metoclopramide can enhance gastric emptying in diabetic patients, blood glucose levels can be affected, which, in turn, can affect dosing of insulin or oral hypoglycemics.
ADVERSE REACTIONS: Various CNS reactions can occur with metoclopramide, some of which are dose-related. Extrapyramidal and/or dystonic reactions are possible during metoclopramide therapy. Tardive dyskinesia has been reported with long-term use. Extrapyramidal effects can include akathisia, dystonia, and, possibly, tardive dyskinesia. These effects are more likely to occur in teenagers and young adults. The incidence is higher with higher doses. Tardive dyskinesia occurs more frequently in elderly female patients and can be irreversible. Although tardive dyskinesia is more likely to occur after prolonged therapy or high dosage, relatively brief therapy has been associated with this effect as well. Extrapyramidal effects usually occur within 24-48 hours of treatment and generally disappear within 24 hours of discontinuation. Other adverse CNS effects include drowsiness, restlessness, fatigue, lassitude, depression, and headache.
The cholinergic-like effects of metoclopramide increase gastric and duodenal motility, which can cause diarrhea.
Metoclopramide can increase prolactin secretion, which can result in breast enlargement, galactorrhea, libido decreases, impotence in males, and menstrual irregularity in women. These effects are generally reversible upon discontinuation of the drug. Serum prolactin levels return to normal in about 1 week, and adverse effects diminish within several weeks to several months.
PATIENT INFORMATION:
What do metoclopramide tablets do?
Metoclopramide (ReglanTM ) has a number of uses; its first use was in helping to control nausea. Metoclopramide also affects the digestive system. It controls reflux esophagitis, a condition in which the stomach contents come back into the tube connecting the stomach and the mouth. Metoclopramide can also help diabetic patients who develop diabetic gastroparesis, a condition that causes bloating, constipation, stomach pain, nausea and vomiting. Generic metoclopramide tablets are available.
What should my doctor, dentist, or pharmacist know before I take metoclopramide?
They need to know if you have any of these conditions:
How should I take this medicine?
Take metoclopramide tablets by mouth. Follow the directions on the prescription label. Swallow the tablets with a drink of water. Take metoclopramide on an empty stomach, about 30 minutes before eating. Take your doses at regular intervals. Do not take your medicine more often than directed.
What if I miss a dose?
If you miss a dose, take it as son as you can. If it is almost time for your next dose, take only that dose. Do not take double or extra doses.
What other medicines can interact with metoclopramide?
Tell your doctor or pharmacist: about all other medicines you are taking, including non-prescription medicines; if you are a frequent user of drinks with caffeine or alcohol; if you smoke; or if you use illegal drugs. These may affect the way your medicine works. Check before stopping or starting any of your medicines.
What side effects may I notice from taking metoclopramide?
Serious or limiting side effects are uncommon, but may include:
breast enlargement in men or women, or production of breast-milk in women who are not breast-feeding
change in the way you walk (shuffling feet)
difficulty speaking or swallowing
drooling, lip smacking, or rapid movements of the tongue
involuntary or uncontrollable movements of the eyes, head, arms and legs
muscle twitches and spasms
rigidity, or difficulty moving
uncontrollable shaking
unusual tiredness or weakness
Call your doctor as soon as you can if you get any of these side effects.
Minor side effects with metoclopramide include:
Let your doctor know about these side effects if they do not go away or if they annoy you.
What do I need to watch for while I take metoclopramide?
You may get drowsy or dizzy. Do not drive, use machinery, or do anything that needs mental alertness until you know how metoclopramide affects you. Alcohol can increase drowsiness or dizziness; avoid alcoholic drinks.
If you are going to have surgery, tell your doctor or dentist that you are taking metoclopramide.
Where can I keep my medicine?
Keep out of the reach of children in a container that small children cannot open.
Store at room temperature between 15 and 30C (59 and 86F). Throw away any unused medicine after the expiration date.
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