Phenytoin injectable

HYDANTOINS Fhenytoin is the most commonly prescribed anticonvulsant because of its effectiveness and relatively low toxicity. However, a genetically linked inability to metabolize phenytoin has been identified. For this reason, it is important to monitor serum concentrations of the drug on a regular basis to detect signs of toxicity Fhenytoin is administered orally and parenterally. If the drug is administered parenterally, the IV route is preferred over the intramuscular route because erratic absorption of phenytoin causes pain and muscle damage at the injection site... 

Fosphenytoin Fosphenytoin is a water-soluble, phospho-ester prodrug of phenytoin that is rapidly converted to phenytoin in the body. It is compatible with most IV solutions and is well tolerated as an IM injection, even with the large volumes associated with loading doses (20 to 30 mL).19 It is dosed in phenytoin equivalents (PE), and it can be infused three times as fast as phenytoin, up to 150 mg PE/minute. The loading dose for patients not taking phenytoin is 15 to 20 mg PE/kg. It can be an advantage to use IM fosphenytoin when IV access cannot be obtained immediately and in patients with poor venous access. Although it has fewer cardiovascular side... 

Absorption/Distrlbutlon - Phenytoin is slowly absorbed from the small intestine. Rate and extent of absorption varies and is dependent on the product formulation. Bioavailability may differ among products of different manufacturers. Administration IM results in precipitation of phenytoin at the injection site, resulting in slow and erratic absorption, which may continue for up to 5 days or more. Plasma protein binding is 87% to 93% and is lower in uremic patients and neonates. Volume of distribution averages 0.6 L/kg. Phenytoin s therapeutic plasma concentration is 10 to 20 mcg/mL, although many patients achieve complete seizure control at lower serum concentrations. 

Acute head injuries A study evaluating the effect of IV valproate in the prevention of posttraumatic seizures in patients with acute head injuries found a higher incidence of death in valproate treatment groups compared with the IV phenytoin treatment group. Until further information is available, it seems prudent not to use valproate sodium injection in patients with acute head trauma for the prophylaxis of posttraumatic seizures. 

Admixture Incompatibilities Physical incompatibilities resulted when linezolid IV injection was combined with the following drugs during simulated Y-site administration amphotericin B, chlorpromazine hydrochloride, diazepam, pentamidine isothionate, erythromycin lactobionate, phenytoin sodium, and trimethoprim-sulfamethoxazole. Additionally, chemical incompatibility resulted when linezolid IV injection was combined with ceftriaxone sodium. 

You are asked to treat a 55-year-old patient for continuing ventricular arrhythmias. The patient is receiving timolol drops for glaucoma, daily insulin injections for diabetes melUtus, and an ACE inhibitor for hypertension. You decide to use phenytoin instead of procainamide because of what pharmacological effect of procainamide ... 

Completely absorbed after IM administration. Protein binding 95%-99%. After IM or IV administration, rapidly and completely hydrolyzed to phenytoin. Time of complete conversion to phenytoin IM 4 hr after injection IV 2 hr after the end of infusion. Half-life for conversion to phenytoin 8-15 min. 

Injection-. 75 mg/ml, equivalent to 50 mg/ml phenytoin, or 50 mg phenytoin equiva-lent/ml (Cerebyx). 

After oral administration peak plasma concentration of phenytoin usually takes 2 to 4 hours with a second peak at 10 to 12 hours. When administered intramuscularly, pheny-toin is eventually absorbed completely, the drug first crystallises out at the injection site and then slowly redissolves in tissue fluids before entering into the circulation. As a result absorption of phenytoin by IM route is too slow to produce a reliable effect. In contrast a phosphate prodrug, fosphenytoin, is more soluble and is well absorbed after IM administration. 

Absorption of phenytoin is highly dependent on the formulation of the dosage form. Particle size and pharmaceutical additives affect both the rate and the extent of absorption. Absorption of phenytoin sodium from the gastrointestinal tract is nearly complete in most patients, although the time to peak may range from 3 to 12 hours. Absorption after intramuscular injection is unpredictable, and some drug precipitation in the muscle occurs this route of administration is not recommended for phenytoin. In contrast, fosphenytoin, a more soluble phosphate prodrug of phenytoin, is well absorbed after intramuscular administration. 

Morphine Sulfate Morphine sulfate precipitates in alkaline media and drugs that are incompatible with it, including aminophylline, sodium salts of barbiturates, and phenytoin. Precipitate was found after 2 horns when morphine sulfate was formulated with acyclovir sodium.70 Incompatibilities also are reported with chlorpromazine hydrochloride injections containing chlorocresol. Admixture of morphine sulfate (1 mg/mL), doxorubicin in doxorubicin hydrochloride... 

Pethidine Hydrochloride Pethidine hydrochloride solutions are not compatible with barbiturates, aminophylline, morphine sulfate, sulfadiazine sodium, methicilline sodium, nitrofurantoin, phenytoin sodium, heparin sodium, sodium iodide, diethanolamine, sulfafurazol, acyclovir sodium, liposomal doxorubicin hydrochloride, frusemide, imipenem, and idarubicin. Visual incompatibilities are reported with mixtures of pethidine hydrochloride and cefoperazone sodium or mezlocillin sodium, nafcillin sodium and minocycline hydrochloride or tetracycline hydrochloride in 5% glucose injection.82 83... 

Thermal decomposition of tetramethylammonium or trimethylanilinium salts was described for phenytoin methylation prior to its GC analysis in plasma [556] and diethyl-stilbestrol in biological fluids [557], Usually a liquid or homogenized sample is extracted into toluene, the respective tetrasubstituted ammonium hydroxide is added and the liquid phase is injected at 260—290°C. 

Phenytoin i.v. 100 mg t.d.s. - Inject slowly undiluted and directly into a large vein through a large-gauge needle or i.v. catheter). Maximum rate 50 mg/min. 

Phenytoin Sodium injection Propylene Glycol and Alcohol Glass, 1.8 M X 2.0mm I.D. silanised S3 (50-80 mesh) Helium 140-190 6/min FID Ethylene Glycol and Methanol USP (24, p. 1326)... 

Prodrugs can be used to increase or decrease the aqueous solubility, mask bitterness, increase lipophili-city, improve absorption, decrease local side effects, and alter membrane permeability of the parent molecule. For example, chloramphenicol has an aqueous solubility of 2.5mg/ml, but chloramphenicol sodium succinate, a prodrug, has an aqueous solubility of lOOmg/ml. Hydantoins also possess low aqueous solu-bilites that result in low and variable availability and precipitation following injection. In an effort to increase the aqueous solubility of phenytoin, Stella et prepared the ethyl and triethylamine esters... 

Fosphenytoin is a prodrug, a compound that undergoes chemical conversion in the body to become the therapeutically active compound phenytoin. Cerebyx dosage will continue to be expressed in PEs. This terminology was adopted in an effort to simplify therapeutic conversions between phenytoin sodium and fosphenytoin sodium (i.e., 500 mg of phenytoin sodium injection is equal to 500 mg PE of fosphenytoin sodium injection). The manufacturer pointed out that by using PEs, prescribers will not have to make dosing... 

Phenytoin is the only widely used hydantoin and, unless otherwise specified, effects discussed here refer to phenytoin. Other hydantoin derivatives include ethotoin (rINN), mephenytoin (rINN), and albutoin (rINN) (all of which are obsolete), and fosphenytoin (rINN). The latter is a water-soluble prodrug that is rapidly hydrolysed to phenytoin after intravenous or intramuscular injection. It causes fewer adverse reactions near the injection site (pain, phlebitis, tissue necrosis, purple hand syndrome) than phenytoin. 

Intravenous phenytoin has been associated with fatal hemodynamic complications and serious reactions at the injection site, including skin necrosis and amputation of extremities. Fosphenytoin, a phenytoin prodrug, has the same pharmacological properties but none of the injection site and cardiac rhythm complications after intravenous administration (64). 

Monoethanolamine is used primarily in pharmaceutical formulations for buffering purposes and in the preparation of emulsions. Other uses include as a solvent for fats and oils and as a stabilizing agent in an injectable dextrose solution of phenytoin sodium. 

Soybean oil emulsions have been reported to be incompatible at 25°C with a number of materials including calcium chloride, calcium gluconate, magnesium chloride, phenytoin sodium, and tetracycline hydrochloride. Lower concentrations of these materials, or lower storage temperatures, may result in improved compatibility. The source of the material may also affect compatibility for example, while one injection from a particular manufacturer might be incompatible with a fat emulsion, an injection with the same amount of active drug substance from another manufacturer might be compatible. 

In several cases the special nature of a formulation will preclude dilution by an aqueous infusion fluid. Injectable products containing phenytoin, digoxin and diazepam may come into this category if they are formulated in a nonaqueous but water-miscible solvent (such as an alcohol-water mixture) or as a solubilised (e.g. micellar) preparation. Addition of the formulation to water may result in precipitation of the dmg, depending on the final concentration of the dmg and solvent. It has been suggested that precipitation of the relatively insoluble diazepam may account for the high (3.5%) incidence of thrombophlebitis which occurs when diazepam is given intravenously. 

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