Metoclopramide antiemetic effects

In a randomized, placebo-controlled trial inl40 patients a combination of metoclopramide 10 mg and droperidol 1.25 mg or two doses of droperidol provided a more effective antiemetic effect than metoclopramide alone (9). The level of sedation was significantly greater in the patients who received two doses of droperidol (8/35) and metoclopramide followed by droperidol (7/35) than in those who received only placebo (0/35) or metoclopramide followed by placebo (0/35). 

DOMPERIDONE, METOCLOPRAMIDE ANTIMUSCARINICS i efficacy of domperidone on gut motility by antimuscarinics Some effects of metodopramide are considered to be due to t release of ACh and t sensitivity of the cholinergic receptors to ACh. Antimuscarinics prevent the effects on muscarinic receptors The gastrointestinal effects of metodopramide will be impaired, while the antiemetic effects may not be. Thus, concurrent use with antimuscarinics is not advised because of effects on the gastrointestinal system... 

Cisapride is structurally similar to metoclopramide, but has no dopamine receptor antagonist activity and hence no central antiemetic effect. However, because it stimulates the release of acetylcholine in the gastrointestinal tract it is effective in conditions such as reflux esophagitis and gastroparesis. During clinical trials, the most frequent unwanted effects were diarrhea (5-11%) and abdominal pain (16% with 20 mg bd). 

The antiemetic effect of combined intravenous ondansetron 8 mg, oral dexamethasone 20 mg, and oral lorazepam 0.5 mg was significantly better than that of intravenous metoclopramide 10 mg, dexamethasone 20 mg, and oral lorazepam 0.5 mg in 30 patients receiving chemotherapy for ovarian cancer in a randomized trial (23). All the antiemetics were given 30 minutes before and 6 hours after chemotherapy. Significantly more patients given metoclopramide (40% versus 13%) complained of adverse effects. The most frequent adverse effects with both regimens were sedation and headache. 

The elucidation of dopaminergic pathways in the brain—and catecholamine pathways generally—became possible only after the development of immuno- and cytofluorescent techniques in the 1960s. These enabled the identification and mapping of pathways and receptor locations of each neurohormone separately. DA receptors and neurons have now been identified in the vomiting center (area postrema), which explains why dopaminergic blockade results in antiemetic effects (e.g., metoclopramide, phenothiazines). 

Effects similar to those of the neuroleptics have also been described for other dopamine-blocking agents. Thus, parkinsonism and tardive symptoms may result from use of metoclopramide, a drug which is commonly used to enhance gastric motility, or certain antiemetics, such as perphenazine. 

Baits containing this antiemetic at an effective concentration of 1 mg/kg BW shortened the median time for death for dogs from 151 min postdose for 1080 baits without metoclopramide to 132 min (Rathore 1985). At tested doses (1 to 16 mg/kg B W), metoclopramide did not decrease the frequency of vomiting by dogs, but did decrease the amount of vomitus (O Brien et al. 1986). 

Chlorpromazine, prochlorperazine, promethazine, methylprednisolone, lorazepam, metoclopramide, dexamethasone, or dronabinol may be used for adult patients. Around the clock dosing should be considered. The choice of specific agent should based on patient specific factors, including potential for adverse drug reactions, and cost. SSRIs are effective for breakthrough nausea and vomiting but they are not superior to the less expensive antiemetics above. 

Most of the antiemetic clinical trials in the last decade have involved metoclopramide (1) either as a single agent or in combination with other drugs. Similarly, most of the chemical modification studies have been designed to optimize antiemetic and/or gastroprokinetic properties of metoclopramide and to eliminate undesirable CNS side-effects which are the consequence of its dopamine D2 receptor blockade [1-3]. 

Metoclopramide, administered at doses higher than those required to inhibit apomorphine-induced emesis, was more effective than haloperidol in antagonizing cisplatin-induced emesis in dogs [80]. This was observed despite the fact that metoclopramide was considerably weaker than haloperidol as a D2-dopamine antagonist [43]. Subsequently, antiemetic efficacy of metoclopramide administered at high doses has been reported in cancer patients... 

A combined administration of metoclopramide and anticholinergic agent to reduce dystonic reactions of metoclopramide, did not diminish antiemetic efficacy in dogs [117], Thus, the inhibitory effect on GI smooth muscle by cholinergic blockade had no significant impact on antiemetic activity of metoclopramide. 

Metoclopramide may be considered as a prototype 5-HT3 antagonist because its antiemetic efficacy both in animals and man could not be adequately explained by D2-dopamine blockade. In fact, metoclopramide was considerably weaker as a D2-antagonist than haloperidol or domperidone and yet it was effective against emesis induced by anticancer agents both in animals [43, 80] and cancer patients [135]. 

Recently, several 5-HT3 antagonists have been identified and found to be effective as antiemetics in animals (Table 7.2). These compounds as a class have been proven to be free of D2-dopamine blocking properties which are responsible for dystonic side-effects seen with metoclopramide. 

Clinical studies in cancer patients have also shown ondansetron to be a highly effective antiemetic drug and to be significantly more effective than metoclopramide [44-46]. As expected, there are no reports of extrapyrami-dal side-effects in patients receiving ondansetron. 

B. Two medicines, ipecac and apomorphine, induce vomiting. Metoclopramide is a prokinetic with antiemetic properties and therefore would have the opposite of the desired effect. Morphine is an opioid with analgesic and sedating properties. Promethazine and ondansetron are also antiemetics, not emetics. 

Sulpiride is a member of a series of neuroleptics, the benzamides, of which the antiemetic drug metoclopramide is another example. The benzamides have a lower propensity to cause extrapyramidal side effects, probably because they show a high degree of selectivity for the D2 dopamine receptors. 

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