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Antiepileptic drugs are drugs used for the treatment of epileptic seizures. They are also being used to treat bipolar disorder as they act as mood stabilizers. Seizures are started by the rapid excessive firing of neurons and thus they act by suppressing them. An effective antiepileptic drug prevents the spreading if the seizure thus preventing any brain damage that can occur by means of the seizure. Most of the epileptic drugs act voltage gated sodium channels, voltage gated calcium channels and components of the GABA system. Some of these drugs have also shown that they prevent further development of the condition, slow it down, or reverse it. Until now no drug has been shown to prevent initial development of this condition.
Phenobarbital, Sodium Valproate and Pregabalin are few of the most common antiepileptic drugs found on the market.
Phenobarbital is a non selective Central Nervous System (CNS) depressant. It is used as a sedative agent, and in sub-hypnotic doses it can be also used as an anticonvulsant. It can be used for treatment of all seizure types with the exception of absence seizures. In contrast to Phenobarbital Valproic acid is used to control seizures including absence seizures, tonic-clonic seizures, complex partial seizures, juvenile epilepsy and also seizures associated with Lennox Gastaut syndrome. Preparations of Valproic acid are also used for the treatment status epilepticus, normally in post traumatic epilepsy. It can be also used for the treatment of manic episodes normally associated with bipolar disorder. In the past few years it has also been used to treat neuropathic pain. Another drug which is used to treat neuropathic pain is Pregabalin, which is used to treat neuropathic pain associated with diabetic peripheral neuropathy. It is also used for partial seizures, fibromyalgia, for generalized anxiety disorder, and is also used for post therapeutic neuralgia.
Phenobarbital acts as inhibitory effect on brain cells and slowing down electrical activity thus preventing summation of excessive electrical impulses which can cause epileptic seizures, as these seizures arise from uncontrolled electrical activity. Sodium Valproate works in a very similar action to Phenobarbital, controlling electrical activity in brain cells. Pregabalin similar to the others, where it regulates the amount electrical impulses generated so as to prevent the possibility of the formation of the seizure.
Phenobarbital has a high affinity for GABAA receptor. The gamma-aminobutyric acid (GABA) is one of the inhibitoriest neurotransmitters used in the Central Nervous System of mammals. It binds to the alpha subunit of the receptor. By binding to the receptor the effect is enhanced. It also blocks the AMPA receptor, which is a type of glutamate receptor. This is the principal excitatory neurotransmitter in the mammalian CNS. Thus CNS depression is caused. In high concentrations, they inhibit neurotransmitters which are Ca2+ dependent to be released. The enhancement of the GABA receptor occurs by opening the chloride ion channel for a longer time, and also the frequency of opening is increased. Sodium
Valproate works in a very similar way to Phenobarbital. It also affects the behaviour of the GABA receptor, acting indirectly as a GABA agonist. It also blocks sodium gated channels, which prevents from certain neurotransmitters which depend on calcium to be released. Valproic acid acts also as an inhibitor of the enzyme histone deacetylase 1. Thus is also prevents gene expression. Pregabalin also acts similar to Phenobarbital and Sodium Valproate by up regulating the action of the alpha subunit of the GABA receptor. It enhances it, thus inhibition occurs since the GABA acts as a neurotransmitter which inhibits impulses rather than promoting them. It also inhibits the calcium voltage gated channels, and thus there is less calcium, limiting the amount of neurotransmitter released, thus once again limiting the number of impulses which are created. By binding to the alpha site it regulates the opening duration, and rate of opening of the chloride ions, the membrane potential http://www.nature.com/nrn/journal/v6/n7/images/nrn1703-i1.gif
becomes more negative and thus the firing of a new action potential is inhibited. By these modes of action these drugs regulate the amount of electrical activity, thus preventing summation which can cause seizures to the body. By limiting calcium influx there are several excitatory neurotransmitters which will be decreased from the brain such as glutamate, noradrenaline, serotonin and dopamine. There are different types of GABA receptors and these include ligand-gated receptors (GABAA), G Protein coupled receptor (GABAB) and also a subclass of the GABAA which are insensitive to allosteric modulators such as barbiturates and benzodiazepines known as GABAC.
These types of drugs limit the electrical activity of the brain, and thus one would expect specific side effects such as sedation, and slowness on reaction time. Phenobarbital several side effects such as hypoventilation, apnea, bradycardia, hypotension and syncope. It also causes GI disturbances such as nausea, vomiting and constipation. Other reported side effects include headache, rashes in the skin, fever and liver damage. Some side effects which can be caused to the Nervous System include agitation, confusion, hyperkinesias, ataxia and CNS depression. Sodium Valproate has side effects which are common as well to Phenobarbital. These common side effects include nausea, sedation and tremors. Other side effects which are characteristic if Sodium Valproate include dyspepsia, weight gain, fatigue, peripheral oedema, hair loss and also hyperammonemia. Some rare side effects can include liver malfunction, jaundice, prolonged coagulation times, and it can also cross the placenta causing congenital anomalies. Pregabalin shares some side effects with these two drugs as well. Some of these side effects include dizziness, peripheral oedema and also gain in weight. Normally side effects of Pregabalin are dose dependent, and thus the higher the dose the more severe the side effects are. Other side effects include somnolence, ataxia, asthenia, dry mouth, and also blurred vision. Normally treatment of these drugs is not stopped abruptly, but the dose is lowered consequently since, abrupt stopping of the treatment may re-onset seizures, or in the worst case scenario cause a severe seizure.
Thus general side effects for these three drugs include dizziness, peripheral oedema, gain in weight, and also liver damage.
Phenobarbital reaches a peak plasma concentration in 8 ââ‚¬" 12 hours when administered orally. It reaches bioavailabilty of 90%. It is long acting and has a very long half life of about 2 ââ‚¬" 7 days. Has a low protein binding, is metabolized by the liver. It undergoes hydroxylation and glucuronidation. It also induces enzymes such as the cytochromeP450. It is eliminated by means of a first order process and has a low clearance ratio like Sodium Valproate but unlike to Pregabalin. It is excreted by means of the kidney and eliminated from the body via urine. Phenobarbital has a number of drug interactions which need to be taken care. It lowers plasma concentration of anticoagulants (dicumarol), enhances metabolism of corticosteroids, interferes with the absorption oral Griseofulvin, and effects the metabolism of Phenytoin can cause an accelerated elimination.
Sodium Valproate like the others has a very good bioavailabilty. Absorption occurs in the small intestines but there is no specific site. Normally absorption depends on the dosage form taken; normally the syrup is the one with the faster absorption. Unlike the others is has a high protein binding, specifically to albumin. This contrasts to Phenobarbital and Pregabalin which do not bind easily with plasma proteins. Normally it 90% protein bound and normally as the dosage increases the amount of free drug increase as well. It is metabolized in the liver, like Phenobarbital but in contrast to Pregabalin, by means of conjugation and oxidation to various metabolites. It is very slowly cleared from the kidneys, and does not dependent of the hepatic blood flow.
Pregabalin is absorbed in a rapid way reaching blood concentrations within 1 hour after administration. The half life is 5.5 to 6.7 hours, and bioavailabilty normally easily exceeds 90%, which is which is very similar to Phenobarbital, but has a much shorter half life than Phenobarbital. Like Phenobarbital it isnââ‚¬â„¢t bound to plasma protein, but in contrast it does not undergo metabolism in the liver, but 98% of the administered dose is excreted unchanged via the kidneys, in the urine. Clearance is reduced in patients with renal impairment. No drug interactions have been recorded.
They have very similar pharmacokinetics, with the exception being that of sodium Valproate which tends to have high protein binding unlike the others which have a rather low fraction of protein binding and thus they have large fractions of free drug in the blood. These types of studies are very important so as to identify the way the drug must be administered so as to avoid errors such as overdose, especially in these types of drugs since and overdose can mean that hypnotic levels are reached which can cause serious danger to the patient to whom that particular drug is administered.