Dopamine Receptor Blocking Drug Research Articles

Single-Dose Haloperidol for the Prophylaxis of Postoperative Nausea and Vomiting After Intrathecal Morphine

Postoperative nausea and vomiting (PONV) occurs frequently with the use of intrathecal morphine. We studied the ability of a single, small dose of the inexpensive, long-acting, dopamine receptor-blocking drug, haloperidol, to prevent PONV after spinal anesthesia using local anesthetic with morphine 0.3 mg. One-hundred-eight adult patients undergoing elective lower limb orthopedic or endoscopic urologic procedures under spinal anesthesia were randomized to receive IM haloperidol 1 mg (H1), haloperidol 2 mg (H2), or placebo (P) after an intrathecal injection. Patients were assessed for 24 h after surgery, with treatment failure being defined as nausea >1 on a 10-cm visual analog scale or any vomiting or request for rescue antiemetic. Most treatment failures occurred during the first 12 h (60% overall), and haloperidol led to a dose-dependent decrease in PONV (first 12 h: 76% P, 56% H1, and 50% H2; P = 0.012). A history of PONV was strongly associated with PONV in the current study, regardless of treatment group. There were no dystonic reactions noted to either dose of haloperidol. We conclude that haloperidol reduces the incidence of PONV after intrathecal morphine, although this incidence remains a significant problem even with treatment. In this randomized, double-blinded, placebo-controlled trial, a single, small IM dose of haloperidol 1 mg or 2 mg reduced the incidence of postoperative nausea and vomiting after spinal anesthesia with local anesthetic and intrathecal morphine.

Metoclopramide for nausea and vomiting of pregnancy: a prospective multicenter international study.

Nausea and vomiting are very common during pregnancy, mainly throughout the first trimester. Metoclopramide is a dopamine receptor blocking drug that is commonly used to treat nausea and vomiting. The aim of this prospective study was to investigate the effect on the fetus of intrauterine exposure to metoclopramide. One hundred and seventy-five women who received metoclopramide and consulted 6 teratogen information centers in Israel, Italy, Brazil, and Canada were studied. Women exposed to metoclopramide were paired for age, smoking and alcohol consumption habits with women exposed to nonteratogens. Women in the metoclopramide group had a significantly higher rate of premature births (8.1%) as compared with the control group (2.4%) ( p = 0.02, relative risk = 3.37, 95% confidence interval 1.12-10.12). Rates of major malformations in the metoclopramide group (4.4%) did not differ from controls (4.8%) ( p = 0.84, relative risk = 0.91, 95% confidence interval 0.34-2.45). According to our findings, metoclopramide use during the first trimester of pregnancy does not appear to be associated with an increased risk of malformations, spontaneous abortions, or decreased birth weight, however, larger studies are needed to confirm these observations.

Dissociated Response of Thyrotropin and Prolactin to Dopamine Receptor Blockade with Domperidone in Hypothyroid Subjects

To investigate the hypothesis of an altered hypothalamic dopaminergic activity in primary hypothyroidism, eight patients with hypothyroidism and seven normal subjects, all female, were studied. All of them were submitted to two tests: TRH stimulation and after the administration of dopamine receptor-blocking drug, Domperidone. The hypothyroid patients with basal TSH values less than or equal to 60 mU/L (4 cases--group 1) had lower PRL levels than the remaining 4 subjects with TSH greater than 60 mU/L (group 2) (p less than 0.001), despite all patients presenting the PRL levels within the normal range. A significant increase occurred for both TSH and PRL after the administration of TRH and Domperidone in normal as well as in the hypothyroid subjects, except for TSH in group 1 after the administration of Domperidone. The area under the curve for PRL response to THR was not different between the normal subjects and both hypothyroid groups, while that under the curve for TSH was greater in the hypothyroidism as a whole than in the normal subjects (p = 0.006) and between the hypothyroid groups, being greater in group 2 than in 1 (p less than 0.009). In relation to Domperidone, the area under the curve for TSH was significantly higher in group 2 when compared to the normal controls (p less than 0.001), while for PRL it was not different between hypothyroid groups in relation to normal controls and when groups I and II were compared. These results suggest that the hypothalamic dopamine activity is not altered in primary hypothyroidism and favor the small relevance of dopamine on the control of TSH secretion.

Failure of metoclopramide to affect thyrotropin concentration in the term human fetus.

Metoclopramide (MET), a potent dopamine receptor-blocking drug, or saline was administered to 125 term pregnant women at various time intervals (5-412 min) before delivery. Maternal serum was obtained before and after MET injection. Cord blood was obtained at delivery in MET-treated and saline-treated (control group) women. No significant changes in serum TSH, T4, T3, or rT3 concentrations were observed in maternal or cord blood after MET administration. These results suggest that, in contrast to euthyroid nonpregnant women and men, MET administration does not induce a rise in serum TSH concentration in term pregnant women or in the term fetus. Thus, the dopaminergic inhibitory effect on anterior pituitary TSH secretion may not be an important factor in TSH regulation during pregnancy or in the fetus, or the dose of MET employed may be unable to overcome the dopamine inhibitory effect.

Acetylcholine (Ach) induced alterations of plasma growth hormone (GH) in normal and pimozide-treated ovariectomized rats

To determine the role of acetylcholine in the control of GH secretion, ovariectomized conscious rats were prepared with cannulae in the third ventricle and external jugular vein. Blood samples were drawn prior to and after the injections to ascertain the effect on plasma GH determined by radioimmunoassay. Control injections into the ventricle of 2 μl 0.9% sodium chloride had no effect on plasma GH. The hormone was rapidly elevated by the injection of 20 μg of acetylcholine into the third ventricle. Conversely. 20 jug of atropine sulfate injected into the ventricle rapidly lowered plasma GH. The elevation in GH induced by acetylcholine was not counteracted by the 20 μg dose of atropine sulfate but was blocked by a 100 μg dose of atropine. Intravenous injection of atropine at doses of 5 or 25 mg/kg had little or no effect on plasma GH. To ascertain if the effects of acetylcholine on GH release were mediated via activation of dopaminergic neurons, a dopamine receptor blocking drug, pimozide, was injected SC at a dose which selectively blocks dopamine receptors. Following injection of pimozide, there was little effect of acetylcholine on plasma GH. Pimozide itself or the tartaric acid vehicle failed to alter plasma GH levels. Surprisingly, following injection of pimozide, intraventricular injection of 20 μg of atropine sulfate induced an elevation instead of a fall in plasma GH. The results are interpreted to mean that acetylcholine acts at the hypothalamic level to either stimulate the release of GH-releasing hormone or inhibit the release of somatostatin or by both actions to elevate GH release. Since the effect was blocked by blockade of dopaminergic receptors, acetylcholine may act by activation of the tuberoinfundibular dopaminergic system which then induces a net stimulatory hypothalamic action on GH release.

ALTERED DOPAMINERGIC REGULATION OF THYROTROPHIN RELEASE IN PATIENTS WITH PROLACTINOMAS: COMPARISON WITH OTHER TESTS OF HYPOTHALAMIC‐PITUITARY FUNCTION

This study was carried out to test the hypothesis that sustained hyperprolactinaemia in patients with prolactinomas stimulates hypothalamic dopaminergic activity via a short loop positive feedback effect of prolactin (PRL). The intensity of dopamine (DA) effects on the pituitary around the adenoma was evaluated by measuring thyroid stimulating hormone (TSH) responses to intravenous injection of domperidone (10 mg) a new DA receptor blocking drug that does not penetrate the blood-brain barrier. TSH responses have been compared with those of PRL to the same agent. Eight females with prolactinomas showed greater TSH release after domperidone than nine normal females (sum of TSH increments over 20 min 17.5 +/- 1.7 v. 8.9 +/- 1.5 mu/l, P less than 0.001) whilst PRL release was reduced (sum of PRL increments over 120 min 5.9 +/- 2.4 v. 21.8 +/- 3.8 mu/l x 10(-3), P less than 0.01). Amongst nineteen hyperprolactinaemic females with apparently normal pituitary fossae (plain skull X-ray), ten showed an exaggerated TSH response (delta TSH, 4.2 +/- 0.6 mu/l, range 2.5-9.0 mu/1) and reduced PRL response to domperidone, comparable with established tumor cases. In the remaining nine normal fossa hyperprolactinaemic females, the TSH and PRL responses to dopaminergic were similar to normal females. These results support the initial hypothesis and indicate the coexistence of a defect in the dopaminergic inhibition of PRL release and increased dopaminergic inhibition of TSH release in patients with prolactinomas. The presence of an exaggerated TSH response to DA antagonism in a euthyroid, radiologically normal (plain skull X-ray), hyperprolactinaemic patient is compatible with the presence of an autonomously-functioning, PRL secreting, pituitary microadenoma and the TSH changes seen in these patients after DA antagonist administration can be readily detected by sensitive TSH radioimmunoassay.

The effect of the dopamine receptor blocking drug pimozide on the stimulant and anorectic actions of dextroamphetamine in man

The effect of the dopamine receptor blocking drug pimozide on the stimulant and anorectic actions of dextroamphetamine in man

Catecholaminergic interactions in the regulation of thyrotropin (TSH) secretion in man.

The TSH responses to the catecholamine depleting agent monoiodotyrosine (1 g po) and the dopamine receptor blocking drug metoclopramide (10 mg po) have been compared in euthyroid and hypothyroid subjects. Both drugs lead to a prompt and significant rise in TSH levels (peak values at 60-75 min) which is very much greater in hypothyroid than euthyroid subjects. The findings lend further support to the inhibitory role of dopamine in the control of TSH release in man, since TSH release follows either dopamine depletion with monoiodotyrosine or dopamine receptor blockade with metoclopramide.

DOPAMINE IS A PHYSIOLOGICAL REGULATOR OF THYROTROPHIN (TSH) SECRETION IN NORMAL MAN

Using a sensitive and precise radioimmunoassay for human TSH we have demonstrated significant elevations in serum TSH levels in euthyroid volunteers following administration of the dopamine receptor blocking drug metoclopramide when compared with placebo. The degree of TSH response is significantly greater in females than in males and is sustained over a 3-hour period after a single oral 10 mg dose of metoclopramide. The degree of TSH release after metoclopramide is inversely related to the basal TSH level suggesting that dopamine is a determinant of low daytime TSH levels and is thus implicated in the circadian rhythm of TSH secretion. Pretreatment with 10 mg of metoclopramide orally, one hour before TRH administration leads to significant enhancement of the TSH response to TRH. Our findings provide further evidence for the physiological inhibitory role of dopamine in the contol of TSH secretion in normal man. The possible mode of action of dopamine and the clinical implications of this neuroregulatory pathway are discussed.

Influence of hyperprolactinaemia due to metoclopramide on gonadal function in men.

Five clinically normal male volunteers were given metoclopramide, 10 mg t.d.s. for 6 weeks. During treatment prolactin concentrations were elevated (over 50 ng/ml) in all. LH, FSH, testosterone and cortisol concentrations were not altered. No change was observed in LH or FSH responses to LHRH testing 4 weeks after the beginning of therapy, compared with pre-treatment values. A reduction in seminal volume and total sperm count were observed in each subject. Four noticed a decrease in libido and three lost spontaneous erections. While the metoclopramide-induced hyperprolactinaemia could be the cause of the observed changes in semen and erectile activity, it is possible that this dopamine receptor blocking drug might directly affect central or peripheral mechanism of erection, the testes or accessory organs.

The role of biogenic amines in the regulation of growth hormone and corticotropin secretion in the trained conscious dog.

We evaluated the regulation of GH secretion in the unanesthetized dog by systemic administration of drugs which affect noradrenergic and dopaminergic receptors. L-Dihydroxyphenylalanine (L-dopa) produced significant increments in plasma GH, but with associated emesis and significant increases in plasma corticoids and blood pressure (BP). Apomorphine, a dopamine receptor agonist, similarly produced GH elevation only when given in emetic doses, again with increases in corticoids and BP. The dopamine receptorblocking drug, pimozide, did not modify the GH or glucose response to L-dopa, although it abolished emesis and changes in BP and corticoids. Inhibition of peripheral decarboxylation of L-dopa with carbidopa completely blocked the GH and glucose responses to L-dopa. Clonidine, an a receptor agonist, produced significant secretion of GH without affecting BP or the concentration of plasma corticoids. The failure of pimozide to modify the GH response to L-dopa, and the stimulatory GH response to clonidine su...

Brain tissue transplanted to the anterior chamber of the eye

Small pieces of fetal rat brain selected to contain a high number of noradrenaline (NA), dopamine (DA), or 5-hydroxytryptamine (5-HT) neuroblasts were transplanted to the anterior chamber of the eye of adult rats. The sympathetic ground plexus of the host iris was removed by superior cervical ganglionectomy so that transmitter mechanisms of the different central monoamine fibers innervating the iris could be selectively studied after intraocular maturation. Such irides, containing NA, DA, or 5-HT nerve terminals were incubated with radiolabelled transmitters and then stimulated by an electrical field while superfused, to investigate the spontaneous and stimulation-induced release of amine, both in drug-free buffer and buffer containing drugs acting on monoamine receptors. The central monoamine neurons of all three types were able to take up exogenous amines and release them upon stimulation by an electrical field, in much the same way as corresponding nerves in situ in slices of cerebral cortex (NA, 5-HT) or olfactory tubercle (DA). The alpha-adrenergic receptor blocking agent phentolamine increased the stimulation-induced release of 3H-NA from central NA fibers on the iris significantly. The dopamine receptor stimulating agent apomorphine decreased the stimulation-induced release of 3H-DA from central DA fibers on the iris. Pimozide, a DA receptor blocking drug tended to increase the 3H-DA release. The 5-HT receptor stimulating agent ergocornine tended to reduce the stimulation-induced release of 3H-5-HT from central 5-HT fibers on the iris. It was concluded that all three types of central monoamine nerve fibers develop essentially normal transmitter storage and release mechanisms also in an environment completely devoid of normal postsynaptic receptors. The drug experiments add strong support to the view that there are presynaptic monoamine receptors ("autoreceptors") able to modulate transmitter release present on the monoamine nerve terminals.