Pharmacodynamics ECG from a person taking<unk> , explaining ST depressions in mainly precordial leads V4 and V5.<unk> 's primary mechanism of action involves inhibition of the sodium potassium adenosine triphosphatase (Na+/K+ ATPase), mainly in the myocardium. This inhibition causes an increase in intracellular sodium levels, resulting in decreased activity of the sodium-calcium exchanger, which normally imports three extracellular sodium ions into the cell and transports one intracellular calcium ion out of the cell. The reversal of this exchanger, triggered by the increase in intracellular sodium, results in an increase in the intracellular calcium concentration that is available to the contractile proteins. The increased calcium concentrations lead to the binding of Calcium to Troponin, and the formation of the Ca+2 troponin complex results in increased inotrophy. Increased intracellular calcium lengthens phase 4 and phase 0 of the cardiac action potential, which leads to a decrease in heart rate. Increased amounts of Ca2+ also leads to increased storage of calcium in the sarcoplasmic reticulum, causing a corresponding increase in the release of calcium during each action potential. This leads to increased contractility (the force of contraction) of the heart without increasing heart energy expenditure. The inhibition of the sodium pump may also improve baroreceptor sensitivity in heart failure and may explain some of the neurohormonal effects of<unk> .<unk>  also has important parasympathetic effects, particularly on the atrioventricular node. While it does increase the magnitude of myocardial contractility, the duration of the contraction is only slightly increased. Its use as an antiarrhythmic drug, then, comes from its direct and indirect parasympathetic stimulating properties. Vagus nerve stimulation slows down conduction at the AV node by increasing the refractory period of cardiac myocytes. The slowed AV node gives the ventricles more time to fill before contracting. This negative chronotropic effect is synergistic with the direct effect on cardiac pacemaker cells. The arrhythmia itself is not affected, but the pumping function of the heart improves, owing to improved filling. Overall, the heart rate is decreased while stroke volume is increased, resulting in a net increase in blood pressure, leading to increased tissue perfusion. This causes the myocardium to work more efficiently, with optimized hemodynamics and an improved ventricular function curve. Other electrical effects include a brief initial increase in action potential, followed by a decrease as the K+ conductance increases due to increased intracellular amounts of Ca2+ ions. The refractory period of the atria and ventricles is decreased, while it increases in the sinoatrial and AV nodes. A less negative resting membrane potential is made, leading to increased irritability. The conduction velocity increases in the atria, but decreases in the AV node. The effect upon Purkinje fibers and ventricles is negligible. Automaticity is also increased in the atria, AV node, Purkinje fibers, and ventricles. ECG changes seen in people taking<unk>  include increased PR interval (due to decreased AV conduction) and a shortened QT interval. Also, the T wave may be inverted and accompanied by ST depression. It may cause AV junctional rhythm and ectopic beats (bigeminy) resulting in ventricular tachycardia and fibrillation. Pharmacokinetics<unk>  is usually given orally, but can also be given by IV injection in urgent situations (the IV injection should be slow, and heart rhythm should be monitored). While IV therapy may be better tolerated (less nausea),<unk>  has a very long distribution half-life into the cardiac tissue, which will delay its onset of action by a number of hours. The half-life is about 36 hours for patients with normal renal function,<unk>  is given once daily, usually in 125 μg or 250 μg doses.<unk>  elimination is mainly by renal excretion and involves P-glycoprotein, which leads to significant clinical interactions with P-glycoprotein inhibitor drugs. Examples commonly used in patients with heart problems include spironolactone, verapamil and amiodarone. In patients with decreased kidney function the half-life is considerably longer, along with decrease in Vd (volume of distribution), calling for a reduction in dose or a switch to a different glycoside, such as<unk> itoxin (not available in the United States), which has a much longer elimination half-life of around seven days and is eliminated by the liver. Effective plasma levels vary depending on the medical indication. For congestive heart failure, levels between 0.5 and 1.0 ng/ml are recommended. This recommendation is based on post hoc analysis of prospective trials, suggesting higher levels may be associated with increased mortality rates. For heart rate control (atrial fibrillation), plasma levels are less defined and are generally titrated to a goal heart rate. Typically,<unk>  levels are considered therapeutic for heart rate control between 0.5 and 2.0 ng/ml (or 0.6 and 2.6 nmol/l). In suspected toxicity or ineffectiveness,<unk>  levels should be monitored. Plasma potassium levels also need to be closely controlled (see side effects, below). Quinidine, verapamil, and amiodarone increase plasma levels of<unk>  (by displacing tissue binding sites and depressing renal<unk>  clearance), so plasma<unk>  must be monitored carefully when coadministered. A study which looked to see if<unk>  affected men and women differently found that<unk>  did not reduce deaths overall, but did result in less hospitalization. Women who took<unk>  died "more frequently" (33%) than women who took placebo (29%).<unk>  increased the risk of death in women by 23%. There was no difference in the death rate for men in the study.<unk>  is also used as a standard control substance to test for P-glycoprotein inhibition. Pharmacomicrobiomics The bacteria Eggerthella lenta has been linked to a decrease in the toxicity of<unk> . These effects have been studied through comparisons of North Americans and Southern Indians, in which a reduced<unk>  metabolite profile correlates with E. lentum abundance. Further studies have also revealed an increase in<unk>  toxicity when used alongside erythromycin or tetracycline, the researches attributed this to the decrease in the E. lentum population. Overall, bacterial inactivation of<unk> , as in<unk>  being inactivated by bacteria in the gut microbiome occurs often. This is why<unk>  is given as a capsule or as a solution in capsule.
Digoxin
Digitoxin
Amiodarone
Metoprolol
Carvedilol
Sotalol
Bisoprolol
Captopril