5,5-Diphenylhydantoin

Absorption

Given its narrow therapeutic index, therapeutic drug monitoring is recommended to help guide dosing. Phenytoin is completely absorbed. Peak plasma concentration is attained approximately 1.5-3 hours, and 4-12 hours after administration of the immediate release formulation and the extended release formulation, respectively. It should be noted that absorption can be markedly prolonged in situations of acute ingestion.

Toxicity

The experience of phenytoin toxicity is not limited to situations of acute ingestion, but may also occur due to drug interactions or due to physiological circumstances that impact serum albumin (ie. kidney disease) or drug metabolism. Other changes that may result in phenytoin toxicity include pregnancy, malnutrition and malignancy.
Phenytoin toxicity most often affects the cardiovascular and nervous systems. The most common presentation of toxicity depends on the route of administration. Cardiovascular adverse effects are most commonly linked to intravenous phenytoin administration, whereas neurological adverse effects are more common with oral phenytoin administration.
Neurotoxicity is usually dependent on serum concentrations. When concentrations range from 10-20 mg/L, mild nystagmus and lateral gaze may occur, while more significant nystagmus is associated with concentrations ranging from 20-30 mg/L. At concentrations of 30-40 mg/L, slurred speech, tremor, nausea, vomiting and ataxia have been reported. In more serious cases where serum levels range from 40-50 mg/L patients are at risk of lethargy, confusion and hyperactivity, and at levels beyond 50 mg/L, coma and seizures may occur.
Phenytoin is classified as an antiarrhythmic and can cause SA and AV nodal blocks as well as dysrhythmias due to its effect on voltage-gated sodium channels. Further, since phenytoin is poorly soluble, the parenteral form is administered with propylene glycol, which is a cardiac depressant. The infusion rate of parenteral phenytoin should not exceed 50 mg per minute due to the risk of hypotension, bradycardia, and asystole.
Treatment for phenytoin toxicity is non-specific and centres around supportive care. One dose of activated charcoal may be used to prevent phenytoin absorption in cases of acute ingestion.
Although hemodialysis is moderately effective at removing phenytoin, it is not normally recommended due to the risks associated with the procedure, and the general effectiveness of supportive care.

Description

The drug was first approved for the treatment of epilepsy by the Food and Drug Administration in 1953 and marketed by Parke-Davis as Dilantin. Its primary mechanism of action appears to block voltage-sensitive sodium channels in the brain (especially in the motor cortex), producing a delay in electrical recovery in neurons and stabilizing the threshold against hyperexcitability.

Description

Phenytoin is an anticonvulsant agent and active metabolite of fosphenytoin . Phenytoin is formed from fosphenytoin by tissue phosphatases. It inhibits neuronal voltage-gated sodium channels in a voltage-dependent manner. Phenytoin reduces the neuronal firing frequency and decreases the amplitude of excitatory post-synaptic potentials (EPSPs) in electrically stimulated rat corticostriatal slices (EC₅₀s = 42.8 and 33.5 μM, respectively). It protects against seizures induced by maximal electroshock (MES) in mice (ED₅₀ = 10 mg/kg). Formulations containing phenytoin have been used in the treatment of tonic-clonic seizures and status epilepticus.

Chemical properties

white crystals or powder

Chemical properties

Phenytoin is a crystalline compound

Originator

Dilantin ,Parke Davis ,US ,1938

The Uses of 5,5-Diphenylhydantoin

5,5-Diphenylhydantoin has been used for phenytoin treatment. It has also been used to slow down or prevent mesoendoderm cell migration.

The Uses of 5,5-Diphenylhydantoin

Reduces incidence of grand mal seizures; appears to stabilize excitable membranes perhaps through effects on Na+, K+, and Ca2+ channels.

The Uses of 5,5-Diphenylhydantoin

A sodium channel protein inhibitor

The Uses of 5,5-Diphenylhydantoin

Phenytoin has the same main effects on the heart as lidocaine. Its use is essentially limited, and it is primarily used only as an oral replacement of lidocaine for paroxysmal tachycardia that is caused particularly by intoxication of digitalis drugs.

Indications

Phenytoin is indicated to treat grand mal seizures, complex partial seizures, and to prevent and treat seizures during or following neurosurgery. Injectable phenytoin and Fosphenytoin, which is the phosphate ester prodrug formulation of phenytoin, are indicated to treat tonic-clonic status epilepticus, and for the prevention and treatment of seizures occurring during neurosurgery.

Background

Phenytoin is classified as a hydantoin derivative and despite its narrow therapeutic index, it is one of the most commonly used anticonvulsants. Since it's introduction about 80 years ago, phenytoin has not only been established as an effective anti-epileptic, but has also been investigated for several other indications such as bipolar disorder, retina protection, and wound healing.
Clinicians are advised to initiate therapeutic drug monitoring in patients who require phenytoin since even small deviations from the recommended therapeutic range can lead to suboptimal treatment, or adverse effects. Both parenteral and oral formulations of phenytoin are available on the market.

What are the applications of Application

5,5-Diphenyl Hydantoin is a sodium channel protein inhibitor

Definition

ChEBI: A imidazolidine-2,4-dione that consists of hydantoin bearing two phenyl substituents at position 5.

Manufacturing Process

10 g of benzophenone (1 mol), 4 g of potassium cyanide (1.22 mols) and 16 g of ammonium carbonate (3.3 mols) are dissolved in 100 cc of 60% (by volume) ethyl alcohol and the mixture warmed under a reflux condenser without stirring at 58° to 62°C. After warming the mixture for 10 hours apartial vacuum is applied and the temperature is raised enough to permit concentration of the reaction mixture to two-thirds of its initial volume.
A slight excess of mineral acid, such as sulfuric or hydrochloric acid is added to acidify the mixture which is then chilled and the solid which separates is filtered off. It is then treated with an aqueous solution of dilute sodium hydroxide to dissolve the hydantoin from the solid unreacted benzophenone. After filtration, the alkaline extract is then acidified to cause the separation of solid pure diphenylhydantoin which is filtered off and dried. It melts at 293° to 296°C.
A net yield of about 95% is obtained by the procedure described above. If the time of warming the reaction mixture is increased three-or four-fold, practically 100% net yields are obtained. The same high net yields are also obtained by heating for even longer periods of time. For example, by heating for 90 hours, a 100% net yield, or 67% gross yield, is obtained.

brand name

Anticonvulsant. Dilantin (Pfizer) [Name previously used: Diphenylhydantoin.].

Therapeutic Function

Antiepileptic

Biological Functions

Phenytoin is a valuable agent for the treatment of generalized tonic–clonic seizures and for the treatment of partial seizures with complex symptoms. The establishment of phenytoin (at that time known as diphenylhydantoin) in 1938 as an effective treatment for epilepsy was more than simply the introduction of another drug for treatment of seizure disorders. Until that time the only drugs that had any beneficial effects in epilepsy were the bromides and barbiturates, both classes of compounds having marked CNS depressant properties. The prevailing view among neurologists of that era was that epilepsy was the result of excessive electrical activity in the brain and it therefore seemed perfectly reasonable that CNS depressants would be effective in antagonizing the seizures. Consequently,many patients received high doses of barbiturates and spent much of their time sedated. Also, since CNS depression was considered to be the mechanism of action of AEDs, the pharmaceutical firms were evaluating only compounds with profound CNS depressant properties as potential antiepileptic agents. It was, therefore, revolutionary when phenytoin was shown to be as effective as phenobarbital in the treatment of epilepsy without any significant CNS depressant activity. This revolutionized the search for new anticonvulsant drugs as well as immediately improving the day-to-day functioning of epileptic patients.
An understanding of absorption, binding, metabolism, and excretion is more important for phenytoin than it is for most drugs. Following oral administration, phenytoin absorption is slow but usually complete, and it occurs primarily in the duodenum. Phenytoin is highly bound (about 90%) to plasma proteins, primarily plasma albumin. Since several other substances can also bind to albumin, phenytoin administration can displace (and be displaced by) such agents as thyroxine, triiodothyronine, valproic acid, sulfafurazole, and salicylic acid.

General Description

Fine white or almost white crystalline powder. Odorless or almost odorless. Tasteless.

Air & Water Reactions

Insoluble in water.

Reactivity Profile

5,5-Diphenylhydantoin is an amide. Amides/imides react with azo and diazo compounds to generate toxic gases. Flammable gases are formed by the reaction of organic amides/imides with strong reducing agents. Amides are very weak bases (weaker than water). Imides are less basic yet and in fact react with strong bases to form salts. That is, they can react as acids. Mixing amides with dehydrating agents such as P2O5 or SOCl2 generates the corresponding nitrile. The combustion of these compounds generates mixed oxides of nitrogen (NOx). 5,5-Diphenylhydantoin is incompatible with strong oxidizers and strong bases.

Fire Hazard

Flash point data for 5,5-Diphenylhydantoin are not available; however, 5,5-Diphenylhydantoin is probably combustible.

Mechanism of action

Phenytoin is indicated for initial monotherapy or adjunct treatment of complex partial or tonic-clonic seizures, convulsive status epilepticus, and prophylaxis. It often is selected for initial monotherapy because of its high efficacy and relatively low incidence of side effects. Phenytoin is not used in the treatment of absence seizures, because it may increase their frequency of occurrence. Phenytoin binds to and stabilizes the inactivated state of sodium channels, thus producing a use-dependent blockade of repetitive firing and inhibition of the spread of seizure activity to adjacent cortical areas.

Pharmacokinetics

Phenytoin is an anticonvulsant with a narrow therapeutic index. Although the recommended therapeutic range is cited to be between 10-20 mg/L, differences in albumin levels, genetics, comorbidities, and body composition can make achieving an ideal phenytoin dose challenging. For example, studies have confirmed that phenytoin metabolism is impacted by CYP2C9 genotype polymorphisms and possibly by CYP2C19 genotype polymorphisms (the latter has not been as extensively studied).
It is worth nothing that although phenytoin is highly protein bound, only the fraction unbound is able to exert a pharmacological effect. Therefore, factors that reduce or increase the percentage of protein bound phenytoin (for example: concomitant administration of drugs that can cause displacement from protein binding sites) can have a marked impact on phenytoin therapy.

Pharmacokinetics

Phenytoin may be administered either orally or intravenously and is absorbed slowly after oral administration, with peak plasma levels achieved after 3 to 12 hours. It is extensively plasma protein bound (~90%), and the elimination half-life is between 15 and 30 hours. These large ranges reflect the considerable variability observed from patient to patient. Parenteral administration of phenytoin is usually limited to the intravenous route. Phenytoin for injection is dissolved in a highly alkaline vehicle (pH 12). This alkaline vehicle is required because phenytoin is weakly acidic and has very poor solubility in its un-ionized form. Reportedly, however, its phosphate ester fosphenytoin has water solubility advantages over phenytoin for injection. Intramuscular phenytoin generally is avoided, because it results in tissue necrosis at the site of injection and erratic absorption because of high alkalinity. In addition, intermittent intravenous infusion is required to reduce the incidence of severe phlebitis.
Phenytoin metabolism is relatively slow and predominantly involves aromatic hydroxylation to p-hydroxylated inactive metabolites. Phenytoin also induces its own metabolism and is subject to large interindividual variability. The major metabolite, 5-p-hydroxyphenyl- 5-phenylhydantoin, accounts for approximately 75% of a dose. This metabolite is excreted through the kidney as the β-glucuronide conjugate. Phenytoin clearance is strongly influenced by its metabolism; therefore, agents that affect phenytoin metabolism may cause intoxication. In addition, because phenytoin is highly plasma protein bound, agents that displace phenytoin also may cause toxicity.

Pharmacology

In terms of its effect on the CNS, phenytoin is considered an excellent antiepileptic drug with insignificant sedative effects. Even in large doses it does not cause hypnosis. It is presumed that phenytoin facilitates secretion of sodium ions from nerve cells, which reduces the stimulation of neurons. This in turn prevents the activation of neurons upon receiving impulses from the epileptogenic center. In addition, phenytoin reduces the incoming flow of potassium ions during repolarization. It is possible that phenytoin significantly slows the distribution of excitation in the brain as a direct result of the redistribution of the ion flow.

Clinical Use

Phenytoin (Dilantin) was originally introduced for the control of convulsive disorders but has now also been shown to be effective in the treatment of cardiac arrhythmias. Phenytoin appears to be particularly effective in treating ventricular arrhythmias in children.
Phenytoin, like lidocaine, is more effective in the treatment of ventricular than supraventricular arrhythmias. It is particularly effective in treating ventricular arrhythmias associated with digitalis toxicity, acute myocardial infarction, open-heart surgery, anesthesia, cardiac catheterization, cardioversion, and angiographic studies.
Phenytoin finds its most effective use in the treatment of supraventricular and ventricular arrhythmias associated with digitalis intoxication. The ability of phenytoin to improve digitalis-induced depression of A-V conduction is a special feature that contrasts with the actions of other antiarrhythmic agents.

Clinical Use

Phenytoin is one of very few drugs that displays zero-order (or saturation) kinetics in its metabolism.At low blood levels the rate of phenytoin metabolism is proportional to the drug’s blood 1evels (i.e., first-order kinetics). However, at the higher blood levels usually required to control seizures, the maximum capacity of drug-metabolizing enzymes is often exceeded (i.e., the enzyme is saturated), and further increases in the dose of phenytoin may lead to a disproportionate increase in the drug’s blood concentration. Since the plasma levels continue to increase in such a situation, steady-state levels are not attained, and toxicity may ensue. Calculation of half-life (t1/2) values for phenytoin often is meaningless, since the apparent half-life varies with the drug blood level.
Acute adverse effects seen after phenytoin administration usually result from overdosage. They are generally characterized by nystagmus, ataxia, vertigo, and diplopia (cerebellovestibular dysfunction). Higher doses lead to altered levels of consciousness and cognitive changes.
A variety of idiosyncratic reactions may be seen shortly after therapy has begun. Skin rashes, usually morbilliform in character, are most common. Exfoliative dermatitis or toxic epidermal necrolysis (Lyellís syndrome) has been observed but is infrequent. Other rashes occasionally have been reported, as have a variety of blood dyscrasias and hepatic necrosis.

Side Effects

The most common side effect in children receiving long-term therapy is gingival hyperplasia, or overgrowth of the gums (occurs in up to 50% of patients). Although the condition is not serious, it is a cosmetic problem and can be very embarrassing to the patient. Hirsutism also is an annoying side effect of phenytoin, particularly in young females. Thickening of subcutaneous tissue, coarsening of facial features, and enlargement of lips and nose (hydantoin facies) are often seen in patients receiving long-term phenytoin therapy. Peripheral neuropathy and chronic cerebellar degeneration have been reported, but they are rare.
There is evidence that phenytoin is teratogenic in humans, but the mechanism is not clear. However, it is known that phenytoin can produce a folate deficiency, and folate deficiency is associated with teratogenesis. Only a few well-documented drug combinations with phenytoin may necessitate dosage adjustment. Coadministration of the following drugs can result in elevations of plasma phenytoin levels in most patients: cimetidine, chloramphenicol, disulfiram, sulthiame, and isoniazid (in slow acetylators). Phenytoin often causes a decline in plasma carbamazepine levels if these two drugs are given concomitantly.
Ethotoin and mephenytoin are congeners of phenytoin that are marketed as AEDs in the United States. They are not widely used.

Side Effects

The rapid IV administration of phenytoin can present a hazard. Respiratory arrest, arrhythmias, and hypotension have been reported.

Safety Profile

Confirmed carcinogen producing lymphoma, Hodgkin's disease, tumors of the skin and appendages. Experimental carcinogenic and tumorigenic data. A human poison by ingestion. Poison experimentally by ingestion, subcutaneous, intravenous, and intraperitoneal routes. Moderately toxic by an unspecified route. Experimental teratogenic and reproductive effects. Human systemic effects by ingestion: dermatitis, change in motor activity (specific assay), ataxia (loss of muscle coordmation), degenerative brain changes, encephalitis, hallucinations, dtstorted perceptions, irritabihty, and jaundice. Human teratogenic effects by ingestion: developmental abnormalities of the central nervous system, carlovascular (circulatory) system, musculoskeletal system, craniofacial area, skin and skin appendages, eye, ear, other developmental abnormalities. Effects on newborn include abnormal growth statistics (e.g., reduced weight gain), physical abnormakties, other postnatal measures or effects, and delayed effects. Human mutation data reported. A drug for the treatment of grand mal and psychomotor seizures. When heated to decomposition it emits toxic fumes of NOx

Synthesis

Phenytoin, 5,5-diphenylimidazolidinedione (9.1.1) is synthesized in two different ways. The first involves a rearrangement on the reaction of benzil with urea to form the desired product (9.1.1) .

The second method involves the reaction of benzophenone with sodium cyanide in the presence of ammonium carbonate, followed by the simultaneous cyclization of the resulting product (carboxyaminonitrile) and its rearrangement under the reaction conditions to form phenytoin .

Potential Exposure

Phenytoin is an amide pharmaceutical used in the treatment of grand mal epilepsy, Parkinson’s syndrome; and in veterinary medicine. Human exposure to phenytoin occurs principally during its use as a drug. Figures on the number of patients using phenytoin are not available, but phenytoin is given to a major segment of those individuals with epilepsy. The oral dose rate is initially 100 mg given 3 times per day and can gradually increase by 100 mg every 2
4 weeks until the desired therapeutic response is obtained. The intravenous dose is 200
350 mg/day.

Drug interactions

Plasma phenytoin concentrations are increased in the presence of chloramphenicol, disulfiram, and isoniazid, since the latter drugs inhibit the hepatic metabolism of phenytoin. A reduction in phenytoin dose can alleviate the consequences of these drug–drug interactions.

Carcinogenicity

Phenytoin and its sodium salt are reasonably anticipated to be human carcinogens based on sufficient evidence from studies in experimental animals.

Environmental Fate

Routes and Pathways
Exposure is usually oral, but the intravenous route may be used to treat status epilepticus.
Relevant Physicochemical Properties
Appearance: clear, colorless, or slightly yellow in solution Solubility: ethyl alcohol

Metabolism

Phenytoin is extensively metabolized and is first transformed into a reactive arene oxide intermediate. It is thought that this reactive intermediate is responsible for many undesirable phenytoin adverse effects such as hepatotoxicity, SJS/TEN, and other idiosyncratic reactions. The arene oxide is metabolized to either a hydroxyphenytoin or phenytoin dihydrodiol metabolite, although the former accounts for about 90% of phenytoin metabolism.
Interestingly, two stereoisomers of the hydroxyphenytoin metabolite are formed by CYP2C9 and CYP2C19: (R)-p-HPPH and (S)-p-HPPH. When CYP2C19 catalyzes the reaction, the ratio of stereoisomers is roughly 1:1, whereas when CYP2C9 catalyzes the reaction, the ratio heavily favours the "S" stereoisomer. Since the metabolism of phenytoin is in part influenced by genetic polymorphisms of CYP2C9 and CYP2C19, this ratio can be utilized to identify different genomic variants of the enzymes.
EPHX1, CYP1A2, CYP2A6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP2E1 and CYP3A4 are responsible for producing the phenytoin dihydrodiol metabolite.
Hydroxyphenytoin can be metabolized by CYP2C19, CYP3A5, CYP2C9, CYP3A4, CYP3A7, CYP2B6 and CYP2D6 to a phenytoin catechol metabolite or undergo glucuronidation by UGT1A6, UGT1A9, UGT1A1, and UGT1A4 to a glucuronide metabolite that can be eliminated in the urine. On the other hand, the phenytoin dihydrodiol entity is only transformed to the catechol metabolite.
The catechol metabolite can undergo methylation by COMT and be subsequently eliminated in the urine, or can spontaneously oxidize to a phenytoin quinone (NQO1 can transform the quinone back to the catechol metabolite).
Of note, although CYP2C18 is poorly expressed in the liver, the enzyme is active in the skin and is involved in the primary and secondary hydroxylation of phenytoin. This CYP2C18 mediated bioactivation may be linked to the manifestation of adverse cutaneous drug reactions associated with phenytoin.

Metabolism

Phenytoin is hydroxylated in the liver to inactive metabolites chiefly 5-(4-hydroxyphenyl)-5- phenylhydantoin by an enzyme system which is saturable. Phenytoin undergoes enterohepatic recycling and is excreted in the urine, mainly as its hydroxylated metabolite, in either free or conjugated form.

Solubility in water

practically insoluble in water. 1 g dissolves in about 75 ml of ethanol or 30 ml of acetone.

Shipping

UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required. UN3249 Medicine, solid, toxic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials.

Purification Methods

Crystallise the hydantoin from EtOH. [Beilstein 24 III/IV 1748.]

Toxicity evaluation

Since metabolism of the drug is a saturable process, much of the toxicity of phenytoin is thought to be due to increased concentrations of the drug, especially of nonprotein-bound drug. The free drug may cross the blood–brain barrier, and if present in excess, could produce some of the adverse neurological manifestations. Other toxicities may be related to folic acid deficiency induced by phenytoin. Reactive intermediates formed during metabolism of phenytoin may also be responsible for some of the drug’s toxicity.

Incompatibilities

Incompatible with oxidizers (chlorates, nitrates, peroxides, permanganates, perchlorates, chlorine, bromine, fluorine, etc.); contact may cause fires or explosions. Keep away from alkaline materials, strong bases, strong acids, oxoacids, epoxides. Similar organic amides react with azo and diazo compounds, releasing toxic gases. Contact with reducing agents can release flammable gases. Amides are very weak bases but they can react as acids, forming salts. Mixing amides with dehydrating agents such as phosphorus pentoxide or thionyl chloride generates the corresponding nitrile.

Precautions

Phenytoin either should not be used or should be used cautiously in patients with hypotension, severe bradycardia, high-grade A-V block, severe heart failure, or hypersensitivity to the drug.
Because of the increase in A-V transmission observed with phenytoin administration, it should not be given to patients with atrial flutter or atrial fibrillation. Phenytoin will probably not restore normal sinus rhythm and may dangerously accelerate the ventricular rate.