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Commonly used conventional antiepileptic drugs for pharmacotherapy in epilepsy are Phenobarbital, Carbamazepine and Valproic Acid. The aim of this paper was to provide 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 disorder characterized by recurrent unprovoked seizures. These seizures occur when messages from the brain to the muscles are not properly passed on by the nerve pathways in the body. (Rhodes, 2009). Epilepsy is a very wide spread disease and effects over 50 million people worldwide. Epilepsy is more common in young children and people over the age of 65 years. In most cases epilepsy can be controlled, but not cured, with medication. However, over 30% of people with epilepsy do not have seizure control even with the best available medications. (book) Not all epilepsy syndromes are lifelong - some forms are confined to particular stages of childhood. Epilepsy should not be understood as a single disorder, but rather as syndromic with vastly divergent symptoms but all involving episodic abnormal electrical activity in the brain. (Webmd, 2009), (Herkes, 2009)
CLINICAL INDICATIONS AND THERAPEUTIC ACTIONS
Commonly 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 use and is safe, effective and inexpensive. (Epilepsy Therapy Project, 2009). Also the common dose is once daily so people are less likely to miss doses. However, conflicting reports exist regarding its teratogenicity and efficacy. (book)
Phenobarbital is used to treat all forms of epilepsy (mainly generalized tonic, clonic, tonic-clonic and partial seizures in children or adults and most seizures in neonates) except absence seizures. Despite relatively slow equilibrium between brain and plasma, the drug retains a place in the treatment of status epilepticus. Phenobarbital belonging to a group of drugs known as Barbiturates are also effective as anxiolytics, hypnotics, anticonvulsants and in anaesthesia. (Epilepsy Therapy Project 2009)
Carbamazepine has quite similar clinical indications as Phenobarbital. It is effective in the treatment of simple partial, complex partial and generalized tonic-clonic seizure. (Epilepsy Therapy Project 2009). Carbamazepine just like Phenobarbital is ineffective against generalized absence seizures. Unlike both Phenobarbital and Valproic Acid Carbamazepine is also used to treat some neurological diseases such as a painful condition of the face called "trigeminal neuralgia" as well as certain psychiatric conditions such as a disorder known as mania episodes of bipolar mood disorders. A study carried out by Mattson et al. showed that a higher percentage of patients with partial seizures was controlled by Carbamazepine than by Phenobarbital. (Perumandla et al, 2009), (Pyle and Mitchell, 2009), (Mohammadpoor, 2009)
Valproic Acid just like Phenobarbital has a wide spectrum of activity. It is used to treat both convulsive and non-convulsive generalized epilepsies. Valproic Acid is effective in myoclonic epilepsies of childhood and adolescents. It is as effective as Phenobarbital in prophylaxis of febrile convulsions. Unlike both Phenobarbital and Carbamazepine which have a heterocyclic ring structure common to anti-convulsants, Valproic Acid has a simple structure consisting of a branched 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 characteristic of Barbiturates. Phenobarbital acts on the GABA (Gamma- Aminobutyric Acid) receptors. This causes an increase in synaptic inhibition which in turn elevates seizure threshold and reduces the spread of seizure activity. Phenobarbital can decrease excitatory transmitter release by inhibiting calcium channels. Phenobarbital also causes sedative-hypnotic effects due to its effect on the polysynaptic midbrain reticular formation, which controls CNS arousal. (Neels et al. 2009)
Carbamazepine on the other hand has 2 mechanisms of action. One way is by stabilizing the inactivated state of sodium channels, meaning that fewer of these channels are available to subsequently open therefore reducing the high-frequency repetitive firing of action potentials. Carbamazepine also acts on synaptic transmission and neurotransmitter receptors including monoamine, acetylcholine and purine. This is different from Phenobarbital wihich acts on the GABA receptor. (Centre for Neuro Skills 2009), (Neels et al. 2009)
The mechanism of Valproic Acid unlike Carbamazepine and Phenobarbital is not clearly understood. However many mechanisms have been proposed. It probably blocks high-frequency, repetitive neuronal firing by blocking voltage-gated sodium channels. It is also thought to restrict GABA-T (GABA transaminase). This enzyme speeds the degradation of GABA. Valproic Acid is also thought to act against T-type calcium currents like those implicated in the spike-wave activity of absence seizures. (Centre for Neuro Skills 2009), (Neels et al. 2009), (Epilepsy Therapy Project 2009)
Phenobarbital has a high bioavailability (approximately 90%) after oral administration. Carbamazepine just like Phenobarbital has a high bioavailability of around 80%. Valproic acid has excellent bioavailability and is absorbed through the intestine with no site specificity. The rate of absorption of these three drugs also depends on their formulation. (Neels et al. 2009), (Garnett 2009).
Phenobarbital disseminates into all body tissues but is only 40-50% plasma protein-bound. It is eliminated by a first-order kinetics. Carbabamazepine also disseminates rapidly to various tissues and organs just like Phenobarbital. However and like Phenobarbital it does not follow simple first order kinetics. Carbamazepine in more protein bound than Phenobarbital and is around 75-85% protein bound. Valproic Acid has the highest protein binding of these three drugs at 90%. This is due to the its small distribution volume. Valproic Acid follows first-order kinetics. (Neels et al. 2009), (ÄorÄ‘eviÄ‡ et al. 2009)
Phenobarbital has the longest half-life among these three drugs. The half-life range is between 24 and 140 hours. The half- life of Carbamazepine and Valproic Acid are 25-65 hours and 9-16 hours respectively. Valproic Acid infact has the shortest half-life out of these three drugs. (Neels et al. 2009).
Excretion of unchanged drug drug is quite similar for all the drugs and is around 3%. However whilst Carbamazepine and Valproic Acid are only excreted renally, Phenobarbital is alsa excreted rectally.
Phenobarbital rarely used for pregnant women since it carries a tetratogenic risk. Also phenobarbital in milk can cause neonatal apathy and drowsiness. Carbamazepine has been reported to increase the cause of birth defects such as spina bifida. However unlike Phenobarbital is compatible with breastfeeding in the full term infant. Just like Carbamazepine Valproic Acid increases the risk of major malformations including spina bifida. (Neels et al. 2009), (Shakya et al. 2009).
TABLE 1 Cytochrome P450 enzymes in the metabolism of anti-epileptics (Neels, 2009)
CYP2C9 CYP2C19 CYP2E1
CYP2C9 CYP3A4 UGT
CYP2C9 CYP2C19 b-oxidation UGT CYP2A6
TABLE 2 Pharmacokinetic data of Phenobarbital, Carbamazepine and Valproic Acid (Hugo M. Neels, 2009)
Tentative target range, mg/l
Toxic concen-traion, mg/l
Protein binding, %
Distribution volume, l/kg
TABLE 3 Side-effects profile of Phenobarbital, Carbamazepine and Valproic Acid (Epilepsy Therapy Project 2009)
Sleepiness or fatigue
Sleepiness or fatigue
Sleepiness or fatigue
Low calcium levels, bone loss
Decreased sexual interest