KNOW ABOUT ONE DRUG EVERY DAY METOCLOPRAMIDE

KNOW ABOUT ONE DRUG EVERY DAY

METOCLOPRAMIDE

Type

A para-aminobenzoic acid derivative used as an anti-emetic and to normalise gastric and small intestinal motility.

Pharmacology & General Information

Pharmacology

• Antagonist at both dopamine D₂ and 5HT₃ receptors. It acts in the enteric nervous system and in the chemo-receptor trigger zone.
• Note: Stimulation of upper gastrointestinal motility can be negated by administration of anticholinergic drugs.

·         Metoclopramide acts as a central antiemetic by blocking the uptake of dopamine at the chemo receptor trigger zone in dogs. Additionally, part of its actions on the upper GI tract include increasing the sphincter pressure in the lower esophagus and reducing gastroesophageal reflux, which also may be helpful for decreasing vomiting.

Physical interactions

• Physical compatibility has been reported (for periods of at least 24 hours) for: "aminophylline, ascorbic acid, atropine sulfate, benztropine mesylate, chlorpromazine HCl, cimetidine HCl, clindamycin phosphate, cyclophosphamide, cytarabine, dexamethasone sodium phosphate, dimenhydrinate, diphenhydramine HCl, doxorubicin HCl, droperidol, fentanyl citrate, heparin sodium, hydrocortisone sodium phosphate, hydroxyzine HCl, insulin (regular), lidocaine HCl, magnesium sulfate, mannitol, meperidine HCl, methylprednisolone sodium succinate, morphine sulfate, multivitamin infusion (MVI), pentazocine lactate, potassium acetate/chloride/phosphate, prochlorperazine edisylate, TPN solution (25% dextrose w/4.25% Travasol® w/ or w/o electrolytes), verapamil and vitamin B-complex w/vitamin C."
• Physical incompatibility has been reported with: "ampicillin sodium, calcium gluconate, cephalothin sodium, chloramphenicol sodium succinate, cisplatin, erythromycin lactobionate, methotrexate sodium, penicillin G potassium, sodium bicarbonate, and tetracycline."
• Note: Physical compatibility is affected by factors such as concentration, pH, temperature and diluents; specialized references should be consulted for more specific information.

Therapeutic Information

Uses/Indications

Activity

Gastrointestinal: Restores normal gastrointestinal motility and facilitates gastric emptying. Gastric contractions are increased in tone and amplitude, the pyloric sphincter is reduced and both duoodenal and jejunal peristalsis are increased; these actions can lead to significant reductions in time to gastric emptying and in intestinal transit time. Increases lower oesophageal sphincter tone and reduces or prevents  gastro-oesophageal reflux (producing a local antiemetic effect).  

CNS: Central anti-emetic effect and stimulation of prolactin secretion.

Dogs and Cats

Metoclopramide is used in a wide variety of gastric motility disorders, including ileus and gastritis. Because so many upper GI emptying disorders present with nausea and vomiting due to abnormal gastric emptying, metoclopramide is particularly useful because of its effects on motility and its function as a central antiemetic. It also may be used to control nausea and vomiting in cases of renal failure, acute hepatic failure and hepatitis, and in animals undergoing chemotherapy.

Horses

Intravenous metoclopramide is used in foals to treat illeus associated with neonatal hypoxia. In these foals, metoclopramide should improve gastric emptying and upper GI function. Metoclopramide occasionally is used in cases of post operative illeus in the adult horse; however, neurologic side effects limit its usefulness in adult horses.

 Appropriate Use

• As an antiemetic, to reduce vomiting in individuals with gastritis (including e.g. uraemic gastritis), or following surgery, or vomiting induced by chemotherapy.
• Treatment of gastric stasis.
• Treatment of ruminal atony.
• Treatment of abomasal atony and dilatation.
• Treatment of oesophageal reflux.
• Treatment of post-operative ileus.
• To allow small intestine intubation.

Limitations

• Does not increase motility of the lower small intestine or the large intestine.

Pharmacokinetics and Drug Interactions

Absorption /Bioavailability

• Oral: well absorbed. Significant first-pass effect in some individuals; in humans it is known this can reduce bioavailability to 30%, but this is highly variable between individuals. Peak plasma levels within two hours of administration.
• Intramuscular: 74 - 96%.

Distribution Well distributed; enters the CNS, crosses the placenta. Concentration in milk about twice the concentration in plasma.  

Plasma Protein binding / Storage About 13-22% plasma protein-bound.  

Elimination Route

In dogs: 

• Mainly metabolised (to glucuronidated or sulphated conjugated forms) then excreted in urine. 
• About 20-25% excreted unchanged in urine.
• About 5% excreted in faeces.

Elimination half-life / Clearance Rate

In dog: half-life about 90 minutes.

Drug Interactions

• Metoclopramide may affect the absorption of other oral medications including cyclosporine and tetracyclines.
• Cholinergic drugs such as bethanechol may increase the effect of metoclopramide on the GI system.
• Metoclopramide may increase the CNS-depressant effects of phenothiazine tranquilizers, sedatives, narcotics, barbiturates, antihistamines and anesthetic agents.
• Extrapyramidal effects of metoclopramide also may be increased with concurrent use of phenothiazine tranquilizers, narcotics and butyrophenones.
• Acute hypotension may occur with IV use of metoclopramide and anesthetic drugs. Hypertension may occur with concurrent use of metoclopramide and MAO inhibitors.
• Opiate analgesics, atropine and other anticholinergic drugs may antagonize any effects on GI motility.

• The gastro-intestinal motility effects of metoclopramide may be negated by anticholinergic compunds such as atropine, and by narcotic analgesics.
• Absorption of many drugs may be affected by the actions of metoclopramide on the gastrointestinal tract:
• Reduced absorption may occur with drugs that dissolve, disintegrate or are absorbed in the stomach (e.g. digoxin).
• Absorption of drugs which are mainly absorbed in the small intestine may be increased.
• Absorption of food may be accelerated; this may affect the required doses or timing of insulin.
• The CNS effects of metoclopramide may be enhanced by sedatives, tranquillisers and narcotics.
• The extrapyramidal effects of metoclopramide may be potentiated by phenothiazines such as acepromazine and chlorpromazine, and by butyrephenones such as droperidol and azaperone.

Administration

Doses / Administration Routes / Frequencies

Dogs and cats: 0.2–0.5 mg/kg, PO or SC, tid; 0.01–0.02 mg/kg/hr, IV infusion

Horses: 0.125–0.25 mg/kg, diluted in 500 mL of polyionic solution and administered IV over 60 min.

Domestic rabbit:

• 0.2 - 1.0 mg/kg orally, subcutaneously, intramuscularly or intravenously twice daily.
• 0.5 mg/kg subcutaneously or orally twice daily. As a motility stimulant.
• Note: "May not be effective in young rabbits."
• 0.5 mg/kg subcutaneously or orally every 6 - 12 hours.
• 0.5 - 1.0 mg/kg subcutaneously or orally every 6 - 12 hours.
• 0.2 - 0.5 mg/kg orally or subcutaneously every 2 - 4 hours.
• 0.5 mg/kg orally or subcutaneously every 8 - 24 hours.

Note: Increased efficacy if given as a constant rate intravenous infusion rather than bolus intravenous injections.

Dosing Information

• The typical dose administered to animals is 0.2 to 0.5 mg/kg every six to eight hours orally, subcutaneously or intravenously.
• It is often recommended to give metoclopramide 30 minutes before meals.
• The duration of administration depends on the condition being treated, response to the medication and the development of any adverse effects. Be certain to complete the prescription unless specifically directed by your veterinarian. Even if your pet feels better, the entire treatment plan should be completed to prevent relapse or prevent the development of resistance.

Monitoring parameters Monitor for clinical efficacy and for adverse effects.  

Toxic Information

Contraindications / Precautions

Precautions

• Metoclopramide should not be used in animals with GI obstruction, perforation or hemorrhage.
• Metoclopramide should not be used in animals with a history of seizures, as it may lower the seizure threshold.
• Metoclopramide should not be used in animals with pheochromocytoma.

Contraindicated in:

• Individuals with known hypersensitivity to this drug.
• Individuals with gastrointestinal haemorrhage, obstruction, or perforation.
• Do not use if there is a suspicion that a gastro-intestinal foreign body may be present.

Use with caution in individuals with epilepsy/seizures.

Note: "In patients with pheochromocytoma, metoclopramide may induce a hypertensive crisis."

Adverse Effects / Side Effects / Warnings

• Dogs: Rare CNS side effects may include either sedation or hyperactivity;
• Cats: Cats may experience hyperactivity or disorientation.
• Dogs and cats: Signs of neurotoxicity may occur in both dogs and cats at therapeutic levels. These signs usually will resolve within a few days of discontinuing the metoclopramide. Diphenhydramine may help reduce movement disorders, such as twisting movements of the face, neck, trunk or limbs, as well as CNS depression, nervousness, restlessness or frenzied behavior (especially in cats). Constipation may occur in both species.
• Adult horses: CNS side effects (alternating both sedation and excitement) and colic may occur with IV administration. Side effects are less common in foals.

• At normal doses, may cause restlessness, excitement and behavioural disturbances in some individuals.
• Cats: Frenzied behaviour and disorientation may occur.
• Dogs: changes in mentation and behaviour reported.
• Horses: with intravenous administration, particularly in adults, sometimes severe CNS effects, with alternating sedation and excitement, and behavioural changes, as well as abdominal pain.
• Skeletal muscle tremors or rigidity may occur (extrapyramidal side effects).
• Sweating and abdominal cramping may occur.
• Transient incoordination may occur occasionally.
• Constipation sometimes occurs in dogs and cats.

Warnings:

• Not recommended by the manufacturer for use in early pregnancy.

Overdose / Acute Toxicity

• Metoclopramide has a high LD50 and, as a consequence, it is unlikely that an oral overdose will cause death.
• Overdose will cause similar but more severe clinical signs discussed under side effects.
• If the overdose was recent, the stomach should be emptied using standard protocols.

• Anticholinergics, such as diphenhydramine, may be used to decrease CNS signs.
• High doses are required to reach toxic levels; oral overdose is unlikely to be fatal.

• Signs of overdose might include "sedation, ataxia, agitation, extrapyramidal effects, nausea, vomiting and constipation."

Treatment:

• Following recent oral overdose, stomach emptying may be beneficial.
• To control CNS effects, use of anticholinergic drugs which enter the CNS may be useful (e.g. benztropine, diphenhydramine).

Detailed Toxicological Information

Acute Toxicity

• Mice: Oral LD₅₀ 465 mg/kg.
• Rats: Oral LD₅₀ 760 mg/kg.
• Rabbits: Oral LD₅₀ 870 mg/kg.