Caffeine Citrate

Absorption

Fosphenytoin at 15 to 20 mg PE/kg infused at 100 to 150 mg PE/min intravenously yields free plasma phenytoin concentrations similar to an equivalent dose of phenytoin sodium administered at 50 mg/min. Single intravenous administration of fosphenytoin shows a linear increase in mean maximum total phenytoin concentration while the mean maximum unbound phenytoin concentrations increase with both dose and infusion rate. Fosphenytoin is rapidly converted to phenytoin following intravenous administration with a half-life of 15 minutes; if administered intramuscularly, the peak plasma phenytoin concentration is not reached until three hours.

Toxicity

Nausea, vomiting, lethargy, tachycardia, bradycardia, asystole, cardiac arrest, hypotension, syncope, hypocalcemia, metabolic acidosis, and death have been reported in cases of overdosage with fosphenytoin. The median lethal dose of fosphenytoin given intravenously in mice and rats was 156 mg PE/kg and approximately 250 mg PE/kg, or about 0.6 and 2 times, respectively, the maximum human loading dose on a mg/m2 basis. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, and hypoactivity.

Description

Cerebyx was launched for the treatment of status epilepticus and for neurosurgery derived seizures. Fosphenytoin is rapidly converted by phosphatases to phenytoin. This compound is readily water soluble thus overcoming an important problem associated with Dilantin.

Originator

Warner-Lambert (USA)

The Uses of Caffeine Citrate

Anticonvulsant.

Background

Fosphenytoin is a water-soluble phenytoin prodrug used only in hospitals for the treatment of epileptic seizures. It works by slowing down impulses in the brain that cause seizures. Its main mechanism is to block frequency-dependent, use-dependent and voltage-dependent neuronal sodium channels, and therefore limit repetitive firing of action potentials.

Indications

Fosphenytoin is indicated for the treatment of generalized tonic-clonic status epilepticus and for the prevention and treatment of seizures occurring during neurosurgery in adult patients. It can also be substituted, short-term, for oral phenytoin in patients aged two years and older when oral phenytoin administration is not possible.

Definition

ChEBI: Fosphenytoin is an imidazolidine-2,4-dione.

Manufacturing Process

By action of formaldehyde and hydrochloric acid on 5,5-diphenylhydantoin was prepared 3-hydroxymethyl-5,5-diphenyl-imidazolidine-2,4-dione which was converted by action PCl3 to 3-chloromethyl-5,5-diphenyl-imidazolidine-2,4- dione by action PCl3. Then the chlorine atom was substituted on P(O)(OBz)Ogroup by action of argentum salt of phosphoric acid dibenzyl ester. Removal of the protecting groups by hydrogenolysis gives the 2,4-imidazolidinedione, 5,5- diphenyl-3-((phosphonooxy)methyl)- (fosphenytoin).
In practice it is usually used as sodium salt.

brand name

Cerebyx (Parke-Davis).

Therapeutic Function

Antiepileptic, Anticonvulsant

Pharmacokinetics

Fosphenytoin is a water-soluble phenytoin prodrug used for the treatment of epileptic seizures. Following parenteral administration of fosphenytoin, fosphenytoin is converted to the anticonvulsant phenytoin by endogenous phosphatases. Each 1.5 mg of fosphenytoin sodium is equivalent to 1.0mg of phenytoin sodium (PE equivalents); care should be taken to calculate the dose required in PE equivalents properly. Serious adverse effects such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN), and hematopoietic complications may occur and indicate an alternate antiepileptic should be used. Withdrawal of fosphenytoin sodium may precipitate seizures and should be done gradually.

Metabolism

Fosphenytoin is metabolized, likely by phosphatases, to phenytoin, phosphate, and formaldehyde; the formaldehyde is subsequently converted into formate. The phenytoin produced is metabolized hepatically by CYP2C9 and, to a lesser extent, by CYP2C19.