Educationals

Cost and availability of drugs

This is probably the most important determinant of which drug to use. Older drugs like PB and PHT are cheap and are available even in rural areas. VPA and CBZ are now reasonably priced and widely available; this may not hold true when the dosage is high, as VPA costs about a rupee a tablet and sometimes the dosage in teenagers may be around 6-8 tablets/day leading to a cost of Rs 180-240/- a month.The newer ADEs are obviously more costly. CLB is around Rs 4/- and LTG about Rs 3/-.The availability of these medicines in small towns and villages may not be regular, leading to forced noncompliance. Then there are drugs like VGB, which are still not marketed in India and available in the gray market for as much as RS 30/- per tablet. Obviously these are available only at certain chemists in metro cities and their availability is erratic.

How to Use Antiepileptic Drugs

General principles

• Dose introduction and titration
  It is important to realize that seizure control may occur at a variety of doses in different individuals. A lot of importance is given to mg/kg dosed and many attempts are made to reach these dosages; seizure control should be the yardstick to decide dosage increases. The method now preferred is introduction of the lowest dose possible and titrating it upwards till seizure control is achieved or side effects occur. This may be a gradual process, if seizures are infrequent and can be fairly rapid when they occur often. Drug steady state should be optimally reached before increasing the doses and this might vary from a few days as in the case of VPA to 3-4 weeks of PB.
  One of the mistakes often made is to increase doses according to body weight even in fully controlled individuals. Introduction at the lowest possible dose reduces the chances of adverse effects. CBZ, PB & BZDs at full dosages often cause unacceptable drowsiness and lead to noncompliance. Slow introduction avoids these problems. PHT can be rapidly loaded within a day especially if rapid control is desired. VPA can also be introduced at the maintenance dose without significant problem. LTG should be introduced at very low doses and titrated upwards over a few months if the dreaded rash is to be avoided.
• Dosage intervals
  For maximum compliance once or twice daily dosing is optimal. Pharmacokinetic considerations make this possible with PB. PHT in young children as opposed to adults is cleared very rapidly and may have to be given three to four times a day. VPA, CBA & CLP are also optimally given three to four times a day; recent introduction of extended release preparations may obviate this problem. It is best to give the drug at mealtimes so that compliance is easier. This is especially true of VPA to minimize gastric effects. It is not necessary to give these doses at exact intervals and as far as possible the child's routine should not be disturbed. Of the newer drugs CLB, VGB & LTG can be given in twice daily dosages, as their half-lives are long. GBP has to be given three times daily.
• Monitoring
  Clinical monitoring of seizures and adverse effects is usually all that is needed. Initially, patient visits should be at one month intervals and later, after stabilization, patients could be monitored only every three to six monthly. There was a lot of interest in monitoring blood counts with CBZ and liver functions with VPA to try and predict the rare bone marrow and liver toxicity. However what is now apparent is that mild leucopenia and rises in liver enzymes are commonplace and have no predictive value, making them pointless and expensive exercises. Similarly plasma drug level monitoring came into vogue in eighties in the west and recently in India and physicians started doing routine monitoring.
  
  However it has now become apparent that this is wasteful practice, as it does not improve seizure control. Situations where blood levels may be useful include monitoring
  during treatment of status epilepticus to guide further therapy; confirmation of toxicity especially when there is polytherapy, and ruling out noncompliance. Some do it before changing the drug to confirm that the drug is truly ineffective even at good levels. The main advantage of blood levels is that it has helped understand pharmacokinetics and drug interactions and has helped us in rationalizing treatment plans. Monitoring EEGs are not required in routine epilepsy. However if seizure control is poor or the child is deteriorating in school performance or in language and other cognitive skills, this must be done to exclude an evolving epileptic encephalopathy.
• Monotherapy
  This became the watchword in epilepsy management in the eighties and is now standard practice, even in India (though there are still combination pills available in rural markets). Single drug therapy has the advantage of fully exploiting the therapeutic effect of the drug. It obviates the need for drug levels in monitoring efficacy and adverse effects and reduces the risk of drug interactions and neuropsychological side effects which maybe additive in polytherapy. If at maximal doses the drug is ineffective, a new drug should be introduced with simultaneous withdrawal of the old drug. One of the common mistakes made is to continue the ineffective drug along with the new addition. It must be realized that changing the drug is effective in controlling the seizures in only 30% of patients who fail the first drug. This figure is probably only true if the first drug was truly appropriate for the patient's seizure or syndrome type.
• `Rational polytherapy'
  This has now come into vogue in intractable epilepsy. The word rational denotes using not more than two drugs at a time and avoiding drugs with similar mechanisms of action i.e.PB & BZDs, PHT & CBZ. Certain combinations like VPA and CLB or LTG may have synergistic actions.
• Pharmacokinetic considerations
  As mentioned earlier, half-lives and clearance rates decide dosing intervals and steady state (usually 5 half-lives) decides time to maximum efficacy. Absorption characteristics and bioavailability decide average doses. These pharmacokinetics change with age and co-administration of other AEDs. Neonates absorb drugs like PHT poorly and erratically with gradual improvement with age. Clearance rates are slow in neonates which might to lead to toxicity, especially if renal and hepatic systems are disturbed as occurs in neonatal HIE. In infants and toddlers clearance rates increase to higher than adult rates e.g. PHT, which makes it necessary to give the drug more frequently. PHT also has zero order kinetics, which means that the drug level does not linearly increase with dosage increases. At higher doses small increases in dose lead to rapid increases in levels, causing toxicity.
  
  Drug interactions are most frequent with enzyme inducers like PHT,PB,PM and CBZ, leading to increased clearance for co-administered drugs and decreased levels. VPA decreases clearance of drugs like PB and LTG increasing their levels and hence appropriate dosage reductions are in order. Newer drugs like VGB & GBP have little interactions and are ideally suited if polytherapy has to be used. Another mechanism for drug interactions is an increase in free levels, as occurs with PHT when VPA is given primarily because of increase in the unbound fraction. Also active drug metabolites may increase causing adverse effects in spite of `normal' drug levels. This is classically seen with an increase in CBZ-epoxide levels when VPA is given with CBZ. As can be seen drug interactions make management unpredictable and necessitate routine monitoring of blood levels. It is therefore wise and less expensive to try and use monotherapy.
• Adverse effects
  A complete list of side effects of all the drugs is beyond the scope of this review. However the most common and also the most subtle are the cognitive and behavioral effects which are most often overlooked. PB,PM,BZDs (CLB is better than CLP & NZP) and the newer drugs like VGB and GBP may cause these problems. Aggression and other severe behavior problems may sometimes be more difficult to manage than the seizures, especially in mentally handicapped children. CBZ may cause language and attention problems if the EEG worsens on it. VPA is fairly safe though at high doses can cause a full-blown encephalopathy. The same applies to PHT.LTG may actually improve neuropsychologic performance. Other neurologic side-effects like sedation are common with CBZ/PM and sometimes with the BZD & PB. The latter more often cause sleep disturbances, that is a special problem with mentally handicapped patients.
  
  Ataxia is really a problem with higher doses of CBZ and PHT, while diplopia is with CBZ. Tremor may be a handicap with VPA. Paradoxical increase in both generalized and sometimes partial seizures is redominantly a problem with CBZ and sometimes PHT. VGB increases myoclonic seizures and LTG may worsen some syndromes like severe myoclonic epilepsy of infancy. Dermatological side effects are sometimes seen in CBZ,PHT and PB and may necessitate discontinuation. Many can be restarted after a brief gap without recurrence of a rash. LTG is probably the one drug with maximal dermatological adverse effects especially if given with VPA and if rapidly increased. Systemic side effects like bone marrow suppression has been overstressed with CBZ and is really a problem only with FBM. Thrombocytopenia is regularly a problem with high doses of VPA though it is most often asymptomatic.
  
  Liver disease is mainly a problem with FBM and again has been over emphasized with VPA. Weight gain or loss can occur with VPA - the former in older children and the latter in infants given the syrup, which often cause gastritis and persistent anorexia and nausea. This regularly responds to antacids.VGB, CLB and sometimes CBZ cause weight gain as well and this is especially a problem in adolescence. Constipation occurs sometimes with CBZ, CLP and NZP cause significant increase in oral and respiratory secretions, causing a problem in handicapped patients. In summary adverse effects are plenty and need to be monitored closely.Fortunately though one-third of patients develop side effects, only 5-10% discontinue the drug due to this.

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