Antiepileptic Drugs and Markers of Vascular Risk

Abstract

The most-used treatments for epilepsy worldwide are older-generation drugs such as phenytoin, carbamazepine, phenobarbital, and valproic acid, which have prominent enzymatic effects. Our sense of comfort with these treatments is starting to fade, however, as more and more potential long-term consequences of these drugs come to light. Epidemiologic studies demonstrate that ischemic disease of the heart and brain is more common among patients with epilepsy. Enzyme-inducing drugs are associated with elevations in a host of surrogate markers of vascular risk, suggesting that they could be responsible for increased rates of cardiovascular and cerebrovascular disease. The enzymeinhibiting drug valproate may have adverse consequences of its own pertaining to glucose and lipid metabolism. These effects stand in addition to those well established in the literature regarding bone metabolism, hormonal abnormalities, and drug-drug interactions. Because patients with epilepsy require medication for years, and often for life, it is difficult to justify the long-term use of these agents when there are capable alternatives. Many of the adverse effects of the older drugs appear to be rapidly reversible, prompting consideration of whether patients who are currently treated with these agents should be switched to alternative therapies, even in the absence of obvious side effects. Newer medications without effects on hepatic enzymes likely do not have these chronic metabolic consequences, and we recommend their use over older-generation drugs whenever possible.

Prevention of Epilepsy by Low-Dose Artesunate + Esomeprazole-Furosemide Sequential Therapy.

“…This effect may largely be explained by these agents upregulating mitochondrial biogenesis. [60][61] [62] The issue of drug resistance by alterations in GABA-A receptor and increased MDR especially in temporal lobe epilepsy may also be significantly addressed by this sequential drug combination therapy. [62][63] For example, artesunate and the PPIs may inhibit P-glycoprotein (P-gp) or multi-drug resistance protein-I.…”

Partners against Mortality in Epilepsy Conference Summary

“…AEDs are implicated because many AEDs induce CYP450 enzymes that participate in cholesterol synthesis. More than ten cross-sectional studies of adults and children have found elevated total cholesterol in carbamazepine-treated patients relative to controls or valproated-treated patients (30). Likewise, a half-dozen studies of phenobarbital showed elevated cholesterol.…”

Late-onset seizures: a subclinical cerebrovascular disorder?

“…In patients with late-onset seizures treated with antiepileptic drugs, treatment itself might indirectly increase the risk of stroke, possibly playing a synergistic effect with the occult cerebrovascular disease. Enzyme-inducing antiepileptic drugs may actually increase total cholesterol, lipoprotein(a), C-reactive protein, and homocysteine levels [16]. Whether this pharmacological effect on surrogate markers of vascular disease is clinically relevant or not remains to be defined.…”