topiramate

1. Topiramate
Done by pharmacist lubna Mohammed
R&D officer at HPI
Supervised by Prof. Yusuf M. Al-Hiari
Done as requirement for medicinal chemistry
course
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2. Presentation topics
• Introduction.
• Mechanism of action.
• Uses.
• Of- label use.
• Side effects.
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3. • Topiramate is an anticonvulsant drug .(I)
• Approved for seizures in 1996.(I)
• Approved for migraine prevention in 2004. (III)
• Topiramate was approved by the (FDA) in combination
with phentermine for weight loss in 2012. (III)
• This medication was discovered in 1979 by Bruce E.
Maryanoff and Joseph F. Gardocki from naturally occurring
sulfamate fructopyranose. (II)
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I. Maryanoff, B. E., et al. (1987). "Anticonvulsant O-alkyl sulfamates. 2,3:4,5-Bis-O-(1-methylethylidene)-beta-D-fructopyranose
sulfamate and related compounds." J Med Chem 30(5): 880-887.
II. Maryanoff, B. E., et al. (1998). "Structure-activity studies on anticonvulsant sugar sulfamates related to topiramate. Enhanced potency
with cyclic sulfate derivatives." J Med Chem 41(8): 1315-1343.
III. Linde, M., et al. (2013). "Topiramate for the prophylaxis of episodic migraine in adults." Cochrane Database Syst Rev(6): CD010610.
3
Introduction

4. • Multiple actions: (I)
• Blocks VgNa+ and VgCa2+ channels.
• Inhibits carbonic anhydrase.
• Inhibits activity of AMPA and kainase subtypes of
glutamate receptors.
• Facilitates GABAergic neurotransmission.
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I. Shank RP et al. Epilepsia. 2000;41(suppl 1):S3-9
4
Mechanism of action

5. Shank RP et al. Epilepsia. 2000;41(suppl 1):S3-9.
Voltage-Gated Ion ChannelsVoltage-Gated Ion Channels
AMPA/kainateAMPA/kainate
receptorreceptor
GABAGABAAA
receptorreceptor
NaNa++
channelchannel
ClCl--
CaCa2+2+
channelchannel
Ligand-Gated Ion ChannelsLigand-Gated Ion Channels
= Topiramate= Topiramate
ClCl--
ClCl--
KK++
channelchannel

6. 07/04/17 6
Mechanism of action

7. • Epilepsy (I , Iv)
• Prevention and treatment of migraines (I,II , III)
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I. "Topamax Prescribing Information" (PDF). United States Food and Drug Administration. Retrieved 11
April 2016.
II. Linde, M., et al. (2013). "Topiramate for the prophylaxis of episodic migraine in adults." Cochrane
Database Syst Rev(6): CD010610.
III. Ferrari, A., et al. (2011). "Clinical pharmacology of topiramate in migraine prevention." Expert Opin
Drug Metab Toxicol 7(9): 1169-1181
IV. youtube
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uses

8. • Bipolar & personality disorder(I,II,III)
• although the available evidence does not support its use
in any phase of bipolar disorder treatment more recent
review, published in 2010, suggested a benefit of
topiramate in the treatment of symptoms of borderline
personality disorder, however the authors note that this
was based only on one randomized controlled trial and
requires replication. Also the authors noted that the
long term effects have not been studied.
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I. Arnone, D. (2005). "Review of the use of Topiramate for treatment of psychiatric disorders." Ann Gen
Psychiatry 4(1): 5.
II. Vasudev K, M. K., Geddes J, Watson S, Young AH ( 2006). "Topiramate for acute affective episodes in
bipolar disorder." Cochrane Database of Systematic Reviews.
III. Lieb, K., et al. (2010). "Pharmacotherapy for borderline personality disorder: Cochrane systematic review
of randomised trials." Br J Psychiatry 196(1): 4-12.
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Off-label use

9. • Alcoholism (I)
Alcohol is reinforced by mesolimbic dopamine release.
Topiramate antagonizes this effect by facilitation of GABA
activity and inhibition of Glutamate function.
(II)
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I. Choi E. A, Ki S. W, Kim S. E, Kim J. W, and Park, J. K. (2005). The efficacy and safety
of topiramate in the treatment of alcohol withdrawal. Journal of the Korean
Neuropsychiatry Association, 44, 328-333.
II. Ait-Daoud N, Malcolm R.J, andJohnson B.A (2006) An overview of medications for the
treatment of alcohol withdrawal and alcohol dependence with an emphasis on the use
of older and newer anticonvulsants. Addictive Behaviors. 31:1628-49 9
Off-label use

10. • obesity and antipsychotic induced weight gain
• Loss of appetite was reported during clinical trials of
topiramate in epilepsy.(I)
• Increases in lipoprotein lipase activity have been
observed with topiramate treatment in animal models,
which suggests a potential to promote substrate
oxidation and increase metabolic rate However, the
mechanism by which topiramate alters energy balance
and induces fat loss is not known and remains under
investigation.(II)
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I. Verrotti, A., et al. (2011). "Topiramate-induced weight loss: a review." Epilepsy Res 95(3):
189-199.
II. Ben-Menachem, E., et al. (2003). "Predictors of Weight Loss in Adults with Topiramate-
Treated Epilepsy." Obesity Research 11(4): 556-562. 10
Off-label use

11. • Very common (>10%):
• Dizziness(II,III)
• Weight loss(II,III)
• Paraesthesia - e.g., pins and needles(I,III)
• Somnolence(II,III)
• Nausea(II,III)
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I. Mirza, N., et al. (2009). "Effect of topiramate on acid-base balance: extent, mechanism and effects." Br
J Clin Pharmacol 68(5): 655-661.
II. "TOPAMAX® Tablets and Sprinkle Capsules PRODUCT INFORMATION"(PDF). TGA eBusiness
Services. JANSSEN-CILAG Pty Ltd. 30 May 2013. Retrieved 18 November 2013.
III. "TOPIRAMATE ( topiramate ) tablet TOPIRAMATE ( topiramate ) tablet [Torrent Pharmaceuticals
Limited]". DailyMed. Torrent Pharmaceuticals Limited. August 2011. Retrieved 18 November 2013.
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Side effects

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