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Epilepsy comes from the Greek word for "attack", and is one of the oldest disorders described in medicine. Epilepsy is a disorder in the brain where clusters of neurons signal defectively. In epilepsy, the normal pathway taken by an electrochemical impulse changes, producing a variety of symptoms, namely: muscle spasms, loss of consciousness and convulsions. This disorder is mainly characterized by seizures and can take up many forms, depending primarily on the part of the brain affected (Anon, 2010).
During an epileptic event, a high frequency electrochemical impulses originating from a point source in the brain spreads to other areas, affecting other parts of the brain. As explained above, the symptoms produced depend on the part of the brain affected and therefore the motor cortex is the main site of convulsions, the hypothalamus is responsible for peripheral autonomic discharge and the participation of the reticular formation in the upper brainstem leads to a loss of conciseness (Rang et al., 2003).
Epilepsy is a very common neurological disorder, affecting 0.5 - 1% (Rang et al., 2003) of the worlds population. The two main forms of epilepsy are tonic-clonic fit (also known as grand mal) and the absence seizure (petit mal). Status epilepticus is also found, which may be life threatening if the seizure activity is left uninterrupted. The abnormal discharge in humans is not yet fully understood and is said to be associated with the release of excitatory amino acids, an impaired inhibitory transmission, or irregular electrical properties of cells (Rang et al., 2003).
Currently, drug therapy is only effective in around 70 - 80% (Rang et al., 2003) of human subjects. Three of these drugs, namely: Sodium Valproate, Lamotrigene and Phenytoin, will be discussed below.
Chemical Structure and Physical Properties of the Drugs
Figure 1: The Chemical structure of Lamotrigene. Obtained from http://en.academic.ru/dic.nsf/enwiki/207879.One of the unique chemical features 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 very similar molecular weight as the aforementioned molecule being 252.3g/mol. The compound contains a total 3 aromatic rings as can be seen in Figure 2. The IUPAC name of the compound is 5,5-Diphenylhydantoin. Sodium valproate is a fairly simple molecule when compared to the other drugs, and is also much lighter, having 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 doesn't contain any aromatic rings or nitrogen atoms in its structure.
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 properties of the drugs are also expected to change with a change in the molecular structure. One notable physical parameter is the solubility as Lamotrigene is sparingly soluble in water (0.17 mg/mL at 25°C) and slightly soluble in acid (1.0 mg/mL at 25°C) with a pKa of 5.56 (DailyMed, 2009) due to the bulky hydrophobic groups present. Phenytoin is slightly more soluble than Lamotrigene (1 in 70 in alcohol) but Sodium Valproate is the most soluble drug of the three due to the presence of the easily ionisable CHCOO-Na+ that is present on the molecule (1.2 mg/mL) (Ellenhorn MJ & Barceloux DG (1988).
Phenytoin is also hygroscopic and gradually absorbs carbon dioxide from the surroundings on exposure with air with the liberation of phenytoin (Reynolds, 1996). Sodium valproate tablets on the other hand should be sealed in airtight containers to protect them from excessive light. The capsules should be stored at a temperature of 15 to 30 0C and freezing should be avoided (Reynolds, 1989; McEvoy, 1991).
Clinical Actions and Therapeutic Actions
An essential feature about epilepsy that must be borne in mind is that at present time, there is no definite cure for the condition, but just a means of suppression of seizures.
Any of the three mentioned anti-epileptic drugs can be used by a patient but the choice essentially depends on a vast array of factors, namely: seizure type, concomitant type, comorbidity, age, sex and plasma drug half life (BNF, 2010).
Sodium valproate and Lamotrigene are usually administered in all types of seizures, whilst Phenytoin cannot be used in the case of absent seizures. Some other cases where Phenytoin is administered are in partial seizures, status epilepticus and tri-geminal neuralgia. Like Phenytoin, Lamotrigene is also effective in partial seizures but can also be taken in the case of secondary generalized tonic clonic seizures, atypical absent seizure in children and atonic seizures (BNF, 2010).
Mode of Action
The mode of action of all three drugs has not yet been fully established but studies had proven that they tend to bind to specific voltage gated sodium channels in the brain in order to exert its anticonvulsant effect by the suppression of repetitive firing of neurons by inhibition of sodium flux through these voltage dependent channels (Francis & Burnham, 1992).
Lamotrigene is also thought to stabilize a number of neuronal membranes and controlling 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 models performed on the drug sodium valproate have suggested that it inhibits GABA transferase and succinic aldehyde dehydrogenase, the enzymes that are important for GABA catabolism. Results from one study have revealed that sodium valproate increases potassium conductance and hence inhibits neuronal activity (McEvoy, 1991). Also, this drug may also inhibit GABA degradative enzymes such as GABA transaminase by inhibiting the reuptake of GABA by neuronal cells (Medsafe, 2010). One main difference with the drug Phenytoin is that it is known to stabilize membranes in the brain and in the heart, and also helps to reduce the convulsive activity from a discharging focus without influencing the focus itself (Reynolds 1996). In addition to this, Phenytoin also decreases the force of contraction of the cardiac muscle, reduces pacemaker action and increases the efficiency of the atrioventricular conduction. Another unique feature of this drug is that it increases the effective refractory period in relation to duration of an action potential (McEvoy, 1995).
Side Effect Profiles
As can be seen in Table 1, the drug that produces the most adverse effect is Phenytoin. The main unwanted effects of the drug start to emerge at a plasma concentration of 100 µmol/l and may become very severe if the concentration exceeds 150 µmol/l (Rang et al., 2003). Some of the most common side effects are hypersensitivity reactions such as rashes, vertigo and ataxia. In a study by Butter (1940), it was noted that in nine of the cases where the treatment was stopped, a vast array of symptoms had been exhibited. In two of these cases, pyrexia and skin rashes had been observed, whilst in another case hypertrophic gingivitis with nausea and vomiting had been seen. However, the other six cases showed the following symptoms: tremulousness, tremor, ataxic gait, nystagmus, slurring speech and insomnia. Most of these toxic effects disappeared when the medication was stopped (Butter, 1940). It is for this reason that side effects such as hirsutism, acne and coarse faces exhibited by Phenytoin that deters its use for most adolescent patients.
Thinning of Hair
Hyperplasia of Gums
Table 1: The main side effects exhibited by the three drugs; Phenytoin, Sodium Valproate and Lamotrigene. The Blue box signifies that the unwanted effect is produced by the drug and the Red box signifies that there are no traces of such an effect when the drug is administered.
Some of the side effects exhibited by Lamotrigene were studied by Brodie and his team (Brodie et al., 1999) as shown in Table 2. Apart from the lack of co-ordination and somnolence, the biggest problem with this drug was skin rash, and it is thought that it has to do with the starting dose of the drug (Chadwick et al., 1984). Therefore, any individual suffering from hypersensitivity reactions should not make use of this drug. Apart from this, Lamotrigene can be used in monotherapy and its effectiveness is broad as it covers all seizure types (Brodie et al., 1999). Its long plasma half-life of 24 hours also makes it particularly useful as dosage can be kept to a minimum of once or twice daily (Rang et al., 2003). Lamotrigene is usually the drug of choice in most patients as its one of the newer drugs on the market and contains the least amount of side effects.
Lamotrigene (n = 102)
Table 2: A case study performed on 102 patients by Brodie et al., (1999). The number given in the second column signifies the amount of people affected by that particular unwanted effect.
Sodium Valproate, compared to other epileptic drugs on the market, is also one of the most desired as it contains fairly minimal side effects. The most notable effect is thinning and curling of hair in about 10% of patients. It has to be noted that one of the most serious side effects is hepatotoxicity, which is due to an increase in serum glutamic oxaloacetic transaminase, however this is quite rare. Sodium Valproate is also teratogenic and should not be taken by pregnant women (Rang et al., 2003).
Well absorbed when given orally. About 80 -90% of the plasma content is bound to albumin. The plasma concentration needed is usually between 40 - 100 micromoles/litre (Medsafe, 2010)
Absorbed well orally, with peak in blood levels occurring within 15 to 60 minutes after ingestion of syrup and 1 to 4 hours after a single oral tablet. Absorption is affected if taken with food, however extent of absorption is not affected. The percentage of free (unbound) drug is usually around 6% and 15% of the total plasma levels. (McEvoy, 1991; Ellenhorn & Barceloux, 1988).
Rapidly and completely absorbed from the gut with no significant pass metabolism. Peak plasma concentrations occur at around 2.5 hours after administration. The time to maximum concentration in the plasma is slightly reduced after food but the amount of absorption is not affected. The pharmacokinetics are linear up to 450mg. These is considerable inter-individual variation in steady state maximum but within individuals, concentrations do not vary so much (Medsafe 2010)
Phenytoin is distributed in the cerebrospinal fluid, saliva, semen, bile and breast milk. Vd = 0.6 -1 litre/kg in Adults = 0.7litres/kg. Phenytoin demonstrates non-linear kinetics (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 & Dam, 1976). Plasma binding is exclusively to albumin. Half life of 24 hours.
Distribution is rapid and most likely restricted to circulation and rapidly exchangeable extracellular water. Sodium valproate doesn't show any linear kinetics due to concentration dependant plasma protein as well as a short half-life of 8-20 hours. The drug is approximately 90% bound to the plasma proteins but only 60% to albumin. Subsequently, if the plasma level of the drug rises above 120 microgram/mxsL, the binding sites may become saturated, causing amount of free drug to rise rapidly. The drug may also displace Phenytoin from protein binding sites (Medsafe, 2010)
Binding to plasma proteins is around 55%; it's very unlikely that the displacement from plasma proteins would result 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:
Metabolised by the hepatic mixed function oxidase system. Metabolism can be enhanced/ inhibited by other drugs that have the same hepatic enzymes.
Complex metabolism. Elimination pathway is via glucuronidation (40-60%). The other is largely metabolised via oxidation pathways, Î²-oxidation accounting for 30-40% (cytochrome P450 dependent). Only around 1-3% of dose is found to be excreted unchanged in the urine (Medsafe, 2010)
UDP-glucuronyl transferases have been identified as the enzyme responsible for this drugs metabolism. Lamotrigine induces its own metabolism, depending on dose. No evidence that the drug affects the pharmacokinetics of other AEDs and evidence suggests that the interactions between Lamotrigene and drugs metabolised by cytochrome P450 enzymes are unlikely to occur (Medsafe 2010).
Metabolised in the liver; the major inactive metabolite is 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH) eliminated in the bile as inactive metabolites which is done by cytochrome P450 2C9 (Veronese et al., 1991, 1993) and then reabsorbed from intestinal tract and excreted in the urine. Also excreted mainly as the glucuronaid (Medsafe, 2010).
The total systematic clearance from plasma is 0.11 mL/minute/kg. Around 1.8% of dose is eliminated unchanged in the urine (Gilman et al., 1990). Eliminated by 1st order kinetics. Plasma clearance after dose is 5 to 10 mL/minute. The unbound drug is removed at a quicker rate at 77 mL/min. Elimination occurs in the form of ketone bodies (Ellenhorn & Barceloux, 1988).
The mean steady state clearance in healthy adults is 39 ± 14mL/minute. Clearance of drug is primarily metabolic with elimination of glucuronide-conjugates material found in the urine. Less than 10% is excreted unchanged from the urine. Around 2% is excreted in the faeces. The elimination half-life in healthy adults is 24 to 35 hours and independent of dose. The mean half-life is reduced to around 14 hours when using the drug concomitantly with other medication such as glucoronidation inducing drugs (Medsafe, 2010).
Table 3: The pharmacokinetic parameters of the three drugs used in the study; Phenytoin, Sodium Valproate and Lamotrigene.
Dosage regimens are largely affected by their pharmacokinetic parameters, most notably, their half-life. It is for this reason that before the dosage regimen for a specific drug can be calculated, one must first determine how drug acts in the body.
The special pharmacokinetic properties exhibited by Phenytoin, such as a narrow therapeutic index, signifies that dosage can only be given in small amounts as any increase might result in toxic side effects. It is for this reason that monitoring of plasma concentration is required to adjust dosage regimen. The pharmacokinetics of the drug show a half-life of 24 hours so dosage is 150-300mg once daily but may be divided in half, giving a twice daily regimen. In a study carried out by Blaine et al., (1981) it was observed that differences in dosage requirements in children and adults may not be due to differences in activities of enzymes that are concerned with the metabolism of phenytoin but may be due to the differences in ratio of liver weight to body weight (Blaine et al., 1981).
Sodium valproate, on the other hand, does not require routine monitoring due to a wider therapeutic index. Half-life of the drug is 12-15 hours and hence needs to be administered twice daily. Great care must be taken when using sodium valproate and phenytoin concomitantly as the former tends to displace the latter, leading to an increase of unbound phenytoin, which could lead to toxic side effects. Sodium valproate is initially given at 600mg daily and usually increased by 200mg every three days. Epilim chrono has also been produced that is a modified release preparation that releases the drug over a period of time, preventing any peaks in concentration from occurring (BNF, 2010).
Lamotrigene is usually administered 100-200mg once daily on an empty stomach in order to reach peak concentration quicker. The half-life and elimination of the drug ranges from 24-35 hours and therefore, like phenytoin, is given once daily. One unique feature about the drug is that if it is administered concomitantly with other drugs (like sodium valproate), the drug dose must be increased as the half-life is reduced.
Due to the high degree of inter-patient variability, it's not recommended that patients change the brands of their epileptic medication due to the possibility that there may be a slight difference in the bioavailability of generics (BNF, 2010).