Trimethaphan

/HUMAN EXPOSURE STUDIES/ ... Group 1 patients (n = 7) received a single intravenous injection of trimethaphan, 0.5 mg/kg, while awake and again during stable halothane-nitrous oxide anesthesia. Group 2 patients (n = 6) were pretreated with intravenous H1 (chlorpheniramine, 0.1 mg/kg) and H2 (cimetidine, 4 mg/kg) receptor antagonists administered 15 min before trimethaphan, 0.5 mg/kg, in the awake and anesthetized states. In Group 3 (n = 6), the effects of infusion of trimethaphan, 3 mg/min for 15 min, were studied during halothane-nitrous oxide anesthesia. In Group 1, bolus doses of trimethaphan were associated with maximal increases in serum histamine from 0.56 +/- 0.14 to 2.56 +/- 0.35 ng/mL (p < 0.01) and from 0.60 +/- 0.11 to 2.58 +/- 0.33 ng/mL (p < 0.01) 2 min after drug administration in the awake and anesthetized states, respectively; there were also clinical manifestations of histamine release. Mean arterial pressure decreased maximally after 5 min in the awake (from 92.0 +/- 3.4 to 69.9 +/- 2.2 mm Hg; p < 0.01) and anesthetized (from 82.6 +/- 3.7 to 57.3 +/- 2.5 mmHg; p < 0.01) states, and was associated with increases in cardiac output and heart rate; stroke volume increased in the awake state only.

/HUMAN EXPOSURE STUDIES/ Urinary excretion of renal tubular cell enzymes, N-acetyl-beta-D-glucosaminidase (NAG) and gamma-glutamyl transpeptidase (gamma-GTP) was evaluated to elucidate the renal cell damage before, during and after the induced hypotension with trimetaphan (TMP) ... under halothane-nitrous oxide-oxygen anesthesia in patients undergoing neurosurgery. ... Urinary excretion of / NAG and gamma-GTP/ in TMP group tended to increase, but its increases were not statistically significant. ... According to the general opinions, degree in stray of renal tubular cell enzyme into urine is thought to parallel with the injury of renal tubular cells. ...

/HUMAN EXPOSURE STUDIES/ In two groups of patients undergoing induced hypotension with sodium nitroprusside or trimetaphan blood concentrations of lactate, pyruvate and standard bicarbonate did not differ significantly between the groups. In the nine patients who received trimetaphan there was a progressive, but statistically non-significant, decrease in mean lactate. ...

/SIGNS AND SYMPTOMS/ Large doses of trimethaphan camsylate in the management of hypertension have caused apnea and respiratory arrest. Respiration must be monitored closely, especially if large doses of the drug are given. /Trimethaphan camsylate/

For more Human Toxicity Excerpts (Complete) data for TRIMETHAPHAN (7 total), please visit the HSDB record page.

/LABORATORY ANIMALS: Acute Exposure/ Twenty-one late-juvenile rhesus monkeys were rendered profoundly hypotensive for 0-, 15-, or 30-minute periods by means of infusion of trimethaphan camsylate. Blood pressure was then restored to prehypotensive levels with phenylephrine infusions. Respiratory gas tensions and pH of arterial blood were maintained within their normal limits throughout experimental and recovery periods. Animals either recovered and showed no sequelae or died 12 to 48 hours later of cardiorespiratory difficulties, often accompanied by brain swelling. Brain injury and death occurred in 64% of cases when arterial blood pressure was maintained at 25 mm Hg for up to 30 minutes. Multifocal myoclonus, depressed electroencephalographic activity, rises in cisternal cerebrospinal (CSF) pressure, respiratory depression, and characteristic changes in serum and cisternal CSF glucose followed episodes of controlled hypotension. Hypoxia and acidosis occurring during insult or recovery periods rather than hypotension itself probably account for neuropathological sequelae described by others. /Trimethaphan camsylate/

/LABORATORY ANIMALS: Acute Exposure/A study was made on the presence or absence and the degree of histopathological renal cell damage, in hypotensive anesthesia models with prostaglandin E1 (PGE1) or trimethaphan. Cell damage was most noticeable in the S3 segment, the straight and second half part of the proximal renal tubule. The lesion was evaluated and semiquantified. The trimethaphan group in this area exhibited degeneration--including cell vacuolation and granule increase in this site, as well as cytoclasis such as cell fragments in the lumen, luminal extension, flattening of epithelial cell and damage of distal renal tubular columns. In the PGE1 group, cell degeneration was milder than in the trimethaphan group, and there were no cytoclasis findings. Renal cell damage in the PGE1 group was slighter than in the trimethaphan group.

/LABORATORY ANIMALS: Acute Exposure/ In 62 dogs, hypotension to a mean arterial pressure of either 40 or 50 torr (equivalent to a cerebral perfusion pressure of 30 or 40 torr, respectively) for one hour was induced by hemorrhage (oligemia), trimethaphan, halothane, or sodium nitroprusside. Before and during the period of hypotension, the following were measured: mean arterial blood pressure, cardiac output, whole-body O2 consumption, cerebral blood flow, cerebral O2 consumption, arterial blood gases, blood O2 content, and lactate, pyruvate, glucose, epinephrine, and norepinephrine concentrations. At the end of the period of hypotension, brain biopsies were taken for determination of adenosine triphosphate, phosphocreatine, lactate, and pyruvate concentrations. In an additional eight dogs following one hour of hypotension (at 40 torr) induced by one of the four techniques, the brains were perfused with carbon black, removed, and examined. In another ten dogs following hypotension (at 40 torr) induced with either halothane or trimethaphan, the animals were observed for three days and then killed for examination of the brain. Dogs maintained at a mean arterial pressure of 40 torr, despite differences in cerebral blood flow, demonstrated metabolic disturbances compatible with systemic and cerebral hypoxia. These were greatest in those dogs given nitroprusside in excess of 1.0 mg/kg, presumably due to cyanide toxicity. In dogs maintained at 50 torr, metabolic disturbances were minimal or absent in the halothane- and nitroprusside-treated dogs but were still apparent in the oligemic and trimethaphan-treated dogs. Carbon black infusions revealed no evidence of non-homogeneous flow. Three of the ten dogs observed for three days had persistent post-hypotension neurologic dysfunction. Two of these were given trimethaphan. The results suggest that the systemic and cerebral effects of halothane and nitroprusside (at doses less than 1.0 mg/kg) are similar and at a mean arterial pressure of 50 torr are of little consequence. By contrast, hypotension induced by trimethaphan or oligemia results in detectable metabolic alterations even at a pressure of 50 torr.

/LABORATORY ANIMALS: Acute Exposure/ The effects of graded systemic hypotension induced by the combination of bleeding and trimethaphan camsylate infusion on brain metabolism were studied in normotensive rats (NTR) and spontaneously hypertensive rats (SHR). Metabolites such as lactate, pyruvate and adenosine triphosphate (ATP) of the brain frozen in situ were measured at the end of 1 hour of hypotension. In SHR, either cerebral lactate or the lactate/pyruvate (L/P) ratio increased rapidly and progressively with a concomitant decrease in ATP, when mean arterial blood pressure (MAP) fell below about 50 mm Hg. In NTR, on the other hand, the metabolites changed little until MAP fell to about 40 mm Hg. Metabolic derangements of the brain during profound hypotension were more marked and severe in SHR than in NTR. These results suggest that the SHR is more vulnerable to severe hypotension than NTR, probably due to hemodynamic difference of the cerebral circulation between the 2 groups. The increased cerebral vascular resistance and upward shift of cerebral autoregulation in hypertension might be responsible for this vulnerability. /Trimethaphan camsylate/

For more Non-Human Toxicity Excerpts (Complete) data for TRIMETHAPHAN (8 total), please visit the HSDB record page.

Pregnant women are extremely sensitive to ganglionic blocking agents. These drugs cross the placenta, decreasing fetal GI motility and resulting in meconium ileus. In addition, trimethaphan-induced hypotension may have other serious adverse effects on the fetus. For these reasons, trimethaphan should be avoided during pregnancy.

Trimethaphan is contraindicated in patients with anemia, hypovolemia, shock (incipient or frank), asphyxia, respiratory insufficiency, or other conditions in which hypotension may subject the patient to undue risk. The drug may also be contraindicated when fluid and blood replacement are impossible and in patients with glaucoma.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

Trimethaphan crosses the placenta. The drug may be metabolized by pseudocholinesterase and is filtered and actively secreted by the kidneys.

Animal studies indicate that trimethaphan camsylate is erratically and incompletely absorbed after oral administration.