Normally used conventional antiepileptic drugs for pharmacotherapy in epilepsy are Phenobarbital, Carbamazepine and Valproic Acid. The purpose of this paper was to supply information about these three anti-epileptic drugs by comparing and contrasting there actions, pharmacokinetic paramaters and side-effects profile.
Epilepsy is a common chronic neurological upset characterized by recurrent motiveless ictuss. These ictuss occur when messages from the encephalon to the musculuss are non decently passed on by the nervus tracts in the organic structure. ( Rhodes, 2009 ) . Epilepsy is a really broad spread disease and effects over 50 million people worldwide. Epilepsy is more common in immature kids and people over the age of 65 old ages. In most instances epilepsy can be controlled, but non cured, with medicine. However, over 30 % of people with epilepsy do non hold ictus command even with the best available medicines. ( book ) Not all epilepsy syndromes are womb-to-tomb – some signifiers are confined to peculiar phases of childhood. Epilepsy should non be understood as a individual upset, but instead as syndromic with immensely divergent symptoms but all affecting episodic unnatural electrical activity in the encephalon. ( Webmd, 2009 ) , ( Herkes, 2009 )
Clinical INDICATIONS AND THERAPEUTIC ACTIONS
Normally used conventional antiepileptic drugs for pharmacotherapy in epilepsy are Phenobarbital, Carbamazepine and Valproic Acid. Phenobarbital, discovered in 1912 is the oldest anti-convulsant in common usage and is safe, effectual and cheap. ( Epilepsy Therapy Project, 2009 ) . Besides the common dosage is one time day-to-day so people are less likely to lose doses. However, conflicting studies exist sing its teratogenicity and efficaciousness. ( book )
Phenobarbital is used to handle all signifiers of epilepsy ( chiefly generalized quinine water, clonic, tonic-clonic and partial ictuss in kids or grownups and most ictuss in newborns ) except absence ictuss. Despite comparatively slow equilibrium between encephalon and plasma, the drug retains a topographic point in the intervention of position epilepticus. Phenobarbital belonging to a group of drugs known as Barbiturates are besides effectual as minor tranquilizers, soporifics, antiepileptics and in anesthesia. ( Epilepsy Therapy Project 2009 )
Carbamazepine has rather similar clinical indicants as Phenobarbital. It is effectual in the intervention of simple partial, complex partial and generalized tonic-clonic ictus. ( Epilepsy Therapy Project 2009 ) . Carbamazepine merely like Phenobarbital is uneffective against generalized absence ictuss. Unlike both Phenobarbital and Valproic Acid Carbamazepine is besides used to handle some neurological diseases such as a painful status of the face called “ trigeminal neuralgy ” every bit good as certain psychiatric conditions such as a upset known as passion episodes of bipolar temper upsets. A survey carried out by Mattson et Al. showed that a higher per centum of patients with partial ictuss was controlled by Carbamazepine than by Phenobarbital. ( Perumandla et al, 2009 ) , ( Pyle and Mitchell, 2009 ) , ( Mohammadpoor, 2009 )
Valproic Acid merely like Phenobarbital has a broad spectrum of activity. It is used to handle both spasmodic and non-convulsive generalised epilepsies. Valproic Acid is effectual in myoclonic epilepsies of childhood and striplings. It is every bit effectual as Phenobarbital in prophylaxis of feverish paroxysms. Unlike both Phenobarbital and Carbamazepine which have a heterocyclic ring construction common to anti-convulsants, Valproic Acid has a simple construction dwelling of a bifurcate fatty acid. ( Epilepsy Therapy Project 2009 ) , ( Sanchez-Alcaraz et al. 2009 )
512px-Carbamazepine_svg.png 533px-Phenobarbital.png 512px-Valproic_acid_svg.png
Carbamazepine Phenobarbital Valproic Acid
MODE OF ACTION
Phenobarbital has a mechanism of action feature of Barbiturates. Phenobarbital acts on the GABA ( Gamma- Aminobutyric Acid ) receptors. This causes an addition in synaptic suppression which in bend elevates seizure threshold and reduces the spread of ictus activity. Sodium thiopental can diminish excitant sender release by suppressing Ca channels. Phenobarbital besides causes sedative-hypnotic effects due to its consequence on the polysynaptic mesencephalon reticulate formation, which controls CNS rousing. ( Neels et al. 2009 )
Carbamazepine on the other manus has 2 mechanisms of action. One manner is by stabilising the inactivated province of Na channels, intending that fewer of these channels are available to later open hence cut downing the high-frequency insistent fire of action potencies. Carbamazepine besides acts on synaptic transmittal and neurotransmitter receptors including monoamine, acetylcholine and purine. This is different from Phenobarbital wihich Acts of the Apostless on the GABA receptor. ( Centre for Neuro Skills 2009 ) , ( Neels et al. 2009 )
The mechanism of Valproic Acid unlike Carbamazepine and Phenobarbital is non clearly understood. However many mechanisms have been proposed. It likely blocks high-frequency, insistent neural fire by barricading voltage-gated Na channels. It is besides thought to curtail GABA-T ( GABA aminotransferase ) . This enzyme speeds the debasement of GABA. Valproic Acid is besides thought to move against T-type Ca currents like those implicated in the spike-wave activity of absence ictuss. ( Centre for Neuro Skills 2009 ) , ( Neels et al. 2009 ) , ( Epilepsy Therapy Project 2009 )
Phenobarbital has a high bioavailability ( about 90 % ) after unwritten disposal. Carbamazepine merely like Phenobarbital has a high bioavailability of around 80 % . Valproic acid has first-class bioavailability and is absorbed through the bowel with no site specificity. The rate of soaking up of these three drugs besides depends on their preparation. ( Neels et al. 2009 ) , ( Garnett 2009 ) .
Phenobarbital disseminates into all organic structure tissues but is merely 40-50 % plasma protein-bound. It is eliminated by a first-order dynamicss. Carbabamazepine besides disseminates quickly to assorted tissues and variety meats merely like Phenobarbital. However and like Phenobarbital it does non follow simple first order dynamicss. Carbamazepine in more protein bound than Phenobarbital and is about 75-85 % protein edge. Valproic Acid has the highest protein binding of these three drugs at 90 % . This is due to the its little distribution volume. Valproic Acid follows first-order dynamicss. ( Neels et al. 2009 ) , ( A?orA‘eviA‡ et Al. 2009 )
Phenobarbital has the longest half life among these three drugs. The half-life scope is between 24 and 140 hours. The half- life of Carbamazepine and Valproic Acid are 25-65 hours and 9-16 hours severally. Valproic Acid infact has the shortest half-life out of these three drugs. ( Neels et al. 2009 ) .
Elimination of unchanged drug drug is rather similar for all the drugs and is about 3 % . However whilst Carbamazepine and Valproic Acid are merely excreted renally, Phenobarbital is alsa excreted rectally.
Phenobarbital seldom used for pregnant adult females since it carries a tetratogenic hazard. Besides phenobarbital in milk can do neonatal apathy and sleepiness. Carbamazepine has been reported to increase the cause of birth defects such as spina bifida. However unlike Phenobarbital is compatible with suckling in the full term baby. Just like Carbamazepine Valproic Acid increases the hazard of major deformities including spina bifida. ( Neels et al. 2009 ) , ( Shakya et al. 2009 ) .
Table 1 Cytochrome P450 enzymes in the metamorphosis of anti-epileptics ( Neels, 2009 )
CYP2C9 CYP2C19 CYP2E1
CYP2C9 CYP3A4 UGT
CYP2C9 CYP2C19 b-oxidation UGT CYP2A6
Table 2 Pharmacokinetic informations of Phenobarbital, Carbamazepine and Valproic Acid ( Hugo M. Neels, 2009 )
Probationary mark scope, mg/l
Toxic concen-traion, mg/l
Protein binding, %
Distribution volume, l/kg
& gt ; 50
& gt ; 12
& gt ; 200
Table 3 Side-effects profile of Phenobarbital, Carbamazepine and Valproic Acid ( Epilepsy Therapy Project 2009 )
Sleepiness or weariness
Sleepiness or weariness
Sleepiness or weariness
Low Ca degrees, bone loss
Decreased sexual involvement