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The earliest described symptoms of epilepsy were recorded by the Sumerian civilization circa 650 B.C. Status Epilepticus was seen as the possession by a demon, and it was recommended to record the day and time of this so called possession.
The term status epilepticus was coined through the translation of Armand Trousseau's lectures in the year 1868.
Clinical studies focusing on status epilepticus were of low importance in the ï¬rst half of the 20th century. It was only in 1962 that a systemic classification for epilepsy was developed at the 10th Marseilles Colloquium.
The first anti-epileptic drug to be used by the medical practitioner was Bromide, which was introduced in the late 19th century. Bromide was quickly replaced by Phenobarbital in 1912.
Following this, Phenytoin was undergoing clinical testing to be used in sedation when it was discovered to have anti-convulsant properties and is now considered one of the major anticonvulsants used.
Variations of these ground breaking drugs were designed to aid in the treatment of the various types of epilepsy. Between 1960 and 1978 three drugs were approved by the FDA (Food and Drug Authority) for use in epilepsy
Nowadays medicinal chemists are continuously developing drugs which have an increase in efficacy and present with lower Side-Effects, leading to the discontinuation of older drugs such as trimethadione, phenacemide.
Gustave FlaubertÂ considered one of the greatestÂ French novelists and Edgar Allan Poe one of the most famous American storytellers suffered from epilepsy during their life.
Fig 1.1: Gustave Flaubert Fig1.2: Edgar Allan Poe
Clinical Studies were started in 1942 by Lennox et al. by analyzing the effects of induced prolonged seizures on cats and their off-springs though the administration of Camphor and Thujone.
Following studies showed that in the initial half hour of the seizure, arterial blood pressure rose with an increase in oxygen content of the cerebral veins. Pyrexia was recorded commonly accompanied by high blood glucose levels. Following these events, arterial pressure and blood glucose levels fell, with cerebral venous oxygen returning to stable levels.
How Anticonvulsants work:
Enhancing GABA-mediated synaptic inhibition
Inhibiting GABA transaminase (Involved in the breakdown of GABA neurotransmitter) or by using drugs with direct GABA properties one enhances the post-synaptic action of GABA which has an inhibiting effect.
Inhibiting Na+ channels
Selective blocking of neurones involved in continuous repetitive excitation through reduction in the electrical excitability of their cell membranes.
Inhibition of Ca2+ channels
Specific T-type Ca2+ channels blockage is used in the prevention of seizures.
Phenytoin is a highly potent Hydantoin (class 1b) anticonvulsant used in a wide variety of seizures having also anti-arrhythmic and muscle relaxing effects.
Phenytoin was being studied to be used in sedation however it was found to be ineffective and it was in 1938 that H. Houston MerrittÂ andÂ Tracy PutnamÂ used this therapeutic failure to their advantage to produce a non-sedating anticonvulsant drug.
Phenytoin was approved by the FDA in 1953 in the control of seizure, however in 2008 a notice for further evaluation was issued as it might be involved in the development of Purple Glove Syndrome where skin extremities swell, become painful and as the name implies has a purple tinge.
Fig 2.1: Phenytoin Structure using Symyx Â®
Systematic name: 5, 5-di(phenyl)imidazolidine-2,4-dione
Generic name: Phenytoin (previously known as diphenylhydantoin) another 14 synonyms exist for Phenytoin.
Trade Name & Dosage Form: DilatinÂ® 100 mg Extended Oral Capsule another 129 trade names exist for Phenytoin.
Main functional system and SAR
Phenytoin forms part of the hydantoin class which is closely related to the pharmacological class of barbiturates. It is an acyclic monoacylureas therefore a weak organic acid with a pKa of 8.33, thus aqueous solutions of Phenytoin sodium generate strong alkaline solutions
As mentioned before it was the first anticonvulsant in which it is clearly demonstrated that anticonvulsant activity could be separated from a sedative-hypnotic activity which was seen with barbiturates.
Useful against all seizure types except absence seizures a type of generalized seizure. Drug is sometimes incompletely or erratically absorbed from sites of administration and this is due to the very low water solubility of the drug due to the two benzene rings.
Phenytoin has a tropistic effect toward non-generalised tonic-clonic seizure rather than antiabsence activity. This is not an intrinsic activity of the Hydantoin ring system.
Fig 2.1: Phenytoin Structure using Symyx Â®
The aryl substitution on the 5 position, corresponding to a branched atom of the general pharmacophore is essential for anticonvulsant activity. As no Alkyl substitutions are present on this position, no sedation is observed like in the barbiturates.
Mode of action
Phenytoin targets Na+ channel protein type IÎ± and Na+ channel protein type VÎ± present on the neuronal cell membrane of the motor cortex, limiting the spread of seizure activity and reducing seizure propagation.
It promotes sodium efflux from the neuron cells, thus stabilizing the threshold against hyper excitability caused by the excessive stimulation or by environmental changes which lead to a decrease in the membrane's sodium gradient. This includes the reduction of post-tetanic potentiating at synapses preventing cortical seizure foci from activating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of tonic-clonic (état de grand mal) seizures.
Physiochemical properties of importance and other chemical Properties:
Phenytoin is a solid white crystalline powder of pure Synthetic origin which has a solubility of 32mg/L in water, slightly soluble in chloroform and ether and is soluble 1 part in 70 parts alcohol, with a melting point of 297oc.
It has a shelf-life of 5 years when stored at 20Â°C and in airtight conditions
Experimental Partition coefficient (LogP) is of 2.2, this indicates a moderate low hydrophobicity. For transport to be efficient a drug has to have a high hydrophobic level enough to partition into the lipid bilayer, however still able to partition out again.
Bioavailability of oral Phenytoin was estimated at 70-100%. A 24.4% bioavailability was recorded for rectal and intravenous administration making oral route the preferred mode of administration. Peak blood concentration is noticed in 1Â½ to 3 hours with a rapid rate of absorption. Phenytoin has a long half life of 22 hours hence has a long lasting effect.
Fig3.1: induced Status epilepticus in Mouse (left) and Rat (left)
Toxicity LD50Â = 150 mg/kg for oral mouse and 1635 mg/kg for oral rat. Symptoms Phenytoin Overdose leads to coma, Speech impairment, and involuntary eye movement, lack of muscle coordination, hypotension, nausea, tremors, and vomiting.
Phenytoin has a serum albumin binding of 90%-95%, this means that only a few amount of unbound drug is needed to elicit a therapeutic effect thus in cases where blood protein levels are lower e.g. in children and elderly, the dose has to be reduced accordingly as more unbound drugs would be present in the system.
Lipinski rule of 5
Christopher Lipinski's rule of 5 notifies the drug designer about the drug likeness of a molecule according to physiochemical properties and structural features of the molecule in question. This rule prevents redundant testing of molecules which later on would be found to be therapeutically ineffective.
It was called the rule of 5 because each criteria was a multiple of 5, however improvements and additions have been made since then:
Criteria which have to be met:
Not more than 5Â nitrogenÂ orÂ oxygenÂ atomsÂ with one or moreÂ hydrogenÂ atoms (bond donors)
Not more than 10Â hydrogen bondÂ acceptors (nitrogenÂ orÂ oxygenÂ atoms)
AÂ molecular weight between 160 and 480
An partition coefficientÂ logÂ PÂ between -0.4 and +5.6
Molecule contains 20 to 70 atoms
Table 3.1: Lipinski Criteria
Only 2 Nitrogen and 2 Oxygen atoms are present in the molecule hence Lipinski rule applies.
The Molecular weight is of 252.27 hence Lipinski rule applies.
Log P is 2.2 which is in the range dictated by the Lipinski rule.
Phenytoin molecule consists of 21 molecules thus it is fully compatible with the Lipinski rule of 5.