248 Dopamine antagonists

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Pharmacology and toxicology

The dopamine antagonists used to treat NVP are metoclopmmide, phenothiazines, domperidone, droperidol, and trimethobenzamide.

Metocloprarnide is an effective antiemetic that acts both centrally (causing dopamine blockade in the chemoreceptor trigger zone and decreasing sensitivity of the visceral nerves that transmit G1 impulses to the central emetic center) and peripherally by stimulating motility of the upper gastrointestinal tract and increasing the lower esophageal sphincter basal tone. Metocloprarnide counteracts some of the physiological changes during pregnancy that may lead to nausea or vomiting, such as decreased lower esophageal sphincter tone (van Thiel 1977), and decreased propulsive motility time and increased transit time of the small intestine.

Metocloprarnide is effective as antiemetic therapy for all stages of NVP, including hyperemesis gravidarum, and has been used to manage NVP successfully at home using a continuous subcutaneous pump (Buttino 2000).

No adverse fetal effects were reported in a number of studies when metocloprarnide was administered during the first and second trimesters, with no significant risk of major malformations (Berkovitch 2002, 2000, Magee 2002, Sorensen 2000). A prospective follow-up of 175 women exposed to metocloprarnide during the first trimester established that the rates of major malformations, spontaneous abortions, and birth weight were comparable with controls, although the metoclopramide group had a significantly higher rate of premature births (8.1% vs 2.4%) (Berkovitch 2002). No adverse birth outcomes (birth weight, major malformations, preterm delivery) were found in a study of 309 women, identified from the Danish Medical Birth Registry, exposed to metoclopramide during the first trimester of pregnancy (Sorcnsen 2000).

Phenothiazincs like chlorpromaziite, perphenazine, prochlorperazine, promethazine, and trifluoperazine significantly decrease NVP (Fitzgerald 1955, task 1953), and a meta-analysis of 2948 patients demonstrated no evidence of teratogenicity (Magee 2002; see also Chapter 2.11).

Dontperidone shows no teratogenicity in animals (Shepard 1992), but there are insufficient data regarding use in humans.

One trial combined droperidol with diphenhydramine for treatment of 80 women with hyperemesis gravidarum. This is the only published trial of exposure to droperidol in the first trimester. In comparison to another group exposed to various antiemetics, the combination of intravenous droperidol (1-1.25 mg/h) and diphenhydramine shortened the length of hospitalization and reduced readmissions (Nageotte 1996).

Pooling the results of three studies on trimethobenzamide (two cohort and one case control), there was no increased risk for malformations. In comparison to placebo alone or in combination with pyridoxine, trimethobenzamide significantly improved symptoms of NVP (Magec 2002).

Recommendation. Dopamine antagonists are widely used for treatment of NVP, especially in countries where Benedectin is unavailable. Metoclopramide seems safe and efficacious, and has less of the sedating properties of the phenothiazines; it should probably be first choice among the dopamine antagonists.

2.4.9 Pyridoxine (vitamin B6)

Pharmacology and toxicology

Pyridoxine has been empirically recommended for NVP for more than 40 years, although no association has ever been found between vitamin B(1 levels and NVP (Schuster 1985). Pyridoxine requirements increase during pregnancy, although low serum concentrations are usually normal until the second or third trimester.

Proof of efficacy has been obtained in two large trials showing a significant reduction of nausea and the number of vomiting episodes (Vutyavanich 1995, Sahakian 1991). The first trial demonstrated efficacy in severe NVP only, but the second trial, larger and more adequately powered, showed efficacy in moderate and mild NVP as well. Pyridoxine was administered for 3-5 days, but the maximum benefit was during the first 3 days of treatment, and the beneficial effect appeared to diminish with time (Vutyavanich 1995). There is no indication for teratogenicity, even with higher than standard doses (Atanackovic 2001). Another study found that 50 mg pyridoxine i.m. along with 10 mg metoclopramide orally (on request every 6 hours) was more efficient in treating hyperemesis during the first trimester than prochlorperazine or promethazin as monotherapy. Again, there was no increased malformation rate in either group (Bsat 2003).

It is important to note that the targe doses of pyridoxine are neuro-logically detrimental in non-pregnant patients, and therefore maximum doses of 80 mg per day are warranted (Schaumburg 1983).

Recommendation. For NVP, 40mg/d should be used initially and the maximum 80mg/d can be tried. If vitamin B6 atone is not successful, then combining with the antihistamine doxylamine (10mg), a combination similar to Didectin (available in Canada), may improve the efficacy.

2.4.10 Thiamine (vitamin B^

Pharmacology and toxicology

Vitamin B] has no antiemetic properties, although it should be kept in mind especially for Ihose cases of hyperemesis gravidarum with vomiting for more than 3 weeks. Thiamine deficiency has been described in 20 cases, causing memory loss, ataxia, nystagmus, visual disturbances, permanent neurological symptoms, and even maternal death (Gardian 1999).

Recommendation. Consider treatment with vitamin Bj as an adjunctive to other antiemetic therapy for prolonged hyperemesis gravidarum: 100-500 mg thiamine intravenously for 3 days, and then maintenance of 2-3 mg daily. Intravenous dextrose should not be given without prior administration of thiamine, as the metabolism of the dextrose consumes the remaining Bt and may worsen symptoms.

2.4.11 Serotonin antagonists

Pharmacology and toxicology

Ondansetron is a selective serotonin-(5-HT3)-antagonist, used for treating chemotherapy-induced nausea and vomiting. Ondansetron binds to the serotonin receptors located on the vagal neurons lining the gastrointestinal tract and blocks signaling to the vomiting center in the brain, thus preventing nausea and vomiting.

Although widely used for severe cases of N VP, there is scarce information regarding fetal safety. In the largest study published to date, the outcome of 176 pregnancies exposed to ondansetron between the fifth and ninth weeks of gestation was no different from a control group with regard to fetal outcome and major malformations. There was a slight but insignificant increase in the rate of hypospadias (three cases); although the sample size lacked power to show the apparent six-fold increase in this anomaly (Einarson 2004). There is insufficient information on the other serotonin-antagonists dolasetron, granisetron, palonosetron, and tropisetron during pregnancy.

Recommendation. Ondansetron should be used only if other antiemetics fail, due to the lack of safety studies. The use of a serotonin antagonist is not, in itself, an indication either for invasive diagnostic procedures or for termination of pregnancy. After use in the first trimester, a detailed fetal ultrasound should be considered.

2.4.12 Glucocorticoids

Pharmacology and toxicology

Corticosteroids have been proposed to modify the chemoreceptor trigger zone in the brain, and are used to control nausea and cme-sis associated with chemotherapy (Italian Group for Antiemetic Research 2000, Safari 1998).

Corticosteroids arc currently used to treat intractable hypereme-sis gravidarum, the most extreme form of NVP. These patients have severe nausea and vomiting, causing weight loss and dehydration and occasionally requiring hospitalization. In the first randomized trial examining intramuscular ACTH versus placebo, 32 women with hyperemesis gravidarum were studied. There was no difference in response between the two groups (Ylikorkal 1979). A number of randomized controlled studies have since been published: 25 patients were randomized to receive 40 mg prednisolone daily versus placebo. The only difference among the groups was that the sense of well-being improved in the prednisolone group (Nelson-Piercy 2001). In a randomized, double-blind trial that compared parenteral followed by oral corticosteroids versus placebo for treatment of intractable hyperemesis gravidarum, the corticosteroids had no effect on the hyperemesis gravidarum and did not reduce recurrent hospitalizations. In addition, all patients were treated with promethazine and inetocloprainidc (Yost 2003). When compared with promethazine, however, a short course of methylpred-nisolone was more effective than promethazine (Safari 1998). Treatment with oral prednisolone promptly resolved symptoms if given specifically to the subset of patients with the more severe hyperemesis, defined as weight loss of greater than 5% (Moran 2002). For safety of glucocorticoids in pregnancy, see Chapter 2.15.

Recommendation. Corticosteroids may be effective therapy for severe intractable hyperemesis gravidarum associated with dehydration. Hieir use is not, in itself, an indication either for invasive diagnostic procedures or for termination of pregnancy.

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