Digitalis has positive inotropic effect-by the virtue of its effect on
Ans. a (Na+-K+ ATPase pump) (Ref. KDT 6th/pg. 493-497)Digitalis increases force of cardiac contraction by a direct action indepen dent of innervation. It selectively binds to extracellular face of the membrane associated Na+K+ ATPase of myocardial fibres and inhibitis this enzyme. Inhibition of this cation pump results in accumulation of Na+intracellularly. 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 infarction/ischemia/hypoxemia- 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# tl/2 = 40 hours# Urinary excretion.Mechanism# Inhibit the Na+/K+ 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 drug's 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 (90-100%)Good (60-80%)2.Plasma protein binding95%25%3.Time course of action* - Onset- Peak- Duration1/2-2 hr6-12 hr2-3 weeks15-30 min2-5 hr2-6 days4.Plasma t 1/25-7 days40 hr5.Plasma concentration - Therapeutic- Toxic15-30 ng/ml> 35 ng/ml0.5 -1.4 ng/ml> 2 ng/ml6.Daily maintenance dose0.05-0.2 mg0.125-0.5 mg7.Daily elimination**10-15%35%8.Route of elimination (predominant)Hepatic metabolismRenal excretion9.AdministrationOralOral, i.v.10.Generally used forMaintenanceRoutine treatment and emergency
Na+- K+ ATPase pump
Na Glucose channels
H+-K+ ATPase pump
Calcium pump
C.V.S