Talk:Abnormal heartbeat

Sudden Death

"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"

Cocaine induced dysfunction

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)."

Cardiovascular effects of Adderall

"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)."