Levetiracetam

This chapter is relevant to the aims of Section K2(iii) from the 2023 CICM Primary Syllabus, which expects the exam candidate to "understand the pharmacology of anti-convulsant drugs". Phenytoin, an old toxic agent losing popularity in clinical practice, has been used for multiple exam questions mainly because it has interesting pharmacokinetic properties which make it inconvenient, and interesting pharmacokinetic effects which make it dangerous outside of a very narrow therapeutic range. In CICM SAQs, it tend to get compared to levetiracetam, which has none of these peculiarities, and which is rather well behaved pharmacologically. Those predictable inoffensive characteristics both make it a boring subject for discussion and an attractive first-line antiepileptic agent to use clinically. 
 Past questions involving levetiracetam:
  • Question 17 from the first paper of 2017 (phenytoin vs levetiracetam)
  • Question 2 from the second paper of 2014 (phenytoin vs levetiracetam)

In summary:

Name Levetiracetam
Class Antiepileptic
Chemistry Racetam
Routes of administration Oral and IV
Absorption Almost 100% oral bioavailability; rapidly and completely absorbed when given orally (96%)
Solubility pKa -2.0; highly acid drug, and very water soluble.
Distribution VOD=0.5-0.7 L/kg; mainly distriubuted into total body water. Minimally protein bound (less than 10%)
Target receptor Multiple potential targets (calcium channels, potasium channels, AMPA and GABA receptors), with what appears to be some selectivity for epileptogenic foci
Metabolism Minimally metabolised; about 30% of the drug is excreted in the urine as an inactive metabolite, the origins of which are unclear and almost certainly non-hepatic
Elimination 70% of the drug is excreted unchanged in the urine
Time course of action Half life is about 7-8 hours in healthy volunteers
Mechanism of action Multiple effects on multiple excitatory and inhibitory neurotransmitters and ion channels. Appears to have some selectivity for abnormally firing tissue, i.e. this drug is selective for epileptic brain tissue. The precise mechanism of its effect remains unknown
Clinical effects Main side-effects are neurocognitive and behavioural. These may include a change in mood, eg. depression, anixety, restlessness or fatugue, personality changes, cognitive decline, and an increased risk of suicide. 
Single best reference for further information Wright et al (2013)
   

For the rare reader who has plenty of time for a deep dive into levetiracetam pharmacology, one can recommend Wright et al (2013) for a birds' eye overview,  Patsalos (2000) for pharmacokinetics, Stockis (2009) for something a bit more clinical and Surges et al (2008) for the cellular mechanisms of action, all free articles.

Chemical class and chemical relatives of levetiracetam

Levetiracetam is the S-enantiomer of etiracetam, a racetam drug like piracetam and aniracetam with which it shares a common pyrrolidone nucleus. It is in  fact the α-ethyl analogue of piracetam. The other racetams are seldom seen in clinical pharmacology and are basically unknown in critical care, but in the community, this group is used as "nootropes", consumed by productivity bros to accelerate their rate of burnout. There's a few related molecules (brivaracetam, seletracetam), but apart from these the other racetam drugs do not tend to demonstrate any antiepileptic activity. Their structures will not be reproduced here because there is an entire column of chemical structures in Wikipedia dedicated to this, and in any case that would be pointless because nobody will ever be asked to draw their chemical structure in any exam.

Pharmacokinetics of levetiracetam

Levetiracetam has pharmacokinetic characteristics which are highly attractive from the viewpoint of clinical use, but also extremely boring from the viewpoint of teaching people about basic pharmacology. Unless otherwise stated, all these numbers are coming from Wright et al (2013).To summarise:

  • Levetiracetam is available as both oral tablets and IV injection, and there is also apparently an easily dispersed formulation which could potentially be used for buccal absorption. 
  • When taken orally, most it (96%) is rapidly absorbed, and oral bioavailability approaches 100% as there is minimal first-pass metabolism
  • It is highly soluble both in lipid and in water. The drug is strongly acidic, with a pKa of less than -2.0, and it distributes mainly into total body water - the apparent volume of distribution is 0.5-0.7L/kg in adults.
  • Levetiracetam is minimally protein-bound, which is fantastic because it is not going to be particularly effected by the hypoalbuminaemia of critical illness, nor is it going to interact with other drugs by displacing them (or being displaced) from protein binding sites.
  • This drug is minimally metabolised. After a dose, about 67% is recovered unchanged in the urine, and a further 27% is recovered as inactive metabolites. Yes, there is a (totally inactive) metabolite, which is referred to as L057, and some radiolabeled levetiracetam seems to have turned into this stuff somehow, but nobody knows how. Perucca & Bialer (1996), in an overview of antiepileptic drug pharmacokinetics, freely admit that we have no idea where it is coming from, and the only thing we can confidently say is the the liver is probably not responsible. There is minimal first pass metabolism, and moreover levetiracetam seems to be completely disinterested in the CYP450 system of enzymes and giving people five times the normal dose does not seem to induce or inhibit them. Likely, some other enzyme system is involved, but twenty years later we still do not know what that is. From the point of view of the pragmatic intensivist, all one needs to know is that dose adjustment is not required in liver disease, but is required in patients with renal failure.
  • Clearance in really normal people is pretty rapid, and the half life is about 7-8 hours (longer in the elderly), which calls for twice-daily dosing.
  • Serum levels of levetiracetam can be measured, but in clinical practice it is almost never necessary to do so. It has no organ-destroying toxicity and its therapeutic index is wide. Moreover it appears that the plasma levels are largely unrelated to the antiepileptic effect, which means that even if you do get levels back from the lab, you really won't know what to do with them. Still, in case you need to monitor it one day (for example in renal failure or to detect noncompliance) the trough is supposed to be 12 to 46 µg/mL (Krasowski et al, 2010)

Pharmacodynamics of levetiracetam

It is difficult to overintellectualise this section because so little can be said about the mechanism of action of levitiracetam, or almost any antiepileptic, for that matter. What follows is really a series of speculations. Reading the academic output of professional researchers on the subject can be likened to listening to an epilepsy expert thinking out loud about potential mechanisms of depressing neurotransmission and neuronal activation, and musing "maybe it does this, as well?" The linked article contains excellent tables on page 17 and 18, a part of which is reproduced here as an unordered list of channel and receptor effects:

  • SV2A galactose transporter is a drug target, and it is involved in the presynaptic regulation of neurotransmitter release. This is probably a dominant effect, as tritated levetiracetam did not bind to the brains of SV2A- knockout mice (Lynch et al, 2004), but what role this plays in the antiepileptic effect is unclear.
  • Sodium channels: no effect whatsoever
  • GABA: no effect whatsoever
  • Calcium channels: some inhibition of N-type and P/Q-type calcium channels
  • Potassium channels: some inhibition of the inward rectifier current, by up to 30%
  • AMPA glutamate receptors: inhibition, but only at very high concentrations
  • GABAA receptors: these are not activated per se, but there is an "alleviation of run-down upon repetitive activation". Also, there is complete reversal of zinc-induced inhibition of these receptors (i.e when zinc is sprinkled upon a neuron culture, this tends to inhibit GABA channels, and levetiracetam reverses this effect, restoring the GABA channels to normal working order)
  • Glycine receptors: Also complete reversal of zinc-induced inhibition
  • Intracellular calcium release: levetiracetam inhibits both IP3-regulated and ryanodine-regulated release of calcium 

So, what does any of this mean? In summary, it appears that the mechanism of action of levetiracetam lays in its ability to restore the normal inhibitory influences on the neurons which are apparently impaired or absent in epilepsy. It does not so much act as a GABA-agonst, but it reverses seizure-induced GABA dysfunction, and does not seem to affect GABA sites which are working normally (i.e. it is selective for epileptic brain tissue). What exactly all those calcium and potassium effects do, remains to be established, and authors simply shrug about it, mouthing noncommittal nothings like "may preferentially modulate neuronal activity".

Putting this molecular nonsense aside, the breadth of effects listed above makes levetiracetam a "broad-spectrum anticonvulsant".  Stockis et al (2009) notes that it is indicated for partial-onset seizures, myoclonic seizures, primary generalized tonic-clonic seizures, and there are many other possible indications, including status myoclonus following hypoxic brain injury (Venot et al, 2011). It is particularly attractive for the latter, as it has minimal sedating effects and therefore should not cloud serial neurological reassessment as benzodiazepines might.

Side effects

Unlike the exciting side-effects of phenytoin (toxic epidermal necrolysis, etc), levetiracetam is not likely to produce some sort of nightmarish whole-body reaction. Its side effects are more subtle, which is not to trivialise them. The side-effects are mainly neurobehavioral, and range from fatigue or restlessness all the way to major personality changes, cognitive decline, and an increased risk of suicide. 

References

Patsalos, P. N. "Pharmacokinetic profile of levetiracetam: toward ideal characteristics." Pharmacology & therapeutics 85.2 (2000): 77-85.

Stockis, Armel, et al. "Clinical pharmacology of levetiracetam for the treatment of epilepsy." Expert review of clinical pharmacology 2.4 (2009): 339-350.

Surges, Rainer, Kirill E. Volynski, and Matthew C. Walker. "Is levetiracetam different from other antiepileptic drugs? Levetiracetam and its cellular mechanism of action in epilepsy revisited." Therapeutic Advances in Neurological Disorders 1.1 (2008): 13-24.

Wright, Chanin Clark, et al. "Clinical pharmacology and pharmacokinetics of levetiracetam.Frontiers in neurology 4 (2013): 192.

Perucca, Emilio, and Meir Bialer. "The clinical pharmacokinetics of the newer antiepileptic drugs." Clinical pharmacokinetics 31.1 (1996): 29-46.

Krasowski, Matthew D. "Therapeutic drug monitoring of the newer anti-epilepsy medications." Pharmaceuticals 3.6 (2010): 1909-1935.

Venot, Marion, et al. "Improvement of early diagnosed post-anoxic myoclonus with levetiracetam." Intensive care medicine 37.1 (2011): 177-179.

Cramer, Joyce A., et al. "A systematic review of the behavioral effects of levetiracetam in adults with epilepsy, cognitive disorders, or an anxiety disorder during clinical trials." Epilepsy & Behavior 4.2 (2003): 124-132.

Lynch, Berkley A., et al. "The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam." Proceedings of the National Academy of Sciences 101.26 (2004): 9861-9866.