专家视点：解毒剂与妊娠

一般而言，孕妇安全的优先级都高于胚胎/胎儿安全。目前在所有解毒剂中仅有2种药物（乙醇和青霉胺）已知可导致胚胎或胎儿受损，但多数解毒剂用于妊娠期的经验都非常有限甚至毫无经验。尽管如此，孕妇的解毒治疗应当采用与非妊娠女性相同的方式。

活性炭可防止肠道吸收有毒物质，而且对母亲和胎儿均无危害。与之相似，催吐药吐根糖浆也可安全用于妊娠期女性。

数种药物可逆转导致呼吸抑制和/或明显镇静的阿片类（天然的或合成的）过量：纳洛酮、纳曲酮和纳美芬(纳曲酮的一种长效衍生物，血浆半衰期约10小时)。在这3种药物中，纳洛酮是人类妊娠期使用经验最丰富的。该药本身无呼吸抑制活性或其他麻醉效应。这些药物均可用于处理妊娠期的急性麻醉剂过量。

乙酰半胱氨酸被用于阻止或减轻摄入潜在肝毒性量对乙酰氨基酚后的肝损伤。这种解毒剂无致畸性或胚胎毒性，并且有限的人类妊娠期应用数据并未显示该药具有胎儿毒性。静脉注射后，乙酰半胱氨酸可透过胎盘，在胎儿体内达到具有保护作用的血药浓度。

对于潜在致死性地高辛过量，可采取静脉注射地高辛免疫抗原结合分段(绵羊)治疗。已报告了该药在44例孕妇中的使用，但其中无1例涉及洋地黄过量(所有孕妇均为重度先兆子痫)。使用该药后未观察到胎儿受损。

氟马西尼适用于逆转苯二氮卓类过量。该药在全身暴露量接近人类的动物中无致畸性或胚胎毒性。基于非常有限的数据，该药似乎可以透过人类胎盘并逆转苯二氮卓类对胎儿的抑制效应。

甲吡唑被用于处理摄入乙二醇或甲醇的情况。该药可抑制乙醇脱氢酶（催化这2种化学物质转化为毒性代谢物的一种酶）。该药在小鼠中无致畸性，但迄今仅报告了1例人类妊娠期暴露于该药的病例，并且该患者的妊娠结局不清楚。乙醇也被用于治疗这2种化学物质中毒。尽管短期(24~48小时)使用乙醇对胎儿的影响尚未得到研究，但有引起神经毒性的可能性。

羧肽酶适用于处理甲氨蝶呤血浆浓度达到毒性水平的情况。该药可将甲氨蝶呤转化为无活性代谢物。尚无该药用于人类或动物妊娠期的报告。由于妊娠期禁用甲氨蝶呤，因此不太可能获得对孕妇使用羧肽酶治疗甲氨蝶呤中毒的报告。

目前有6种药物可用于治疗重度金属(砷、金、铁、铅和汞)中毒：地拉罗司(铁)、去铁胺(铁)、二羟基丙醇(砷、金、铅和汞)、依地酸钙钠(铅)、青霉胺(铜和汞)和琥硫酸(铅)

地拉罗司适用于因输血引起的慢性铁过载。已有3篇报告描述了该药在妊娠期前半段的使用，未见胚胎或胎儿损伤。

去铁胺被用于治疗急性和慢性铁过载。尽管该药在2种动物中可引起毒性，但在人类妊娠期使用的经验较丰富，尚未报告与该药有关的胚胎或胎儿不良反应。

二羟基丙醇(英国抗路易斯毒气剂，BAL)被用于治疗砷、金和急性汞中毒(对慢性汞中毒无效)。该药还与依地酸钙钠联用治疗铅中毒。大剂量的二羟基丙醇在小鼠中具有胚胎毒性和致畸性。已发表的人类妊娠期使用该药的经验比较有限，而且均涉及孕早期之后的暴露。在2例孕妇的新生儿中观察到了高浓度的砷或铅。

依地酸钙钠可与多种金属形成稳定的螯合物，但主要被用于治疗铅过量，单用或联用二羟基丙醇均可。仅有若干篇该药在人类妊娠期使用的报告，均发生在孕晚期。该药治疗的一种潜在并发症是母体低血压，后者可危及胎盘灌注。该药还能螯合锌，从而引起锌缺乏。这种作用机制还被认为涉及动物中的致畸效应。

青霉胺除了作为治疗Wilson病铜代谢障碍的螯合剂之外，还被用于治疗汞中毒(1篇报告)。孕早期暴露于该药与结缔组织异常(主要是皮肤松弛症)风险有关。

琥硫酸(二巯基琥珀酸，DMSA)已被用于治疗铅、砷、汞和镉中毒。它还能非常高效地螯合锌。该药在小鼠和大鼠中具有毒性和/或致畸性，但其中一部分可能是锌缺乏的继发效应。由于完全没有人类妊娠期使用该药的经验，琥硫酸之外的解毒剂很可能更佳。

碳酸镧和司维拉姆适用于降低终末期肾病患者的血清磷酸盐浓度。在肠道消化食物的过程中，二者可与膳食中的磷酸盐结合。尚无在人类妊娠期使用这2种药物的报告。二者的全身生物利用度很低，理论上对胚胎或胎儿无影响。然而，这2种药物可能阻止肠道对维生素的吸收，尤其是脂溶性维生素。

胆碱能药物毒扁豆碱能够逆转抗胆碱能药物(例如莨菪碱和三环类抗抑郁药)的中枢神经系统效应。见诸报道的人类妊娠期用药经验仅限于孕晚期。

亚甲蓝已被用于治疗氰化物中毒。在人类中，当采用羊膜内注射给药时，该药具有致畸性和胎儿毒性，但作为解毒剂由孕妇口服尚无报道。氰化物解毒包内有亚硝酸戊酯、亚硝酸钠和硫代硫酸钠。这些药物对人类妊娠的影响尚不明确，大剂量羟钴胺素(一种同样用于治疗氰化物中毒的维生素B₁₂类似物)也是如此。

解磷定(2-PAM)可使被有机磷酸酯农药和具有抗胆碱酯酶活性的化学物质灭活的胆碱酯酶再活化，从而缓解呼吸肌麻痹。该药有自助注射器剂型，在暴露于具有抗胆碱酯酶活性的神经药物(有机磷酸酯中毒)的情况可迅速使用。尚未开展过解磷定的动物生殖实验，在人类妊娠期使用该药的经验也仅限于少量农药中毒的病例(孕中期和孕晚期)。这些病例之后均诞下了健康的婴儿。

目前有4种市售的抗毒素可用于治疗急性毒液螫入：黑寡妇蜘蛛抗毒素、蝎子免疫F(ab\')₂(马)、响尾蛇多价免疫Fab(绵羊)(北美响尾蛇)和北美珊瑚蛇抗毒素(马)。此外，肉毒七价抗毒素(马)被用于处理由神经毒性肉毒杆菌导致的食物中毒。尚未对这些药物开展动物生殖研究，用于人类的报告很少或缺如。

沙丙蝶呤(苯丙氨酸羟化酶的一种辅因子)可降低苯丙酮尿症患者血中苯丙氨酸的浓度。该药的用法为，当仅凭饮食不足以控制母体苯丙氨酸水平时每日使用该药。

还有多种药物在其主要适应证之外也可被归类为解毒剂，原因是它们可逆转其他药物的毒性效应。这些解毒剂包括阿托品(重度心动过缓、有机磷酸酯类和氨基甲酸盐中毒)、氯化钙或葡糖酸盐(重度低钙血症、钙通道阻滞剂过量、氢氟酸暴露)、胰高血糖素(低血糖症)、亚叶酸(甲氨蝶呤过量)、鱼精蛋白(肝素过量)、吡哆醇(异烟肼诱发性惊厥、乙二醇中毒的辅剂)和维生素K(植物甲萘醌)(华法林过量)。在妊娠期使用这些药物的数据往往非常丰富，未提示明显的胚胎或胎儿风险。

作者介绍：GERALD G. BRIGGS是美国加州长滩米勒儿童医院妇女纪念医疗中心门诊部的临床药剂师，加州大学旧金山分校的临床药学教授，南加州大学的药学副教授，曾参与撰写《妊娠期与哺乳期用药》，参与编辑《产科疾病、并发症与药物治疗》。他没有相关利益冲突披露。联系方式：。

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By: BY GERALD G. BRIGGS, B. PHARM., FCCP

By their very nature, antidotes and detoxification agents are needed in situations where the health and well-being of the mother are in jeopardy. In nearly all such cases, the mother’s condition will take priority over the safety of the embryo-fetus. Only two of the drugs (ethanol and penicillamine) are known to cause embryo or fetal harm but, for most of these drugs, the reported human pregnancy experience is very limited or absent. Nevertheless, pregnant women should be treated the same way as nonpregnant women.

Activated charcoal prevents absorption of substances from the gut and is no risk to the mother or her pregnancy. Similarly, ipecac syrup, which is used to induce vomiting, is safe in pregnancy.

Several agents are available for the reversal of opioid (natural or synthetic) overdose that is causing respiratory depression and/or marked sedation: naloxone, naltrexone, and nalmefene, a long-acting derivative of naltrexone (plasma half-life about 10 hours). Of the three agents, naloxone is the one for which there is the most human pregnancy experience. It has no intrinsic respiratory depressive activity or other narcotic effects of its own. All of these agents can be used in pregnancy for acute narcotic overdose.

Acetylcysteine is used to prevent or lessen hepatic injury following the ingestion of potentially hepatic toxic doses of acetaminophen. The antidote is not teratogenic or embryo toxic, and limited human pregnancy data have not shown fetal toxicity. After IV administration, acetylcysteine crosses the placenta in sufficient amounts to achieve protective serum levels in the fetus.

Potentially life-threatening digoxin overdose can be treated with IV digoxin immune Fab (ovine). The use of the agent has been reported in 44 pregnancies, but none of the cases involved digitalis overdose (all women had severe preeclampsia). No fetal harm secondary to the drug was observed.

Flumazenil is indicated for the reversal of benzodiazepine overdose. The drug is not teratogenic or embryo-fetal toxic in animals at systemic exposures near those obtained in humans. Based on very limited data, it appears to cross the human placenta and to reverse the depressive effects of benzodiazepines on the fetus.

Fomepizoleis used for the treatment of ethylene glycol or methanol ingestion. It inhibits alcohol dehydrogenase, an enzyme that catalyzes the oxidation of the two chemicals to their toxic metabolites. The drug was not teratogenic in mice, but only one case of human pregnancy exposure has been reported, and the pregnancy outcome was unknown. Ethanol also has been used for poisonings with these two chemicals. Although the fetal effects of this short-term (24-48 hours) use have not been studied, neurotoxicity is a potential complication.

Glucarpidase is indicated for the treatment of toxic plasma methotrexate levels. It converts methotrexate to inactive metabolites. There are no reports of its use in human or animal pregnancies. Human reports are unlikely because methotrexate is contraindicated in pregnancy.

There are six agents available to treat heavy metal (arsenic, gold, iron, lead, and mercury) intoxication: deferasirox (iron), deferoxamine(iron), dimercaprol (arsenic, gold, lead, and mercury), edetatecalcium disodium (lead), penicillamine (copper and mercury), and succimer (lead).

Deferasirox is indicated for chronic iron overload due to blood transfusions. Three reports have described its use in the first half of pregnancy without embryo or fetal harm.

Deferoxamine is used for the treatment of both acute and chronic iron overload. Although the drug causes toxicity in two animal species, the human pregnancy experience is substantial, and no embryo or fetal adverse effects attributable to the agent have been reported.

Dimercaprol (British anti-Lewisite; BAL) is used for the treatment of arsenic, gold, and acute mercury poisoning (not effective for chronic mercury poisoning). It is also combined with edetate calcium disodium for lead poisoning. High doses are embryotoxic and teratogenic in mice. The published human pregnancy experience is limited and all involved exposures after the first trimester. High levels of arsenic or lead were found in the newborns in two cases.

Edetate calcium disodium forms stable chelates with a number of metals, but it is primarily used for lead overdose, either alone or in combination with dimercaprol. There are only a few reports of its use in human pregnancy, all occurring late in gestation. A potential complication of therapy is maternal hypotension that could jeopardize placental perfusion. The agent also chelates zinc, resulting in zinc deficiency. This mechanism was thought to be involved in the teratogenic effects seen in animals.

Penicillamine has been used in mercury poisoning (one report), in addition to its indication as a chelating agent for copper in the treatment of Wilson’s disease. Exposure in the first trimester is related to a risk of connective tissue anomalies, primarily cutis laxa.

Succimer(dimercaptosuccinic acid; DMSA) has been used for lead, arsenic, mercury, and cadmium poisoning. It also chelates zinc quite effectively. The agent is toxic and/or teratogenic in mice and rats, but some of the effects may have been secondary to zinc deficiency. Because of the complete absence of human pregnancy experience, antidotes other than succimer probably are preferable.

Lanthanum carbonate and sevelamer are indicated to reduce serum phosphate levels in patients with end-stage renal disease. The drugs bind dietary phosphate from food during digestion in the gut. There are no reports of their use in human pregnancy. The systemic bioavailability is minimal, and the drugs should have no effect on the embryo or fetus. However, they may prevent intestinal vitamin absorption, especially of fat-soluble vitamins.

The cholinergic agent physostigmine is capable of reversing the central nervous system effects of anticholinergics, such as scopolamine and tricyclic antidepressants. The reported human pregnancy experience is limited to the third trimester.

Methylene blue has been used for cyanide poisoning. In humans, it is teratogenic and fetal toxic when given by intra-amniotic injection, but its oral use as an antidote in pregnancy has not been reported. The cyanide antidote package contains amyl nitrite, sodium nitrite, and sodium thiosulfate. The effects of these agents on human pregnancy also are unknown, as are the effects of high-dose hydroxocobalamin, an analogue of vitamin B₁₂also used in cyanide poisoning.

Pralidoxime(2-PAM) reactivates cholinesterase that has been inactivated by organophosphate pesticides and chemicals with anticholinesterase activity, thereby relieving the paralysis of the muscles of respiration. The drug is available in an autoinjector that can be used rapidly in cases of exposure to nerve agents possessing anticholinesterase activity (organophosphate poisoning). Animal reproduction tests have not been conducted with pralidoxime, and the human pregnancy experience is limited to a few cases of insecticide poisoning (second and third trimesters). Healthy infants were later delivered in these cases.

Four antivenins are commercially available for acute envenomation: black widow spider antivenin, Centruroides (scorpion) immune F(ab\')₂(equine), crotalidae polyvalent immune Fab (ovine) (North American rattlesnake), and North American coral snakeantivenin (equine). In addition, botulism antitoxin heptavalent (equine) is used for food poisoning caused by the neurotoxic bacterium Clostridium botulinum. Animal reproduction studies have not been conducted with these products, and human reports are limited or absent.

Sapropterin, a cofactor for the enzyme phenylalanine hydroxylase, reduces blood phenylalanine levels in patients with phenylketonuria. The drug is given daily if diet alone does not control maternal phenylalanine levels. Use of the drug in human pregnancy has not been reported.

A number of other agents can be classified as antidotes, in addition to their primary indications, because they can reverse the toxic effects of other agents. These antidotes include atropine (severe bradycardia, poisonings with organophosphates and carbamates), calcium chloride or gluconate (severe hypocalcemia, calcium-channel-blocker overdose, exposure to hydrofluoric acid), glucagon (hypoglycemia), folinic acid (methotrexate overdose), protamine (heparin overdose), pyridoxine (isoniazid-induced seizures; adjunct in ethylene glycol poisoning), and vitamin K (phytonadione) (warfarin overdose). The pregnancy data are extensive for many of these agents and are not suggestive of significant embryo or fetal risk.

Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He had no relevant financial disclosures. Contact him at .