Therapeutic options


The dual goals of therapy are I) No seizures and II) No adverse effects.

Patients with non-refractory forms of epilepsy will by definition attain Goal I, although breakthrough seizures can still occur in cases of medication non-adherence, change in therapy, etc. For this patient population, attaining seizure control is the more pressing goal.

Goal II—or more importantly, an optimum between the aims of Goals I and II—becomes more important in patients who are drug-resistant. In these patients, aggressive medical therapy may marginally reduce seizure frequency but the gains may not be justified by the increase in adverse effects (AEs), especially from polytherapy.


What they are

Antiseizure drugs (ASDs) are also called antiepileptic drugs. ASDs do not appear to have any affect on the underlying predisposition in epilepsy. The correlation between seizure-free interval on medications and probability of drug-free seizure freedom appears to have more to do with severity of the underlying disease than with a disease-modifying ability. ASDs therefore offer symptomatic control of seizures as a primary effect, and only incidentally (if at all) helping with other symptoms.

Classificatory dimensions

Existing antiseizure drugs (ASDs) may be grouped diachronically by generation. The first generation includes the very first effective ASDs extending from phenobarbital (PB) to valproate (VPA). It essentially includes all the ASDs introduced in 1914–1980. As a rule the first generation includes meds that have the potential for significant short- and long-term AEs and drug-drug interactions.

The second generation includes those drugs introduced in 1980–2008. The third generation roughly begins with lacosamide (LCM) and is ongoing.

Second and third generation drugs are not necessarily more efficacious. In general they are more tolerable and have fewer long-term AEs.

The ASDs can also be classified on the basis of mechanism of action. By far the most common mechanism is blockade of voltage-gated sodium channels. Enhancement of GABAergic currents is second most popular. And there’s a hodgepodge of other effects at various calcium channels, ionotropic glutamate receptors, and with neurotransmitter vesicle machinery.

One can also classify the meds by structure. CBZ, OXC, and ESL are all examples of dicarbazepine rings; the second and third examples of which were engineered to avoid developing toxic epoxide metabolites. The racetams LEV and BRV both target the synaptic vesical protein 2A (SV2A), but BRV more specifically so. ZNS and TPM are in some senses dissimilar, as TPM is a modified saccharide and ZNS a modifed sulfamate antibiotic, but both bear a sulfamate group and have weak carbonic anhydrase actions. Clobazam is a modified benzodiazepine whose heterocyclic ring has nitrogen at positions 1,5; CLZ, LRZ, and DZP are all conventional benzodiazepines with nitrogne positions at 1,4 and various substitutions. There were originally other hydantoin derivatives on the market but phenytoin remains the last surviving member. Primidone is a prodrug for both phenobarbital (PB) and other aromatic compounds. The others are all a hodgepodge of different structures.

They can also be grouped by mechanism of action. In this sense they are members of fuzzy groups and can be put into several at once. Traditional NavNa_v blockers include PHT, CBZ, ESL, OXC, LTG, TPM, ZNS, VPA, RUF. LCM is a half-member because its effects on NavNa_v are mediated “slowly”—ie, only after rapid Na spiking has been achieved. GABAergic drugs include direct GABAR ligands such as BZDs, CLB, PB, and PMD, but also drugs suspected of increasing GABA levels through interactions with GABA transaminase (inter alia) such as VPA, VGB, GBP, PGB, and TGB. AMPAR may be touched by both PER and LEV; NMDA perhaps by FBM. SV2A is touched by LEV and BRV. K channels were opened by RTG but this has been removed from the market.


The single useful tool principle

Capitalism tries to sell you all sorts of schlock and among the dreck there are innumerable tools that are supposed to be amalgamations of useful tools whose ease of use is therefore augmented by their unholy union into a single product. (And whose usefulness is, somehow, unimpaired.) The closest we have got in the real world to such a useful thing is a claw hammer. Nevertheless the litany of badly-build things bombarding your ad box.

We will need seek to use a hammer and screwdriver combo. Until the day sonic screwdrivers are truly available and bug-free, we use the correct tool for the job. (So long as we do not develop the fallacious view that, holding a screwdriver, all problems benefit from driving screws.)

The temptation can be great to use ASDs as two-in-the-bush agents. Or dual-murdering stone hurler drugs. ASDs are not really a class into themselves but a pseudoclass best defined in terms of its effects on epilepsy. They have indications and effects outside of epilepsy.

Best to use the drugs for epilepsy (Indication A) and to use alternate agents for the other indications (B, C, and D). The advantages are:

  1. When A is going well but B and C are troublesome, the temptation is to push up the dose; which given other ASDs for A may be a toxic choice.
  2. When A is not going well but B, C, and D are fine or only tweakable, augmenting the dose of ASD for A may throw off AE profiles and efficacy for the other indications.
  3. When A is under the evaluation and management of an epileptologist and the other indications are under the E&M of Bologists, Cologists, etc, who has the right and who nominates the others to make changes to the ASD? Shall we dare to say there will be constant communication or patient safety rounds? Because in 2018 that is risible.

Morever be sure you are not elevating the putative hammering characteristics of your chisel in an effort to be cute and parsimonious with therapy: lamotrigine has antimanic properties, ’tis sure, and some antidepressant effects especially in bipolar depression—but if you’re trying to treat behavioral anomalies and major depression choose something from your tier one bank of agents, please.

A little PK is just enough dangerous

With a few exceptions, all the ASDs have approximately linear first-order kinetics.

What this means is, when they take the drug the concentration will peak soon after and then it will drop over time. It drops not in a linear way, but an inverse exponential way. Equal amounts of time will eliminate equal ratios of drug. If eight hours eliminates half the drug, another eight hours will eliminate half of the remaining drug. And so on.

In the metabolism of salicylates, warfarin, and ethanol, the same amount of drug is metabolized each period of time. So if 25% is gone after an hour, 50% of the original total is gone after two hours. All of it is gone after four.

Linear PK is important because it gives us a few useful properties.


Equilibrium levels take about 5 half-lives to achieve. A half-life is the time for 50% of the drug to disappear. Make a change and it’s 5 half-lives to get to equilibirium. Take administration away and it’s five half-lives until it’s gone. (Ie, 125=132\frac{1}{2}^5 = \frac{1}{32} which apparently is pharmacist-equivalent to zero.)

Make a change and expect about 5 half-lives for a change in effect.


Corollary: if you want a change in effect right now you have got to bolus the patient. Figure out what level you want them to have, calculate the volume of distribution (based on past levels) and give them a big dose to catch up. Then immediately start giving the new equilibrium daily dose.


Trough levels are usually most informative. At the bottom of the curve before taking meds again, small changes in time of sample acquisition have only small effects on the measure concentration. Trough levels are more reliable and consistent.


Changing a dose will change the equilibrium trough level by the same ratio. If you double the dose than the trough level (in about 5 half-lives) will be about double what it was before. Halve it, and it will be halved,


The nature of linear PK is that it’s peaky. When administered esp by mouth, there will be a peak in concentration anywhere from 30 min to 2 h after admin. That’s when peak-concentration AEs set in. But after a while concentration sinks. If it sinks too low, it might not impart enough antiseizure effect and the patient may be at additional risk of seizing.


How do you change the shape and level of ASD PK? You can change the therapeutic band with more or less often dosing. More closely-spaced dosing (given the same daily dose) can result int shallower peaks and higher troughs. At the cost naturally of harder-to-adhere-to regimens. Trough levels can be adjusted through total daily dose amounts. Additional coverage can be attained by unequal infradian doses. And long-acting or extended-release formulations can be helpful in smoothing out the concentration curve. If they prove somewhat peaky themselves, even dividing ER doses to twice a day can be helpful.


There are exceptions. Presumably the newer ASDs operate in a dose-dependent manner but the “therapeutic” limits recommended by whatever level test you send out are meaningless in terms of therapeutics. The dose that keeps seizures at bay is the therapeutic dose, damn the numbers.

Some drugs such as VGB do not require therapeutic doses themselves: they are hired killers since they act as irreversible inhibitors of GABA transaminase. Levels of the latter would be more useful than of the former.

PHT is famous for having a biphasic PK response. At lower doses it operates approximately linearly. A doubling of dose brings a doubling of level. Somewhere above a random total level of 15 μg/dL the degradation enzymes are saturated and it becomes eliminated in zero-order just like alcohol. So small dose changes (often above 300 mg/d) can result in expectedly high or severe levels in the upper 20s or 30s.

Moreover, all 100 mg PHT caps are extended-release, so you can give them all at once and draw random total levels. Compare free levels if there’s low albumin or other protein-bound drugs.

Beware of classic CYP450 or ubiquitinase degradation pathways and their inhibitors and inducers. CBZ and PHT increase LTG elimination; VPA deceases LTG elimination. CBZ induces its own elimination. LTG notwithstanding, second and third generation drugs are less amenable to drug-drug interactions.


Somewhere between 1/4 and 1/3 of PWE will have seizure control alone with medications. Failure to end seizures with one medication predicts a marginally-lower probability of ending them with another.

This has been the case for 100 years. Nothing in the EILAT conferences (which talk turkey about new ASDs) suggests a radically new approach or anything resembling an actual antiepileptogenic as opposed to a mere antiseizure drug.

Drugs which initially do well but without full control may be retained, usually at a reduced dose of 10–20%, with the addition of a second drug. Alternately, esp if the first drug was of questionable utility, a second drug in monotherapy can be started.

Polytherapy usually means more AEs. There are certainly patients and famililes who swear by five-drug combos, but in many cases combos above two ASDs may not be doing much therapeutically.

There is a ratchet however in epilepsy care. Seizures are unpredictable and the underlying parameter that controls seizure frequency probably varies within a person. So a patient has more seizures, asks for help, gets a new drug. Seizures get better either because of the new drug or because of regression to the mean; patients are reluctant however to give up any of their newly-enlarged pharmacopeia despite explicit evidence of more AEs. What’s a doc to do?

It’s important to know that in certain syndromes subclasses of meds should be off-limits and may exacerbate seizures. It’s important to know what you’re treating and with what you’re treating.

But in generaly failure of 2–3 ASDs at reasonable doses means drug-resistance; and it means a surgical cure should be sought wherever possible.