Epilepsy comes from the Grecian word for “ onslaught ” , and is one of the oldest upsets described in medical specialty. Epilepsy is a upset in the encephalon where bunchs of nerve cells signal defectively. In epilepsy, the normal tract taken by an electrochemical urge alterations, bring forthing a assortment of symptoms, viz. : musculus cramps, loss of consciousness and paroxysms. This upset is chiefly characterized by ictuss and can take up many signifiers, depending chiefly on the portion of the encephalon affected ( Anon, 2010 ) .

During an epileptic event, a high frequence electrochemical urges arising from a point beginning in the encephalon spreads to other countries, impacting other parts of the encephalon. As explained above, the symptoms produced depend on the portion of the encephalon affected and hence the motor cerebral mantle is the chief site of paroxysms, the hypothalamus is responsible for peripheral autonomic discharge and the engagement of the reticulate formation in the upper brain-stem leads to a loss of concision ( Rang et al. , 2003 ) .

Epilepsy is a really common neurological upset, impacting 0.5 – 1 % ( Rang et al. , 2003 ) of the universes population. The two chief signifiers of epilepsy are tonic-clonic tantrum ( besides known as expansive mal ) and the absence ictus ( petit mal ) . Status epilepticus is besides found, which may be life endangering if the ictus activity is left uninterrupted. The unnatural discharge in worlds is non yet to the full understood and is said to be associated with the release of excitatory amino acids, an impaired inhibitory transmittal, or irregular electrical belongingss of cells ( Rang et al. , 2003 ) .

Presently, drug therapy is merely effectual in about 70 – 80 % ( Rang et al. , 2003 ) of human topics. Three of these drugs, viz. : Sodium Valproate, Lamotrigene and Phenytoin, will be discussed below.

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Chemical Structure and Physical Properties of the Drugs

Figure 1: The Chemical construction of Lamotrigene. Obtained from hypertext transfer protocol: //en.academic.ru/dic.nsf/enwiki/207879.One of the alone chemical characteristics of Lamotrigene that makes it stand out from the other drugs, is that it is chemically unrelated to all the other anti-epileptic drugs. Its UIPAC name is 3,5-diamino-6- ( 2,3-dichlorophenyl ) -as-triazine and has a molecular weight of 256.09g/mol ( Figure 1 ) . Phenytoin has a really similar molecular weight as the aforesaid molecule being 252.3g/mol. The compound contains a entire 3 aromatic rings as can be seen in Figure 2. The IUPAC name of the compound is 5,5-Diphenylhydantoin. Sodium valproate is a reasonably simple molecule when compared to the other drugs, and is besides much lighter, holding a molecular weight of 166.2g/mol. Its IUPAC name is Sodium di-n-propylacetic acid and it differs from the other two drugs in that it does n’t incorporate any aromatic rings or N atoms in its construction.

Figure 2: The Chemical Structure of Phenytoin. Obtained from Medsafe, 2010.

Figure 3: The Chemical Structure of Sodium Valproate. Obtained from Medsafe, 2010. The physical belongingss of the drugs are besides expected to alter with a alteration in the molecular construction. One noteworthy physical parametric quantity is the solubility as Lamotrigene is meagerly soluble in H2O ( 0.17 mg/mL at 25A°C ) and somewhat soluble in acid ( 1.0 mg/mL at 25A°C ) with a pKa of 5.56 ( DailyMed, 2009 ) due to the bulky hydrophobic groups present. Phenytoin is somewhat more soluble than Lamotrigene ( 1 in 70 in intoxicant ) but Sodium Valproate is the most soluble drug of the three due to the presence of the easy ionisable CHCOO-Na+ that is present on the molecule ( 1.2 mg/mL ) ( Ellenhorn MJ & A ; Barceloux DG ( 1988 ) .

Phenytoin is besides hygroscopic and bit by bit absorbs C dioxide from the milieus on exposure with air with the release of diphenylhydantoin ( Reynolds, 1996 ) . Sodium valproate tablets on the other manus should be sealed in air-tight containers to protect them from inordinate visible radiation. The capsules should be stored at a temperature of 15 to 30 0C and freeze should be avoided ( Reynolds, 1989 ; McEvoy, 1991 ) .

Clinical Actions and Curative Actions

An indispensable characteristic about epilepsy that must be borne in head is that at present clip, there is no definite remedy for the status, but merely a agency of suppression of ictuss.

Any of the three mentioned anti-epileptic drugs can be used by a patient but the pick basically depends on a huge array of factors, viz. : ictus type, attendant type, comorbidity, age, sex and plasma drug half life ( BNF, 2010 ) .

Sodium valproate and Lamotrigene are normally administered in all types of ictuss, whilst Phenytoin can non be used in the instance of absent ictuss. Some other instances where Phenytoin is administered are in partial ictuss, position epilepticus and tri-geminal neuralgy. Like Phenytoin, Lamotrigene is besides effectual in partial ictuss but can besides be taken in the instance of secondary generalized tonic clonic ictuss, untypical absent ictus in kids and atonic ictuss ( BNF, 2010 ) .

Mode of Action

The manner of action of all three drugs has non yet been to the full established but surveies had proven that they tend to adhere to specific electromotive force gated Na channels in the encephalon in order to exercise its anticonvulsant consequence by the suppression of insistent fire of nerve cells by suppression of Na flux through these voltage dependant channels ( Francis & A ; Burnham, 1992 ) .

Lamotrigene is besides thought to stabilise a figure of neural membranes and commanding the presynaptic release of excitatory amino acids such as glutamate aspartate and has a weak affinity for 5-HT3 receptor ( Keck and McElroy, 2002 ) . Animal theoretical accounts performed on the drug Na valproate have suggested that it inhibits GABA transferase and succinic aldehyde dehydrogenase, the enzymes that are of import for GABA katabolism. Consequences from one survey have revealed that Na valproate additions potassium conductance and hence inhibits neural activity ( McEvoy, 1991 ) . Besides, this drug may besides suppress GABA degradative enzymes such as GABA aminotransferase by suppressing the re-uptake of GABA by neural cells ( Medsafe, 2010 ) . One chief difference with the drug Phenytoin is that it is known to stabilise membranes in the encephalon and in the bosom, and besides helps to cut down the spasmodic activity from a dispatching focal point without act uponing the focal point itself ( Reynolds 1996 ) . In add-on to this, Phenytoin besides decreases the force of contraction of the cardiac musculus, reduces pacemaker action and increases the efficiency of the auriculoventricular conductivity. Another alone characteristic of this drug is that it increases the effectual furnace lining period in relation to continuance of an action potency ( McEvoy, 1995 ) .

Side Effect Profiles

As can be seen in Table 1, the drug that produces the most inauspicious consequence is Phenytoin. The chief unwanted effects of the drug start to emerge at a plasma concentration of 100 Aµmol/l and may go really terrible if the concentration exceeds 150 Aµmol/l ( Rang et al. , 2003 ) . Some of the most common side effects are hypersensitivity reactions such as roseolas, dizziness and ataxy. In a survey by Butter ( 1940 ) , it was noted that in nine of the instances where the intervention was stopped, a huge array of symptoms had been exhibited. In two of these instances, fever and tegument roseolas had been observed, whilst in another instance hypertrophic gingivitis with sickness and emesis had been seen. However, the other six instances showed the undermentioned symptoms: tremulousness, shudder, atactic pace, nystagmus, slurring address and insomnia. Most of these toxic effects disappeared when the medicine was stopped ( Butter, 1940 ) . It is for this ground that side effects such as hirsuteness, acne and coarse faces exhibited by Phenytoin that deters its usage for most adolescent patients.

Side Consequence

Diphenylhydantoin

Sodium Valproate

Lamotrigene

Acne

A

A

A

Hirsuteness

A

A

A

Coarse Face

A

A

A

Nausea

A

A

A

Vomiting

A

A

A

Constipation

A

A

A

Insomnia

A

A

A

Transient Jitteriness

A

A

A

Tremor

A

A

A

Parestesia

A

A

A

Dizziness

A

A

A

Concern

A

A

A

Anorexia

A

A

A

Gastric Irritation

A

A

A

Diarrhea

A

A

A

Weight Gain

A

A

A

Cutting of Hair

A

A

A

Hepatotoxicity

A

A

A

Teratogenic

A

A

A

Rashs

A

A

A

Sedation

A

A

A

Fever

A

A

A

Facial Edema

A

A

A

Hypersensitivity Syndrome

A

A

A

Dizziness

A

A

A

Ataxia

A

A

A

Nystagmus

A

A

A

Hyperplasia of Gums

A

A

A

Megaloblastic Anemia

A

A

A

Table 1: The chief side effects exhibited by the three drugs ; Phenytoin, Sodium Valproate and Lamotrigene. The Blue box signifies that the unwanted consequence is produced by the drug and the Red box signifies that there are no hints of such an consequence when the drug is administered.

Some of the side effects exhibited by Lamotrigene were studied by Brodie and his squad ( Brodie et al. , 1999 ) as shown in Table 2. Apart from the deficiency of co-ordination and sleepiness, the biggest job with this drug was skin roseola, and it is thought that it has to make with the get downing dosage of the drug ( Chadwick et al. , 1984 ) . Therefore, any single agony from hypersensitivity reactions should non do usage of this drug. Apart from this, Lamotrigene can be used in monotherapy and its effectivity is wide as it covers all ictus types ( Brodie et al. , 1999 ) . Its long plasma half life of 24 hours besides makes it peculiarly utile as dose can be kept to a lower limit of one time or twice day-to-day ( Rang et al. , 2003 ) . Lamotrigene is normally the drug of pick in most patients as its one of the newer drugs on the market and contains the least sum of side effects.

Side Consequence

Lamotrigene ( n = 102 )

Poor co-ordination

13

Sleepiness

12

Dizziness

10

Rash

9

Concern

9

Constipation

9

Vomiting

9

Diarrhea

7

Table 2: A instance survey performed on 102 patients by Brodie et al. , ( 1999 ) . The figure given in the 2nd column signifies the sum of people affected by that peculiar unwanted consequence.

Sodium Valproate, compared to other epileptic drugs on the market, is besides one of the most coveted as it contains reasonably minimum side effects. The most noteworthy consequence is thinning and curving of hair in approximately 10 % of patients. It has to be noted that one of the most serious side effects is hepatotoxicity, which is due to an addition in serum glutamic oxaloacetic aminotransferase, nevertheless this is rather rare. Sodium Valproate is besides teratogenic and should non be taken by pregnant adult females ( Rang et al. , 2003 ) .

A

Diphenylhydantoin

Sodium Valproate

Lamotrigene

Absorption

Well absorbed when given orally. About 80 -90 % of the plasma content is bound to albumin. The plasma concentration needed is normally between 40 – 100 micromoles/litre ( Medsafe, 2010 )

Absorbed good orally, with extremum in blood degrees happening within 15 to 60 proceedingss after consumption of sirup and 1 to 4 hours after a individual unwritten tablet. Absorption is affected if taken with nutrient, nevertheless extent of soaking up is non affected. The per centum of free ( unbound ) drug is normally about 6 % and 15 % of the entire plasma degrees. ( McEvoy, 1991 ; Ellenhorn & A ; Barceloux, 1988 ) .

Quickly and wholly absorbed from the intestine with no important base on balls metamorphosis. Peak plasma concentrations occur at around 2.5 hours after disposal. The clip to maximum concentration in the plasma is somewhat reduced after nutrient but the sum of soaking up is non affected. The pharmacokinetics are additive up to 450mg. These is considerable inter-individual fluctuation in steady province upper limit but within persons, concentrations do non change so much ( Medsafe 2010 )

Distribution

Phenytoin is distributed in the cerebrospinal fluid, spit, seeds, gall and chest milk. Vd = 0.6 -1 litre/kg in Adults = 0.7litres/kg. Phenytoin demonstrates non-linear dynamicss ( Medsafe, 2010 ) . 87 – 93 % is bound to protein and the volume of distribution is 0.5 to 0.8 L/kg ( Gugler et al. , 1976 ; Hvidberg & A ; Dam, 1976 ) . Plasma binding is entirely to albumin. Half life of 24 hours.

Distribution is rapid and most probably restricted to circulation and quickly exchangeable extracellular H2O. Sodium valproate does n’t demo any additive dynamicss due to concentration dependent plasma protein every bit good as a short half life of 8-20 hours. The drug is about 90 % edge to the plasma proteins but merely 60 % to albumin. Subsequently, if the plasma degree of the drug rises above 120 microgram/mxsL, the binding sites may go concentrated, doing sum of free drug to lift quickly. The drug may besides displace Phenytoin from protein adhering sites ( Medsafe, 2010 )

Adhering to plasma proteins is about 55 % ; it ‘s really improbable that the supplanting from plasma proteins would ensue in toxicity. Volume of distribution is 0.92 to 1.22 L/kg ( Medsafe, 2010 ) . Half life is between 24.1 and 35 hours ( Garnett, 1997 ) . Pharmacokinetic Parameters:

A

Diphenylhydantoin

Sodium Valproate

Lamotrigene

Metamorphosis

Metabolised by the hepatic assorted map oxidase system. Metamorphosis can be enhanced/ inhibited by other drugs that have the same hepatic enzymes.

Complex metamorphosis. Elimination tract is via glucuronidation ( 40-60 % ) . The other is mostly metabolised via oxidization tracts, I?-oxidation accounting for 30-40 % ( cytochrome P450 dependant ) . Merely around 1-3 % of dosage is found to be excreted unchanged in the piss ( Medsafe, 2010 )

UDP-glucuronyl transferases have been identified as the enzyme responsible for this drugs metamorphosis. Lamotrigine induces its ain metamorphosis, depending on dosage. No grounds that the drug affects the pharmacokinetics of other AEDs and grounds suggests that the interactions between Lamotrigene and drugs metabolised by cytochrome P450 enzymes are improbable to happen ( Medsafe 2010 ) .

Elimination

Metabolised in the liver ; the major inactive metabolite is 5- ( p-hydroxyphenyl ) -5-phenylhydantoin ( HPPH ) eliminated in the gall as inactive metabolites which is done by cytochrome P450 2C9 ( Veronese et al. , 1991, 1993 ) and so reabsorbed from enteric piece of land and excreted in the piss. Besides excreted chiefly as the glucuronaid ( Medsafe, 2010 ) .

The entire systematic clearance from plasma is 0.11 mL/minute/kg. Around 1.8 % of dosage is eliminated unchanged in the piss ( Gilman et al. , 1990 ) . Eliminated by 1st order dynamicss. Plasma clearance after dosage is 5 to 10 mL/minute. The unbound drug is removed at a quicker rate at 77 mL/min. Elimination occurs in the signifier of ketone organic structures ( Ellenhorn & A ; Barceloux, 1988 ) .

The mean steady province clearance in healthy grownups is 39 A± 14mL/minute. Clearance of drug is chiefly metabolic with riddance of glucuronide-conjugates material found in the piss. Less than 10 % is excreted unchanged from the piss. Around 2 % is excreted in the fecal matters. The riddance half life in healthy grownups is 24 to 35 hours and independent of dosage. The average half life is reduced to around 14 hours when utilizing the drug concomitantly with other medicine such as glucoronidation bring oning drugs ( Medsafe, 2010 ) .

Table 3: The pharmacokinetic parametric quantities of the three drugs used in the survey ; Phenytoin, Sodium Valproate and Lamotrigene.

Dose Governments

Dose regimens are mostly affected by their pharmacokinetic parametric quantities, most notably, their half life. It is for this ground that before the dose regimen for a specific drug can be calculated, one must foremost find how drug acts in the organic structure.

The particular pharmacokinetic belongingss exhibited by Phenytoin, such as a narrow curative index, signifies that dose can merely be given in little sums as any addition might ensue in toxic side effects. It is for this ground that monitoring of plasma concentration is required to set dose regimen. The pharmacokinetics of the drug demo a half life of 24 hours so dosage is 150-300mg one time day-to-day but may be divided in half, giving a twice day-to-day regimen. In a survey carried out by Blaine et al. , ( 1981 ) it was observed that differences in dose demands in kids and grownups may non be due to differences in activities of enzymes that are concerned with the metamorphosis of diphenylhydantoins but may be due to the differences in ratio of liver weight to organic structure weight ( Blaine et al. , 1981 ) .

Sodium valproate, on the other manus, does non necessitate everyday monitoring due to a wider curative index. Half life of the drug is 12-15 hours and therefore demands to be administered twice daily. Great attention must be taken when utilizing Na valproate and phenytoin concomitantly as the former tends to displace the latter, taking to an addition of unbound diphenylhydantoin, which could take to toxic side effects. Sodium valproate is ab initio given at 600mg day-to-day and normally increased by 200mg every three yearss. Epilim chrono has besides been produced that is a modified release readying that releases the drug over a period of clip, forestalling any extremums in concentration from happening ( BNF, 2010 ) .

Lamotrigene is normally administered 100-200mg one time daily on an empty tummy in order to make peak concentration quicker. The half life and riddance of the drug ranges from 24-35 hours and hence, like diphenylhydantoin, is given one time day-to-day. One alone characteristic about the drug is that if it is administered concomitantly with other drugs ( like Na valproate ) , the drug dosage must be increased as the half life is reduced.

Due to the high grade of inter-patient variableness, it ‘s non recommended that patients change the trade names of their epileptic medicine due to the possibility that there may be a little difference in the bioavailability of generics ( BNF, 2010 ) .

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