298-46-4FFGPTBGBLSHEPO-UHFFFAOYSA-NFFGPTBGBLSHEPO-UHFFFAOYSA-N
CarbamazepineCarbazepine
5H-Dibenz[b,f]azepine-5-carboxamide
5-Carbamoyl-5H-dibenz[b,f]azepine
5H-Dibenzo [b,f] azepine-5-carboxamide
Amizepin
Calepsin
Carbamazepen
Carbamazepin
carbamazepina
Carbatrol
Carbelan
Finlepsin
Geigy 32883
Karbamazepin
Karbelex
Karberol
Neurotol
Neurotop
NSC 169864
Stazepine
Tegretal
Tegretol
Tegretol XR
Telesmin
Timonil
DTXSID402273197240-79-4KJADKKWYZYXHBB-XBWDGYHZSA-NKJADKKWYZYXHBB-XBWDGYHZSA-N
Topiramateβ-D-Fructopyranose, 2,3:4,5-bis-O-(1-methylethylidene)-, sulfamate
2,3:4,5-Bis-O-(1-methylethylidene) β-D-fructopyranose sulfamate
Epitoma
Epitomax
Topamac
Topamax
Topimax
Topomax
β-D-Fructopyranose, 2,3:4,5-bis-O-(1-methylethylidene)-, 1-sulfamate
DTXSID80236881951-25-3IYIKLHRQXLHMJQ-UHFFFAOYSA-NIYIKLHRQXLHMJQ-UHFFFAOYSA-N
AmiodaroneMethanone, (2-butyl-3-benzofuranyl)[4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl]-
2-Butyl-3-[3,5-diiodo-4-(2-diethylaminoethoxy)benzoyl]benzofuran
2-Butyl-3-benzofuranyl p-[(2-diethylamino)ethoxy]-m,m-diiodophenyl ketone
2-n-Butyl-3',5'-diiodo-4'-N-diethylaminoethoxy-3-benzoylbenzofuran
Amidorone
Amiodaron
amiodarona
Ancaron
Ketone, 2-butyl-3-benzofuranyl 4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl
Sedacoron
Sedacorone
DTXSID702259268291-97-4UBQNRHZMVUUOMG-UHFFFAOYSA-NUBQNRHZMVUUOMG-UHFFFAOYSA-N
Zonisamide1,2-Benzisoxazole-3-methanesulfonamide
DTXSID9046023137-58-6NNJVILVZKWQKPM-UHFFFAOYSA-NNNJVILVZKWQKPM-UHFFFAOYSA-N
LidocaineAcetamide, 2-(diethylamino)-N-(2,6-dimethylphenyl)-
2-(Diethylamino)-2',6'-acetoxylidide
2-(Diethylamino)-N-(2,6-dimethylphenyl)acetamide
2',6'-Acetoxylidide, 2-(diethylamino)-
2-Diethylamino-2,6'-acetoxylidide
Anbesol
Anestacon
Aritmal
Cuivasil
Dalcaine
Duncaine
ELA-Max
Esracaine
Isicaina
Isicaine
Jetocaine
Leostesin
Lida-Mantle
Lidocadren
Lidocain
lidocaina
Lidoderm
Lignocaine
Maricaine
NSC 40030
Remicaine
Rucaina
Solarcaine
Solcain
Trachisan
Xycaine
Xylestesin
Xylocain
XYLOCAINE
Xylocitin
α-Diethylamino-2,6-acetoxylidide
DTXSID1045166PR:000002095sodium channel protein type 1 subunit alphaD054537atrioventricular blockD001919decreased heart rateC565682Amputation, CongenitalGO:0019871sodium channel inhibitor activityGO:0023052signalingMP:0001954respiratory distressMP:0005039hypoxiaGO:0001508action potential2decreased1increasedCarbamazepine2016-11-29T18:42:272016-11-29T18:42:27Topiramate2016-11-29T18:42:272016-11-29T18:42:27Tetrodotoxin2016-11-29T18:42:272016-11-29T18:42:27Amiodarone2016-11-29T18:42:272016-11-29T18:42:27Phenytoin2016-11-29T18:42:272016-11-29T18:42:27Valproate2016-11-29T18:42:272016-11-29T18:42:27Zonisamide2016-11-29T18:42:272016-11-29T18:42:27Lidocaine2016-11-29T18:42:272016-11-29T18:42:27WikiUser_4Human, rat, mouseInhibition, sodium channelInhibition, sodium channelMolecular<p>Voltage-gated sodium channels consist of an alpha subunit and auxiliary beta subunits. The alpha subunit is the ion pore-forming component of the channel and is organized into four homologous domains (I- IV), each with six trans-membrane alpha helices (S1-S6). Between the S5 and S6 segments, there is a pore loop which is a primary target for anti-epileptic drugs. The segments between S5 and S6 in each of the four domains create extracellular pore loops. Amino acid changes in the poor loops within domains II and IV determine if the ion channel is sensitive to sodium or calcium ions. Anti-epileptic, anti-arrhythmic and anesthetics all may bind this same site, but their action may be voltage-specific. For example, phenytoin is an ineffective block of hyperpolarized (e.g., -100mV) sodium channels, but is more effective at blocking progressively depolarized potentials (e.g., -80 to -30 mV).
</p><p><em>
Voltage-clamp recordings of sodium currents is a general means of detection. ToxCast assay NVS_IC_rNaCh_site 2 also measures binding to the sodium channel receptor.
</em>
</p>CL:0000255eukaryotic cell<p>Ragsdale, D.S. and Avoli, M. 1998. Sodium channels as molecular targets for antiepileptic drugs. Brain Research Reviews 26:16-28.
</p><p>Pless, S.A., Galpin, J.D., Frankel, A., and Ahern, C.A. 2011. Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels. Nat Commun 2:351.
</p>2016-11-29T18:41:252017-09-16T10:15:48Increased, Atrioventricular block and bradycardiaIncreased, Atrioventricular block and bradycardiaOrgan<p>The rhythm of conduction between the atria and ventricles of the heart regulate heart rate. Disruption of heart rhythm can lead to reduced heart rate.
</p><p>Atrioventricular block and heart rate can be measured with an electrocardiogram (ECG).
</p><p>This key event is only relevant to organisms with a heart.
</p>UBERON:0000948heart2016-11-29T18:41:242017-09-16T10:14:30Respiratory distress/arrestRespiratory distress/arrestOrgan<ul>
<li dir="ltr">
<p dir="ltr">Acute respiratory failure describes the inability of the lungs to exchange gas effectively and to maintain a normal acid-base balance as a result of failure of the respiratory system anywhere from the medullary respiratory controllers to the chest bellows and the lungs, including the upper airways (Chokroverty 2011 in Carey 2013). Respiratory failure is a multi-factorial process; including a direct depressant effect on the respiratory center in the brainstem, constriction of and increased airway secretions, and paralysis of respiratory muscles ((Bartholomew et al., 1985; Rickett et al., 1986) in Carey 2013). </p>
</li>
<li dir="ltr">
<p dir="ltr">Respiratory failure can occur from local muscarinic effects (bronchoconstriction, bronchorrhea, pulmonary edema), central depression of the respiratory center, or flaccid paralysis through depolarization of respiratory muscles (Hulse 2014).</p>
</li>
<li dir="ltr">
<p dir="ltr">Other pulmonary complications commonly seen during acute cholinergic syndrome include local airway effects, alveolar fluid and bronchorrhea, acute respiratory distress syndrome (ARDS), central nervous system effects, and neuromuscular junction effects (Hulse 2014).</p>
</li>
<li dir="ltr">
<p dir="ltr">Respiratory distress is characterized symptomatically through gasping and difficulty breathing.</p>
</li>
</ul>
<ul>
<li dir="ltr">
<p dir="ltr">In humans, spirometry is used to measure lung function. The ratio of volume of air expired in one second (FEV1) to forced vital capacity (FVC) should be close to 80%. A decreased FEV 1/FVC is indicative of impaired ventilation. Other common pulmonary function tests include airway resistance and measurements of maximal flow rate, diffusion capacity, and oxygen and carbon dioxide content of arterial and venous blood. Blood gas analysis measures the arterial partial pressure of oxygen and carbon dioxide to determine gas exchange (Leikauf). </p>
</li>
<li dir="ltr">
<p dir="ltr">In animals, common pulmonary function measurements include tests of lung compliance and airway resistance. The lung is deflated and then inflated with incremental volumes and pressure is recorded; the lung is then deflated with incremental volumes and again recorded. Compliance is calculated as the slope of the volume-pressure curve, and indicates the properties of the lung parenchyma. Airway resistance, a measure of bronchoconstriction, can be measured by plethysmography (Leikauf).</p>
</li>
<li dir="ltr">
<p dir="ltr">Measurements of cardio-respiratory function in fish exposed to aqueous solutions of toxic chemicals may be conducted in respirometer metabolism chambers. Anesthetized fish are immobilized by spinal transection, and inserted with a urine catheter, dorsal aortic cannula, electrodes, and attachment of an oral membrane. Predose measurements are taken before chemical exposure. Fish are monitored for 24 to 48 hours, and measurements taken every 2 hours. Ventilation rate (VR) and cough response (CR) are determined using freestanding stainless steel electrodes. Ventilation volume (V), oxygen consumption (VO), and oxygen utilization (U) may be obtained using dissolved oxygen (DO) concentrations in inspired and expired water from the chambers (McKim 1987).</p>
</li>
<li dir="ltr">
<p dir="ltr">In humans, bronchoconstriction is characterized by coughing, wheezing, rapid shallow breathing, a sensation of chest tightness, substernal pain, and dyspnea. Airway hyperreactivity, a lowered threshold dose of a toxicant needed to induce bronchoconstriction, is tested by measuring airway resistance following inhalation of increasing doses of a metacholine aerosol (Leikauf).</p>
</li>
<li dir="ltr">
<p dir="ltr">In animals, pulmonary edema is measured by lung wet weight: dry weight ratio. Lung water content, expressed as the wet (undessicated) weight of the whole lung or that of a single lobe, is normalized to the weight of the lung or the animal after dessication. Pulmonary edema can also be detected by pulmonary lavage, in which the fluid lining the pulmonary epithelium is recovered and analyzed for signs of inflammation or damage (Leikauf).</p>
</li>
<li dir="ltr">
<p dir="ltr">In animals, inhalation studies are used to expose an organism within a chamber to a toxicant at a concentration for a period of time (Leikauf).</p>
</li>
<li dir="ltr">
<p dir="ltr">Morphological techniques include gross and histological examination of the nasal passages, larynx, bronchi, and parenchyma for inflammation or structural damage (Leikauf).</p>
</li>
<li>In vitro tests such as isolated perfused lung, airway microdissection, and lung tissue culture (Leikauf).</li>
</ul>
<ul>
<li dir="ltr">
<p dir="ltr">This key event is thought to be applicable to terrestrial, air-breathing organisms. The relevance of this event to fish or other animals without lungs is questionable.</p>
</li>
<li dir="ltr">
<p dir="ltr">Central respiratory depression is the predominant mechanism causing death in humans; in other animals, the predominant mechanism varies by species. Nonhuman primates dosed with lethal sarin and soman vapor experienced apnea, hypoxia, and phrenic nerve signal failure within 5 minutes. Diaphragmatic NMJ function was 70 to 80% of normal, indicating the predominance of central effects at the time of arrest (Hulse 2014).</p>
</li>
</ul>
<ul>
<li dir="ltr">
<p dir="ltr">Monkeys have a respiratory system that most closely resembles that of humans. Rats and mice are commonly used, but display differences in respiratory anatomy and function that may complicate extrapolation to humans (Leikauf).</p>
</li>
<li dir="ltr">
<p dir="ltr">A study of respiratory failure in multiple species - mouse, rat, guinea-pig, rabbit, cat, dog, monkey, sheep, and goat - exposed to anticholinergic drugs, found that impaired respiration in animals treated with AChE inhibiting drugs with specific effects dependent on species, drug used, and administered dose (De Candole, 1953).</p>
</li>
</ul>
UBERON:0000171respiration organ<ul>
<li dir="ltr">
<p dir="ltr">Carey, J.L., Dunn, C., Gaspari, R.J. 2013. Central respiratory failure during acute organophosphate poisoning. Respiratory Physiology & Neurobiology. 189(2), 403-410.</p>
</li>
<li dir="ltr">
<p dir="ltr">Chokrovetry, S. 2011. Chapter 64- Sleep and breathing in neuromuscular disorders. Handbook of Clinical Neurology. 99, 1087-1108.</p>
</li>
<li dir="ltr">
<p dir="ltr">De Candole, C.A., Douglas, W.W., Evans, C.L., Holmes, R., Spencer, K.E., Torrance, R.W., Wilson, K.M. 1953. The failure of respiration in death by anticholinesterase poisoning. Br J Pharmacol Chemother. 8(4):466-75.</p>
</li>
<li dir="ltr">
<p dir="ltr">Leikauf, G.D. Toxic responses of the Respiratory System. In Casarett and Doull's Toxicology: The Basic Science of Poisons. 9th ed. pp 793-837.</p>
</li>
<li dir="ltr">
<p dir="ltr">Hulse, E.J., Davies, J.O., John Simpson, A., Sciuto, A.M., Eddleston, M. 2013. Respiratory Complications of Organophosphorus Nerve Agent and Insecticide Poisoning. Implications for Respiratory and Critical Care. American Journal of Respiratory and Critical Care Medicine. 190(12).</p>
</li>
<li dir="ltr">
<p dir="ltr">McKim, J.M., Schmieder, P.K., Carlson, R.W., Hunt, E.P. (1987). Use of respiratory-cardiovascular responses of rainbow trout (Salmo gairdneri) in identifying acute toxicity syndromes in fish: Part 1. Pentachlorophenol, 2,4-dinitrophenol, tricaine methanesulfonate and 1-octanol. Environmental Toxicology and Chemistry, Vol. 6, 295-312.</p>
</li>
</ul>
2016-11-29T18:41:242019-12-20T15:42:48N/A, hypoxiaN/A, hypoxiaTissue2016-11-29T18:41:252016-12-03T16:37:50Increased, amputationsIncreased, amputationsIndividualNot Specified2016-11-29T18:41:252016-12-03T16:37:50Decreased, Sodium conductance 1Decreased, Sodium conductance 1Cellular<p>The quick rise and fall of an electrical membrane potential of a cell, known as an action potential, is either diminished or eliminated.
</p><p>Action potentials are found throughout multicellular organisms (plants, invertebrates, and vertebrates). Sponges are multicellular eukaryotes that do not transmit action potentials.
</p>CL:0000255eukaryotic cell2016-11-29T18:41:252017-09-16T10:15:4970dd8e9a-472f-4254-93d6-096f3aa03e21ec800aa1-aa47-494a-8950-0a31d032f8b12016-11-29T18:41:342016-12-03T16:37:58ec800aa1-aa47-494a-8950-0a31d032f8b1ab9b1a54-1520-4f93-878a-b36247d1bbfb2016-11-29T18:41:342016-12-03T16:37:58ab9b1a54-1520-4f93-878a-b36247d1bbfb51af363a-4644-487e-9a5b-d19f5d44df042016-11-29T18:41:342016-12-03T16:37:58574831d0-45be-4f55-9a9e-6c22728690ff615c47f9-b343-4d7b-892c-129df7aed6f42016-11-29T18:41:342016-12-03T16:37:58615c47f9-b343-4d7b-892c-129df7aed6f470dd8e9a-472f-4254-93d6-096f3aa03e212016-11-29T18:41:342016-12-03T16:37:58Sodium channel inhibition leading to congenital malformationssodium channel inhibition 3<p>Kellie Fay</p>
Under Development: Contributions and Comments WelcomeUnder Development1.29<p>Anti-epileptic and anti-arrhythmic drugs which block voltage-gated ion channels (e.g., voltage-gated sodium channels) are associated with major congenital malformations including amputations.</p>
<p> </p>
adjacentNot SpecifiedModerateadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedHighadjacentNot SpecifiedModeratenon-adjacentNot SpecifiedModerate<p><a href="#Molecular_Initiating_Event">Molecular Initiating Event Summary</a>, <a href="#Key_Events"> Key Event Summary</a><br />
<em>Rat whole embryo cultures exposed to sodium channel blockers (experimental drugs AZA and AZB)for 1 hr had severly reduced heart rates (bradycardia) but returned to normal within 1 hr of drug washout (Nilsson et al., 2013). </em></p>
<p> </p>
HighFoetalNot Specified<p><a href="#Life_Stage_Applicability">Life Stage Applicability</a>, <a href="#Taxonomic_Applicability"> Taxonomic Applicability</a>, <a href="#Sex_Applicability"> Sex Applicability</a><br />
<em>Mammals exposed in utero to sodium channel blockers (or similar) have significantly higher rates of cardiovascular anomalies and amputations (shortened limbs, missing digits, etc). Hypoxic conditions generated from poor heart function during development result in hemorrhages in distal parts of the embryo/fetus (Danielsson et al., 2003; Webster et al., 1996; Webster 2007). Similar amputations may not be relevant for species which develop in an egg and receive their oxygen supply via diffusion from the surrounding environment (air or water). </em></p>
<p><a href="#Molecular_Initiating_Event">Molecular Initiating Event Summary</a>, <a href="#Key_Events"> Key Event Summary</a><br />
<em>Rat whole embryo cultures exposed to sodium channel blockers (experimental drugs AZA and AZB)for 1 hr had severly reduced heart rates (bradycardia) but returned to normal within 1 hr of drug washout (Nilsson et al., 2013). </em></p>
<p> </p>
<p>Danielsson, B.R., Skold, A., and Azarbayjani, F. 2001. Class III Antiarrhythmics and Phenytoin: Teratogenicity due to embryonic cardiac dysrhythmia and reoxygenation damage. Current Pharmaceutical Design 7:787-802.</p>
<p>Webster, W., Brown-Woodman, P., Snow, M., and Danielsson, B. 1996. Teratogenic potential of almokalant, dofetilide, and d-sotalol: drugs with potassium channel blocking activity. Teratology 53:168-175.</p>
<p>Webster, W.S. and Abela, D. 2007. The effect of hypoxia in development. Birth Defects Research Part C: Embryo Today: Reviews 81:215-228.</p>
2016-11-29T18:41:162023-04-29T16:02:57