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Levetiracetam Group 1

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Sara Dunbar

on 6 November 2014

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Transcript of Levetiracetam Group 1


Abstract
Introduction
Epilepsy is a serious neurological disorder characterized by recurrent epileptic seizures, caused by aberrant excessive (and often synchronous) neuronal activity in the brain. According to the WHO, epilepsy is the most common serious neurological disorder worldwide; It has been estimated that up to 1 in every 200 people suffer from epilepsy.

The clinical classification of epilepsy is based on the type of seizures experienced; generalized, or partial. Both forms can be further classified as simple or complex. In a simple seizure consciousness is not lost.

Most patients are adequately treated by monotherapy, but about 20% have shown a resistance or adverse effects to established anticonvulsants such as phenytoin, phenobarbitol, carbamazepine, and valproic acid.

Levetiracetam (an ethylated derivative of the nootropic piracetam) was originally designed to improve cognitive function in Alzheimer's disease, but was later discovered to have anticonvulsant activity. LEV has relatively favorable pharmacokinetic, drug interaction, and side effect profiles, making clinical use fairly straightforward. This presentation explores LEV's characteristics in detail.

Levetiracetam (LEV) is a novel antiepileptic drug primarily used to treat partial and generalized tonic-clonic seizures, and is occasionally used for bipolar disorder, neuropathic pain, and migraines.

LEV exerts its anticonvulsant effects via several mechanisms. The drug binds to synaptic vesicle protein 2A (SV2A) interfering with neurotransmitter release. SV2A, an integral membrane protein, is located throughout the CNS and endocrine cells. Levetiracetam also selectively inhibits N-type calcium channels, inhibits release of calcium from intracellular stores, and blocks the effects of negative allosteric modulators (zinc and beta-carbolines) of GABA(A) and glycine receptors. LEV is given orally or intravenously, with excellent bioavailaility, and has favorable pharmacokinetic and drug interaction profiles. The drug is mostly (66%) renally eliminated, with 24% of the dose undergoing enzymatic amide hydrolysis to an inactive, renally excreted metabolite.

LEV is the subject of ongoing research in order to determine its exact mechanisms of action.
Unique among AEDs, LEV binds to synaptic vesicle protein 2A (SV2A).

SV2A is a major vesicular protein structurally resembling membrane transporters. It's function is currently unknown, but it appears to function directly or indirectly in synaptic vesicle exocytosis.

The affinity of the LEV/SV2A interaction correlates very strongly with anti-epileptic potency in animal models, suggesting that
SV2A binding may be the main mechanism of LEV action
.

LEV/SV2A binding inhibits synaptic vesicle exocytosis
; several alternative mechanistic hypotheses have been proposed:

SV2A may have a regulatory function as a "calcium sink"
; LEV may have a stimulatory effect on SV2A's ability to bind calcium. If this is the case, LEV/SV2A interaction would reduce the calcium accumulation that typically occurs during repetitive action potentials, leading to decreased neurotransmission.

SV2A may be directly involved in synaptic vesicle exocytosis
,
either as a
calcium-binding "trigger" for exocytosis
or as a
direct mediator of vesicle docking and/or fusion
. In either case, LEV's disruption of SV2A function would cause decreased exocytosis.

Variants of these hypotheses exist, of course. These hypotheses could be further explored by investigating the distribution of SV2A between inhibitory and excitatory neurons.

The exact MOA of Levetiracetam (LEV) is not entirely understood. However, it is known to act via several distinct mechanisms, some of them unique among anti-epileptic drugs (AEDs):
Mechanism of Action
LEV decreases presynaptic cytosolic calcium influx:
At therapeutic concentrations (1-300 μM),
LEV directly inhibits several types of high-voltage activated calcium channels
(mainly N-type, but also P- and Q-type to a lesser extent), causing an 18 - 40% inhibtion of calcium current.
LEV also inhibits release of calcium into the cytosol from intracellular calcium stores
, which is a process regulated by inositol triphosphate (IP3) receptors and ryanodine receptors (~50% inhibition at therapeutic concentrations.
Thus, LEV inhibits the calcium-dependent processes involved in synaptic vesicle exocytosis and subsequent neurotransmitter release.
However, the mechanisms of LEV/receptor interaction are not fully understood.

The magnitude of this effect's contribution to LEV's anti-epileptic action is unknown
, for two main reasons. No in vivo data is available, since it is difficult to perform an in vivo assay of specific channel inhibition for a drug with multiple effects. The authors of the above research only investigated the effects of LEV applied relatively acutely (maximum one hour duration), so the HVA-blocking effects of more prolonged application are unknown.
The GABA and glycine receptors are the two main inhibitory ionotropic receptors in the CNS; they are both ligand-gated chloride channels.

LEV has specific effects on postsynaptic GABA- and glycine-gated ion currents, and these effects are distinct from those of other AEDs:
Alone, LEV has no effect on ion flux through these channels.
However, LEV binding reverses the inhibitory effects of zinc and beta-carbolines, both negative allosteric modulators of GABA- and glycine- gated ion channels.

Thus,
LEV is a
null allosteric modulator
of GABA- and glycine-gated ion channels
: at therapeutic concentrations, LEV binding to these ionotropic channels affects the binding/effects of other allosteric modulators, while causing no direct change in classical ligand/receptor binding interactions.
In this case, the effect is one of positive allosteric modulation
.

These effects were confirmed in vivo by investigating the antagonistic relationship between beta-carbolines and LEV.
Effects on Synaptic Vesicles
Effects on Presynaptic Calcium Flux
Effects on Postsynaptic Receptors
These findings have relevant implications:

Beta-carboline mediated inhibition is unlikely to be physiologically relevant. However, zinc is a physiologically important ion:

Abnormal sprouting of granule cell axons ("mossy fibers") into the inner layer of the dentate gyrus is associated with temporal lobe epilepsy.

Many of these fibers are glutamatergic (excitatory) neurons, which sequester zinc in their synaptic vesicles; zinc is involved in glutamatergic transmission as a negative allosteric modulator (e.g. of NMDA receptors).

Thus, increased extracellular zinc concentration (as a result of local glutamatergic transmission) may cause increased allosteric inhibition of GABA- and glycinergic inhibitory synapses, leading to increased neurotransmission.

Through its effects of inhibiting zinc binding to GABA and glycine receptors, LEV would directly oppose the effect described above, and lead to decreased neurotransmission.
Pharmacokinetics
Levetiracetam
IUPAC name:
(S)-2-(2-oxopyrrolidin-1-yl)butanamide

Levetiracetam (LEV) is the (S)-enantiomer of eracitam; the (R)-enantiomer has no physiological effects.

LEV is structurally dissimilar from other anti-epileptic drugs (AEDs).

Originally developed as a nootropic (a cognitive enhancement drug), LEV is an ethylated analogue of the prototypical nootropic drug, Piracetam.

LEV is sold by UCB Pharmaceuticals, Inc. as brand-name
Keppra®
(FDA approved in 1999) as an oral tablet (250mg - 1000mg), oral solution (100mg/mL), and injectable IV infusion (100mg/mL).

Generic LEV was approved for use by the FDA in 2008, and is available from a range of pharmaceutical companies.

LEV is broadly available in Europe, Canada, and USA (as UCB's Keppra® or as generic LEV from many pharmaceutical companies).

In Canada, LEV is available, with variable coverage under provincial insurance schemes: The drug is fully covered in AB and SK, covered under restricted circumstances in NL, QC, BC, NS, NB, and PE, and is not covered in MB, ON, and the territories.
http://en.wikipedia.org/wiki/File:Levetiracetam.svg
Clinical Indications and Dosages
Partial Onset Seizures

Juvenile Myoclonic Epilepsy
Primary Generalized Tonic-Clonic Seizures
Adults > 16 yrs old:
1000 mg/day (no greater than 3000 mg) PO
Pediactric patients:
1-6 months: 42 mg/kg (start: 14 mg/kg) PO
6 m-4 yrs: 50 mg/kg (start: 20 mg/kg) PO
4-16 yrs: 60 mg/kg (start: 20 mg/kg) PO
Doses are to be divided into two doses per day and vary depending on age, indication, and renal function. In pediatric patients, dosage is based upon weight. Doses are given in tablet form or vial solutions of 500mg/5ml. Solutions are diluted in 100 ml of dilutant and given over a 15 min infusion.
Keppra is use alongside other anti-epileptic drugs to treat onset seizures for patients > 1 month old.
Keppra is also used as adjunctive therapy for the treatment of myoclonic seizures in patients > 12 yrs old with JME.
Patients >12 yrs old: 3000 mg/day (start: 1000 mg) PO
Adults >16 yrs: 3000 mg/day (start: 1000 mg) PO
Pediatric patients:
6-16 yrs old: 60 mg/kg (start 20 mg/kg) PO
Keppra is used as an adjunctive therapy for tonic-clonic seizures in patients older than 6 yrs with idiopathic generalized epilepsy.
References
http://www.meltingmama.net/.a/6a00d8345190c169e2017d42f74854970c-320wi
http://allsideeffects.net/wp-content/uploads/2012/09/Keppra
Contraindications
Abrupt withdrawal of Levetiracetam should be avoided
,
since it may result in withdrawal symptoms and/or a return of the initial condition (i.e. increased breakthrough seizures).

Levetiracetam is excreted in breast milk, which may be cause for caution
(consult your physician if relevant). Little research exists on LEV's effect on the breastfeeding infant, but it appears to be minimal. Both the American Academy of Neurology and the American Epilepsy Society recommend breastfeeding while on LEV therapy.

It may be harmful to co-administer LEV and carbamazepine
: some evidence indicates a pharmacodynamic drug interaction, leading to carbamazepine toxicity.

Allergies to pyrrolidone analogues.

Patients should use caution if they suffer from
renal impairment

(since LEV is renally eliminated) or a
psychiatric disorder.
How Keppra XR® (levetiracetam) Works
Figure 9: Schematic of an NMDA receptor, an important type of glutamate receptor.
http://journals.prous.com/journals/dnp/20021504/html/dn150226/images/Smith_f4
http://www.pitt.edu/~german/The%20Mossy%20Fiber%20Pathway
Figure 8: Histological section of the Hippocampus showing the mossy fibers and Dentate Gyrus
http://www.biochem.uni-erlangen.de/MouseDB/imgs/GlyR
Figure 7: Schematic of a typical glycine receptor.
(zinc allosteric binding site not shown)
http://huguenard-lab.stanford.edu/beta3/gaba
Figure 6: Schematic of a typical GABA receptor showing the zinc allosteric binding site.
Figure 5: Schematic of the generalized synapse, including action sites of various AEDs.
Synaptic vesicle exocytosis (and thus neurotransmitter release) is a calcium-dependent process involving several essential proteins which function as calcium "sensors" to trigger the exocytosis process.

Therefore,
calcium influx through presynaptic voltage-gated channels regulates neurotransmission
.
http://link.springer.com/static-content/images/377/prt%253A978-3-540-29832-8%252F5/MediaObjects/3-540-29832-0_5_Part_Fig6_HTML
Figure 4: Calcium-dependent exocytosis.
Figure 3: Chemical structure of Levetiracetam
Desired Effects
http://www.keppraxr.com/about/how.aspx
http://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summary_pr?p_JournalId=6&p_RefId=723686&p_IsPs=N
Table 1: Summary of relevant pharmacokinetic parameters of levetiracetam.
Figure 10: Video illustration of the SV2A binding of Keppra XR
®
LEV is well absorbed orally
, free of complications due to food ingestion.

Bioavailability is good

(over 95%)

LEV exhibits
little to no plasma protein binding
.

LEV has a relatively
low volume of distribution (0.5-0.7 L/kg)
,
a consequence of its

good water solubility.

The drug has a
plasma half-life of approximately 7 hours
, and is
mostly (66%) eliminated unchanged in the urine
, but approximately 24% of the dose undergoes enzymatic (amidase) hydrolysis of the acetamide group, yielding ammonium and "UCB L057", the carboxylic acid analogue of levetiracetam, which is an
inactive, renally eliminated metabolite
.

To date,
LEV is not known to be associated with any pharmacokinetic drug interactions
.
Aggression
Anxiety
Change in personality
Crying
Cough
Diarrhea
Dry mouth
Euphoria
Fever
Unwanted Effects
Minor

Major

Joint pain
Loss of appetite
Nausea
Nervousness
Paranoia
Short breath
Vomiting
Fatigue
Bleeding nose
Double vision
Earache
Loss of memory
Loss of bladder control
Seizures
Spinning
Shakiness
Problems with coordination
Pharmacodynamic Effects
Other Effects

To date,

LEV has not been associated with any pharmacokinetic drug interactions.

One observational study of epileptic patients (2002, n=4) reported a
suspected pharmacodynamic drug interaction between LEV and carbamazepine
, with symptoms consistent with those of carbamazepine toxicity. However, no detailed information on the interaction is available to date.

Thus,
LEV has a favorable drug interaction profile, making clinical use fairly uncomplicated.
A pharmacokinetic interaction occurs when one drug affects another drug's absorption, distribution, metabolism, or elimination.
A pharmacodynamic interaction occurs when two drugs have additive or antagonistic effects.
Drug Interactions
What are the physiological effects resulting from levetiracetam's mechanisms of action?
General inhibition of CNS neurotransmission
via the described mechanisms:

Inhibits HVA calcium channels
Binds SV2A, inhibiting vesicle exocytosis
Decreases negative allosteric modulation of inhibitory (GABAergic/glycinergic) neurons.

This effectively limits the excessive firing characteristic of epilepsy, resulting in
decreased frequency and severity of epileptic seizures
.
LEV has a fairly good pharmacodynamic profile; it doesn't really have
direct
unwanted effects.
However, negative effects arise from the general inhibition of neurotransmission:

Drowsiness/sleepiness.

General feeling of weakness.

A wide range of personality and/or mood changes, such as aggression, anxiety, depression, euphoria, paranoia, et cetera.

Other neurogenic side effects
(a more comprehensive list is in the "unwanted effects" section).
Abdominal pain
Swelling in glands and joints
Bleeding and bruising
Red lesions with purple center
Figure 2: Keppra® in 500 mg tablets
Figure 11: Keppra as offered in 250, 500, and 750 mg tablets.
Figure 10: Red lesions with purple center (erythema multiforme).
http://www.ncbi.nlm.nih.gov/pubmed/23473282
Alternative Treatment Options
Levetiracetam
Carbamazepine
Divalproex sodium
Ethosuximide
Felbamate
Gabapentin
Lamotrigine
Oxcarbazepine
Topiramate
Sara Dunbar
Kianna Csolle
Michael McGregor
David Kokubun
Megan Edwards
Raafa Abdulla
A diet rich in fat and low in carbohydrates
(this is called a
ketogenic diet
).
The brain is mostly dependent on glucose as an energy source, and a low-carbohydrate diet does not supply this need.
Therefore, the brain is forced to catabolize fatty acids to form
ketone bodies
, which the brain can utilize as metabolic fuel.

Such a diet has been observed to decrease the frequency of seizures in some individuals unresponsive to drug therapy, although the
mechanism is unknown
. This is a possible area of further study: Do the starvation-like conditions of the ketogenic diet encourage a general decrease in CNS activity (energy-conserving), thus decreasing the chance of the excessive firing characteristic of epilepsy?
Focal seizures

Seizures that begin as focal and spread

Unilateral multifocal epilepsy with infantile hemiplesia
Surges, R., Volynski, K., & Walker, M. (2008). Is Levetiracetam Different from Other Antiepileptic Drugs? Levetiracetam and its Cellular Mechanism of Action in Epilepsy Revisited.
Ther Adv Neurol Disord. 1(1). 13-24. doi: 10.1177/1756285608094212.
Rigo, J-M., Hans, G., Nguyen, L., Rocher, V., Belachew, S., Malgrange, B., Leprince, P., Moonen, G., Selak, I., Matagne, A., Klitgaard. (2002). The anti-epileptic drug leveteracetam reverses the inhibition by negative allosteric modulators of neuronal GABA- and glycine-gated currents.
Br J Pharmacol
, 136(5), 659-672. doi: 10.1038/sj.bjp.0704766
Buckmaster, PS. (2012).
Mossy Fiber Sprouting in the Dentate Gyrus
. In: Noebels, JL., Avoli, M., Rogawski, MA., et al., editors. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Bethesda (MD): National Center for Biotechnology Information (US). Retrieved from: http://www.ncbi.nlm.nih.gov/books/NBK98174/
Paoletti, P, Vergnano, AM., Barbour, B., Casado, M. (2009) Zinc at glutamatergic synapses. Neuroscience. 158(1). 126-36. doi: 10.1016/j.neuroscience.2008.01.061. Epub 2008 Feb 15.
Levetiracetam structure. (2009). Retrieved from http://en.wikipedia.org/wiki/File:Levetiracetam.svg
Ndegwa, S. (2011). Levetiracetam for the Treatment of Epilepsy.
Environmental Scan
. (30) Ottawa: Canadian Agency for Drugs and Technologies in Health. Retrieved from: http://www.cadth.ca/products/environmental-scanning/environmental-scans/environmental-scan-30
Schematic diagram of the N-methyl-d-aspartate (NMDA) subtype of glutamate receptor. (2002). Retrieved from: http://journals.prous.com/journals/dnp/20021504/html/dn150226/images/Smith_f4.jpg
The mossy fiber pathway. (2012). Retrieved from: http://www.pitt.edu/~german/The%20Mossy%20Fiber%20Pathway
Glycine Receptor. Retrieved from: http://www.biochem.uni-erlangen.de/MouseDB/imgs/GlyR.jpg
Gaba.jpg. Retreived from: http://huguenard-lab.stanford.edu/beta3/gaba.jpg
Pang, ZP., Melicoff, E., Padgett, D,. Liu, Y., Teich, AF., Dickey, BF., Lin, W., Adachi, R., Südhof, TC. (2006) Synaptotagmin-2 is essential for survival and contributes to Ca2+ triggering of neurotransmitter release in central and neuromuscular synapses.
Neuroscience
, 26(52), 13493-504. Retreived from: http://www.ncbi.nlm.nih.gov/pubmed/17192432.
European Medicines Agency. (2013). Keppra : EPAR - Summary for the public. Retrieved from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000277/WC500041334.pdf
Drugs.com. (2014). Generic Keppra Availability. Retrieved from: http://www.drugs.com/availability/generic-keppra.html
Patsalos, PN., (2004). Clinical Pharmacokinetics of Levetiracetam.
Clin Pharmacokinet,
43(11), 707-24. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/15301575
Patsalos, P.N., (2003). The pharmacokinetic characteristics of levetiracetam.
Methods Find Exp Clin Pharmacol
, 25(2), 123. doi:10.1358/mf.2003.25.2.723686

Comprehensive Epilepsy Center. Levetiracetam (Keppra). NYU Langone Medical Center. Retrieved from: http://epilepsy.med.nyu.edu/treatment/medications/levetiracetam#sthash.hOWIg6eO.J3mOTCMI.dpbs
Yesilova, Y., Turan, E., Sonmez, A., Ozardali, I. (2013). A case of erythema multiforme developing after levetiracetam therapy.
Dermatol Online J
, 19(2), 12. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/23473282

Medscape. (2013). Levetiracetam (Rx). Retrieved from: http://reference. medscape. com/drug/keppra-levetiracetam-343013#0.
These effects are seen more commonly.
These effects are less common. For those indicated in
red
, the incidence is not known.
Suicidal ideation
Bleeding gums
High fever
Increase in heart rate
Changes in vision
Peeling or loosening of skin
Relevant Surgical Procedures:

Lobectomy or lesionectomy
Multiple subpial transection
Corpus callosotomy
Hemispherectomy
Device implant
Surgery to target other conditions that may cause seizures
In severe cases where the patient does not respond well to drug therapy, surgical intervention can be helpful.
Three categories of epilepsy can be successfully treated with surgery:
Other Anticonvulsant Drugs
Other seizure medications:
Benzodiazepines and barbiturates*
Pentobarbital
Phenobarbital
Clorazepam
Clorazepate
Diazepam (Valium)
*These are effective at controlling seizures, therefore useful in emergencies.
The patient should contact a physician immediately if any of these effects are noticed while taking Levetiracetam.
Group 1
EMedTv. (2013). Alternatives to Keppra. Retrieved from: http://epilepsy.emedtv.com/keppra/alternatives-to-keppra.html
WebMD. (2013). Contraindications for levetiracetam. Retrieved from: http://www.webmd.com/drugs/drug-17855-levetiracetam+oral.aspx?drugid=17855&drugname=levetiracetam+oral&pagenumber=5
Crepeau, A., Amy Z., Treiman D., (2010). Levetiracetam: a comprehensive review. Expert of Neurotherapeutics, 10.2. Health Refernce Center Academic.Retrieved from: http://go.galegroup.com/ps/i.do?id=GALE%7CA251006387&v=2.1&u=ubcolumbia&it=r&p=HRCA&sw=w&asid=3a584e0e1ca8cfca5a466b7dc92f8031
Epocrates. (2014). Levetiracetam contraindications. Retrieved from: https://online.epocrates.com/u/1032280/levetiracetam/Contraindications+Cautions
Rang, H.P., Dale, M.M., Ritter, J.M., Flower, R.J., Henderson, G. Rang and Dale's Pharmacology (2012) 7th ed. Elsevier Inc.
Surgery
Diet
http://www.nature.com/nrd/journal/v9/n1/fig_tab/nrd2997_F1.html
http://www.indiahospitaltour.com/neurosurgery/epilepsy-treatment-india.html
Figure 11: Surgical procedures used in epilepsy treatment.
Figure 1: EEG before, during, and after a grand mal seizure.
http://lifeafterbeingaleedsstudent.blogspot.ca/2012/06/neurological-diseases.html
India Hospital Tour. (2010). Epilepsy. Retrieved from: http://www.indiahospitaltour.com/neurosurgery/epilepsy-treatment-india.html
Breedlove, Watson, Rosenweig (2010). Biological Psychology 6e. Retrieved from: http://lifeafterbeingaleedsstudent.blogspot.ca/2012/06/neurological-diseases.html
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