Antiepileptic drug pharmacology in status epilepticus

As fast drug absorption is essential in status epilepticus, all drugs are ideally administered parenterally. It is desirable in status epilepticus for drugs to have a rapid onset and a prolonged duration of action. In order to accomplish this, the drugs need to cross the blood-brain barrier readily. Antiepileptic drugs achieve this either by being lipid soluble (for example, diazepam, midazolam, chlormethiazole, propofol) or by having an active transport mechanism (for example, valproate). Drugs with high lipid solubility have a biphasic concentration versus time curve. The initial phase is due to rapid redistribution from the serum to peripheral compartments (fat and muscle), and the later phase is due to elimination (usually much slower). Thus, after a single intravenous injection, there is a rapid fall in serum and consequently cerebral drug levels; the initial injection therefore can have a short-lived effect. Repeat doses, however, lead to accumulation and so a significant decrease in volume of distribution, and a decrease in the contribution of the redistribution phase to the drug's kinetics.27 This results in greater peak concentrations and relative persistence of high serum levels. Furthermore, the cerebral drug levels following repeat dosing are maintained for longer than would be predicted from the serum data, probably due to accumulation within the brain from non-specific binding to lipid components.27 These high, prolonged levels can precipitate hypotension, sedation, or cardiorespiratory failure - a serious risk with the repeated administration of diazepam, midazolam, chlormethiazole, clonazepam, pentobarbitone, or thiopentone. Less lipid-soluble drugs are relatively slower to act, but have a much longer lasting effect without a high risk of accumulation (for example, phenytoin, lorazepam, phenobarbitone). For lipid-soluble drugs, the rate of injection must also be carefully monitored, as too rapid administration will cause very high cerebral levels in the first pass through the cerebral circulation; this can result in sudden cardiorespiratory arrest or hypotension. For less lipid-soluble drugs (such as lorazepam), the rate of injection is not so critical.

An ideal antiepileptic drug should:

• have no active metabolites (diazepam, midazolam, lidocaine (lignocaine), and thiopentone have active metabolites)

• not interact with other medication

• not have saturable metabolism (both phenytoin and thiopentone have saturable pharmacokinetics at therapeutic levels)

• not be unduly affected by hepatic or renal blood flow or disease (chlormethiazole is an example of a drug whose metabolism is greatly affected by both hepatic disease and changes in hepatic blood flow)

• show no tendency to autoinduction (thiopentone, phenobarbitone, and phenytoin are all subject to strong autoinduction)

• have strong antiepileptic action (the non-barbiturate anaesthetics have little or no intrinsic antiepileptic action -a conundrum for their use in status epilepticus, the implications of which have not been fully considered)

• be stable in solution and unreactive with giving sets (a problem with paraldehyde, diazepam, and thiopentone).

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