DIGOXIN
INTRODUCTION
Digoxin is obtained mainly from Digitalis lanata; it consists of sugars and the aglycone digoxigenin. Digoxin has positive inotropic and negative chronotropic activity. It is used for atrial fibrillation and congestive heart failure. Its use in congestive heart failure and sinus rhythm is less certain. The margin between toxic and therapeutic doses is small.
 Digitalis is an example of a cardio-active , in other words a steroid which has the ability to exert a specific and powerful action on the cardiac muscle in animals, and has been used in the treatment of heart problems ever since its discovery in 1775.
Digoxin is the primary cardiac glycoside in clinical use. 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. The role of digoxin in the treatment of each of these disease states has changed in recent years as a better understanding of the pathophysiology of these conditions has been gained and new drug therapies have been developed. The treatment of chronic CHF, angiotensin I converting enzyme inhibitors (ACE inhibitors) and diuretics are the primary pharmacotherapeutic agents with angiotensin II receptor antagonists, spironolactone, and β-blockers playing key roles.For the treatment of acute or severe heart failure, agents that decrease cardiac preload (diuretics, nitrates) or afterload (vasodilators) and ACE inhibitors (decreases both preload and afterload) are used in conjunction with potent intravenously administered inotropic agents (dobutamine, dopamine, adrenergic agonists) to balance the current cardiovascular status of the patient.
 In either the acute or severe heart failure situations, digoxin can be used when a mild inotropic or oral agent is needed.
STRUTURE



PLASMA CONCENTRATION-RESPONSE RELATIONSHIP
<0.5mcg/L:-   no clinical effect
0.7 mcg/L:-  some positive inotropic
0.8-2 mcg/L:-  optimum therapeutic range
2-2.5 mcg/L:-  increased risk of toxicity
>2.5  mcg/L:-  GI,CVS and CNS toxicity
PHARMACOKINATICS
ABSORPTION

Digoxin is well absorbed in the gastrointestinal intestinal tract, and there is no massive hepatic first pass effect. Digoxin's oral bioavailability (70%-80%), even though considerable  metabolism of digoxin in GI by hydrolysis in the acidic environment of the stomach or by digestion by intestinal bacteria. Therefore, when give with antibiotics it increase their bioavailability.
DISTRIBUTION
Digoxin has a large volume of distribution, due to its affinity toward skeletal and cardiac muscles, intestines and kidney. Digoxin has a distinct distribution time 6-8 hrs and thus its disposition is best described by a two-compartment model. Adipose tissue is not a reservoir for digoxin; therefore, dosing should be based on the estimated lean body mass. Binding to plasma proteins, mostly albumin, averages 20-30%. Digoxin incompletely distributes across the placental membrane .
METABOLISM
A small amount of digoxin is metabolized by the liver and approximately 8% undergo an enterohepatic cycle. The eliminationhalf-life of digoxin is long. Therefore, in the absence of a  loading dose, the time required to reach steady state, after the initiation of a repeated administration regimen, is around 5 to 7 days.
ELIMINATION
Most of the digoxin is eliminated unchanged by the kidneys. Renal clearance of digoxin exceeds by glommerular filtration, thus indicating a tubular secretion component. Tubular secretion is mediated by the multidrug active transporter, p-glycoprotein. This p-glycoprotein may be inhibited by some drugs such as quinidin etc. Renal impairment also decreases the clearance of digoxin, and may cause accumulation to toxic levels if dosage is not adapted thoroughly.
HALF LIFE
36–48 hr (↑ in renal impairment)



MECHANISM OF ACION
Digoxin inhibits the Na-K-ATPase membrane pump, resulting in an increase in intracellular sodium. The sodium calcium exchanger (NCX)in turn tries to extrude the sodium and in so doing, pumps in more calcium. Increased intracellular concentrations of calcium may promote activation of contractile proteins (e.g., actin, myosin). Digoxin also acts on the electrical activity of the heart, increasing the slope of phase 4 depolarization, shortening the action potential duration, and decreasing the maximal diastolic potential.

INDICATION
 Digoxin is used to treat  heart failure, usually along with other medications. It is also used to treat certain types of irregular heartbeat (such as chronic atrial fibrillation). Treating heart failure may help maintain your ability to walk and  exercise and may improve the strength of your  heart. Treating an irregular heartbeat can decrease the risk for   blood clots, an effect that may reduce your risk for a heart attack or  stroke Paroxysmal atrial tachycardia.

CONTARAINDICATIONS
Hypersensitivity;
Uncontrolled ventricular arrhythmias;
AV block (in absence of pacemaker);
Idiopathic hypertrophic subaortic stenosis;
Constrictive pericarditis;
Known alcohol intolerance (elixir only).
Lactation: Similar concentrations in serum and breast milk result in subtherapeutic levels in infant, use with caution

ADVERSE DRUG REACTION

CNS: fatigue, headache, weakness.
EENT: blurred vision, yellow or green vision
CV: ARRHYTHMIAS, bradycardia, ECG changes, AV block, SA block
GI: anorexia, nausea, vomiting, diarrhea
Hemat: thrombocytopenia
Metabolic: electrolyte imbalances with acute digoxin toxicity
* CAPITALS indicate life-threatening. Underline indicates most frequent.


PRACTICAL IMPLECATION
Using population averages it is possible to predict plasma concentration from specific dosage particularly since the time to reach the steady state is long. Population value are only average and  individual value may very. A number of disease and drugs effect digoxin disposition such as congestive hear failure, hapetic and renal disease all decrease elimination of digoxin. The hypothyroidism increases the plasma concentration and increase the sensitivity of heart to digoxin. hypokalemia ,  hypocalcaemia, hypomagnesaemia also increase the sensitivity of heart.

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