Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0600097 (Sedation)
 1,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 34-year-old woman with a history of renal insufficiency induced by long-term cocaine use was admitted with acute shortness of breath remarkable for submandibular and anterior throat swelling. She required intubation, mechanical ventilation, and sedation. Sedation was administered with daily infusions of intravenous lorazepam 65, 313, and 305 mg for 3 days, respectively. Forty-eight hours into the infusion the patient experienced anion gap metabolic acidosis with hyperlactatemia, hyperosmolality, and increased osmolal gap. Propylene glycol (PG), a component of lorazepam intravenous formulation, was considered the potential source of the metabolic abnormality. The patient received greater than 40 times the acceptable recommended amount of PG over 72 hours. Cessation of lorazepam produced major improvements in lactic acid, serum osmolality, and anion and osmolal gaps. The large PG exposure associated with long-term cocaine-induced renal insufficiency produced a toxic metabolic state. Agents containing PG should be avoided in patients with compromised renal function (creatinine clearance < or = 30 ml/min) induced by cocaine use.
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PMID:Short-term lorazepam infusion and concern for propylene glycol toxicity: case report and review. 1156 Feb 4

Propylene glycol monomethyl ether (PM), along with its acetate, is the most widely used of the propylene glycol ether family of solvents. The most common toxic effects of PM observed in animal studies include sedation, very slight alpha(2u)-globulin mediated nephropathy (male rats only) and hepatomegally at high exposures (typically > 1000 ppm). Sedation in animal studies usually resolves within a few exposures to 3000 ppm (the highest concentration used in subchronic and chronic inhalation studies) due to the induction of metabolizing enzymes. Data from a variety of pharmacokinetic and mechanistic studies have been incorporated into a PBPK model for PM and its acetate in rats and mice. Published controlled exposure and workplace biomonitoring studies have also been included for comparisons of the internal dosimetry of PM and its acetate between laboratory animals and humans. PM acetate is rapidly hydrolyzed to PM, which is further metabolized to either glucuronide or sulfate conjugates (minor pathways) or propylene glycol (major pathway). In vitro half-lives for PM acetate range from 14 to 36 min depending upon the tissue and species. In vivo half-lives are considerably faster, reflecting the total contributions of esterases in the blood and tissues of the body, and are on the order of just a few minutes. Thus, very little PM acetate is found in vivo and, other than potential portal of entry irritation, the toxicity of PM acetate is related to PM. Regardless of the source for PM (either PM or its acetate), rats were predicted to have a higher Cmax and AUC for PM in blood than humans, especially at concentrations greater than the current ACGIH TLV of 100 ppm. This would indicate that the major systemic effects of PM would be expected to be less severe in humans than rats at comparable inhalation exposures.
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PMID:Development of a physiologically based pharmacokinetic model for propylene glycol monomethyl ether and its acetate in rats and humans. 1570 96