4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide;hydron;dichloride;hydrate

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide;hydron;dichloride;hydrate
• 化学式: C14H26Cl3N3O3
• 分子量: 390.7
• InChiKey: IRQVJPHZDYMXNW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.02
• 重原子数：
  23
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  68.6
• 氢给体数：
  5
• 氢受体数：
  5

ADMET

毒理性

• 在妊娠和哺乳期间的影响

哺乳期间的使用总结：甲氧氯普胺以可变数量分泌入乳汁中。口服和鼻内给药后，大多数婴儿接收到的药量不到母亲体重调整剂量的10%，但有些婴儿接收到的剂量能达到产生药理活性的血清水平，血清催乳素升高，可能出现胃肠道副作用。尽管大多数研究在母亲使用甲氧氯普胺期间未发现对哺乳婴儿的不良影响，但许多研究并未充分观察副作用。 甲氧氯普胺可增加血清催乳素，并曾被用作催乳剂。一项对5项安慰剂对照研究的荟萃分析得出结论，2周的甲氧氯普胺治疗并未使血清催乳素较安慰剂升高，但3周的治疗则使其升高。一项更近期的荟萃分析得出结论，甲氧氯普胺对早产儿母亲的催乳作用并无益处。第三项对8项试验的荟萃分析，涉及342名哺乳妇女和早产或足月婴儿，发现甲氧氯普胺增加了血清催乳素，但并未增加乳汁供应。甲氧氯普胺在增加乳汁供应的临床价值上存在疑问。催乳剂不应替代对影响乳汁生产的可改变因素的评估和咨询。在精心设计的研究中，评估了甲氧氯普胺作为催乳剂在优化哺乳技术后仍难以产生乳汁的妇女中的效果，发现其并无额外益处。对早产儿母亲的预防性使用也显示出很少或无益处。 甲氧氯普胺尚未正式确定用于增加乳汁供应的剂量。大多数研究使用甲氧氯普胺的剂量为10毫克，每日2或3次，持续7至14天。一些研究在治疗最后几天使用递减剂量，以避免停药后乳汁供应的急剧下降。没有已发表的文献支持更高剂量、更长治疗期或重复疗程的疗效或安全性。 产后母亲患产后抑郁症的风险相对较高，甲氧氯普胺可能作为副作用导致抑郁。因此，甲氧氯普胺可能应避免用于有重大抑郁病史的妇女，在任何母亲在这段时间内也不应长期使用，因为这段时间她们对抑郁症的易感性较高。长期使用甲氧氯普胺也会增加迟发性运动障碍的风险。在哺乳母亲中报告的其他副作用包括疲劳、恶心、头痛、腹泻、口干、乳房不适、眩晕、不安腿、肠气、脱发、易怒和焦虑。在美国对哺乳母亲的调查中，32人曾使用甲氧氯普胺作为催乳剂，所有人都报告称药物引起了不良反应。在对使用甲氧氯普胺增强泌乳的妇女进行的更大规模的调查中，发现4.8%的妇女出现心悸或心率加快，12%报告抑郁，1至7%报告其他中枢神经系统副作用，从头晕和头痛到不自主的鬼脸和颤抖。腹泻、易怒和疲劳也相对常见。 对哺乳婴儿的影响：在一份早期报告中，5名婴儿在母亲接受甲氧氯普胺治疗7至10天期间（口服剂量为10毫克，每日3次）哺乳，未观察到不良反应。 在一项对37名妇女进行的甲氧氯普胺对乳汁产量影响的安慰剂对照研究中，一名婴儿的母亲口服甲氧氯普胺15毫克，每日3次，据报道该婴儿出现肠道不适。母亲服用5或10毫克，每日3次或安慰剂的婴儿均未出现不良反应。甲氧氯普胺可能是不良反应的原因。 十七位有哺乳困难的母亲接受口服甲氧氯普胺10毫克，每日3次，持续3周的治疗。一位母亲报告称，在治疗期间她和她的婴儿都出现了肠胀气增加。甲氧氯普胺可能是不良反应的原因。 给32位有完全或部分哺乳失败的妇女口服甲氧氯普胺10毫克，每日3次，持续10天，并建议她们每3小时哺乳一次。这些母亲中没有人在她们的婴儿中报告不良反应。 二十三名早产儿，其母亲在维持乳汁生产方面有困难，在母亲接受甲氧氯普胺治疗期间，体重稳步增长，与喂养耐受性或大便频率无关的不良反应。这些母亲从平均32天产后开始口服甲氧氯普胺10毫克，每日3次，持续7天，随后2天逐渐减量。 对4至20周产后的13名乳汁不足的妇女进行随机分组，接受甲氧氯普胺或安慰剂10毫克口服，每日3次。在母亲治疗3周后，两组婴儿的平均血浆催乳素水平没有差异。 十一名哺乳婴儿，其母亲在产后第1天开始口服甲氧氯普胺10毫克，每日3次，持续5天，与未接受甲氧氯普胺的11名匹配母亲的婴儿进行比较。两组之间的平均血清催乳素没有发现差异，这表明通过乳汁转移到婴儿的药物量很少。 研究了5名哺乳婴儿，其母亲在产后第3至9天因乳汁不足开始服用甲

◉ Summary of Use during Lactation:Metoclopramide is excreted in variable amounts in breastmilk. After oral and intranasal administration, most infants would receive less than 10% of the maternal weight-adjusted dosage, but some receive doses that achieve pharmacologically active serum levels, elevated serum prolactin and possible gastrointestinal side effects. Although most studies have found no adverse effects in breastfed infants during maternal metoclopramide use, many did not adequately observe for side effects. Metoclopramide increases serum prolactin and has been used as a galactogogue. A meta-analysis of 5 placebo-controlled studies concluded that 2 weeks of metoclopramide caused no increase of serum prolactin over placebo, but 3 weeks of treatment did. A more recent meta-analysis concluded that metoclopramide was of no benefit as a galactogogue in the mothers of preterm infants. A third meta-analysis of 8 trials involving 342 lactating women with a preterm or fullterm infant found that metoclopramide increased serum prolactin, but did not increase milk supply. The clinical value of metoclopramide in increasing milk supply is questionable. Galactogogues should never replace evaluation and counseling on modifiable factors that affect milk production. In well-designed studies that evaluated the effectiveness of metoclopramide as a galactogogue in women who continue to have difficulty producing milk after nursing techniques have been optimized, it was of no additional benefit. Prophylactic use in the mothers of preterm infants has also shown little or no benefit. Metoclopramide has no officially established dosage for increasing milk supply. Most studies have used metoclopramide in a dosage of 10 mg 2 or 3 times daily for 7 to 14 days. Some studies used a tapering dosage for the last days few of the regimen to avoid an abrupt drop in milk supply after drug discontinuation. No published literature supports the efficacy or safety of higher dosages, longer treatment periods or repeated courses of therapy. Postpartum mothers are at a relatively high risk for postpartum depression and metoclopramide can cause depression as a side effect. Therefore, metoclopramide should probably be avoided in women with a history of major depression and not used for prolonged periods in any mothers during this time of high susceptibility. Long-term uses of metoclopramide also increases the risk of tardive dyskinesia. Other reported side effects in nursing mothers include tiredness, nausea, headache, diarrhea, dry mouth, breast discomfort, vertigo, restless legs, intestinal gas, hair loss, irritability and anxiety. In a survey of nursing mothers in the United States, 32 had used metoclopramide as a galactogogue and all reported having experienced an adverse reaction from the drug. A larger survey of women taking metoclopramide for lactation enhancement found that 4.8% of women had either palpitations or racing heart rate, 12% reported depression, and 1 to 7% reported other central nervous system side effects ranging from dizziness and headache to involuntary grimacing and tremors. Diarrhea, irritability and fatigue were also relatively common. ◉ Effects in Breastfed Infants:In an early report, 5 infants were nursed during 7 to 10 days of maternal metoclopramide therapy at a dosage of 10 mg orally 3 times daily. No adverse effects were noted. In a placebo-controlled study of the effect of metoclopramide on milk production in 37 women, an infant whose mother was taking oral metoclopramide 15 mg 3 times daily reportedly had intestinal discomfort. No infants whose mothers were taking a dosage of 5 or 10 mg 3 times daily or placebo had any adverse effects. Metoclopramide was possibly the cause of the adverse reaction. Seventeen mothers with poor lactation were treated with oral metoclopramide 10 mg 3 times daily for 3 weeks. One mother reported that she and her infant had increased intestinal gas formation during treatment. Metoclopramide was possibly the cause of the adverse reaction. Thirty-two mothers with complete or partial lactation failure were given oral metoclopramide 10 mg 3 times daily for 10 days and advised to nurse every 3 hours. None of the mothers reported adverse effects in their infants. Twenty-three premature infants whose mothers were having difficulty maintaining milk production had steady weight gain and no adverse effects related to feeding tolerance or stool frequency during maternal metoclopramide therapy. The mothers were taking oral metoclopramide 10 mg 3 times daily for 7 days, with a tapering dosage for 2 more days, beginning at an average of 32 days postpartum. Thirteen women with insufficient milk production who were 4 to 20 weeks postpartum were randomized to receive metoclopramide or placebo 10 mg orally 3 times daily. The average plasma prolactin levels before therapy and after 3 weeks of maternal therapy were no different in the infants of women who received metoclopramide or placebo. Eleven breastfed infants whose mothers were given oral metoclopramide 10 mg 3 times daily for 5 days beginning on day 1 postpartum were compared to the infants of 11 matched mothers who received no metoclopramide. No difference in average serum prolactin was found between the groups, indicating little transfer of the drug to the infants via breastmilk. Five breastfed infants were studied whose mothers were taking metoclopramide 10 mg orally 3 times daily beginning on the day 3 to 9 postpartum because of an insufficient milk supply. Before therapy, their plasma prolactin levels were similar to their mothers'. On day 4 of maternal therapy, 3 of the infants had plasma prolactin levels higher than the highest levels of control infants of the same age, and on day 14, one infant had a plasma prolactin level higher than the highest levels of control infants of the same age. Plasma levels in 3 other infants were in the normal range during therapy. A 21-week-old breast-fed boy presented with an unexplained acute extrapyramidal syndrome that occurred 48 hours after his mother used a metoclopramide 10 mg rectal suppository. Metoclopramide was found in the infant’s blood and a hair sample. The adverse reaction was probably caused by metoclopramide in milk. ◉ Effects on Lactation and Breastmilk:Metoclopramide increases serum prolactin in lactating and nonlactating women. This effect is thought to be caused by the drug's antidopaminergic effect. Galactorrhea has been reported after long-term use of metoclopramide for nausea associated with migraine. The patient was taking 10 to 40 mg 1 to 4 times weekly for about 4 months. Another case of galactorrhea was reported in a woman after 5 days of treatment and having a slightly low serum prolactin level. Numerous papers have reported studies that used metoclopramide to increase milk production. All studies were small with 40 or fewer patients. Most of the studies have designs that would not be considered valid using today's standards of evidence-based medicine. Many of the studies had no placebo control; only 7 studies employed randomization; and only 2 studies were clearly and adequately blinded. The studies that meet or come close to meeting current evidence-based medicine standards are described in more detail below. In one early double-blind study, 20 women who had undergone delivery by emergency or elective cesarean section were randomized to take oral metoclopramide 10 mg 3 times daily (n=10) or placebo for 7 days (n=10) beginning on the first day after cesarean section. All mothers expressed a desire to breastfeed their infants for at least 3 months and received daily visits by an investigator to discuss breastfeeding problems and were given advice and encouragement to breastfeed. The mothers in the 2 groups were closely matched except that 3 preterm infants in the metoclopramide group were separated from their mothers in the intensive care unit and were nursed there initially and fed expressed milk until discharge. At 10 days postpartum, there were no differences in the number of infants being breastfed in each group; at 6 weeks postpartum, 9 women were breastfeeding in the metoclopramide group and 8 in the placebo group; and 3 months postpartum 4 were breastfeeding in each group. Although this was a small study, it was well designed and executed. It provided preliminary evidence of the benefit of patient counseling and encouragement on breastfeeding success. Thirteen primiparous nursing mothers without breastfeeding difficulties and normal infants were given either oral metoclopramide 10 mg 3 times daily (n=7) or placebo (n=6) for 8 days beginning on the first day postpartum in a randomized, double-blind study. No attempt was made to improve nursing technique, but mothers nursed on a 3-hour schedule beginning at 6:30 am on the day following delivery. No mention was made of the type of feeding, or the number of feedings that the infants received between birth and the initiation of breastfeeding or any differences in the two groups of infants in this regard. All women completed the trial. No differences were found in serum prolactin of treated and control women throughout 28 days of observation. Milk intake as measured by infant weight change before and after the second daily feeding on days 3 through 8 was greater by an average of 24.3 mL (51.1 mL vs 75.4 mL) in the infants of treated mothers; however, statistically significant differences in milk production did not occur until day 5 postpartum. This paper has several serious flaws related to its analysis. One is that the paper does not state the number of feedings per day, so the fraction of the infant's daily feedings that this one feeding represented is unknown. The study also failed to report serial infant weight gain during the study period. These serious problems invalidate the study results. Fifty mothers who had complete or partial lactation failure received extensive instruction on how to increase their milk supply. Their infants were hospitalized for various illnesses and ranged from 29 to 100 day of age. Maternal lactation history was comparable in the two groups. Mothers were randomized either to receive or not receive metoclopramide 10 mg 3 times daily for 10 days. Although no specific metoclopramide placebo was given to control mothers, all mothers received multivitamins, iron, and folic acid daily which the authors used to obscure to the mother whether she was receiving an active drug or not. No statistically significant differences were found between the groups in the time to initiation of milk secretion, to partial restoration of breastfeeding, or to complete breastfeeding or in the weight gain of the infants during the study period of 96 days. The authors concluded that successful relactation can be accomplished without galactogogues such as metoclopramide. This study lacked a true placebo control; however, it employed excellent breastfeeding instruction and infant evaluation techniques and had the best overall design of any of the studies on mothers who had older infants and well documented insufficient milk supplies at the start of the study. In a well-controlled and analyzed, randomized, double-blinded study of the mothers of premature (23 to 34 weeks) infants, mothers received either metoclopramide 10 mg 3 times daily (n=31) or placebo (n=29) for 10 days beginning within 96 hours of delivery. The groups were well matched and all mothers received standardized instructions from a lactation consultant and provided access to breastfeeding support. No selection was made for mothers who were having difficulties producing milk. Six subjects each in the drug and placebo groups dropped out for a relatively high dropout rate of 17.4%. Although by far the best designed and executed study to date on any galactogogue, the study enrolled all mothers of preterm infants without any evaluation of their ability to produce milk. This population may in general need lactation support, but the possible inclusion of women in both the active drug and placebo groups who would have had little difficulty in milk production may have minimized differences between the groups. A study of 20 primiparous mothers whose infant were not gaining weight adequately compared metoclopramide (n = 10) to placebo (n = 10) for increasing milk supply. All mothers passed a brief training course on improving breastfeeding technique and the benefits of breastfeeding before entering the study. All infants gained weight over the next 2 weeks. The increase in weight in the metoclopramide group was not different from the placebo group. Two women whose infants were born via a surrogate pregnancy. One woman stopped metoclopramide 1 week prior to the expected delivery date and the other continued metoclopramide postpartum. They also underwent postpartum nipple stimulation with an electric breast pump. Lactation was established and they were each able to partially breastfeed their infants for 3 months. A double-blind randomized study compared the effect on milk production of metoclopramide 10 mg to placebo 3 times daily for 10 days in the mothers of preterm infants born at 28 to 34 weeks of gestation. At the beginning of investigation, all participating women were taught a standard breastfeeding method. Mothers used a breast pump for 10 to 15 minutes every 2 hours and the volume of milk was measured and recorded at each pumping for 10 days. No difference in daily milk volumes between the two groups occurred until day 7 postpartum, when treated mothers pumped an average of 373 mL compared with 352 mL in the mothers receiving placebo. This difference of about 20 mL per day persisted until the end of the study on day 10 when the treated group pumped 446 mL and the placebo group pumped 422 mL. The clinical importance of the extra 20 mL of milk per day is questionable. A randomized, double-blind study of 26 mothers who delivered at 34 weeks of gestation or less, compared metoclopramide 10 mg 3 times daily to placebo. The drug or placebo was taken for 8 days beginning within 36 hours of delivery. All women were provided breast pumps and support from a lactation consultant. The total volume of milk pumped per day was recorded by the women, 19 of whom completed the entire protocol. Although milk production increased over the 8-day period, metoclopramide was no better than placebo and the standard care provided. No difference in reported side effects was found. Mothers who were expressing milk for their infants in a neonatal intensive care unit (mean gestational age 28 weeks) were given instructions on methods for increasing milk supply. If they were producing less than 160 mL of milk per kg of infant weight daily after several days, mothers were randomized to receive either domperidone or metoclopramide 10 mg by mouth 3 times daily for 10 days in a double-blinded fashion. Thirty-one mothers who received domperidone and 34 who received metoclopramide provided data on daily milk volumes during the 10 days. Milk volumes increased over the 10-day period by 96% with domperidone and 94% with metoclopramide, which was not statistically different between the groups. Some mothers continued to measure milk output after the end of the medication period. Results were similar between the 2 groups. Side effects in the domperidone group (3 women) included headache, diarrhea, mood swings and dizziness. Side effects in the metoclopramide group (7 women) included headache (3 women), diarrhea, mood swings, changed appetite, dry mouth and discomfort in the breasts. Of 29 women who took metoclopramide after the trial ended, 8 reported side effects including diarrhea, mood swings, depression (2 women), itchy skin, tiredness, restless legs and less effective milk stimulation. The lack of a placebo group and the projection of milk volumes to impute missing data from some mothers detract from the findings of this study. In a survey of nursing mothers in Australia, 21 mothers were taking metoclopramide as a galactogogue. On average, mothers rated metoclopramide as being between “slightly effective” and “moderately effective” on a Likert scale. Twenty-nine percent of mothers taking metoclopramide reported experiencing adverse reactions, most commonly weight gain, nausea, headache, dry mouth, fatigue, irritability, depression and involuntary movements.

来源:Drugs and Lactation Database (LactMed)