<prompt> Digitalis has positive inotropic effect-by the virtue of its effect onNa- K ATPase pumpNa Glucose channelsH-K ATPase pumpCalcium pump  <response>: Ans. a Na-K ATPase pump Ref. KDT 6thpg. 493-497Digitalis increases force of cardiac contraction by a direct action indepen dent of innervation. It selectively binds to extracellular face of the membrane associated NaK ATPase of myocardial fibres and inhibitis this enzyme. Inhibition of this cation pump results in accumulation of Naintracellularly. This indirectly results in intracellular Ca2 accumulation.CARDIAC GLYCOSIDESMechanism of Action These inhibit the monovalent cation transport enzyme-coupled Na-K-ATPase and increase intracellular ; the latter, in turn, increases intracellular through a Na-Ca2 exchange carrier mechanism. The increased myocardial augments Ca2 released to the myofilaments during excitation and, therefore, invokes a positive inotropic response. Cardiac glycosides causes increased automaticity and ectopic impulse activity. They also prolong the effective refractory period of the atrioventricular node and thereby slow ventricular rate in atrial flutter and fibrillation.Pharmacokinetics Digoxin is not extensively metabolized in humans; almost two-thirds is excreted unchanged by the kidneys. Its renal clearance is proportional to creatinine clearance. Liver impairment does not significantly prolong the half-life of digitoxin. Digitoxin is metabolized in the liver and excreted into the gut via the bile. Cardioactive metabolites which include digoxin as well as unchanged digitoxin can then be reabsorbed from the intestine, thus establishing an enterohepatic circulation that contributes to the very long half-life of this agent. Digoxin toxicity is enhanced by renal failure as it is excreted through kidneys, whereas digitoxin toxicity is enhanced by liver failure because it is eliminated by hepatic metabolism. Hepatic dysfunction does not affect digoxin elimination. Reduced tolerance to digoxin may be seen in:- Advanced age- Acute myocardial infarctionischemiahypoxemia- Magnesium depletion- Hypercalcemia- Hypothyroidism- Renal insufficiency- Electrical cardioversion. The administration of following drugs raises the serum concentration of digoxin by reducing both the renal and nonrenal elimination of digoxin and by reducing its volume of distribution- Quinidine- Verapamil- Amiodarone- PropafenoneCardiac GlycosidesPharmacology Digoxin-75 bioavailabiliity 20-40 protein bound tl2 40 hours Urinary excretion.Mechanism Inhibit the NaK ATPase of cell membrane, causing intracellular Na, Na-Ca2 antiport does not function as efficiently, causing intracellular Ca2, leads to positive inotropy. May cause PR, QT, sccoping of ST segment, T-wave inversion on ECG.Clinical use CHF contractility; Atrial fibrillation conduction at AV node.Toxicity Nausea, vomiting, diarrhea. Blurry yellow vision think Van Gogh. Arrhythmia. Toxicities of digoxin are by renal failure excretion, hypokalemia potentiates drugs effects, and quinidine digoxin clearance; displaces digoxin from tissue binding sites.Antidote Slowly normalize K Lidocaine Cardiac pacer Anti-dig Fab fragments DlgitoxinDigoxin1.Oral absorptionV. good 90-100Good 60-802.Plasma protein binding95253.Time course of action - Onset- Peak- Duration12-2 hr6-12 hr2-3 weeks15-30 min2-5 hr2-6 days4.Plasma t 125-7 days40 hr5.Plasma concentration - Therapeutic- Toxic15-30 ngml 35 ngml0.5 -1.4 ngml 2 ngml6.Daily maintenance dose0.05-0.2 mg0.125-0.5 mg7.Daily elimination10-15358.Route of elimination predominantHepatic metabolismRenal excretion9.AdministrationOralOral, i.v.10.Generally used forMaintenanceRoutine treatment and emergency 