Talk:Abnormal heartbeat

"sudden cardiac death may be a result of cocaine-induced cardiac arrhythmias, related to direct actions on cardiac myocyte ion channels, associated with myocardial ischemia, or related to increased sympathomimetic tone"^[1]

"There is increasing evidence that cocaine can have serious adverse effects on the heart. Angina, myocardial infarction, coronary artery spasm, arrhythmia, and sudden death have been reported in association with its use."^[2]

"Unlike cocaine, the effects of amphetamines on the cardiovascular system are less well described. The most commonly reported vascular complication of amphetamine abuse is intracerebral hemorrhage.139 However, reports of pulmonary hypertension,144 acute aortic dissection,145 ruptured berry aneurysm,145,146 and sudden death147 have also been described."^[3]

Regular Heartbeat Conditions "Under resting conditions (phase 4 of the action potential), the potential across the membrane is –85 to –95 mV, which is generated by the permeability of the cardiac myocyte membrane to various ions and their relative intracellular and extracellular concentrations. The predominant intracellular cation is potassium, whereas the predominant extracellular cation is sodium, and these concentrations are maintained by the sodium–potassium exchange pump, the sodium–calcium exchanger current, and the inwardly rectifying potassium current (IKi). The initial phase of the depolarization of the cardiac myocyte is known as phase 0 and occurs when voltage-dependent sodium channels open.

Under resting conditions, voltage-dependent sodium channels are closed. During depolarization, these channels open and allow influx of sodium along the electrochemical gradient into the cell. This is followed by inactivation of the sodium channels (phase 1), and the small drop in the action potential in phase 1 is due to movement of potassium and chloride ions extracellularly and intracellularly, respectively. These two phases of the cardiac action potential correspond to the R and S waves of the electrocardiogram. The continued plateau phase of the action potential (phase 2) is due to movement of calcium ions intracellularly through L-type calcium channels and extracellular movement of potassium ions through the slow delayed rectifier potassium channels (IKs). The return of the myocyte resting potential to its resting phase (phase 3) is due to closure of the L-type calcium channels, while the slow delayed rectifier potassium channels remain open. As the membrane potential returns to its resting value of –85 to –90 mV, the inward rectifying potassium channels open, allowing a return to the equilibrium state with predominant intracellular potassium concentrations and extracellular sodium concentrations."

Cocaine Induced Changes

"Cocaine has slow on/off binding and dissociation characteristics with the cardiac sodium channel and tends to block the sodium channel in the inactive state, thus preventing its return to the closed state (27)."

"Although the major metabolites of cocaine, benzoylecgonine and ecgonine methyl ester, have little or no effect on the cardiac sodium channel, the ethanol derived metabolite, cocaethylene, is more potent than parent cocaine at slowing cardiac sodium channel function (32)."

"As pH becomes more acidic, a greater proportion of cocaine will be in the ionized form and therefore there will be greater binding to cardiac myocyte sodium channels, and as a result, there is a greater risk of sodium-channel-dependent cardiotoxicity. Changes in extracellular pH directly affect cocaine binding, with changes in intracellular pH having little or no effect."

"The interaction of cocaine and its metabolites on the delayed rectifier potassium current and/or HERG channel function is complex, although it is likely that cocaine and its major metabolites bind to the “open” HERG channels, inhibiting inward movement of potassium ions and prolongation of QT interval (71). In human embryonic kidney cells transfected with HERG potassium channels, both cocaine and cocaethylene produced significant blockade of the HERG potassium channel activity, with 50% inhibition of the HERG channel function (IC50) at 4.4 and 1.1 μM, respectively (72). This demonstrates that cocaethylene is more potent than cocaine itself at inhibiting potassium channel function, similar to that seen with sodium channel blockade. The other two major metabolites, benzoylecgonine and ecgonine methyl ester, had no significant effects on the HERG channel currents measured. Although the major metabolite of crack cocaine, methylecgonidine, has been demonstrated to have no significant effects on HERG channel function, they are still at risk of QT/QTc prolongation secondary to the parent cocaine (73). When reported concentrations of cocaine in humans (cocaine – 0.7 μM in volunteer studies and 1.4 μM in nonfatal trauma victims; cocaethylene – 0.4 μM in non-fatal trauma victims) and the effects of cocaine on HERG channel function in cell studies are extrapolated, these typical concentrations of cocaine are likely to result in between 14 and 24% blockade of potassium channels (26,74). Additionally, cocaethylene is more potent at blocking the potassium channel, which is important because 60–85% of people co-ingest ethanol with their cocaine (75). Low concentrations of cocaine inhibit the delayed rectifier potassium current (IKr), which is associated with prolongation of the action potential and the repolarization changes seen (76,77)."^[1]

"Nonetheless, because of cocaine’s sodium-channel–blocking properties and its ability to induce an enhanced sympathetic state, it is considered likely to produce or exacerbate cardiac arrhythmias, particularly under certain pathologic conditions. The development of lethal arrhythmias with cocaine use may require a substrate of abnormal myocardium. In support of this theory, studies in animals have shown that cocaine precipitates ventricular arrhythmias and fibrillation in the presence — but not the absence — of myocardial ischemia.70 In humans, life-threatening arrhythmias and sudden death caused by arrhythmia related to cocaine use occur most often in patients with myocardial ischemia or infarction or in those with nonischemic myocellular damage. Long-term cocaine use is associated with increased left ventricular mass and wall thickness, which is known to be a risk factor for ventricular dysrhythmias.55 In some cocaine users, this may provide the substrate that facilitates the development of arrhythmias. Cocaine may affect the generation and conduction of cardiac impulses by several mechanisms. First, as a sympathomimetic agent, it may increase ventricular irritability and lower the threshold for fibrillation.71 Second, it inhibits the generation and conduction of the action potential (i.e., it prolongs the durations of the QRS and QT intervals) as a result of its sodiumchannel–blocking effects.29,72,73 In so doing, cocaine acts in a manner similar to that of a class I antiarrhythmic agent. Third, cocaine increases the intracellular calcium concentration, which may result in afterdepolarizations and triggered ventricular arrhythmias.74 Fourth, it reduces vagal activity — a change that is manifested as a reduction in the variability of the heart rate — which potentiates cocaine’s sympathomimetic effects.75"^[4]

"Cocaine exhibits properties of a class I antiarrhythmic agent by sodium-channel blockage. It also prolongs the duration of the QT interval by inhibiting myocyte repolarization that normally occurs by the efflux of potassium. A cocaine-associated long QTc interval may be related to its effect on conduction in the human ether-ago-go related gene (HERG)-encoded potassium channel. Cocaine also increases intracellular calcium with resultant afterdepolarizations, reduces vagal activity, and increases myocyte irritability by inducing ischemia. When coupled with its ability to produce an enhanced sympathetic state, arrhythmias may occur.26 – 28 Cocaine has been reported to produce a transient Brugada-type electrocardiographic pattern, the clinical importance of which is not known.29 Of importance, studies in animals and humans have shown that cocaine precipitates ventricular arrhythmias and fibrillation mainly in the presence of myocardial ischemia, infarction, or in those with nonischemic myocellular damage.26 – 28"^[5]

"There are inconsistent findings to whether the side effects of Adderall are dose related. The overall incidence of adverse effects is low and comparable with other stimulants (4). The most commonly reported adverse cardiovascular effects are elevated blood pressure and heart rate, seen in both short-and long-term treatment trials. This rise is generally thought to be statistically but not clinically significant (7). It has been suggested that there is the potential risk that chronically and consistently elevated blood pressure and heart rate could contribute to later cardiovascular morbidity. Thus, it may be prudent to undertake ongoing blood pressure and heart rate monitoring for children who are on stimulants (8,9)."

"On February 9, 2006, the Drug Safety and Risk Management Advisory Committee of the FDA recommended a ‘black box’ warning describing the cardiovascular risks of stimulants used to treat ADHD (1)."^[6]

"The illicit use of amphetamines has been shown to lead to tachyarrhythmias and sudden death [5,6]"

"Gap junctions play an important role for arrhythmogenesis [9,10]. The cardiac myocytes express multiple gap junction proteins (connexins) [11 – 13]. Connexin43 (Cx43) is the physiological predominant connexin of myocardial cells [14]. There is growing evidence suggesting that changes in pattern and velocity of conduction of myocardial electrical activity can affect cardiac rhythm and coordination of contraction [15]. An abnormal coupling between cardiomyocytes through gap junctions is, therefore, increasingly considered an important factor in various pathophysiologic conditions including potentially life-threatening arrhythmias"

"JNK and MAP kinase have been reported to be important intracellular signaling pathways that regulate Cx43 [27,28]. In this study, we demonstrated the complete inhibition of Cx43 by SP600125, a potent inhibitor of JNK [29] and partial inhibition of Cx43 by PD98059, a potent p42/p44 MAP kinase inhibitor. We also demonstrated that the JNK1 dsRNAi completely inhibited the Cx43 expression induced by amphetamine. Double-stranded RNAi can regulate gene expression at a translational level through interactions with its target messenger RNA [30]. JNK1 dsRNAi has been demonstrated to successfully block the JNK pathway [31]. The activation of JNK activity in cardiac myocytes after addition of amphetamine is correlated with the upregulation of Cx43. These data implicated that JNK pathway, but not the p42/p44 MAP kinase pathway, is the major pathway involved in the induction of Cx43 by amphetamine. Our findings differ from those of Petrich et al. [28] who have= demonstrated that activation of JNK mediates the downregulation of Cx43 in cardiac myocytes under the stimulation of anisomycin (a protein synthesis inhibitor) and sorbitol (an osmotic stressor)."^[7]

"Cocaine, amphetamine, and ecstasy all share similar adverse effects on the cardiovascular system, related predominantly to sympathetic nervous system activation. (...) Sympathetic activation can lead to varying degrees of tachycardia, vasoconstriction, unpredictable blood pressure effects, and arrhythmias, depending on the dose taken and the presence or absence of coexisting cardiovascular disease."

Blood pressure changes

The high levels of circulating catecholamines and sympathetic activation commonly cause hypertension. However, hypotension can also occur (see box).2

Myocardial ischemia and infarction

Cocaine and amphetamine can cause myocardial ischemia and infarction in patients with or without coronary artery disease. The mechanism is uncertain, but may be related to the elevated catecholamine concentration, which increases myocardial oxygen demand, coronary artery spasm, platelet aggregation, and thrombus formation.2,3,4 Cocaine can produce a procoagulant effect by decreasing concentrations of protein C and antithrombin 3 and potentiating thromboxane production.2

Long-term use of cocaine and amphetamine can cause repetitive episodes of coronary spasm and paroxysms of hypertension, which may result in endothelial damage, coronary artery dissection, and acceleration of atherosclerosis.

Cardiomyopathy

Prolonged administration of cocaine or amphetamines can also lead to a dilated cardiomyopathy.2 Etiologic mechanisms include repeated episodes of subendocardial ischemia and fibrosis and myocyte necrosis produced by exposure to excessive catecholamine concentrations, infectious agents, and heavy metal contaminants (manganese is present in some cocaine preparations).

Arrhythmias

The adverse cardiovascular changes and sympathetic stimulation associated with cocaine and amphetamine ingestion predispose to myocardial electrical instability, precipitating a wide and unpredictable range of supraventricular and ventricular tachyarrhythmias. The presence of fibrotic scars, myocardial ischemia, and left ventricular hypertrophy can act as a substrate for arrhythmogenesis. Cocaine possesses class 1 antiarrhythmic properties (blocks sodium channels) and can impair cardiac conduction causing prolongation of the PR interval, QRS complex, and QT interval. Cocaine can also cause a wide range of bradyarrhythmias, including sinus arrest and atrioventricular block.

Inhalants

"Cardiac arrhythmias are presumed to be the main cause of death from volatile substance abuse. Volatile substances may induce supraventricular or ventricular tachyarrhythmias by sympathetic activation or by myocardial sensitization to circulating catecholamines.7 Some abusers spray the substances directly into the mouth, which can result in intense vagal stimulation and a reflex bradycardia. Profound bradycardia can evolve into asystole or secondary ventricular tachyarrhythmias."

LSD and Psilocybin

"The adrenergic effects of these drugs are usually mild and can give rise to general sympathetic arousal leading to dilated pupils, tachycardia, hypertension, and hyperreflexia. Although cardiovascular complications are rarely serious, supraventricular tachyarrhythmias and myocardial infarction have been reported.5 Changes in serotonin-induced platelet aggregation and sympathetically induced arterial vasospasm may have been contributory factors leading to the onset of myocardial infarction.5"

Morphine and analogues

"These autonomic changes, combined with histamine release from mast cell degranulation, can result in bradycardia and hypotension. Cardiac arrhythmias—including premature atrial and ventricular ectopic activity, atrial fibrillation, idioventricular rhythm, and ventricular tachyarrhythmias—have all been reported.2 Bacterial endocarditis, affecting mainly right-sided cardiac structures, is a well-known complication of intravenous narcotic drug abuse, and it is sometimes associated with pulmonary abscesses. Heroin overdose can cause noncardiogenic pulmonary edema, the onset of which can be delayed for up to 24 hours after admission.6 A disruption in alveolar-capillary membrane integrity has been suggested as a mechanism."

Cannabis

"Cannabis has a biphasic effect on the autonomic nervous system, depending on the dose absorbed.3 Low or moderate doses can increase sympathetic and reduce parasympathetic activity, producing a tachycardia and an increase in cardiac output. In contrast, higher doses inhibit sympathetic and increase parasympathetic activity, resulting in bradycardia and hypotension. Reversible ECG abnormalities affecting the P and T waves and the ST segment have been reported.9"^[8]

"indeed there are important safety concerns, given ibogaine can prolong QT interval (Koenig and Hilber, 2015), potentially evolving to fatal cardiac arrhythmias (Koenig et al., 2014). This critically differentiates ibogaine's safety profile from other psychedelics. However, given the seriousness of drug addiction and the difficulty to treat these patients, observational and retrospective studies for opioid (Brown and Alper, 2017; Noller et al., 2017) and psychostimulant addiction (Schenberg et al., 2014, 2016, 2017) reporting considerable success suggests Phase 2 trials focusing on cardiac safety should be performed."^[9]

"In research with healthy volunteers, occurrences of hypertension, tachycardia and hyperthermia are below 1/3 of cases, not leading to serious adverse events (Vizeli and Liechti, 2017). In clinical populations, serious adverse events were very rare, with only one brief and self-limiting case of increased ventricular extrasystoles in more than 1,260 sessions (MAPS, 2017)."^[9]

"Holter monitoring did not show any increased risk of cardiac arrhythmias in the psilocybin group compared to the niacin group.16"^[10]

"Caffeine is thought to be arrhythmogenic. Prineas et al235 demonstrated an association between excessive caffeine consumption and premature ventricular beats on a random 2-minute echocardiographic examination. Moderate caffeine ingestion does produce a small but significant prolongation of signal-averaged QRS complexes.236 However, Myers et al237 reported no significant differences in the proportion of patients who had ventricular ectopic activity or the total number and complexity of premature ventricular contractions after caffeine versus placebo. They did, however, demonstrate an increase in mean blood pressure at 4 hours and an increase in plasma epinephrine at 3 hours after caffeine ingestion, whereas the plasma norepinephrine level did not change. They demonstrated no increase in the occurrence or severity of ventricular arrhythmias. Other studies have confirmed this observation with modest coffee consumption.196

A relationship between serum cholesterol, homocysteine, and chronic coffee ingestion has been described but appears not to be related to caffeine itself but to other materials in coffee and the mode of brewing.238,239 Fatal intoxications with caffeine, including sudden death, have been described but are rare.193 The cause of death is suspected to be arrhythmia. Toxic doses are usually in the 5-g to 10-g range, but fatalities have been described with as little as 1 g (15 mg/kg). Signs of severe nonfatal toxicity include palpitations, hypotension, and chest pain.19"^[11]

"Several large randomized controlled trials demonstrate that inhaled anticholinergic agents ipratropium and tiotropium increase the risk of serious cardiovascular events, including cardiovascular mortality. Tiotropium Respimat is associated with a statistically significant increased risk of mortality (RR 1.52; 95% CI 1.06 to 2.16) and cardiovascular death (RR 2.05; 95% CI 1.06 to 3.99) compared with placebo in a meta-analysis of clinical trials. In the largest study, the subgroup of patients with COPD in the Respimat group with known rhythm and cardiac disorders at baseline had an especially high risk for cardiac death (RR 8.6; 95% CI 1.1 to 67.2). Although there was no significantly increased risk of mortality (HR 0.89; 95% CI 0.79 to 1.02) or myocardial infarction (MI) (RR 0.73; 95% CI 0.53 to 1.00) with tiotropium handihaler in the Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial, the reported excess of angina (RR 1.44; 95% CI 0.91 to 2.26), imbalance in strokes related to ischaemia and rates of supraventricular tachyarrhythmias are consistent with the pro-ischemic and pro-arrhythmic effects."^[12]

"Solvent abuse also affects the heart causing fatal arrhythmias after inhalation"^[13]

"Bufotoxins, found in the parotid glands of different toad species, are toxic substances with psychoactive properties. In Central America, toads of the Bufo genus secrete a milky toxic substance to dissuade predators. Animals that ingest the venom, or eat the toad, may experience cardiovascular and gastrointestinal symptoms. The most severe forms of intoxication may provoke cardiac arrhythmia, diarrhoea, convulsions, or even death due to cardiac arrest.

The Sonoran Desert toad, Bufo alvarius, contains a variety of bufotoxins including 5-methoxy-N,Ndimethyltryptamine and bufotenin, both of which are hallucinogenic. Other toad species produce bufotenin only; while this substance is psychoactive if smoked or ingested, it is somewhat less potent than other compounds"^[14]

"Atropine and scopolamine are competitive antagonists of muscarinic cholinergic receptors and are central nervous system depressants (Brown & Taylor, 2001)"

"In overdose, these drugs induce a toxic delirium marked by pronounced anterograde amnesia, confusion, dissociation, hallucinations, delusions, and an excited, giddy affect (Ardila & Moreno, 1991). Coordination is also impaired, vision becomes blurry with increasing pupillary dilation, and overly dry mucous membranes may make it difficult to talk or swallow. Overdose can be lethal with fever, tachycardia, and arrhythmia. Reports of bizarre self-injury are not uncommon because the intoxication lasts for many hours, or even days, and the delirium can induce a dramatic disconnection from reality."^[15]

"δ1-opioid receptor stimulation is cardioprotective against myocardial ischemia and sublethal arrhythmias and suggest a role for the mitochondrial KATP channel in mediating these cardioprotective effects."^[16]

κ- but not δ-opioid receptors mediate effects of ischemic preconditioning on both infarct and arrhythmia in rats

Anti-arrhythmic Effect of κ -opioid Receptor Stimulation in the Perfused Rat Heart: Involvement of a cAMP-dependent Pathway

Anti-arrhythmic activities of opioid agonists and antagonists and their stereoisomers

κ-Opioid Receptor Stimulation Induces Arrhythmia in the Isolated Rat Heart via the Protein Kinase C/Na+–H+Exchange Pathway

Cardiac Dys-Synchronization and Arrhythmia in Hyperhomocysteinemia

A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome

Molecular mechanism for an inherited cardiac arrhythmia

[https://www.ahajournals.org/doi/full/10.1161/01.RES.0000090361.45027.5B Respiratory Sinus Arrhythmia. Endogenous Activation of Nicotinic Receptors Mediates Respiratory Modulation of Brainstem Cardioinhibitory Parasympathetic Neurons]

Prevention and elimination of heart arrhythmias by adaptation to intermittent high altitude hypoxia

Evaluation of the Cardiotoxicity of Mitragynine and Its Analogues Using Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes