Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Ajmaline: Difference between pages

{{short description|Chemical compound}}

| verifiedrevid =

| IUPAC_name = (17''R'',)-ajmalan-17,21-diol<br />OR<br />(1''R'',9''R'',10''S'',13''R'',14''R'',16''S'',18''S'')- 13-ethyl- 8-methyl- 8,15-diazahexacyclo [14.2.1.0^1,9.0^2,7.0^10,15.0^12,17] nonadeca- 2(7),3,5-triene- 14,18-diol

| image2 = Ajmaline-from-xtal-3D-bs-17.png

| tradename =

| routes_of_administration =

| excretion =

| KEGG = D00199

| ChEMBL = 1230919

<!--Chemical data-->

| C=20 | H=26

| N=2 | O=2

'''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 elevations|ST elevation]].

The compound was first isolated by [[Salimuzzaman Siddiqui]] in 1931 <ref>{{cite journal | author-link1 = Salimuzzaman Siddiqui | vauthors = Siddiqui S, Siddiqui RH | title = Chemical examination of the roots of Rauwolfia serpentina Benth | date = 1931 | journal = J. Indian Chem. Soc. | volume = 8 | pages = 667–80 }}</ref> from the roots of ''[[Rauvolfia serpentina]]''. He named it ''ajmaline'', after [[Hakim Ajmal Khan]], one of the most illustrious practitioners of [[Unani|Unani medicine]] in [[South Asia]].<ref name="sandilvi">{{cite web | vauthors = Sandilvi AN | name-list-style = vanc | url = http://www.dawn.com/weekly/science/archive/030412/science5.htm | title = Salimuzzaman Siddiqui: pioneer of scientific research in Pakistan | archive-url = https://web.archive.org/web/20070927220628/http://www.dawn.com/weekly/science/archive/030412/science5.htm | archive-date = 2007-09-27 | work = [[Dawn (newspaper)|Daily Dawn]] | date = 12 April 2003 }}</ref> Ajmaline can be found in most species of the genus ''[[Rauvolfia]]'' as well as ''[[Catharanthus roseus]]''.<ref name="Alkaloids">{{cite book | vauthors = Roberts MF, Wink M | date = 1998 | title = Alkaloids: Biochemistry, Ecology, and Medical applications | publisher = [[Springer Science+Business Media|Plenum Press]] }}</ref> 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 (alkaloid)|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.<ref name="Alkaloids"/>

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.<ref name="Neo-gilurythman">{{cite journal | vauthors = Hinse C, Stöckigt J | title = The structure of the ring-opened N beta-propyl-ajmaline (Neo-Gilurytmal) at physiological pH is obviously responsible for its better absorption and bioavailability when compared with ajmaline (Gilurytmal) | journal = Die Pharmazie | volume = 55 | issue = 7 | pages = 531–532 | date = July 2000 | pmid = 10944783 }}</ref>

==Biosynthesis==

Ajmaline is widely dispersed among 25 plant genera, but is of significant concentration in the [[Apocynaceae]] family.<ref name>{{cite book | vauthors = Namjoshi OA, Cook JM | chapter = Sarpagine and Related Alkaloids | volume = 76 | pages = 63–169 | date = 2016 | pmid = 26827883 | pmc = 4864735 | doi = 10.1016/bs.alkal.2015.08.002 | isbn = 9780128046821 | title = The Alkaloids: Chemistry and Biology }}</ref>

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.<ref name>{{cite journal | vauthors = Wu F, Kerčmar P, Zhang C, Stöckigt J | title = Sarpagan-Ajmalan-Type Indoles: Biosynthesis, Structural Biology, and Chemo-Enzymatic Significance | journal = The Alkaloids. Chemistry and Biology | volume = 76 | pages = 1–61 | date = 2015 | pmid = 26827882 | doi = 10.1016/bs.alkal.2015.10.001 }}</ref>

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 [[Cytochrome P450|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.<ref name>{{Cite journal|display-authors=etal|vauthors= Turpin V|date=2020|title= Biosynthetically Relevant Reactivity of Polyneuridine Aldehyde |journal= European Journal of Organic Chemistry |volume=2020 |issue= 45|pages= 6989–6991|doi= 10.1002/ejoc.202000963|s2cid= 225501365}}</ref><ref name>{{cite journal | vauthors = Wu F, Kerčmar P, Zhang C, Stöckigt J | title = Sarpagan-Ajmalan-Type Indoles: Biosynthesis, Structural Biology, and Chemo-Enzymatic Significance | journal = The Alkaloids. Chemistry and Biology | volume = 76 | pages = 1–61 | date = 2015 | pmid = 26827882 | doi = 10.1016/bs.alkal.2015.10.001 }}</ref>

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 [[Nicotinamide adenine dinucleotide phosphate|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.<ref name>{{cite journal | vauthors = Wu F, Kerčmar P, Zhang C, Stöckigt J | title = Sarpagan-Ajmalan-Type Indoles: Biosynthesis, Structural Biology, and Chemo-Enzymatic Significance | journal = The Alkaloids. Chemistry and Biology | volume = 76 | pages = 1–61 | date = 2015 | pmid = 26827882 | doi = 10.1016/bs.alkal.2015.10.001 }}</ref>

[[File:Ajaline1.jpg| thumb|392 px|center| Ajmaline Biosynthesis]]

==Mechanism of action==

[[File:SinusRhythmLabels.png|thumb|left|alt=Schematic diagram of normal sinus rhythm for a human heart as seen on ECG (with English labels)|Schematic diagram of normal sinus rhythm for a human heart as seen on an electrocardiogram''.]]

Ajmaline <ref>{{Cite web|url=https://www.ajmal.pk/shop/heart-diseases-medicine/high-blood-pressure/ajmaleen-54/|title=Ajmaleen 54 {{!}} Unani Medicine for High blood Pressure {{!}} Ajmal.pk|website=Dawakhana Hakim Ajmal Khan|date=14 June 2019 |language=en-US|access-date=2019-08-09}}</ref> was first discovered to lengthen the [[Refractory period (physiology)|refractory period]] of the heart by blocking sodium ion channels,<ref name="Alkaloids"/> 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.<ref name="hERG">{{cite journal | vauthors = Kiesecker C, Zitron E, Lück S, Bloehs R, Scholz EP, Kathöfer S, Thomas D, Kreye VA, Katus HA, Schoels W, Karle CA, Kiehn J | display-authors = 6 | title = Class Ia anti-arrhythmic drug ajmaline blocks HERG potassium channels: mode of action | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 370 | issue = 6 | pages = 423–435 | date = December 2004 | pmid = 15599706 | doi = 10.1007/s00210-004-0976-8 | s2cid = 22310415 }}</ref> 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 [[depolarization|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.

==Diagnosis of Brugada syndrome==

[[File:Brugada EKG Schema.jpg|thumb|alt=Normal electrocardiograms compared to electrocardiograms of people with Brugada Syndrome|(A) Normal electrocardiogram pattern in the precordial leads, (B) changes in Brugada syndrome. The arrow indicates the characteristic elevated ST segment.]][[Brugada syndrome]] is a genetic disease that can result in mutations in the sodium ion channel (gene [[SCN5A]]) of the [[myocytes]] in the heart.<ref name="Genetics Brugada">{{cite journal | vauthors = Hedley PL, Jørgensen P, Schlamowitz S, Moolman-Smook J, Kanters JK, Corfield VA, Christiansen M | title = The genetic basis of Brugada syndrome: a mutation update | journal = Human Mutation | volume = 30 | issue = 9 | pages = 1256–1266 | date = September 2009 | pmid = 19606473 | doi = 10.1002/humu.21066 | doi-access = free }}</ref> Brugada syndrome can result in [[ventricular fibrillation]] and potentially death. It is a major cause of [[Sudden unexpected death syndrome|sudden unexpected cardiac death]] in young, otherwise healthy people.<ref>{{cite journal | vauthors = Kusumoto FM, Bailey KR, Chaouki AS, Deshmukh AJ, Gautam S, Kim RJ, Kramer DB, Lambrakos LK, Nasser NH, Sorajja D | display-authors = 6 | title = Systematic Review for the 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society | journal = Circulation | volume = 138 | issue = 13 | pages = e392–e414 | date = September 2018 | pmid = 29084732 | doi = 10.1161/CIR.0000000000000550 | doi-access = free }}</ref> 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.<ref name="Challenge">{{cite journal | vauthors = Rolf S, Bruns HJ, Wichter T, Kirchhof P, Ribbing M, Wasmer K, Paul M, Breithardt G, Haverkamp W, Eckardt L | display-authors = 6 | title = The ajmaline challenge in Brugada syndrome: diagnostic impact, safety, and recommended protocol | journal = European Heart Journal | volume = 24 | issue = 12 | pages = 1104–1112 | date = June 2003 | pmid = 12804924 | doi = 10.1016/s0195-668x(03)00195-7 | doi-access = free }}</ref> 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 [[ST elevation|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.<ref>{{cite journal | vauthors = Ciconte G, Monasky MM, Vicedomini G, Borrelli V, Giannelli L, Pappone C | title = Unusual response to ajmaline test in Brugada syndrome patient leads to extracorporeal membrane oxygenator support | journal = Europace | volume = 21 | issue = 10 | pages = 1574 | date = October 2019 | pmid = 31157372 | doi = 10.1093/europace/euz139 }}</ref>

== See also ==

* [[Hellmuth Kleinsorge]] (1920–2001) German medical doctor

== References ==

{{Reflist}}

{{Antiarrhythmic agents}}

[[Category:Alkaloids found in Rauvolfia]]

[[Category:Antiarrhythmic agents]]

[[Category:Diagnostic cardiology]]

[[Category:Quinolizidine alkaloids]]

[[Category:Secondary alcohols]]

[[Category:Sodium channel blockers]]

[[Category:Tryptamine alkaloids]]

[[Category:Unani medicine]]