Metoclopramide antiemetic

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). 

Metoclopramide is used for its antiemetic properties in patients with diabetic gastroparesis and with dexamethasone for prophylaxis of delayed nausea and vomiting associated with chemotherapy administration. 

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. 

A number of other conditions must also be excluded, such as medication-induced parkinsonism (e.g., induced by antipsychotics, phenothiazine antiemetics, or metoclopramide). Other diagnostic criteria include lack of other neurologic impairment. 

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]. 

In general, ketones, alcohols and ethers of formula (3) showed comparable protection against cisplatin-induced emesis in the dog and ferret with that of metoclopramide. Erythro (cis) alcohols (3c, 3g, 3i) were found to be more potent than the corresponding threo-(trans) isomers (3d, 3h, 3j). Optical isomer (.R) (3e) was found to be somewhat more potent than its (S )-enantiomer (3f) as an antagonist of cisplatin-induced emesis in the ferret. In the dog, both isomers showed similar activity. A number of heterocyclic analogues were also studied but with the exception of (3k), all were inferior in potency as antiemetic agents compared with other compounds (3) shown in Table 7.1. Lead compound, BMY 25801, batanopride, (3a) is presently under clinical investigation. 

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. 

Gavini E, Rassu G, Sanna V, Cossu M, Giunchedi P (2005) Mucoadhesive microspheres for nasal administration of an antiemetic drug, metoclopramide in-vitro/ex-vivo studies. J Pharm Pharmacol 57 287-294. 

Other examples of secondary benzamides include the therapeutic class of orthopramides, which are, again, markedly resistant to hydrolysis. Thus, hydrolysis of the amide bond is a minor metabolic pathway in humans for the antiemetic drug metoclopramide (4.76) [49]. Clebopride (4.77), an anti-dopaminergic agent, was found to be hydrolyzed to a limited extent in rabbit liver homogenates and in dogs to 4-amino-5-chloro-2-methoxybenzoic acid (4.78) and to the amine 4.79 [48] [50], Attempts to detect in vivo formation of this metabolite in rats, rabbits, or humans were not successful [50],... 

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. 

Metoclopramide (Region, Clopro, Octamide) [Antiemetic/ Dopamine Antagonist] Uses Tx NA Action T UGI motility, blocks dopamine in chemoreceptor trigger zone Dose Adults. 10 mg IV, 10-20 mg IM Peds. 1-2 mg/kg IV/IM Caution [B, -] Drugs w/ extrapyramidal ADRs Contra ... 

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. 

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