Rivastigmine: Difference between revisions

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* 2006 Sales: $220 Million<ref>Irena Melnikova, Therapies for Alzheimer's disease, Nature Reviews Drug Discovery 6, 341-342 (May 2007)</ref>
* 2006 Sales: $220 Million<ref>Irena Melnikova, Therapies for Alzheimer's disease, Nature Reviews Drug Discovery 6, 341-342 (May 2007)</ref>
* Importance: One of the the first treatments for the symptoms of [[Alzheimer's Disease]], although no definitive proof exists as to whether it alters the progression of the disease.  
* Importance: One of the the first treatments for the symptoms of [[Alzheimer's Disease]], although no definitive proof exists as to whether it alters the progression of the disease.  
* The following is a list of Pharmacokinetic Parameters. See: [[Pharmaceutical Drugs]] for more information
* See: [[Pharmaceutical Drugs]] for more information about other drugs and disorders


===Mechanism of Action===
===Mechanism of Action===


<scene name='1gqr/Com_view/1'>Rivastigmine (Exelon)</scene> is a [http://en.wikipedia.org/wiki/Carbamate carbamate] inhibitor of AChE, and it is currenly used in therapy of [http://en.wikipedia.org/wiki/Alzheimer's_disease Alzheimer's disease]. Rivastigmine (colored yellow) interacts with ''Tc''AChE <font color='lime'><b>(colored lime)</b></font> at the <scene name='1gqr/Active_site/4'>active-site gorge</scene> ([[1gqr]]). The carbamyl moiety of rivastigmine is <scene name='1gqr/Active_site/9'>covalently bound</scene> to the active-site S200 Oγ. The second part of rivastigmine (the leaving group), NAP ((−)-S-3-[1-(dimethylamino)ethyl]phenol) is also held in the active-site gorge, but it is <scene name='1gqr/Active_site/6'>separated</scene> from the carbamyl moiety, hence, carbamylation took place. The <scene name='1gqr/Active_site/7'>crystal structure</scene> of ''Tc''AChE/<font color='magenta'><b>NAP (colored magenta)</b></font> is known ([[1gqs]]). The <font color='violet'><b>''Tc''AChE active-site residues</b></font> which are interacting with NAP are <font color='violet'><b>colored violet</b></font>. NAP is located in a similar region of ''Tc''AChE active site, but with different orientation than that of the NAP part (colored yellow) in the  ''Tc''AChE/rivastigmine complex. Only H440 and F330 significantly change their side-chain conformations. <scene name='1gqr/Active_site/8'>Overlap</scene> of the ''Tc''AChE active sites in 4 different structures (<font color='lime'><b>''Tc''AChE</b></font>/rivastigmine ([[1gqr]]), <font color='violet'><b>''Tc''AChE</b></font>/<font color='magenta'><b>NAP</b></font> ([[1gqs]]), <font color='cyan'><b>native ''Tc''AChE</b></font> ([[2ace]]), and ''Tc''AChE/'''VX''' ([[1vxr]], ''Tc''AChE colored white and VX black) reveals that the conformation of H440 in the ''Tc''AChE/NAP structure is very similar its conformation in the native ''Tc''AChE ([[2ace]]), but the distance between H440 Nδ and E327 Oε is significantly longer in the ''Tc''AChE/rivastigmine and the ''Tc''AChE/'''VX''' complexes. This structural change disrupts the [http://en.wikipedia.org/wiki/Catalytic_triad catalytic triad] consisting of S200, E327, H440. This could explain the very slow kinetics of AChE reactivation after its inhibition by rivastigmine <ref name="Bar-On">PMID:11888271</ref>.
Rivastigmine is an [[Acetylcholinesterase]] (AChE) inhibitor. It binds to the active site of <scene name='Rivastigmine/Acetylcholinesterase/1'>AChE</scene>, utilizing many of the same residues which bind and break down acetylcholine. By inhibiting AChE, the important neurotransmitter, [[acetylcholine]], is degraded at a slower rate, helping reverse the marked decrease in neuronal function evident in [[Alzheimer's Disease]] patients. Rivastigmine is rapidly metabolized into its principal components (carbamyl and NAP moieties) which are powerful Acetylcholine inhibitors. These components primarily <scene name='Rivastigmine/Bound/1'>primarily interact with residues</scene> GLy 117, Gly 118, Gly 119 Ala 201, Trp 233, Phe 290, Trp 84, Phe 330, His 440, & Phe 288 in tightly binding to the AChE binding site via pi stacking and hydrogen bond interactions. Rivastigmine outcompetes acetylcholine for the active site of AChE, inhibiting the esterase.<ref>PMID:11888271</ref>


===Pharmacokinetics===
===Pharmacokinetics===
{| class="wikitable" border="1" width="52%" style="text-align:center"
<table style="background: cellspacing="0px" align="" cellpadding="0px" width="42%">  
|-
<tr>
!  colspan="7" align="center"| Aceylcholinesterase Inhibitor [[Pharmaceutical_Drugs#Pharmacokinetics_Translated|Pharmacokinetics]]<ref>PMID:17113365</ref><ref>PMID: 19935404</ref><ref>PMID:7605915</ref><ref>PMID:1404819</ref><ref>doi:10.1053/cp.1999.v66.103404001</ref><ref>doi:10.1038/sj.clpt.6100242</ref><ref>PMID:12734391</ref><ref>PMID: 11741490</ref>
<td style="width:100%; vertical-align:top;border-width:0px; border-style:inset">
|-
<div style="height:100%; width: 100%">
! Parameter
{{:Acetylcholinesterase Inhibitor Pharmacokinetics}}
! [[Donepezil]]
</div>
! [[Tacrine]]
</td>
! [[Rivastigmine]]
</tr>
! [[Galantamine]]
</table>
|-
! [[Pharmaceutical_Drugs#Tmax|T<sub>max</sub>]] (hr)
! 3.6
! 1.5
! .3
! 1.2
|-
! [[Pharmaceutical_Drugs#Cmax|C<sub>max</sub>]] (ng/ml)
! 6.5
! 15.7
! 29.3
! 42.6
|-
! [[Pharmaceutical_Drugs#Bioavailability_.28F.29|Bioavailability]] (%)
! 100
! 17
! 36
! 100
|-
! [[Pharmaceutical_Drugs#Protein_Binding|Protein Binding]] (%)
! 96
! 55
! 40
! 10
|-
! [[Pharmaceutical_Drugs#Half_Life_.28T1.2F2.29|T<sub>1/2</sub>]] (hr)
! 70
! 3
! 5
! 7.3
|-
! [[Pharmaceutical_Drugs#Area_Under_the_Curve_.28AUC.29|AUC]] (ng/ml/hr)
! 380
! 80.4
! 191
! 427
|-
! [[Pharmaceutical_Drugs#Inhibitory_Concentration_.28IC50.29|IC<sub>50</sub>]] (nM)
! 6.7 <br/>(Rat)
! 450 <br/>(Human)
! 1535 <br/>(Human)
! 1995 <br/>(Rat)
|-
! Dosage (mg)
! 5
! 160
! 6
! 8
|-
! Metabolism
! Hepatic (CYP2D6 & CYP3A4) & Cholinesterase
! Hepatic (CYP1A2) & Cholinesterase
! Cholinesterase
! Hepatic (CYP3A4 & CYP2D6) & Cholinesterase
|}
 


===References===
===References===

Latest revision as of 23:37, 9 December 2010

Rivastigmine, also known as Exelon

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Better Known as: Exelon

  • Marketed By: Novartis
  • Major Indication: Alzheimer's Disease
  • Drug Class: Acetylcholinesterase Inhibitor
  • Date of FDA Approval (Patent Expiration): 2007 (
  • 2006 Sales: $220 Million[1]
  • Importance: One of the the first treatments for the symptoms of Alzheimer's Disease, although no definitive proof exists as to whether it alters the progression of the disease.
  • See: Pharmaceutical Drugs for more information about other drugs and disorders

Mechanism of Action

Rivastigmine is an Acetylcholinesterase (AChE) inhibitor. It binds to the active site of , utilizing many of the same residues which bind and break down acetylcholine. By inhibiting AChE, the important neurotransmitter, acetylcholine, is degraded at a slower rate, helping reverse the marked decrease in neuronal function evident in Alzheimer's Disease patients. Rivastigmine is rapidly metabolized into its principal components (carbamyl and NAP moieties) which are powerful Acetylcholine inhibitors. These components primarily GLy 117, Gly 118, Gly 119 Ala 201, Trp 233, Phe 290, Trp 84, Phe 330, His 440, & Phe 288 in tightly binding to the AChE binding site via pi stacking and hydrogen bond interactions. Rivastigmine outcompetes acetylcholine for the active site of AChE, inhibiting the esterase.[2]

Pharmacokinetics

Acetylcholinesterase Inhibitor Pharmacokinetics
Parameter Donepezil Tacrine Rivastigmine Galantamine
Tmax (hr) 3.6 1.5 .3 1.2
Cmax (ng/ml) 6.5 15.7 29.3 42.6
Bioavailability (%) 100 17 36 100
Protein Binding (%) 96 55 40 10
T1/2 (hr) 70 3 5 7.3
AUC (ng/ml/hr) 380 80.4 191 427
IC50 (nM) 6.7
(Rat) 		450
(Human) 		1535
(Human) 		1995
(Rat)
Dosage (mg) 5 160 6 8
Metabolism Hepatic (CYP2D6 & CYP3A4) & AChE Hepatic (CYP1A2) & AChE AChE Hepatic (CYP3A4 & CYP2D6) & AChE

For Pharmacokinetic Data References, see: References

References

  1. ↑ Irena Melnikova, Therapies for Alzheimer's disease, Nature Reviews Drug Discovery 6, 341-342 (May 2007)
  2. ↑ Bar-On P, Millard CB, Harel M, Dvir H, Enz A, Sussman JL, Silman I. Kinetic and structural studies on the interaction of cholinesterases with the anti-Alzheimer drug rivastigmine. Biochemistry. 2002 Mar 19;41(11):3555-64. PMID:11888271


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