Ketamine/midazolam/ondansetron Disease Interactions

The use of benzodiazepines with alcohol is not recommended. Patients with acute alcohol intoxication exhibit depressed vital signs. The central nervous system depressant effects of benzodiazepines may be additive with those of alcohol, and severe respiratory depression and death may occur. Therapy with benzodiazepines should be administered cautiously in patients who might be prone to acute alcohol intake.

The manufacturers consider the use of benzodiazepines to be contraindicated in patients with acute angle-closure glaucoma or untreated open-angle glaucoma. These agents do not possess anticholinergic activity but have very rarely been associated with increased intraocular pressure.

Benzodiazepines may cause respiratory depression and apnea, usually when given in high dosages and/or by intravenous administration. However, some patients may be susceptible at commonly used dosages, including the elderly, debilitated or severely ill patients, those receiving other CNS depressants, and those with limited ventilatory reserve, chronic pulmonary insufficiency or other respiratory disorders. Therapy with benzodiazepines should be administered cautiously in these patients. Appropriate monitoring and individualization of dosage are particularly important, and equipment for resuscitation should be immediately available if the parenteral route is used. Benzodiazepines, especially injectable formulations, should generally be avoided in patients with sleep apnea, severe respiratory insufficiency, or hypoxia.

The use of benzodiazepines in patients with seizure disorders may increase the incidence or precipitate the onset of generalized tonic-clonic seizures (grand mal). Appropriate anticonvulsant medication might need to be initiated or the dosage increased. Abrupt cessation of benzodiazepine therapy may precipitate seizures and other withdrawal symptoms, particularly after prolonged use and/or excessive dosages. Status epilepticus may occur in patients with a history of seizures withdrawn rapidly from benzodiazepine therapy. Following chronic administration, cessation of benzodiazepine therapy should occur gradually with incrementally reduced dosages. Patients should be advised not to discontinue medication without first consulting with the physician.

Benzodiazepines should not be administered by injection to patients in shock or coma. The hypnotic and hypotensive effects of these agents may be prolonged and intensified in such patients.

The use of ketamine is contraindicated in patients whom a significant elevation of blood pressure would constitute a serious hazard. It is recommended to monitor cardiac function continually during a procedure in patients with hypertension or cardiac decompensation.

Parenteral medications formulated in multidose vials often contain benzyl alcohol as a preservative. Their use is considered by drug manufacturers to be contraindicated in neonates, particularly premature infants and infants of low birth weight. When used in bacteriostatic saline intravascular flush and endotracheal tube lavage solutions, benzyl alcohol has been associated with fatalities and severe respiratory and metabolic complications in low-birth-weight premature infants. Thus, single-dose formulations should always be used in infants whenever possible. However, many experts feel that, in the absence of benzyl alcohol-free equivalents, the amount of the preservative present in these formulations should not necessarily preclude their use if they are clearly indicated. The American Academy of Pediatrics considers benzyl alcohol in low doses (such as when used as a preservative in some medications) to be safe for newborns. However, the administration of high dosages of these medications must take into account the total amount of benzyl alcohol administered. The level at which toxicity may occur is unknown.

Injectable midazolam should not be administered in adult or pediatric patients in shock or coma or in acute alcohol intoxication with depression of vital signs. Particular care should be exercised in the use of intravenous midazolam in patients with uncompensated acute illnesses, such as severe fluid or electrolyte disturbances.

In patients with congestive heart failure, there appears to be a two-fold increase in the elimination half-life, a 25% decrease in the plasma clearance, and a 40% increase in the volume of distribution of midazolam. Therapy with midazolam should be administered cautiously at reduced initial dosages in patients with congestive heart failure, particularly if they are elderly. The possibility of profound and/or prolonged effect should be considered.

Midazolam is metabolized by the liver, and the metabolites are excreted in the urine. Reduced drug clearance and prolonged elimination half-life of parent drug and metabolites have been reported in patients with renal and/or hepatic impairment. Therapy with midazolam should be administered cautiously at reduced initial dosages in such patients. The possibility of profound and/or prolonged effect should be considered.

ECG changes including QT interval prolongation have been observed in patients receiving ondansetron. Additionally, there have been some postmarketing reports of Torsade de Pointes cases. The use of ondansetron should be avoided in patients with congenital long QT syndrome. ECG monitoring is recommended in patients with electrolyte abnormalities such as hypokalemia or hypomagnesemia, patients with congestive heart failure, bradyarrhythmias, or patients taking other medicines that could lead to QT prolongation.

Benzodiazepines depress the central nervous system and may cause or exacerbate mental depression and cause suicidal behavior and ideation. Episodes of mania and hypomania have also been reported in depressed patients treated with some of these agents. Therapy with benzodiazepines should be administered cautiously in patients with a history of depression or other psychiatric disorders. Patients should be monitored for any changes in mood or behavior. It may be prudent to refrain from dispensing large quantities of medication to these patients.

The plasma half-lives of benzodiazepines may be prolonged in obese patients, presumably due to increased distribution into fat. Marked increases in distribution (> 100%) have been reported for diazepam and midazolam, and moderate increases (25% to 100%) for alprazolam, lorazepam, and oxazepam. Therapy with benzodiazepines should be administered cautiously in obese patients, with careful monitoring of CNS status. Longer dosing intervals may be appropriate. When dosing by weight, loading doses should be based on actual body weight, while maintenance dose should be based on ideal body weight to avoid toxicity.

Paradoxical reactions, including excitability, irritability, aggressive behavior, agitation, nervousness, hostility, anxiety, sleep disturbances, nightmares and vivid dreams, have been reported with the use of benzodiazepines in psychiatric patients and pediatric patients with hyperactive aggressive disorders. Such patients should be monitored for signs of paradoxical stimulation during therapy with benzodiazepines. The manufacturers do not recommend the use of benzodiazepines for the treatment of psychosis.

Ketamine should be used with caution in the chronic alcoholic and the acutely alcohol-intoxicated patient.

Ondansetron is extensively metabolized by the liver. The plasma clearance of ondansetron may be substantially decreased and the half-life prolonged in patients with impaired hepatic function. During clinical trials in patients receiving concomitant chemotherapy, transient elevations of serum transaminases and isolated cases of jaundice have been reported. Therapy with ondansetron should be administered cautiously at reduced dosages in patients with liver disease. The manufacturer recommends a maximum daily dosage of 8 mg in severe hepatic impairment.