DIGOXIN
Introduction
• Digoxin is a digitalis glycoside that exerts positive inotropic and negative chronotropic effects on the heart.
• Digoxin is used for the treatment of congestive heart failure (CHF) because of its inotropic effects on the myocardium and for the treatment of atrial fibrillation because of its chronotropic effects on the electrophysiological system of the heart.
• It is the most commonly used cardiac glycosides.
_The positive inotropic effect of digoxin is caused by binding to sodium- and potassium activated adenosine triphosphatase, also known as Na+/K+ -ATPase or the sodium pump. _Digoxin-induced inhibition of Na+/K+ -ATPase leads to decreased transport of sodium out of myocardial cells and increased intracellular sodium concentrations that aid calcium entry and decrease calcium elimination via the sodium-calcium exchanger.
_In the heart, increased intracellular calcium causes more calcium to be released by the sarcoplasmic reticulum, thereby making more calcium available to bind to troponin-C, which increases contractility (inotropy).
_ The chronotropic effects (decreases heart rate; negative chronotropy) of digoxin are mediated via increased parasympathetic activity and vagal tone.
• Digoxin is used for the treatment of congestive heart failure (CHF) because of its inotropic effects on the myocardium and for the treatment of atrial fibrillation because of its chronotropic effects on the electrophysiological system of the heart.
• It is the most commonly used cardiac glycosides.
_The positive inotropic effect of digoxin is caused by binding to sodium- and potassium activated adenosine triphosphatase, also known as Na+/K+ -ATPase or the sodium pump. _Digoxin-induced inhibition of Na+/K+ -ATPase leads to decreased transport of sodium out of myocardial cells and increased intracellular sodium concentrations that aid calcium entry and decrease calcium elimination via the sodium-calcium exchanger.
_In the heart, increased intracellular calcium causes more calcium to be released by the sarcoplasmic reticulum, thereby making more calcium available to bind to troponin-C, which increases contractility (inotropy).
_ The chronotropic effects (decreases heart rate; negative chronotropy) of digoxin are mediated via increased parasympathetic activity and vagal tone.
ONSET
• INITIAL RESPONSE
– Oral: 30 minutes to 2 hours.
– Intravenous: 5 to 30 minutes.
– Intramuscular: 30 minutes to 2 hours.
– Intravenous: 5 to 30 minutes.
– Intramuscular: 30 minutes to 2 hours.
• PEAK RESPONSE
– Oral: within 2 to 6 hours.
– Intravenous: 1.5 to 4 hours.
– Intramuscular: 2 to 6 hours.
– Intravenous: 1.5 to 4 hours.
– Intramuscular: 2 to 6 hours.
ABSORPTION
• BIOAVAILABILITY (F):
– Oral, tablets: 70%
– Pediatric elixir: 80%
– capsule (90%)
• Digoxin is not usually administered intramuscularly due to erratic absorption and severe pain at the injection site.
• The major site of absorption is the small Intestine
• Impaired absorption has been reported due to
– mucosal abnormalities,
– gastrointestinal irradiation,
– alteration in gastrointestinal motility and
– Oral, tablets: 70%
– Pediatric elixir: 80%
– capsule (90%)
• Digoxin is not usually administered intramuscularly due to erratic absorption and severe pain at the injection site.
• The major site of absorption is the small Intestine
• Impaired absorption has been reported due to
– mucosal abnormalities,
– gastrointestinal irradiation,
– alteration in gastrointestinal motility and
– neomycin.
• EFFECTS OF FOOD.
– Reduce the rate of absorption.
– Meals high in bran fiber may reduce the extent of absorption.
– Meals high in bran fiber may reduce the extent of absorption.
DISTRIBUTION
• Protein Binding: 20% to 25%
• Highest levels occur in heart muscle, kidneys, and liver.
• Red blood cells.
• Vd is proportional to lean body mass
• Vd is increased in hyperthyroid
• Vd is reduced in hypothyroidism and impaired renal function.
• Highest levels occur in heart muscle, kidneys, and liver.
• Red blood cells.
• Vd is proportional to lean body mass
• Vd is increased in hyperthyroid
• Vd is reduced in hypothyroidism and impaired renal function.
DISTRIBUTION
• VD =7 L/kg
• VD is larger in children and neonates
• Digoxin does not distribute into adipose tissue.
• Thyroid hormone regulates basal metabolic rate, and thyroid status will influence every major organ system in the body including the heart (heart rate and cardiac output), liver (liver blood flow and microsomal drug-metabolizing enzyme function), and kidney (renal blood flow and glomerular filtration rate).
• Hyperthyroid patients have faster metabolic rates and eliminate Digoxin faster than euthyroid patients (t1/2 = 24 hours with normal renal function).
• Hyperthyroid patients can present with atrial fibrillation which may be treated with Digoxin.
• Generally, these patients require higher Digoxin doses to control ventricular rate because of the increase in Digoxin clearance.
• VD is larger in children and neonates
• Digoxin does not distribute into adipose tissue.
• Thyroid hormone regulates basal metabolic rate, and thyroid status will influence every major organ system in the body including the heart (heart rate and cardiac output), liver (liver blood flow and microsomal drug-metabolizing enzyme function), and kidney (renal blood flow and glomerular filtration rate).
• Hyperthyroid patients have faster metabolic rates and eliminate Digoxin faster than euthyroid patients (t1/2 = 24 hours with normal renal function).
• Hyperthyroid patients can present with atrial fibrillation which may be treated with Digoxin.
• Generally, these patients require higher Digoxin doses to control ventricular rate because of the increase in Digoxin clearance.
EXCRETION
• Kidney: ~ 75%. by glomerular filtration and active tubular secretion of unchanged drug without significant reabsorption by the renal tubule.
• The remainder of a digoxin dose (~ 25%) is removed by hepatic metabolism or biliary excretion.
• dose is excreted in urine within 6 to 12 hours.
• dieresis does not appear to significantly increase Digoxin excretion.
• The remainder of a digoxin dose (~ 25%) is removed by hepatic metabolism or biliary excretion.
• dose is excreted in urine within 6 to 12 hours.
• dieresis does not appear to significantly increase Digoxin excretion.
METABOLISM
• LIVER
• It is not dependent upon the cytochrome P- 450 system.
• METABOLITES
• It is not dependent upon the cytochrome P- 450 system.
• METABOLITES
– Digoxigenin bisdigitoxoside, (active).
– Digoxigenin monodigitoxoside, (active).
– Digoxigenin monodigitoxoside, (active).
HALF-LIFE
• HALF-LIFE: 1.3 to 2.2 days.
• Average half-life is 1.5 to 1.8 days in normal patients.
• Average half-life is 1.5 to 1.8 days in normal patients.