Tedisamil

Tedisamil

File:Tedisamil.svg
Clinical data
ATC code	C01BD06 (WHO)
Identifiers
IUPAC name 3,7-bis(cyclopropylmethyl)-3,7-diazaspiro[bicyclo[3.3.1]nonane-9,1'-cyclopentane]
CAS Number	90961-53-8 Y
PubChem CID	65825
IUPHAR/BPS	2567
UNII	A5VAY2U3R8
KEGG	D06652 Y
ChEMBL	ChEMBL113461 N
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C19H32N2
Molar mass	288.470 g/mol
3D model (JSmol)	Interactive image
SMILES C1CCC2(C1)C3CN(CC2CN(C3)CC4CC4)CC5CC5
NY (what is this?)  (verify)

WikiDoc Resources for Tedisamil
Articles
Most recent articles on Tedisamil Most cited articles on Tedisamil Review articles on Tedisamil Articles on Tedisamil in N Eng J Med, Lancet, BMJ
Media
Powerpoint slides on Tedisamil Images of Tedisamil Photos of Tedisamil Podcasts & MP3s on Tedisamil Videos on Tedisamil
Evidence Based Medicine
Cochrane Collaboration on Tedisamil Bandolier on Tedisamil TRIP on Tedisamil
Clinical Trials
Ongoing Trials on Tedisamil at Clinical Trials.gov Trial results on Tedisamil Clinical Trials on Tedisamil at Google
Guidelines / Policies / Govt
US National Guidelines Clearinghouse on Tedisamil NICE Guidance on Tedisamil NHS PRODIGY Guidance FDA on Tedisamil CDC on Tedisamil
Books
Books on Tedisamil
News
Tedisamil in the news Be alerted to news on Tedisamil News trends on Tedisamil
Commentary
Blogs on Tedisamil
Definitions
Definitions of Tedisamil
Patient Resources / Community
Patient resources on Tedisamil Discussion groups on Tedisamil Patient Handouts on Tedisamil Directions to Hospitals Treating Tedisamil Risk calculators and risk factors for Tedisamil
Healthcare Provider Resources
Symptoms of Tedisamil Causes & Risk Factors for Tedisamil Diagnostic studies for Tedisamil Treatment of Tedisamil
Continuing Medical Education (CME)
CME Programs on Tedisamil
International
Tedisamil en Espanol Tedisamil en Francais
Business
Tedisamil in the Marketplace Patents on Tedisamil
Experimental / Informatics
List of terms related to Tedisamil

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Tedisamil (3,7-dicyclopropylmethyl-9,9-tetramethylene-3,7-diazabicyclo-3,3,1-nonane) is an experimental class III antiarrhythmic agent currently being investigated for the treatment of atrial fibrillation. Tedisamil blocks multiple types of potassium channels in the heart resulting in slowed heart rate. While the effects of tedisamil have been demonstrated in both atrial and ventricular muscle, repolarization is prolonged more efficiently in the atria. Tedisamil is administered intravenously and has a half-life of approximately 8 –13 hours in circulation. Tedisamil is being developed as an alternative to other antiarrhythmics as incidence of additional arrhythmic events is lower compared to other class III agents. Tedisamil also has significant anti-ischemic properties and was initially investigated as a potential treatment for angina until its antiarrhythmic effects were discovered. Tedisamil is manufactured by Solvay Pharmaceuticals Inc. under the proposed trade name Pulzium and is currently in phase III of clinical testing for atrial fibrillation.

Molecular Problem

Arrhythmias are broadly defined as abnormal electrical activity in the heart and can affect both the atria and ventricles. Atrial arrhythmias are the most common type of arrhythmia with several subtypes currently described, including atrial fibrillation. In atrial fibrillation, there is continual quivering of the atria as contraction of the muscle is uncoordinated. Under normal conditions, an electrical impulse from the sinoatrial (SA) node is distributed rapidly throughout the atria causing coordinated excitement and inactivation of atrial muscle cell ion channels resulting in uniform contraction and relaxation of the muscle fibres. During fibrillation, other electrical signals overwhelm the SA node and ion channel excitement is no longer uniform throughout the atria. This results in inappropriate activation properties, further preventing uniform contraction and relaxation of the muscle. Subsequent action potentials from the SA node will not be able to uniformly excite the muscle as not all of the channels will be available to open as some will still be held in the inactivation phase. This results in disjointed contraction, or quivering, seen in the atrial muscle during fibrillation.

Mechanism of Action

Tedisamil acts to restore normal electrical rhythm in the heart by prolonging the inactivation phase of the muscle. Both atrial and ventricular repolarization is lengthened by tedisamil by blocking multiple potassium channels including the transient outward (Ito), the adenosine triphosphate-dependent (IK-ATP), and the delayed rectifier potassium currents (IKr and IKs). Tedisamil action is dose dependent as currents are blocked longer and more effectively at higher concentrations. Tedisamil activity is greatest on Ito and acts by binding to the channel in its open configuration. This produces a blocked state and delays its inactivation. To restore normal function, tedisamil must unbind from the channel so that it can inactivate and eventually reopen. Similar mechanisms have been observed on the IKr and IKs currents. In both Ito and delayed rectifier channels, the tedisamil binding site appears to be internal as both binding and unbinding occur more effectively when tedisamil is applied inside the cell. Tedisamil also appears to provide specific, single channel blocking of IK-ATP at high concentrations. As the potassium channels are responsible for restoring the resting membrane potential during an action potential, lengthening their inactivation will stop the cycle of fibrillation by preventing muscle contraction until all ion channels are available to open. Regular use of tedisamil will prevent further fibrillation and restore normal electrical rhythm. Tedisamil’s antiarrythmic activity also appears to be supported by inhibiting sodium currents in cardiac muscle. However this is only observed at concentrations above 20μM, concentrations 20-fold higher than required for potassium channel blocks.