![]() | |
![]() | |
Clinical data | |
---|---|
Trade names | Gilurytmal, Ritmos, Aritmina |
AHFS/Drugs.com | International Drug Names |
ATC code | |
Identifiers | |
| |
CAS Number | |
PubChem CID | |
DrugBank | |
ChemSpider | |
UNII | |
KEGG | |
ChEMBL | |
CompTox Dashboard (EPA) | |
ECHA InfoCard | 100.022.219 |
Chemical and physical data | |
Formula | C20H26N2O2 |
Molar mass | 326.440 g·mol−1 |
3D model (JSmol) | |
| |
| |
![]() ![]() |
Ajmaline (also known by trade names Gilurytmal, Ritmos, and Aritmina) is an alkaloid that is classified as a 1-A antiarrhythmic agent. It is often used to induce arrhythmic contraction in patients suspected of having Brugada syndrome. Individuals suffering from Brugada syndrome will be more susceptible to the arrhythmogenic effects of the drug, and this can be observed on an electrocardiogram as an ST elevation.
The compound was first isolated by Salimuzzaman Siddiqui in 1931 [1] from the roots of Rauvolfia serpentina . He named it ajmaline, after Hakim Ajmal Khan, one of the most illustrious practitioners of Unani medicine in South Asia. [2] Ajmaline can be found in most species of the genus Rauvolfia as well as Catharanthus roseus . [3] In addition to Southeast Asia, Rauvolfia species have also been found in tropical regions of India, Africa, South America, and some oceanic islands. Other indole alkaloids found in Rauvolfia include reserpine, ajmalicine, serpentine, corynanthine, and yohimbine. While 86 alkaloids have been discovered throughout Rauvolfia vomitoria , ajmaline is mainly isolated from the stem bark and roots of the plant. [3]
Due to the low bioavailability of ajmaline, a semisynthetic propyl derivative called prajmaline (trade name Neo-gilurythmal) was developed that induces similar effects to its predecessor but has better bioavailability and absorption. [4]
Ajmaline is widely dispersed among 25 plant genera, but is of significant concentration in the Apocynaceae family. [5] Ajmaline is a monoterpenoid indole alkaloid, composed of an indole from tryptophan and a terpenoid from iridoid glucoside secologanin. Secologanin is introduced from the triose phosphate/pyruvate pathway. [6] Tryptophan decarboxylase (TDC) remodels tryptophan into tryptamine. Strictosidine synthase (STR), uses a Pictet–Spengler reaction to form strictosidine from tryptamine and secologanin. Strictosidine is oxidized by P450-dependent sarpagan bridge enzymes (SBE); to make polyneuridine aldehyde. Of the sarpagan-type alkaloids, polyneuridine is a key entry into the ajmalan-type alkaloids. [7] [6] Polyneuridine Aldehyde is methylated by polyneuridine aldehydeesterase (PNAE), to synthesize 16-epi-vellosimine, which is acetylated to vinorine by vinorine synthase (VS). Vinorine is oxidized by vinorine hydroxylase (VH) to make vomilenine. Vomilenine reductase (VR) conducts a reduction of vomilenine to 1,2-dihydrovomilenine, using the cofactor NADPH. 1,2-dihydrovomilenine, is reduced by 1,2-dihydrovomilenine reductase (DHVR) to 17-O-acetylnorajmaline, with the same cofactor as VR: NADPH. 17-O-acetylnorajmaline is deacetylated by acetylajmalan esterase (AAE), to form norajmaline. Finally, norajmaline methyl transferase (NAMT) methylates norajmaline resulting in our desired compound: ajmaline. [6]
Ajmaline [8] was first discovered to lengthen the refractory period of the heart by blocking sodium ion channels, [3] but it has also been noted that it is also able to interfere with the hERG (human Ether-a-go-go-Related Gene) potassium ion channel. [9] In both cases, Ajmaline causes the action potential to become longer and ultimately leads to bradycardia. When ajmaline reversibly blocks hERG, repolarization occurs more slowly because it is harder for potassium to get out due to less unblocked channels, therefore making the RS interval longer. Ajmaline also prolongs the QR interval since it can also act as sodium channel blocker, therefore making it take longer for the membrane to depolarize in the first case. In both cases, ajmaline causes the action potential to become longer. Slower depolarization or repolarization results in a lengthened QT interval (the refractory period), and therefore makes it take more time for the membrane potential to get below the threshold level so the action potential can be re-fired. Even if another stimulus is present, action potential cannot occur again until after complete repolarization. Ajmaline causes action potentials to be prolonged, therefore slowing down firing of the conducting myocytes which ultimately slows the beating of the heart.
Brugada syndrome is a genetic disease that can result in mutations in the sodium ion channel (gene SCN5A) of the myocytes in the heart. [10] Brugada syndrome can result in ventricular fibrillation and potentially death. It is a major cause of sudden unexpected cardiac death in young, otherwise healthy people. [11] While the characteristic patterns of Brugada syndrome on an electrocardiogram may be seen regularly, often the abnormal pattern is only seen spontaneously due to unknown triggers or after challenged by particular drugs. Ajmaline is used intravenously to test for Brugada syndrome since they both affect the sodium ion channel. [12] In an afflicted person who was induced with ajmaline, the electrocardiogram would show the characteristic pattern of the syndrome where the ST segment is abnormally elevated above the baseline. Due to complications that could arise with the ajmaline challenge, a specialized doctor should perform the administration in a specialized center capable of extracorporeal membrane oxygenator support. [13]
Aconitine is an alkaloid toxin produced by various plant species belonging to the genus Aconitum, commonly known by the names wolfsbane and monkshood. Aconitine is notorious for its toxic properties.
Brugada syndrome (BrS) is a genetic disorder in which the electrical activity of the heart is abnormal due to channelopathy. It increases the risk of abnormal heart rhythms and sudden cardiac death. Those affected may have episodes of syncope. The abnormal heart rhythms seen in those with Brugada syndrome often occur at rest. They may be triggered by a fever.
Antiarrhythmic agents, also known as cardiac dysrhythmia medications, are a class of drugs that are used to suppress abnormally fast rhythms (tachycardias), such as atrial fibrillation, supraventricular tachycardia and ventricular tachycardia.
Unlike the action potential in skeletal muscle cells, the cardiac action potential is not initiated by nervous activity. Instead, it arises from a group of specialized cells known as pacemaker cells, that have automatic action potential generation capability. In healthy hearts, these cells form the cardiac pacemaker and are found in the sinoatrial node in the right atrium. They produce roughly 60–100 action potentials every minute. The action potential passes along the cell membrane causing the cell to contract, therefore the activity of the sinoatrial node results in a resting heart rate of roughly 60–100 beats per minute. All cardiac muscle cells are electrically linked to one another, by intercalated discs which allow the action potential to pass from one cell to the next. This means that all atrial cells can contract together, and then all ventricular cells.
In neuroscience, repolarization refers to the change in membrane potential that returns it to a negative value just after the depolarization phase of an action potential which has changed the membrane potential to a positive value. The repolarization phase usually returns the membrane potential back to the resting membrane potential. The efflux of potassium (K+) ions results in the falling phase of an action potential. The ions pass through the selectivity filter of the K+ channel pore.
Andersen–Tawil syndrome, also called Andersen syndrome and long QT syndrome 7, is a rare genetic disorder affecting several parts of the body. The three predominant features of Andersen–Tawil syndrome include disturbances of the electrical function of the heart characterised by an abnormality seen on an electrocardiogram and a tendency to abnormal heart rhythms, physical characteristics including low-set ears and a small lower jaw, and intermittent periods of muscle weakness known as hypokalaemic periodic paralysis.
The Pictet–Spengler reaction is a chemical reaction in which a β-arylethylamine undergoes condensation with an aldehyde or ketone followed by ring closure. The reaction was first discovered in 1911 by Amé Pictet and Theodor Spengler. Traditionally, an acidic catalyst in protic solvent was employed with heating; however, the reaction has been shown to work in aprotic media in superior yields and sometimes without acid catalysis. The Pictet–Spengler reaction can be considered a special case of the Mannich reaction, which follows a similar reaction pathway. The driving force for this reaction is the electrophilicity of the iminium ion generated from the condensation of the aldehyde and amine under acid conditions. This explains the need for an acid catalyst in most cases, as the imine is not electrophilic enough for ring closure but the iminium ion is capable of undergoing the reaction.
Indole alkaloids are a class of alkaloids containing a structural moiety of indole; many indole alkaloids also include isoprene groups and are thus called terpene indole or secologanin tryptamine alkaloids. Containing more than 4100 known different compounds, it is one of the largest classes of alkaloids. Many of them possess significant physiological activity and some of them are used in medicine. The amino acid tryptophan is the biochemical precursor of indole alkaloids.
Salimuzzaman Siddiqui, was a Pakistani organic chemist specialising in natural products, and a professor of chemistry at the University of Karachi.
Sodium channel protein type 5 subunit alpha, also known as NaV1.5 is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. NaV1.5 is found primarily in cardiac muscle, where it mediates the fast influx of Na+-ions (INa) across the cell membrane, resulting in the fast depolarization phase of the cardiac action potential. As such, it plays a major role in impulse propagation through the heart. A vast number of cardiac diseases is associated with mutations in NaV1.5 (see paragraph genetics). SCN5A is the gene that encodes the cardiac sodium channel NaV1.5.
In enzymology, a 1,2-dihydrovomilenine reductase (EC 1.3.1.73) is an enzyme that catalyzes the chemical reaction
Strictosidine synthase (EC 4.3.3.2) is an enzyme in alkaloid biosynthesis that catalyses the condensation of tryptamine with secologanin to form strictosidine in a formal Pictet–Spengler reaction:
The enzyme polyneuridine-aldehyde esterase (EC 3.1.1.78) catalyzes the following reaction:
In enzymology, a vinorine synthase is an enzyme that catalyzes the chemical reaction
Ajmalan is a parent hydride used in the IUPAC nomenclature of natural products and also in CAS nomenclature. It is a 20-carbon alkaloid with six rings and seven chiral centres.
Toxiferine, also known as c-toxiferine I, is one of the most toxic plant alkaloids known. It is derived from several plant species, including Strychnos toxifera and Chondrodendron tomentosum. Historically, it has been used as an arrow poison by indigenous peoples in South America for its neuromuscular blocking properties, allowing them to paralyze animals during hunting, but also possibly kill due to paralysis of the respiratory muscles. Toxiferine functions as an acetylcholine receptor (AChR) antagonist. The paralysis caused by toxiferine can in turn be antagonized by neostigmine.
KCNE1-like also known as KCNE1L is a protein that in humans is encoded by the KCNE1L gene.
Ajmalicine, also known as δ-yohimbine or raubasine, is an antihypertensive drug used in the treatment of high blood pressure. It has been marketed under numerous brand names including Card-Lamuran, Circolene, Cristanyl, Duxil, Duxor, Hydroxysarpon, Iskedyl, Isosarpan, Isquebral, Lamuran, Melanex, Raunatin, Saltucin Co, Salvalion, and Sarpan. It is an alkaloid found naturally in various plants such as Rauvolfia spp., Catharanthus roseus, and Mitragyna speciosa.
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.
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).
{{cite book}}
: |journal=
ignored (help)