Chemistry – A derivative of para-aminobenzoic acid, metoclopramide HCl occurs as an odorless, white, crystalline powder with pKas of 0.6 and 9.3. One gram is approximately soluble in 0.7 ml of water or 3 ml of alcohol. The injectable product has a pH of 3-6.5.

Storage/Stability/Compatibility – Metoclopramide is photosensitive and must be stored in light resistant containers. All metoclopramide products should be stored at room tem­perature. Metoclopramide tablets should be kept in tight containers.

The injection is reportedly stable in solutions of a pH range of 2-9 and with the following IV solutions: D5W, 0.9% sodium chloride, D5-1/2 normal saline, Ringer’s, and lactated Ringer’s injection.

The following drugs have been stated to be compatible with metoclopramide for at least 24 hours: 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.

Metoclopramide is reported to be incompatible with the following drugs: ampicillin sodium, calcium gluconate, cephalothin sodium, chloramphenicol sodium succinate, cis­platin, erythromycin lactobionate, methotrexate sodium, penicillin G potassium, sodium bicarbonate, and tetracycline. Compatibility is dependent upon factors such as pH, concen­tration, temperature and diluents used. It is suggested to consult specialized references for more specific information (e.g., Handbook on Injectable Drugs by Trissel; see bibliography).

Pharmacology – The primary pharmacologic effects of metoclopramide are associated with the GI tract and the CNS. In the GI tract, metoclopramide stimulates motility of the upper GI without stimulating gastric, pancreatic or biliary secretions. While the exact mechanisms for these actions are unknown, it appears that metoclopramide sensitizes up­per GI smooth muscle to the effects of acetylcholine. Intact vagal innervation is not neces­sary for enhanced motility, but anticholinergic drugs will negate metoclopramide’s effects. Gastrointestinal effects seen include increased tone and amplitude of gastric contractions, relaxed pyloric sphincter, and increased duodenal and jejunal peristalsis. Gastric emptying and intestinal transit times can be significantly reduced. There is little or no effect on colon motility. Additionally, metoclopramide will increase lower esophageal sphincter pressure and prevent or reduce gastroesophageal reflux. The above actions evidently give metoclopramide its local antiemetic effects.

In the CNS, metoclopramide apparently antagonizes dopamine at the receptor sites. This action can explain its sedative, central anti-emetic (blocks dopamine in the chemo-receptor trigger zone), extrapyrimidal, and prolactin secretion stimulation effects.

Uses/Indications – Metoclopramide has been used in veterinary species for both its GI stimulatory and antiemetic properties. It has been used clinically for gastric stasis disor­ders, gastroesophageal reflux, to allow intubation of the small intestine, as a general antiemetic (for parvovirus, uremic gastritis, etc.) and as an antiemetic to prevent or treat chemotherapy induced vomiting.

Pharmacokinetics – Metoclopramide is absorbed well after oral administration, but a significant first-pass effect in some human patients may reduce systemic bioavailability to 30%. There apparently is a great deal of interpatient variation with this effect. Bioavailability after intramuscular administration has been measured to be 74-96%. After oral dosing, peak plasma levels generally occur within 2 hours.

The drug is well distributed in the body and enters the CNS. Metoclopramide is only weakly bound to 13-22% of plasma proteins. The drug also crosses the placenta and enters the milk in concentrations approximately twice those of the plasma.

Metoclopramide is primarily excreted in the urine in humans. Approximately 20-25% of the drug is excreted unchanged in the urine. The majority of the rest of the drug is me­tabolized to glucuronidated or sulfated conjugate forms and then excreted in the urine. Approximately 5% is excreted in the feces. The half-life of metoclopramide in the dog has been reported to be approximately 90 minutes.

Contraindications/Precautions – Metoclopramide is contraindicated in patients with GI hemorrhage, obstruction or perforation and in those hypersensitive to it. It is relatively contraindicated in patients with seizure disorders. In patients with pheochromocytoma, metoclopramide may induce a hypertensive crisis.

Adverse Effects/Warnings – In dogs, the most common (although infrequent) adverse re­actions seen are changes in mentition and behavior. Cats may exhibit signs of frenzied be­havior or disorientation. Both species can develop constipation while taking this medica­tion.

In adult horses, IV metoclopramide administration has been associated with the devel­opment of severe CNS effects. Alternating periods of sedation and excitement, behavioral changes and abdominal pain have been noted. These effects are less common in foals. Because of the incidence of adverse effects one group of authors (Clark and Becht 1987) does not at the present time recommend its use in adult horses.

Other adverse effects that have been reported in humans and are potentially plausible in animals include extrapyrimidal effects, nausea, diarrhea, transient hypertension and ele­vated prolactin levels.

Overdosage – The oral LD50 doses of metoclopramide in mice, rats, and rabbits are 465 mg/kg, 760 mg/kg and 870 mg/kg, respectively. Because of the high dosages required for lethality, it is unlikely an oral overdose will cause death in a veterinary patient. Likely symptoms of overdosage include sedation, ataxia, agitation, extrapyramidal effects, nau­sea, vomiting and constipation.

There is no specific antidotal therapy for metoclopramide intoxication. If an oral inges­tion was recent, the stomach should be emptied using standard protocols. Anticholinergic agents (diphenhydramine, benztropine, etc.) that enter the CNS may be helpful in control­ling extrapyrimidal effects. Peritoneal dialysis or hemodialysis is thought not to be effec­tive in enhancing the removal of the drug.

Drug Interactions – Atropine (and related anticholinergic compounds) and narcotic analgesics may negate the GI motility effects of metoclopramide. The GI stimulatory effects of metoclopramide may affect the absorption of many drugs. Drugs that dissolve, disintegrate and/or are absorbed in the stomach (e.g., digoxin) may be absorbed less. Due to its small particle size, Lanoxin® brand of digoxin is apparently unaf­fected by metoclopramide administration. Metoclopramide may enhance absorption of drugs that are absorbed primarily in the small intestine (e.g., cimetidine, tetracycline, aspirin, & diazepam). Metoclopramide may accelerate food absorption and thereby alter insulin doses and/or timing of insulin effects. Phenothiazines (e.g., acepromazine, chlorpromazine, etc.) and butyrephenones (e.g., droperidol, azaperone) may potentiate the extrapyramidal effects of metoclopramide. The CNS effects of metoclopramide may be enhanced by other sedatives, tranquilizers and narcotics.

Doses –

Horses:

To stimulate the gastrointestinal tract in foals:

a) 0.02 – 0.1 mg/kg IM or IV 3 – 4 times a day (Clark and Becht 1987)

Elephants:

a) 250-400 mg/elephant IV as an antiemetic; author’s clinical experience (Cheeran, 1995).

Elephant References:

a) Cheeran,J.V., Chandrasekharan,K., and Radhakrishnan,K., 1995. Principles and Practice of Fixing Dose of Drugs for Elephants. In: Daniel,J.C. (Editor), A Week with Elephants; Proceedings of the International Seminar on Asian Elephants. Bombay Natural History Society; Oxford University Press, Bombay, India pp. 430-438

Monitoring Parameters –

1) Clinical efficacy and adverse effects

Client Information – Contact veterinarian if animal develops symptoms of involuntary movement of eyes, face, or limbs, or develops a rigid posture.

Dosage Forms/Preparations/FDA Approval Status/Withholding Times –

Veterinary-Approved Products: None

Human-Approved Products: All doses expressed in terms of metoclopramide base.

Metoclopramide HCl Tablets 5 mg, 10 mg; Reglan® (Robins); Clopra® (Quantum); Maxolon® (Beecham); Octamide® (Adria); Reclomide® (Major); Generic; (Rx)

Metoclopramide HCl Oral Solution (syrup) 1 mg/ml in pints, unit-dose (10 ml); Reglan® (Robins), Generic; (Rx)

Metoclopramide HCl Injection 5 mg/ml in 2 & 10 ml amps, and 2, 10, 30, 50 & 100 ml vials (some contain preservatives, some are preservative free and labeled for single-use only); Reglan® (Robins); Metoclopramide HCl® (Quad); Generic; (Rx)