Chemical formula: C₄₁H₆₄O₁₄ Molecular mass: 780.939 g/mol PubChem compound: 2724385
Digoxin increases contractility of the myocardium by direct activity. This effect is proportional to dose in the lower range and some effect is achieved with quite low dosing; it occurs even in normal myocardium although it is then entirely without physiological benefit. The primary action of digoxin is specifically to inhibit adenosine triphosphatase, and thus sodium-potassium (Na+ - K+) exchange activity, the altered ionic distribution across the membrane resulting in an augmented calcium ion influx and thus an increase in the availability of calcium at the time of excitation-contraction coupling. The potency of digoxin may therefore appear considerably enhanced when the extracellular potassium concentration is low, with hyperkalaemia having the opposite effect.
Digoxin exerts the same fundamental effect of inhibition of the Na+ - K+ exchange mechanism on cells of the autonomic nervous system, stimulating them to exert indirect cardiac activity. Increases in efferent vagal impulses result in reduced sympathetic tone and diminished impulse conduction rate through the atria and atrio-ventricular node. Thus, the major beneficial effect of digoxin is reduction of ventricular rate.
Intravenous administration of a loading dose produces an appreciable pharmacological effect within 5 to 30 mins, while using the oral route the onset of effect occurs in 0.5 to 2 hours.
The Tmax following IV administration is approximately 1 to 5 hours, while the Tmax for oral administration is 2 to 6 hours. Upon oral administration, digoxin is absorbed from the stomach and upper part of the small intestine. When digoxin is taken after meals, the rate of absorption is slowed, but the total amount of digoxin absorbed is usually unchanged. When taken with meals high in fibre, however, the amount absorbed from an oral dose may be reduced.
The bioavailability of orally administered digoxin is approximately 63% in tablet form and 75% as oral solution.
The initial distribution of digoxin from the central to the peripheral compartment generally lasts from 6 to 8 h. This is followed by a more gradual decline in serum digoxin concentration, which is dependent upon digoxin elimination from the body. The volume of distribution is large (Vdss=510 litres in healthy volunteers), indicating digoxin to be extensively bound to body tissues. The highest digoxin concentrations are seen in the heart, liver and kidney, that in the heart averaging 30-fold that in the systemic circulation. Although the concentration in skeletal muscle is far lower, this store cannot be overlooked since skeletal muscle represents 40% of total body weight. Of the small proportion of digoxin circulating in plasma, approximately 25% is bound to protein.
The majority of digoxin is excreted by the kidneys as an intact drug, although a small fraction of the dose is metabolised to pharmacologically active and inactive metabolites. The main metabolites of digoxin are dihydrodigoxin and digoxygenin.
The major route of elimination is renal excretion of the unchanged drug.
Digoxin is a substrate for P-glycoprotein. As an efflux protein on the apical membrane of enterocytes, P-glycoprotein may limit the absorption of digoxin. P-glycoprotein in renal proximal tubules appears to be an important factor in the renal elimination of digoxin.
Following I.V. administration to healthy volunteers, between 60 and 75% of a digoxin dose is recovered unchanged in the urine over a six day follow-up period. Total body clearance of digoxin has been shown to be directly related to renal function, and percent daily loss is thus a function of creatinine clearance. The total and renal clearances of digoxin have been found to be 193 ± 25 ml/min and 152 ± 24 ml/min in a healthy control population.
In a small percentage of individuals, orally administered digoxin is converted to cardioinactive reduction products (digoxin reduction products or DRPs) by colonic bacteria in the gastrointestinal tract. In these subjects over 40% of the dose may be excreted as DRPs in the urine. Renal clearances of the two main metabolites, dihydrodigoxin and digoxygenin, have been found to be 79 ± 13 ml/min and 100 ± 26 ml/min, respectively.
In the majority of cases however, the major route of digoxin elimination is renal excretion of the unchanged drug.
The terminal elimination half-life of digoxin in patients with normal renal function is 30 to 40 h.
Since most of the drug is bound to the tissues rather than circulating in the blood, digoxin is not effectively removed from the body during cardiopulmonary by-pass. Furthermore, only about 3% of a digoxin dose is removed from the body during 5h of haemodialysis.
In the newborn period, renal clearance of digoxin is diminished and suitable dosage adjustments must be observed. This is especially pronounced in the premature infant since renal clearance reflects maturation of renal function. Digoxin clearance has been found to be 65.6 ± 30 ml/min/1.73m² at three months, compared to only 32 ± 7 ml/min/1.73m² at one week. By 12 months digoxin clearance of 88 ± 43 ml/min/1.73m² has been reported. Beyond the immediate newborn period, children generally require proportionally larger doses than adults on the basis of body weight and body surface area.
The terminal elimination half-life of digoxin is prolonged in patients with impaired renal function, and in anuric patients may be of the order of 100 h.
Hepatic impairment has little effect on digoxin clearance.
Age-related declines in renal function in elderly patients can result in a lower rates of digoxin clearance than in younger subjects, with reported digoxin clearance rates in the elderly of 53 ml/min/1.73m².
Digoxin clearance is 12%–14% less in females than males and may need to be considered in dosing calculations.
Digoxin showed no genotoxic potential in in vitro studies (Ames test and mouse lymphoma). No data are available on the carcinogenic potential of digoxin.
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