4-Amino-5-chloro-N-(2-(diethylamino)ethyl)-2-methoxybenzamide

Absorption

Metoclopramide is rapidly absorbed in the gastrointestinal tract with an absorption rate of about 84%. The bioavailability of the oral preparation is reported to be about 40.7%, but can range from 30-100%.
Nasal metoclopramide is 47% bioavailable. A 15mg dose reaches a Cmax of 41.0 ng/mL, with a Tmax of 1.25 h, and an AUC of 367 ng*h/mL.

Toxicity

The rat oral LD50 of metoclopramide is 750 mg/kg.
Some symptoms of an overdose with metoclopramide include drowsiness, disorientation, and extrapyramidal reactions. Drugs that manage Parkinson's disease or anticholinergic drugs or antihistamines with anticholinergic properties should be employed to treat extrapyramidal symptoms. Normally, these symptoms subside within 24 hours. Unintentional overdose in infants receiving the oral solution of metoclopramide resulted in seizures, extrapyramidal symptoms, in addition to a lethargic state.
In addition, methemoglobinemia has been found to occur in premature and full-term neonates after a metoclopramide overdose. Intravenous methylene blue may treat metoclopramide-associated methemoglobinemia. It is important to note that methylene blue administration may lead to hemolytic anemia in patients who suffer from G6PD deficiency, which can result in fatality. Dialysis has not been shown to be effective in sufficiently eliminating metoclopramide in an overdose situation due to low plasma distribution of this drug.

Chemical properties

White or almost white, fine powder.

Originator

Primperan,Delagrange,France,1964

The Uses of 4-Amino-5-chloro-N-(2-(diethylamino)ethyl)-2-methoxybenzamide

antidiabetic

The Uses of 4-Amino-5-chloro-N-(2-(diethylamino)ethyl)-2-methoxybenzamide

Metoclopramide is a treatment of choice of post-operative nausea and vomiting (PONV) prophylaxis.

Background

Diabetic gastroparesis is a condition that causes frequent nausea and vomiting, which has a negative impact on quality of life and poses a significant burden on the healthcare system. Metoclopramide is a dopamine antagonist used to treat nausea and vomiting that may be associated with diabetic gastroparesis in addition to gastroesophageal reflux disease (GERD). It can also be used to prevent nausea or vomiting associated with chemotherapy or certain surgical or diagnostic procedures.
One unique property of this drug is that it does not increase gastric acid secretion. It is available in the oral tablet form or in solution, and can also be administered through the intravenous route. Metoclopramide was initially approved by the FDA in 1980.

Indications

Metoclopramide in the oral tablet form is used for symptomatic treatment of both acute and recurrent diabetic gastroparesis, in addition to the treatment of gastroesophageal reflux disease (GERD) in patients who have failed to respond to traditional therapy. A nasal spray formulation is also indicated to treat adults with acute, recurrent diabetic gastroparesis.
In the intravenous injection form, it is indicated for the above conditions as well as for the prevention of vomiting that may follow emetogenic chemotherapy or nausea and vomiting after surgery. Intravenous metoclopramide facilitates intubation of the small bowel and stimulates gastric emptying and barium flow in patients who require radiological examination of the stomach or small intestine. In some cases, the delay of gastrointestinal emptying interferes with the radiographic visualization of the gastrointestinal tract, and metoclopramide is used to facilitate emptying in these cases, allowing for adequate diagnostic visualization.
Some off-label uses of metoclopramide include the management of radiation-induced nausea and vomiting, gastric bezoars, intractable hiccups, and migraine pain.

Definition

ChEBI: A member of the class of benzamides resulting from the formal condensation of 4-amino-5-chloro-2-methoxybenzoic acid with the primary amino group of N,N-diethylethane-1,2-diamine.

Manufacturing Process

The N-(diethylaminoethyl)-2-methoxy-4-aminobenzamide used as the starting material may be prepared from o-toluidine. The o-toluidine is initially nitrated with nitric acid to produce 4-nitro-o-toluidine. The 4-nitro-o-toluidine is then converted to 2-hydroxy-4-nitrotoluene by heating with nitrous acid. By reacting the resulting 2-hydroxy-4-nitrotoluene with dimethyl sulfate, 2- methoxy-4-nitrotoluene is formed. The 2-methoxy-4-nitrotoluene is oxidized with potassium permanganate to produce 2-methoxy-4-nitrobenzoic acid. The latter substituted benzoic acid is treated with thionyl chloride to form 2- methoxy-4-nitrobenzoyl chloride. A methyl ethyl ketone solution of the 2- methoxy-4-nitrobenzoyl chloride is added over a period of about 1? hours to a methyl ethyl ketone solution containing an equal molecular quantity of N,Ndiethylethylene diamine while stirring and maintaining the temperature between 0°C and 5°C. The N-(diethylaminoethyl)-2-methoxy-4- nitrobenzamide hydrochloride formed precipitates. It is filtered, washed twice with methyl ethyl ketone, dissolved in alcohol, and reduced catalytically in an absolute isopropyl alcohol solution to form N-(diethylaminoethyl)-2-methoxy- 4-aminobenzamide. The base is obtained by precipitating with sodium hydroxide.
80 g (0.3mol) of N-(2-diethylaminoethyl)-2-methoxy-4-aminobenzamide are dissolved in small portions in 150 cc of acetic acid. The mixture is cooled and 45 g (0.45 mol) of acetic anhydride are added, and the solution obtained is heated for two hours on a water bath. After cooling, the solution is decanted into a round-bottomed flask with a stirrer, a thermometer and a tube for introducing the chlorine. It is stirred and the current of chlorine is passed through, the temperature being maintained between 20°C and 25°C. The stirring is continued for one hour after the completion of the absorption of the chlorine.
The mixture obtained is poured into 2 liters of water and the base is precipitated with 30% soda. The precipitated base is extracted with 400 cc of methylene chloride. After evaporation of the solvent, the N-(2- diethylaminoethyl)-2-methoxy-4-acetamino-5-chlorobenzamide formed crystallizes. The melting point is 86°C to 87°C and the yield is 95%.
To obtain the corresponding amino derivative, 109 g of base are heated under agitation in a round-bottomed flask with 300 cc of 35-36% concentrated hydrochloric acid and 600 cc of water. It is heated on a water bath until dissolution is complete, then maintained at boiling point for 90 minutes, cooled, diluted with 1 liter of water, and neutralized with about 350 cc of 30% soda. The N-(2-diethylaminoethyl)-2-methoxy-4-amino-5-chlorobenzamide formed crystallizes, is centrifuged and washed in water. Its melting point is 122°C and the yield is 74%.
To obtain the corresponding dihydrochloride, the base is dissolved in absolute alcohol (3 volumes) and to that solution is added 5 N alcoholic hydrochloric acid. The dihydrochloride precipitates, is centrifuged and washed with alcohol. It is a solid white material, having a melting point of 134°C to 135°C.

brand name

Maxolon (King); Reglan (Baxter Healthcare); Reglan (Robins); Reglan (Schwarz Pharma).

Therapeutic Function

Antiemetic

General Description

Metoclopramide is typically employed as an antiemetic drug or a gastrointestinal prokinetic drug in adults and children.

Pharmacokinetics

Metoclopramide increases gastric emptying by decreasing lower esophageal sphincter (LES) pressure. It also exerts effects on the area postrema of the brain, preventing and relieving the symptoms of nausea and vomiting. In addition, this drug increases gastrointestinal motility without increasing biliary, gastric, or pancreatic secretions.
Because of its antidopaminergic activity, metoclopramide can cause symptoms of tardive dyskinesia (TD), dystonia, and akathisia, and should therefore not be administered for longer than 12 weeks.

Metabolism

Metoclopramide undergoes first-pass metabolism and its metabolism varies according to the individual. This drug is metabolized by cytochrome P450 enzymes in the liver. CYP2D6 and CYP3A4 both contribute to its metabolism, with CYP2D6 being more heavily involved. CYP1A2 is also a minor contributing enzyme. The process of N-4 sulphate conjugation is a primary metabolic pathway of metoclopramide.