DIGOXIN
Dr. Ashish Yadav
Professor
Department of Pharmacology
MRA Medical College
Introduction
• It is a cardiac glycoside obtained from Digitalis
purpurea (Foxglove) plant.
• Oswald Schmiedeberg isolated the active
principal which was digitoxin.
• Cardiac glycosides remained the only drugs for
CHF till diuretics became available.
Mechanism
• Digoxin inhibits Na-K ATPase mildly at
therapeutic concentrations leading to mild
increase in intracellular Na.
• Na-Ca exchanger (NCX) which depends on Na,
extrudes intracellular Na with the intake of Ca.
• Increased intracellular Ca leads to increased
contractility.
Mechanism
• As cardiac output improves, the sympathetic
system status returns towards normal.
• As a result, HR, PVR, preload, afterload,
cardiac wall stress and myocardial oxygen
consumption decrease.
• As renal perfusion improves, Renin-
Angtiotensin-Aldosterone axis also returns
towards normal causing diuresis and further
decreasing preload.
Pharmacological Actions
• Electrophysiological Actions
– Higher intracellular Ca, inhibits L-type Ca channels
thereby shortening refractory period.
• Chances of re-entrant arrhythmia increases
– Decreased intracellular K and increased intracellular
Na increases resting membrane potential
• Depolarization becomes easier leading to re-entrant
arrhythmias
– At higher Digoxin concentrations, Ca overload in
sarcoplasmic reticulum occurs where Ca is released
spontaneously
• Automaticity increases (extrasystoles and pulsus bigemini in
ECG)
• High risk of ventricular arrhythmias
Pharmacological Actions
• Extra – Cardiac Actions
(Digoxin inhibits Na-K ATPase at other sites)
– At lower concentrations, Digoxin stimulates vagus and
sensitizes baroreceptors.
• Both these actions decrease heart rate and cardiac work.
• Since, at low digoxin concentrations, inotropic effect is less,
this may be the main mechanism of digoxin at therapeutic
concentrations
– At higher concentrations, intracellular Ca in vascular
smooth muscles increases.
• Mesentric artery occlusion or ischemia can occur leading to
intestinal necrosis.
Pharmacological Actions
• Indirect Actions
– Vagotonic and Sympatholytic effects lead to AV
prolongation and bradycardia.
– ACh causes shortened atrial action potentials
which along with direct action of Digoxin
promotes atrial flutter and fibrillation
Pharmacological Actions
• Interaction with K, Mg, Ca
– Hyperkalemia
• Reduces Digoxin binding with Na-K ATPase
• Hyperkalemia by itself causes AV prolongation
– Hypokalemia
• Increases Digoxin binding with Na-K ATPase
• Hypokalemia by itself decreases repolarizing currents
Automaticity and hence arrhythmias increase
– Hypomagnesimia and Hypercalcemia
• Both cause overloading of sarcoplasmic reticulum and
spontaneous Ca release events leading to arrhythmias.
Adverse Effects
• Therapeutic Index of Digoxin is extremely
narrow (~2).
• The therapeutic drug concentration range is
0.5 – 0.8 ng/ml. Levels above 1.2 ng/ml are
associated with increased mortality
Adverse Effects
• Arrhythmias
– Extreme bradycardia, AV block, Atrial fibrillation are
more common in healthy individuals
– Ventricular extrasystoles, ventricular tachycardia,
bigemini, and fibrillation are seen more frequently in
persons with structural cardiac defect.
– All types of arrhythmias can occur with Digoxin except
Type-II Mobitz block.
• GI effects
– Nausea, vomiting (due to stimulation of CTZ)
– Mesentric artery spasm leading to intestinal necrosis
in extreme cases
Adverse Effects
• Visual defect
– Altered color perception and halos
• Other
– Headache, fatigue, sleeplessness can be early
signs of Digoxin toxicity.
Treatment of Digoxin Toxicity
• Bradyarrhythmias
– Atropine
– Pace-maker if atropine fails
• Tachyarrhythmias
– K infusion
• Overdose
– Fab fragments from bovine antisera (DigiBind)
--- End of Topic ---