METOCLOPRAMIDE HCL
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 ofwater or 3 ml of alcohol. The injectable product has a pH of 3-6.5.
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 IVsolutions: D5W, 0.9% sodium chloride, D5-1/2 normal saline, Ringer's, and lactated Ringer'sinjection.
The following drugs have been stated to be compatible with metoclopramide for at least 24hours: aminophylline, ascorbic acid, atropine sulfate, benztropine mesylate, chlorpromazine HCl, cimetidine HCl, clindamycin phosphate, cyclophosphamide, cytarabine, dexamethasone sodiumphosphate, 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, erythromycinlactobionate, 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).
In the CNS, metoclopramide apparently antagonizes dopamine at the receptor sites. This actioncan 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 stimulatoryand antiemetic properties. It has been used clinically for gastric stasis disorders, gastroesophagealreflux, to allow intubation of the small intestine, as a general antiemetic (for parvovirus, uremicgastritis, etc.) and as an antiemetic to prevent or treat chemotherapy induced vomiting.
The drug is well distributed in the body and enters the CNS. Metoclopramide is only weaklybound to 13-22% of plasma proteins. The drug also crosses the placenta and enters the milk inconcentrations approximately twice those of the plasma.
Metoclopramide is primarily excreted in the urine in humans. Approximately 20-25% of the drugis excreted unchanged in the urine. The majority of the rest of the drug is metabolized toglucuronidated or sulfated conjugate forms and then excreted in the urine. Approximately 5% isexcreted 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 inpatients with seizure disorders. In patients with pheochromocytoma, metoclopramide may induce ahypertensive crisis.
In adult horses, IV metoclopramide administration has been associated with the development ofsevere 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 ofadverse 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 animalsinclude 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 isunlikely an oral overdose will cause death in a veterinary patient. Likely symptoms of overdosageinclude sedation, ataxia, agitation, extrapyramidal effects, nausea, vomiting and constipation.
There is no specific antidotal therapy for metoclopramide intoxication. If an oral ingestion wasrecent, 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 enhancingthe removal of the drug.
The GI stimulatory effects of metoclopramide may affect the absorption of many drugs. Drugsthat 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 absorbedprimarily in the small intestine (e.g., cimetidine, tetracycline, aspirin, & diazepam).
Metoclopramide may accelerate food absorption and thereby alter insulin doses and/or timing ofinsulin effects.
Phenothiazines (e.g., acepromazine, chlorpromazine, etc.) and butyrephenones (e.g., droperidol, azaperone) may potentiate the extrapyramidal effects of metoclopramide. The CNS effects ofmetoclopramide may be enhanced by other sedatives, tranquilizers and narcotics.
Storage, Stability, Compatibility
Metoclopramide is photosensitive and must be stored in lightresistant 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 IVsolutions: D5W, 0.9% sodium chloride, D5-1/2 normal saline, Ringer's, and lactated Ringer'sinjection.
The following drugs have been stated to be compatible with metoclopramide for at least 24hours: aminophylline, ascorbic acid, atropine sulfate, benztropine mesylate, chlorpromazine HCl, cimetidine HCl, clindamycin phosphate, cyclophosphamide, cytarabine, dexamethasone sodiumphosphate, 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, erythromycinlactobionate, 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 - METOCLOPRAMIDE HCL
The primary pharmacologic effects of metoclopramide are associated with the GItract and the CNS. In the GI tract, metoclopramide stimulates motility of the upper GI withoutstimulating gastric, pancreatic or biliary secretions. While the exact mechanisms for these actionsare unknown, it appears that metoclopramide sensitizes upper GI smooth muscle to the effects ofacetylcholine. Intact vagal innervation is not necessary for enhanced motility, but anticholinergicdrugs will negate metoclopramide's effects. Gastrointestinal effects seen include increased tone andamplitude of gastric contractions, relaxed pyloric sphincter, and increased duodenal and jejunalperistalsis. Gastric emptying and intestinal transit times can be significantly reduced. There is littleor no effect on colon motility. Additionally, metoclopramide will increase lower esophagealsphincter pressure and prevent or reduce gastroesophageal reflux. The above actions evidently givemetoclopramide its local antiemetic effects.In the CNS, metoclopramide apparently antagonizes dopamine at the receptor sites. This actioncan 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 stimulatoryand antiemetic properties. It has been used clinically for gastric stasis disorders, gastroesophagealreflux, to allow intubation of the small intestine, as a general antiemetic (for parvovirus, uremicgastritis, etc.) and as an antiemetic to prevent or treat chemotherapy induced vomiting.
Pharmacokinetics - METOCLOPRAMIDE HCL
Metoclopramide is absorbed well after oral administration, but a significantfirst-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 intramuscularadministration has been measured to be 74-96%. After oral dosing, peak plasma levels generallyoccur within 2 hours.The drug is well distributed in the body and enters the CNS. Metoclopramide is only weaklybound to 13-22% of plasma proteins. The drug also crosses the placenta and enters the milk inconcentrations approximately twice those of the plasma.
Metoclopramide is primarily excreted in the urine in humans. Approximately 20-25% of the drugis excreted unchanged in the urine. The majority of the rest of the drug is metabolized toglucuronidated or sulfated conjugate forms and then excreted in the urine. Approximately 5% isexcreted 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 inpatients with seizure disorders. In patients with pheochromocytoma, metoclopramide may induce ahypertensive crisis.
Adverse Effects, Warnings
In dogs, the most common (although infrequent) adverse reactionsseen 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 ofsevere 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 ofadverse 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 animalsinclude 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 isunlikely an oral overdose will cause death in a veterinary patient. Likely symptoms of overdosageinclude sedation, ataxia, agitation, extrapyramidal effects, nausea, vomiting and constipation.
There is no specific antidotal therapy for metoclopramide intoxication. If an oral ingestion wasrecent, 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 enhancingthe removal of the drug.
Drug Interactions
Atropine (and related anticholinergic compounds) and narcotic analgesicsmay negate the GI motility effects of metoclopramide.The GI stimulatory effects of metoclopramide may affect the absorption of many drugs. Drugsthat 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 absorbedprimarily in the small intestine (e.g., cimetidine, tetracycline, aspirin, & diazepam).
Metoclopramide may accelerate food absorption and thereby alter insulin doses and/or timing ofinsulin effects.
Phenothiazines (e.g., acepromazine, chlorpromazine, etc.) and butyrephenones (e.g., droperidol, azaperone) may potentiate the extrapyramidal effects of metoclopramide. The CNS effects ofmetoclopramide may be enhanced by other sedatives, tranquilizers and narcotics.