The cardiocirculatory changes caused by intravenous Dilantin and its solvent

Louis, Sydney; Kutt, Henn; McDowell, Fletcher

doi:10.1016/0002-8703(67)90011-7

Cited by 110 publications

(36 citation statements)

References 7 publications

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“…Louis et al reported that transient hypotension, a brief period of apnea, and bradycardia were observed in epileptic model cats infused rapidly with PG at a dose of 0.5 to 1 mL/kg. 7) These authors also noted that similar cardiorespiratory events occurred after the rapid infusion of phenytoin sodium injection (10 to 25 mg/ kg). 7) Because many of these events were prevented by phenytoin, they mentioned that the adverse effects of a rapid i.v.…”

Section: Discussionmentioning

confidence: 80%

“…In addition to its small contribution as solubilizing agent, PG carries a risk of severe adverse effects on the cardiorespiratory system and potentially causes fatalities. 7,14) Excessive i.v. administration of PG is known to be hazardous.…”

Section: Discussionmentioning

confidence: 99%

“…push has a risk of serious adverse effects on the cardiorespiratory system. [5][6][7] In contrast, the addition of phenytoin sodium injection to an i.v. infusion is not recommended because of its low solubility and resultant precipitation; this means that continuous infusion should be avoided.…”

mentioning

confidence: 99%

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A 5% Glucose Infusion Fluid Provokes Significant Precipitation of Phenytoin Sodium Injection via Interruption of the Cosolvent Effect of Propylene Glycol.

Onuki

Ikegami-Kawai

Ishitsuka

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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The precipitation of phenytoin sodium injection provoked by mixing with infusion fluids renders its use in clinical practice difficult, as rapid intravenous (i.v.) push and i.v. infusion are supposed to be avoided. As some of its aspects remain unclear, this study tried to elucidate this precipitation mechanism. In particular, this study focused on the significant precipitation induced by glucose infusion fluid. The precipitation provoked by 5% glucose infusion fluid was obviously different from the precipitation that accompanied simple pH reduction, in terms of the growth mode and morphology of crystals. In addition, the effect of glucose was partially unrelated to pH reduction. NMR measurements including a two-dimensional nuclear Overhauser effect spectroscopy (2D-NOESY) spectrum indicated the specific interaction between glucose and propylene glycol, which is incorporated into phenytoin sodium injection as a solubilizing agent. These results led to the conclusion that this interaction was crucial for the precipitation of phenytoin, as it diminished the solubilizing effect of propylene glycol, resulting in the enhancement of the crystallization of phenytoin. The determination of phenytoin solubility in aqueous solutions at different pH values revealed that phenytoin incorporated in the admixture could be dissolved completely, as long as the injection was diluted with saline or water. These findings offer a profound insight into the formulation design of phenytoin sodium injection and its use in clinical practice.Key words phenytoin; precipitation; glucose infusion fluid; propylene glycol; 2-dimensional nuclear Overhauser effect spectroscopy Phenytoin sodium injection is indicated for the control of status epilepticus of the grand mal type and for the prevention and treatment of seizures that occur during neurosurgery. As phenytoin is a weak-acid drug (pK a =8.3) 1) with low solubility at biological pH values, 2,3) phenytoin sodium injection is prepared using an organic cosolvent consisting of 40% (v/v) propylene glycol and 10% (v/v) ethanol, with the pH adjusted to 12.The intravenous (i.v.) administration of phenytoin sodium has long represented a dilemma. The rate of administration is strictly limited; the delivery of the injection is recommended at a rate not exceeding 50 mg/min, 4) as a rapid i.v. push has a risk of serious adverse effects on the cardiorespiratory system.5-7) In contrast, the addition of phenytoin sodium injection to an i.v. infusion is not recommended because of its low solubility and resultant precipitation; this means that continuous infusion should be avoided.Many reports in the literature describe precipitation occurring by mixing phenytoin sodium injection with various infusion fluids. [8][9][10][11][12][13][14][15] The reduction in pH that accompanies the dilution with the infusion fluids is widely recognized as the principal cause of the precipitation; 16,17) the pH of the admixture is reduced once the phenytoin sodium injection is diluted in an excessive amount of infusion fluids. ...

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

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A 5% Glucose Infusion Fluid Provokes Significant Precipitation of Phenytoin Sodium Injection via Interruption of the Cosolvent Effect of Propylene Glycol.

Onuki

Ikegami-Kawai

Ishitsuka

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…169 Rapid infusion of concentrated propylene glycol-containing drugs has also been associated with respiratory depression, arrhythmias, hypotension, and seizures. 170 Inadvertent administration of a highly concentrated solution can occur during manual push infusions; a piggyback infusion is preferred. 171 Seizures and respiratory depression have also occurred in children who have ingested oral liquid medications containing propylene glycol.…”

Section: Propylene Glycolmentioning

confidence: 99%

“Inactive” Ingredients in Pharmaceutical Products: Update (Subject Review)

1997

Pediatrics

141

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ABSTRACT. Because of an increasing number of reports of adverse reactions associated with pharmaceutical excipients, in 1985 the Committee on Drugs issued a position statement 1 recommending that the Food and Drug Administration mandate labeling of over-thecounter and prescription formulations to include a qualitative list of inactive ingredients. However, labeling of inactive ingredients remains voluntary. Adverse reactions continue to be reported, although some are no longer considered clinically significant, and other new reactions have emerged. The original statement, therefore, has been updated and its information expanded.ABBREVIATIONS. FDA, Food and Drug Administration; MDIs, metered-dose inhalers Pharmaceutical products often contain agents that have a variety of purposes, including improvement of the appearance, bioavailability, stability, and palatability of the product. Excipients (substances added to confer a suitable consistency or form to a drug, such as the vehicle, preservatives, or stabilizers) frequently make up the majority of the mass or volume of oral and parenteral drug products. These pharmaceutical adjuvants are usually considered to be inert and do not add to or affect the intended action of the therapeutically active ingredients.Some 773 chemical agents have been approved by the Food and Drug Administration (FDA) for use as inactive ingredients in drug products.2 Inasmuch as these compounds are classified as "inactive," no regulatory statutes require listing on product labeling. Pharmacopeial guidelines, enforceable under the Food, Drug, and Cosmetic Act, do require labeling of inactive ingredients for topical, ophthalmic, and parenteral preparations; orally administered products are currently exempt. Because of pressure from professional and consumer organizations asking the FDA to require complete disclosure of all ingredients, voluntary labeling was adopted by the two major pharmaceutical industry trade associations. These voluntary guidelines contain an exemption for "trade secret" components and do not require complete disclosure of all fragrance and flavoring ingredients.Current problems encountered with "inactive" ingredients include benzalkonium chloride-induced bronchospasm from antiasthmatic drugs, aspartameinduced headache and seizures, saccharin-induced cross-sensitivity reactions in children with sulfonamide allergy, benzyl alcohol toxicity in neonates receiving high-dose continuous infusion with preserved medications, dye-related cross-reactions in children with aspirin intolerance, lactose-induced diarrhea, and propylene glycol-induced hyperosmolality and lactic acidosis. Although many other excipients have been implicated in causing adverse reactions, these are the most significant in the pediatric population. ANTIASTHMATIC MEDICATIONSIt is readily appreciated that some percentage of asthmatic children will develop a "paradoxical" bronchospasm after they inhale their medication. Because many of these reactions were attributed to sulfite, which had been highly publicized ...

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“…push carries the risk of serious adverse effects on the cardiorespiratory system. [5][6][7] Second, although the continuous infusion is currently in great demand, diluting the phenytoin sodium injection with i.v. infusion fluid should be avoided.…”

mentioning

confidence: 99%

Contribution of Glucose to Crystallization of Phenytoin in Injectable Dosage Form by Dilution with Infusion Fluids

Onuki

Hasegawa

Ikegami-Kawai

et al. 2014

CHEMICAL & PHARMACEUTICAL BULLETIN

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The crystallization of phenytoin occurring after its dilution with infusion fluid is a major concern in the clinical use of injectable phenytoin. To gain further understanding of the crystallization, this study assessed details of the involvement of glucose in this action. For sample preparation, phenytoin crystals were created by diluting the injectable phenytoin with infusion fluids with different glucose concentrations at different temperature, and then the characteristics of the crystallization (e.g., crystal size in the long direction, accumulated amount over 24 h, and crystallization rate constant) were measured. Results of the analysis of variance indicated that the glucose concentration and temperature had significant impacts on the crystallization. The mode of action of the glucose concentration was suggested to be different from that of the incubation temperature. This study also examined the molecular mobility of components (i.e., glucose, propylene glycol, phenytoin) in the admixtures using diffusion NMR techniques. The findings will provide valuable information for the clinical use of injectable phenytoin.

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The cardiocirculatory changes caused by intravenous Dilantin and its solvent

Cited by 110 publications

References 7 publications

A 5% Glucose Infusion Fluid Provokes Significant Precipitation of Phenytoin Sodium Injection via Interruption of the Cosolvent Effect of Propylene Glycol.

A 5% Glucose Infusion Fluid Provokes Significant Precipitation of Phenytoin Sodium Injection via Interruption of the Cosolvent Effect of Propylene Glycol.

“Inactive” Ingredients in Pharmaceutical Products: Update (Subject Review)

Contribution of Glucose to Crystallization of Phenytoin in Injectable Dosage Form by Dilution with Infusion Fluids

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