![]() | |
Clinical data | |
---|---|
ATC code | |
Identifiers | |
| |
CAS Number | |
PubChem CID | |
IUPHAR/BPS | |
ChemSpider | |
UNII | |
KEGG | |
ChEMBL | |
CompTox Dashboard (EPA) | |
Chemical and physical data | |
Formula | C19H32N2 |
Molar mass | 288.479 g·mol−1 |
3D model (JSmol) | |
| |
| |
![]() ![]() |
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. [1] Tedisamil is administered intravenously and has a half-life of approximately 8 –13 hours in circulation. [1] Tedisamil is being developed as an alternative to other antiarrhythmics as incidence of additional arrhythmic events is lower compared to other class III agents. [1] Tedisamil also has significant anti-ischemic properties and was initially investigated as a potential treatment for angina until its antiarrhythmic effects were discovered. [2] Tedisamil is manufactured by Solvay Pharmaceuticals Inc. under the proposed trade name Pulzium. [3]
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. [4] 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. [4] During fibrillation, other electrical signals overwhelm the SA node and ion channel excitement is no longer uniform throughout the atria. [4] This results in inappropriate activation properties, further preventing uniform contraction and relaxation of the muscle. [4] 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. [4] This results in disjointed contraction, or quivering, seen in the atrial muscle during fibrillation.
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). [5] [6] [7] Tedisamil action is dose dependent as currents are blocked longer and more effectively at higher concentrations. [1] Tedisamil activity is greatest on Ito and acts by binding to the channel in its open configuration. [5] This produces a blocked state and delays its inactivation. [5] To restore normal function, tedisamil must unbind from the channel so that it can inactivate and eventually reopen. [5] Similar mechanisms have been observed on the IKr and IKs currents. [6] 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. [6] Tedisamil also appears to provide specific, single channel blocking of IK-ATP at high concentrations. [7] 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. [5] However this is only observed at concentrations above 20μM, concentrations 20-fold higher than required for potassium channel blocks. [5]
Ventricular fibrillation is an abnormal heart rhythm in which the ventricles of the heart quiver. It is due to disorganized electrical activity. Ventricular fibrillation results in cardiac arrest with loss of consciousness and no pulse. This is followed by sudden cardiac death in the absence of treatment. Ventricular fibrillation is initially found in about 10% of people with cardiac arrest.
Quinidine is a class IA antiarrhythmic agent used to treat heart rhythm disturbances. It is a diastereomer of antimalarial agent quinine, originally derived from the bark of the cinchona tree. The drug causes increased action potential duration, as well as a prolonged QT interval. As of 2019, its IV formulation is no longer being manufactured for use in the United States.
The cardiac conduction system transmits the signals generated by the sinoatrial node – the heart's pacemaker, to cause the heart muscle to contract, and pump blood through the body's circulatory system. The pacemaking signal travels through the right atrium to the atrioventricular node, along the bundle of His, and through the bundle branches to Purkinje fibers in the walls of the ventricles. The Purkinje fibers transmit the signals more rapidly to stimulate contraction of the ventricles.
The cardiac action potential is a brief change in voltage across the cell membrane of heart cells. This is caused by the movement of charged atoms between the inside and outside of the cell, through proteins called ion channels. The cardiac action potential differs from action potentials found in other types of electrically excitable cells, such as nerves. Action potentials also vary within the heart; this is due to the presence of different ion channels in different cells.
Sotalol, sold under the brand name Betapace among others, is a medication used to treat and prevent abnormal heart rhythms. Evidence does not support a decreased risk of death with long term use. It is taken by mouth or given by injection into a vein.
Procainamide (PCA) is a medication of the antiarrhythmic class used for the treatment of cardiac arrhythmias. It is a sodium channel blocker of cardiomyocytes; thus it is classified by the Vaughan Williams classification system as class Ia. In addition to blocking the INa current, it inhibits the IKr rectifier K+ current. Procainamide is also known to induce a voltage-dependent open channel block on the batrachotoxin (BTX)-activated sodium channels in cardiomyocytes.
Azimilide is a class ΙΙΙ antiarrhythmic drug. The agents from this heterogeneous group have an effect on the repolarization, they prolong the duration of the action potential and the refractory period. Also they slow down the spontaneous discharge frequency of automatic pacemakers by depressing the slope of diastolic depolarization. They shift the threshold towards zero or hyperpolarize the membrane potential. Although each agent has its own properties and will have thus a different function.
Potassium voltage-gated channel subfamily E member 1 is a protein that in humans is encoded by the KCNE1 gene.
Potassium voltage-gated channel subfamily E member 4, originally named MinK-related peptide 3 or MiRP3 when it was discovered, is a protein that in humans is encoded by the KCNE4 gene.
Pilsicainide (INN) is an antiarrhythmic agent. It is marketed in Japan as サンリズム (Sunrythm). It was developed by Suntory Holdings Limited and first released in 1991. The JAN applies to the hydrochloride salt, pilsicainide hydrochloride.
KCNE1-like also known as KCNE1L is a protein that in humans is encoded by the KCNE1L gene.
Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults – is called tachycardia, and a resting heart rate that is too slow – below 60 beats per minute – is called bradycardia. Some types of arrhythmias have no symptoms. Symptoms, when present, may include palpitations or feeling a pause between heartbeats. In more serious cases, there may be lightheadedness, passing out, shortness of breath, chest pain, or decreased level of consciousness. While most cases of arrhythmia are not serious, some predispose a person to complications such as stroke or heart failure. Others may result in sudden death.
The cardiac transient outward potassium current (referred to as Ito1 or Ito ) is one of the ion currents across the cell membrane of heart muscle cells. It is the main contributing current during the repolarizing phase 1 of the cardiac action potential. It is a result of the movement of positively charged potassium (K+) ions from the intracellular to the extracellular space. Ito1 is complemented with Ito2 resulting from Cl− ions to form the transient outward current Ito.
BRL-32872 is an experimental drug candidate that provides a novel approach to the treatment of cardiac arrhythmia. Being a derivative of verapamil, it possesses the ability to inhibit Ca+2 membrane channels. Specific modifications in hydrogen bonding activity, nitrogen lone pair availability, and molecular flexibility allow BRL-32872 to inhibit K+ channels as well. As such, BRL-32872 is classified as both a class III (K+ blocking) and class IV (Ca+2 blocking) antiarrhythmic agent.
Celivarone is an experimental drug being tested for use in pharmacological antiarrhythmic therapy. Cardiac arrhythmia is any abnormality in the electrical activity of the heart. Arrhythmias range from mild to severe, sometimes causing symptoms like palpitations, dizziness, fainting, and even death. They can manifest as slow (bradycardia) or fast (tachycardia) heart rate, and may have a regular or irregular rhythm.
Budiodarone (ATI-2042) is an antiarrhythmic agent and chemical analog of amiodarone that is currently being studied in clinical trials. Amiodarone is considered the most effective antiarrhythmic drug available, but its adverse side effects, including hepatic, pulmonary and thyroid toxicity as well as multiple drug interactions, are discouraging its use. Budiodarone only differs in structure from amiodarone through the presence of a sec-butyl acetate side chain at position 2 of the benzofuran moiety. This side chain allows for budiodarone to have a shorter half-life in the body than amiodarone which allows it to have a faster onset of action and metabolism while still maintaining similar electrophysiological activity. The faster metabolism of budiodarone allows for fewer adverse side effects than amiodarone principally due to decreased levels of toxicity in the body.
AZD1305 is an experimental drug candidate that is under investigation for the management and reversal of cardiac arrhythmias, specifically atrial fibrillation and flutter. In vitro studies have shown that this combined-ion channel blocker inhibits rapidly the activating delayed-rectifier potassium current (IKr), L-type calcium current, and inward sodium current (INa).
HBI-3000 is an experimental drug candidate that is currently in phase II of human clinical trials as an antiarrhythmic agent. Clinical investigation will test the safety and efficacy of HBI-3000 as a treatment for both atrial and ventricular arrhythmias.
XEN-D0101 is an experimental drug that was developed to treat atrial fibrillation. Xention, a biopharmaceutical company based in Cambridge, England, created XEN-D0101 along with other ion channel-modulating drugs. XEN-D0101 is a selective antagonist of the voltage-gated potassium channel Kv1.5. Atrial fibrillation is the main focus of Xention’s drug development, as it is the most common cardiac arrhythmia seen in patients.
QT prolongation is a measure of delayed ventricular repolarisation, which means the heart muscle takes longer than normal to recharge between beats. It is an electrical disturbance which can be seen on an electrocardiogram (ECG). Excessive QT prolongation can trigger tachycardias such as torsades de pointes (TdP). QT prolongation is an established side effect of antiarrhythmics, but can also be caused by a wide range of non-cardiac medicines, including antibiotics, antidepressants, antihistamines, opioids, and complementary medicines. On an ECG, the QT interval represents the summation of action potentials in cardiac muscle cells, which can be caused by an increase in inward current through sodium or calcium channels, or a decrease in outward current through potassium channels. By binding to and inhibiting the “rapid” delayed rectifier potassium current protein, certain drugs are able to decrease the outward flow of potassium ions and extend the length of phase 3 myocardial repolarization, resulting in QT prolongation.