Pharmacomechanistic Approach to AED Combinations

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Combining drugs with different mechanisms of action is a common strategy in the treatment of many medical disorders. Polytherapy is also used routinely in some neurological conditions, even at treatment initiation. Thus, in patients with Parkinson's disease, levodopa is combined with a dopa decarboxylase or catechol-o-methyltransferase inhibitor to reduce its systemic breakdown. Likewise, it is plausible to obtain a synergistic (supra-additive) effect in the drug treatment of epilepsy by combining agents with potentially complementary mechanisms of action (Table 8.3). It might even be argued that, since many AEDs possess multiple (and possibly undiscovered) modes of action [30, 31], mechanistic combinations already exist even when a single drug is used. Deckers and colleagues [32] comprehensively reviewed the available animal and human data and concluded that combinations involving a Na+ channel blocker and a drug with y-aminobutyric acid (GABA)-ergic properties appeared to be particularly beneficial. Observation from the Glasgow database tended to support the addition of an AED with multiple mechanisms of action [33]. However, selecting drug combinations based on their mode of action remains an untested hypothesis. In addition, while it is convenient to conceptualize and categorize the mechanisms of action of AEDs, it is important to bear in mind that our understanding of the pathogenesis of seizure generation and propagation and, indeed, how drugs modulate these processes in the individual patient, remains rudimentary. It is likely, too, that some AEDs possess as yet unrecognized modes of action. Thus, many possible AED combinations remain to be evaluated, and only a few have hinted at evidence of particular efficacy.

Table 8.3 Perceived mechanisms of action of anti-epileptic drugs [30, 31]

i Na+ channels

i Ca2+ channels*

Î GABA transmission

i Glutamate transmission

Established anti-epileptic drugs

Benzodiazepines

+ +

Carbamazepine

+ +

Ethosuximide

+ + (T-type)

Phenobarbital

?

+ +

?

Phenytoin

+ +

Valproate

?

? (T-type)

+

?

New anti-epileptic drugs

Felbamate

+

?

+

+

Gabapentin

?

++ (a 2 8)

+

Lamotrigine

+ +

?

Levetiracetamt

?

?

?

Oxcarbazepine

+ +

Pregabalin

++ (a28)

Tiagabine

+ +

Topiramate

+

+

+

+

Vigabatrin

+ +

Zonisamide

+

+ (T-type)

+ +, primary action; +, probable action; ?, possible action. 'Unless otherwise stated, action on high voltage activated Ca2+ channels. tLevetiracetam acts by binding to synaptic vesicle protein 2A (SV2A). GABA, y-aminobutyric acid.

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