Digoxin Load Calculator

DIGOXIN INTRODUCTION ❖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. ❖ For the treatment of chronic CHF, angiotensin I–converting enzyme inhibitors (ACE inhibitors), βblockers, and diuretics (for patients who are fluid overloaded) are the primary pharmacotherapeutic agents. Angiotensin II receptor antagonists (ARB), aldosterone antagonists, and the combination of hydralazine and nitrates also play key roles. ❖In either the acute or chronic heart failure situations, digoxin can be used when a mild inotropic or oral agent is needed. INTRODUCTION ❖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. ❖The increased intracellular calcium is stored in the endoplasmic reticulum so that action potential–induced calcium release is augmented causing enhanced myocardial contractility. The chronotropic effects of digoxin are mediated via increased parasympathetic activity and vagal tone THERAPEUTIC AND TOXIC CONCENTRATIONS ❖When given as oral or intravenous doses, the serum digoxin concentration/time curve follows a two-compartment model and exhibits a long and large distribution phase of 8-12 hours. ❖During the distribution phase, digoxin in the serum is not in equilibrium with digoxin in the tissues, so digoxin serum concentrations should not be measured until the distribution phase is finished. ❖When drug distribution is complete, digoxin serum and tissue concentrations will be proportional to each other so that digoxin serum concentrations reflect concentrations at the site of action. THERAPEUTIC AND TOXIC CONCENTRATIONS ❖When a digoxin serum concentration is very high but the patient is not exhibiting signs or symptoms of digitalis overdose, clinicians should consider the possibility that the blood sample for the determination of a digoxin serum concentration was obtained during the distribution phase, is too high because digoxin has not had the opportunity to diffuse out of the bloodstream into the myocardium, and is not reflective of myocardial tissue concentrations. Digoxin serum concentrations after 250 mcg doses given intravenously (circles and solid line) and orally as a tablet (squares with dashed line). After an intravenous dose, digoxin serum concentrations are very high because the entire quantity of drug is initially contained in the blood. THERAPEUTIC AND TOXIC CONCENTRATIONS ❖During the distribution phase, digoxin begins to move out of the vascular system into the tissues. It is also cleared from the body during this phase. ❖Digoxin serum concentrations decline relatively rapidly over an 8-12 hour time period until the blood and tissues are in pseudo-equilibrium with each other. ❖During the elimination phase, digoxin serum concentrations in patients with good renal function (creatinine clearance > 80 mL/min) decline with a half-life of about 36 hours. ❖After oral tablet administration, about 70% of a digoxin dose is absorbed from the gastrointestinal tract. ❖Maximum, or peak, concentrations occur about 1.5-2 hours after oral dosing with tablets, and the distribution phase still lasts 8-12 hours. During the elimination phase, intravenous and oral digoxin have the same terminal half-lives. THERAPEUTIC AND TOXIC CONCENTRATIONS ❖There is a great deal of inter and intra patient variability in the pharmacodynamic responses to digoxin. Clinically beneficial inotropic effects of digoxin are generally achieved at steady-state serum concentrations of 0.5-1 ng/mL. ❖Increasing steady-state serum concentrations to 1.2-1.5 ng/mL may provide some minor, additional inotropic effect. Chronotropic effects usually require higher digoxin steady-state serum concentrations of 0.8-1.5 ng/mL. ❖Additional chronotropic effects may be observed at digoxin steady-state serum concentrations as high as 2 ng/mL. Because of pharmacodynamic variability, clinicians should consider these ranges as initial guidelines and rely heavily on patient response to monitor digoxin therapy. THERAPEUTIC AND TOXIC CONCENTRATIONS ❖Steady-state digoxin serum concentrations above 2 ng/mL are associated with an increased incidence of adverse drug reactions. At digoxin concentrations of 2.5 ng/mL or above ~50% of all patients will exhibit some form of digoxin toxicity. ❖Most digoxin side effects involve the gastrointestinal tract, central nervous system, or cardiovascular system ❖Most of the gastrointestinal and central nervous system side effects of digoxin are nonspecific and could be caused by many different things. Because of this, clinicians should pay close attention to any new symptoms reported by patients receiving cardiac glycosides. THERAPEUTIC AND TOXIC CONCENTRATIONS ❖Cardiac side effects commonly include second or third degree atrioventricular block, atrioventricular dissociation, bradycardia, premature ventricular contractions, or ventricular tachycardia ❖Central nervous system side effects are headache, fatigue, insomnia, confusion, or vertigo. Visual disturbances can also occur and are manifested as blurred vision and changes in color vision or colored halos around objects oftentimes involving the yellow-green spectrum. ❖In the case of life-threatening digoxin overdose, digoxin antigen-binding fragments or digoxin immune FAB (DigiFab) are portions of digoxin specific antibodies that can be used to rapidly reverse the adverse symptoms PHARMACOKINETIC PARAMETERS: BIOAVAILABILITY ❖Average bioavailability constants (F) for the tablet and oral solution are 0.7 and 0.8. The elixir appears to have a bioavailability of approximately 0.8, and soft gelatine capsules of digoxin appear to be completely absorbed. ❖Digoxin is not usually administered intramuscularly due to erratic absorption and severe pain at the injection site. ❖St. John wort has been reported to reduce the bioavailability of digoxin by approximately 25%. ❖In most cases, antibiotics appear to increase the bioavailability, supposedly by suppressing bacteria in the gastrointestinal tract that metabolize digoxin. The most common class of antibiotics that have been reported to increase digoxin concentrations are macrolides ❖Coadministration of cholestyramine has been reported to decrease the bioavailability of digoxin, and both cholestyramine and charcoal have been suggested as a treatment modality in patients who are digitalis toxic. PHARMACOKINETIC PARAMETERS: VOLUME OF DISTRIBUTION ❖The average volume of distribution for patients without disease states and conditions that change this parameter is 7 L/kg. This V is decreased in patients with renal disease ❖The weight factor used in this calculation for obese patients is ideal body weight (IBW) (if actual body weight is >30% over IBW). ❖Otherwise, the actual body weight is used ❖For a 70kg patient with good renal function, the estimated volume of distribution would be 490 L (V = 7 L/kg • 70kg = 490 L). ❖. For an obese patient with normal renal function whose ideal body weight is 55 kg and total body weight is 95 kg, the estimated volume of distribution would be 385 L: V = 7 L/kg • IBW = 7 L/kg (55 kg) = 385 L. PHARMACOKINETIC PARAMETERS: VOLUME OF DISTRIBUTION ❖For patients with renal dysfunction (creatinine clearance ≤ 30 mL/min), creatinine clearance should be used to provide an improved volume of distribution estimate (V in L) using the following formula: ❖where CrCl is the patient’s creatinine clearance in mL/min. ❖ For example, a 70 kg patient with significant renal dysfunction (CrCl = 10 mL/min) is to receive a loading dose of digoxin and an estimate of digoxin volume of distribution is needed. The estimated volume of distribution for this patient would be 302 L: ❖In patients who are more than 30% above their ideal body weight, volume of distribution (V) estimates should be based on ideal body weight, so the weight factor used in the equation would be IBW. PHARMACOKINETIC PARAMETERS: CLEARANCE ❖Digoxin is predominately eliminated unchanged in the urine, and there is a good relationship between creatinine clearance and digoxin clearance ❖This relationship allows the estimation of the digoxin clearance for a patient which can be used to compute an initial dose of the cardiac glycoside. ❖Mathematically, the equation for the straight line shown in the figure ❖Cl = 1.303 (CrCl) + ClNR, where Cl is the digoxin clearance in mL/min Patients with [circles with solid line] and without [squares with dashed line] moderate severe (NYHA Class III or IV) heart failure PHARMACOKINETIC PARAMETERS: CLEARANCE ❖CrCl is creatinine clearance in mL/min, and ClNR is digoxin nonrenal clearance ❖ A digoxin nonrenal clearance value of 40 mL/min is used for patients without heart failure or who have only mild signs and symptoms of heart failure (NYHA CHF classes I or II) ❖Patients with moderate or severe heart failure (NYHA CHF classes III or IV) have significant decreases in cardiac output which leads to a reduction in liver blood flow and digoxin hepatic clearance. ❖In these cases, digoxin nonrenal clearance is set to equal 20 mL/min in the equation. WHY? PHARMACOKINETIC PARAMETERS: CLEARANCE ❖For example, the estimated digoxin clearance for an individual with a creatinine clearance of 10 mL/min is 53 mL/min if the patient has no symptoms or mild symptoms of heart failure Cl = 1.303 (10 mL/min) + 40 = 53 mL/min, if the patient has moderate to severe symptoms of heart failure Cl = 1.303 (10 mL/min) + 20 = 33 mL/min ❖Taking the patient’s renal function into account when deriving initial doses of digoxin is the single most important characteristic to assess. PHARMACOKINETIC PARAMETERS: CLEARANCE ❖Thyroid hormone regulates basil 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). ❖ Patients who are hypothyroid will have slower metabolic rates and eliminate digoxin more slowly than euthyroid patients (t1/2 = 48 hours with normal renal function). ❖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. intravenous administration of digoxin to hypothyroid, hyperthyroid, and euthyroid patients following a single dose PHARMACOKINETIC PARAMETERS: CLEARANCE: HALF-LIFE ❖The half-life for digoxin is approximately 2 days in patients with normal renal function. ❖In anephric patients, the half-life increases to approximately 4 to 6 days. ❖This increase in the digoxin half-life is less than might be expected based on the reduction in clearance because the volume of distribution is also decreased in patients with diminished renal function ❖Although not unique to digoxin, a change in volume of distribution with decreased renal function is uncommon. DRUG INTERACTIONS ❖Digoxin has an extensive list of drug interactions with other agents. ❖Inhibition of P-glycoprotein, a drug efflux pump which is found in the kidney, liver, and intestine, appears to be involved in the majority of digoxin interactions. ❖ Clinicians should consult a current drug interaction reference when other medications are prescribed to patients receiving digoxin therapy. ❖Quinidine decreases both the renal and nonrenal clearance of digoxin and also decreases the volume of distribution of digoxin. ❖Inhibition of P-glycoprotein may be involved in this interaction. The result of this complex interaction is that concurrent quinidine therapy increases the average steady-state digoxin concentration by 30%-70%. DRUG INTERACTIONS ❖ Verapamil, diltiazem, and bepridil inhibit digoxin clearance and increase mean digoxin steady-state concentrations by various degrees. Of these calcium channel blockers, verapamil is the most potent inhibitor of digoxin clearance, and increases digoxin steady-state serum concentrations up to 70%. ❖Diltiazem and bepridil therapy each increase average digoxin steady-state serum concentrations by about 30%. ❖Amiodarone, and propafenone are antiarrhythmic agents that decrease digoxin clearance. In addition to this drug interaction mechanism, amiodarone also simultaneously increases digoxin oral bioavailability, and it is likely that Pglycoprotein inhibition is involved in the drug interaction between these two drugs. Digoxin steady-state serum concentrations increase two three times over baseline values with concomitant amiodarone therapy DRUG INTERACTIONS ❖Because amiodarone has a very long half-life (~50 hours), the onset of the drug interaction with digoxin can be very long. As serum concentrations of amiodarone slowly increase and approach steady-state values, digoxin clearance and bioavailability are simultaneously slowly changing. ❖The insidious nature of the amiodarone–digoxin drug interaction can make it difficult to detect in patients. ❖Propafenone therapy increases mean digoxin steady-state concentrations by 30%60% in a dose-dependent fashion with propafenone doses of 450 mg/d causing digoxin concentration changes in the lower end of the range and propafenone doses of 900 mg/d causing digoxin concentration changes in the upper end of the range. DRUG INTERACTIONS ❖Cyclosporin has been reported to increase average steady-state digoxin concentrations up to 50%. P-glycoprotein inhibition by cyclosporine is the primary mechanism for this drug interaction ❖About 10% of patients receiving digoxin therapy have significant amounts of Eubacterium lentum in their gastrointestinal tract that metabolizes orally administered digoxin before it can be absorbed. Erythromycin, clarithromycin, and tetracycline are antibiotics that can kill this bacteria. ❖Digoxin steady-state serum concentrations increase an average of 30% in these select patients when one of these three antibiotics have been prescribed. ❖P-glycoprotein inhibition may be one of the mechanisms involved with this interaction involving macrolide antibiotics. TIME TO SAMPLE ❖Plasma samples for routine digoxin level monitoring are ideally obtained 7 to 14 days after a maintenance regimen is initiated or changed. ❖This delay in obtaining digoxin samples helps to ensure that steady state has been attained on the current dosing regimen. ❖Samples may be obtained before steady state is achieved, but caution should be used in assessing the relationship between the current dosing regimen and the eventual steady-state concentration. ❖In addition, in patients with end-stage renal disease, it may take 15 to 20 days to achieve steady state because of the prolonged half-life. ❖Plasma samples obtained within 24 hours of an initial loading dose may help confirm the relationship between the digoxin plasma concentration and pharmacologic response or establish the apparent volume of distribution. TIME TO SAMPLE ❖When plasma samples are obtained this early, however, they are of little value in evaluating the maintenance regimen. ❖Once steady state has been achieved, routine plasma samples for digoxin monitoring should be drawn just before the next dose (trough levels); however, any sampling time that avoids the distribution phase (at least 4 hours following an IV dose or 6 hours following an oral dose) is acceptable. ❖Patients taking digoxin who are to be given amiodarone/dronedarone are likely to require digoxin plasma level monitoring to determine the extent to which the digoxin pharmacokinetics is altered. SERUM DIGOXIN CONCENTRATION AND MORTALITY *Rathore, Saif S., et al. "Association of serum digoxin concentration and outcomes in patients with heart failure." SELECTION OF APPROPRIATE PHARMACOKINETIC MODEL AND EQUATIONS ❖When given by intravenous injection or orally, digoxin follows a two-compartment pharmacokinetic model . ❖After the end of intravenous infusion or after peak concentration has been reached after an oral dose, serum concentrations drop over an 8-12 hour time period because of distribution of drug from blood to tissues (a or distribution phase). ❖After distribution of digoxin is complete, drug concentrations decline more slowly, and the elimination rate constant for this segment of the concentration/time curve is the one that varies with renal function (b or elimination phase). While this model is the most correct from a strict pharmacokinetic viewpoint, it cannot easily be used clinically because of its mathematical complexity. ❖During the elimination phase of the concentration/time curve, digoxin serum concentrations drop very slowly due to the long elimination half-life (36 hours with normal renal function, 5 days with end-stage renal disease). SELECTION OF APPROPRIATE PHARMACOKINETIC MODEL AND EQUATIONS ❖Because of this, a very simple pharmacokinetic equation that computes the average digoxin steady-state serum concentration is widely used and allows maintenance dosage calculation: ❖Css = [F*(X0/τ)]/Cl or X0/τ = (Css • Cl)/F ❖where F is the bioavailability fraction for the oral dosage form (F = 1 for intravenous digoxin), D is the digoxin dose in mcg is the dosage interval in days, and Cl is digoxin clearance in L/d. ❖The equation used to calculate loading dose (LD in mcg) is based on a simple onecompartment model: LD = (Css*V)/F, where Css is the desired digoxin steady-state concentration in mcg/L which is equivalent to ng/mL, V is the digoxin volume of distribution, and F is the bioavailability fraction for the oral LOADING DOSE ❖Loading doses of digoxin are almost always administered in divided doses so that the patient can be evaluated for toxicity and efficacy in the course of receiving the total loading dose. If the patient appears to develop toxicity or is therapeutically controlled, the remainder of the calculated loading dose is withheld. ❖ The usual procedure is to give one-half of the calculated loading dose initially, followed by two doses of one-fourth, and, in some cases, IV doses are divided into four equal parts. ❖However, doses are based on practically, taking into consideration that oral tablets are available as 125 and 250 mcg LOADING DOSE ❖Historically, 6 hours is the usual interval between oral doses because it is the approximate time to ensure that the oral dose of digoxin has been absorbed and distributed into the myocardium. ❖Even following an IV injection, 2 to 4 hours are required for a single dose of digoxin to exhibit most of the effect. ❖In an emergency, when it is important to rapidly achieve pharmacologic effects, clinical decisions about efficacy/toxicity can be made 1 to 2 hours following an IV dose. This is because the majority of digoxin will have been distributed into the tissue compartment, and ≈75% to 90% of the pharmacologic effect can be evaluated at this time. It would still be too soon, however, to evaluate plasma concentrations because of the distribution phase. DOSE CALCULATION ❖The goal of initial dosing of digoxin is to compute the best dose possible for the patient given their set of disease states and conditions that influence digoxin pharmacokinetics and the cardiovascular disorder being treated. ❖In order to do this, pharmacokinetic parameters for the patient will be estimated using average parameters measured in other patients with similar disease state and condition profiles. 1- Estimate creatinine clearance 2- Estimate digoxin clearance 3- Compute digoxin loading dose (if needed) 4- Compute digoxin maintenance dose based on average steady state concentration EXAMPLE 1 ❖MJ is a 50 year-old, 70kg (height = 178 cm) male with atrial fibrillation for less than 24 hours. His current serum creatinine is 0.9 mg/dL, and it has been stable over the last 5 days since admission. Compute an intravenous digoxin dose for this patient to control ventricular rate. EXAMPLE 1 1. Estimate creatinine clearance This patient has a stable serum creatinine and is not obese. The Cockcroft-Gault equation can be used to estimate creatinine clearance➔ CrCL=97 ml/min 2. Estimate digoxin clearance The drug clearance versus creatinine clearance relationship is used to estimate the digoxin clearance for this patient (ClNR = 40 mL/min since the patient does not have moderate severe heart failure) Cl = 1.303 (97 mL/min) + 40 = 167 mL/min 3. Use average steady-state concentration equation to compute digoxin maintenance dose ❖For a patient with atrial fibrillation, the desired digoxin concentration would be 0.8-1.5 ng/mL. A serum concentration equal to 1.2 ng/mL will be chosen for this patient, and intravenous digoxin will be used (F = 1). ❖X0/τ = (Css • Cl)/F ➔1.2 mcg/L*167 ml/min*1440 min/day/(1000ml/L)=288 mcg/day ➔ rounded to 250 mcg/day EXAMPLE 1 ❖Use loading dose equation to compute digoxin loading dose (if needed). ❖The patient has good renal function and is nonobese. Therefore, a volume of distribution equal to 7 L/kg and actual body weight can be used to compute the digoxin loading dose. An intravenous loading dose (F = 1) could be used in this patient to achieve the desired pharmacologic effect quicker than would occur if maintenance doses alone were used and concentrations allowed to accumulate over 3-5 half-lives. V=7*70=490 L Loading dose=Css*V/F ➔ 1.2 mcg/L*490 L= 588 mcg rounded to 500 mcg ❖When digoxin loading doses are administered, they are usually given in divided doses separated by 4-6 hours (50% of dose at first, followed by two additional doses of 25%). In this case, an initial intravenous dose of 250 μg would be given initially, followed by two additional intravenous doses of 125 μg each. One of the loading doses could be withheld if pulse rate was less than 50-60 beats/min or other undesirable digoxin adverse effects were noted. EXAMPLE 2 ❖MJ is a 50 year-old, 70kg (height = 178 cm) male with NYHA Class III moderate heart failure. His current serum creatinine is 3.5 mg/dL, and it has been stable over the last 5 days since admission. Compute an oral digoxin tablet maintenance dose for this patient.. EXAMPLE 2 1. Estimate creatinine clearance This patient has a stable serum creatinine and is not obese. The Cockcroft-Gault equation can be used to estimate creatinine clearance➔ CrCL=25 ml/min 2. Estimate digoxin clearance The drug clearance versus creatinine clearance relationship is used to estimate the digoxin clearance for this patient (ClNR = 20 mL/min since the patient have moderate severe heart failure) Cl = 1.303 (25 mL/min) + 20 = 53 mL/min 3. Use average steady-state concentration equation to compute digoxin maintenance dose ❖For a patient with heart failure, the desired digoxin concentration would be 0.5-1 ng/mL. A serum concentration equal to 0.8 ng/mL will be chosen for this patient, and oral digoxin will be used (F = 0.7). Note that for concentration units ng/mL = μg/L, and this conversion will be made before the equation is used. Also, conversion factors are needed to change milliliter units to liter (1000 mL/L) and minute units to days (1440 min/d). ❖X0/τ = (Css • Cl)/F ➔(0.8 mcg/L*53 ml/min*1440 min/day)/(0.7* 1000mL/day)= 87 mcg/day OR 174 every two days➔ rounded to 125 mcg every two days EXAMPLE 3 ❖OI is a 65yearold, 170kg (height 165.6 cm) female with NYHA Class III moderate heart failure. Her current serum creatinine is 4.7 mg/dL and is stable. Compute an intravenous digoxin loading and maintenance dose for this patient EXAMPLE 3 1. Estimate creatinine clearance This patient has a stable serum creatinine and is obese. The Salazar and Corcoran equation can be used to estimate creatinine clearance: 22 ml/min 2. Estimate digoxin clearance The drug clearance versus creatinine clearance relationship is used to estimate the digoxin clearance for this patient (ClNR = 20 mL/min since the patient has moderate-severe heart failure): Cl = 1.303 (22 mL/min) + 20 = 48 mL/min . EXAMPLE 3 3. Use average steady-state concentration equation to compute digoxin maintenance dose ❖For a patient with heart failure, the desired digoxin concentration would be 0.5-1 ng/mL. A serum concentration equal to 0.8 ng/mL will be chosen for this patient, and intravenous digoxin will be used (F = 1). ❖X0/τ = (Css • Cl)/F ➔0.8 mcg/L*48 ml/min*1440 min/day/(1000ml/L)= 55 mcg/day ➔ This intravenous dose would be rounded to 125mcg every other day. ❖Loading dose: The patient has poor renal function and is obese. Therefore, the volume of distribution equation that adjusts the parameter estimate for renal dysfunction can be used to compute the digoxin loading dose, and ideal body weight will be used as the weight factor. An intravenous loading dose (F = 1) could be given in this patient to achieve the desired pharmacologic effect quicker than would occur if maintenance doses alone were used to allow concentrations to accumulate over 3-5 half-lives. EXAMPLE 3 ❖When digoxin loading doses are administered, they are usually given in divided doses separated by 4-6 hours (50% of dose at first, followed by two additional doses of 25%). In this case, an initial intravenous dose of 125 μg would be given initially, followed by two additional intravenous doses of 62.5 μg each. One of the loading doses could be withheld if pulse rate was less than 50-60 beats/min or other undesirable digoxin adverse effects were noted. USE OF DIGOXIN SERUM CONCENTRATIONS TO ALTER DOSAGES ❖When digoxin serum concentrations are measured in patients and a dosage change is necessary, clinicians should seek to use the simplest, most straightforward method available to determine a dose that will provide safe and effective treatment. In most cases, a simple dosage ratio can be used to change digoxin doses since digoxin follows linear pharmacokinetics. ❖Sometimes, it is not possible to simply change the dose because of the limited number of oral dosage strengths, and the dosage interval must also be changed. ❖Available digoxin tablet strengths are 125 mcg and 250 mcg while digoxin oral solution is available at a concentration of 0.05 mg/mL. In some situations, it may be necessary to compute the digoxin pharmacokinetic parameters for the patient and utilize these to calculate the best drug dose USE OF DIGOXIN SERUM CONCENTRATIONS TO ALTER DOSAGES ❖Finally, computerized methods that incorporate expected population pharmacokinetic characteristics (Bayesian pharmacokinetic computer programs) can be used in difficult cases where renal function is changing, serum concentrations are obtained at suboptimal times, or the patient was not at steady-state when serum concentrations were measured. ❖An additional benefit of this dosing method is that a complete pharmacokinetic workup (determination of clearance, volume of distribution, and half-life) can be done with one or more measured concentrations that do not have to be at steady-state. LINEAR PHARMACOKINETICS METHOD ❖Because digoxin follows linear, dose-proportional pharmacokinetics, steady-state serum concentrations change in proportion to dose according to the following equation: ❖ Dnew/Cssnew = Dold/Cssold or ❖Dnew = (Cssnew/Cssold)Dold ❖In this equation, D is the dose in μg, Css is the steady-state concentration in ng/mL, old indicates the dose that produced the steady-state concentration that the patient is currently receiving, and new denotes the dose necessary to produce the desired steady-state concentration. ❖The advantages of this method are that it is quick and simple. The disadvantages are that steady-state concentrations are required. ❖Also, because of a limited number of solid oral dosage strengths, it may not be possible to attain desired serum concentrations by only changing the dose. In these cases, dosage intervals are extended for patients receiving tablets so that doses can be given as multiples of 125 μg. LINEAR PHARMACOKINETICS METHOD ❖The estimated times to achieve steady-state concentrations on a stable digoxin dosage regimen varies according to renal function ❖An alternative to this way of estimating time to steadystate is to compute the expected digoxin half-life (t1/2 in days) for a patient using digoxin clearance (Cl in L/d) and volume of distribution (V in L) and allow 3-5 halflives to pass before obtaining digoxin serum concentrations: ❖ t1/2 = (0.693 • V)/Cl. EXAMPLE 4 ❖OI is a 65-yearold, 170kg (height = 178) female with NYHA Class III heart failure. Her current serum creatinine is 4.7 mg/dL and is stable. A digoxin dose of 125 μg/d given as tablets was prescribed and expected to achieve steady-state concentrations equal to 1 ng/mL. ❖ After the 3 weeks of therapy, a steady-state digoxin concentration was measured and equaled 2.5 ng/mL. Calculate a new digoxin dose that would provide a steadystate concentration of 1.2 ng/mL. EXAMPLE 4 ❖Based on linear method ❖Dnew = (Cssnew/Cssold)Dold ❖Dnew = (1.2/2.5)*125 =60 mcg/day ❖This would be rounded to digoxin tablets 125 mcg every other day. ❖The new suggested dose would be 125 mcg every other day given as digoxin tablets to be started at next scheduled dosing time. ❖Since the dosage interval is being changed, a day would be skipped before the next dose is given. USE OF DIGOXIN BOOSTER DOSES TO IMMEDIATELY INCREASE SERUM CONCENTRATIONS ❖If a patient has a subtherapeutic digoxin serum concentration in an acute situation, it may be desirable to increase the digoxin concentration as quickly as possible. A rational way to increase the serum concentrations rapidly is to administer a booster dose of digoxin. ❖ A modified loading dose equation is used to accomplish computation of the booster dose (BD), which takes into account the current digoxin concentration present in the patient ➔ BD = [(Cdesired − Cactual) V]/F, ❖where Cdesired is the desired digoxin concentration, Cactual is the actual current digoxin concentration for the patient, F is the bioavailability fraction of the digoxin dosage form, and V is the volume of distribution for digoxin. If the volume of distribution for digoxin is known for the patient, it can be used in the calculation. However, this value is not usually known and is assumed to equal the population average for the patient. EXAMPLE 5 ❖BN is a 52 yearold, 85kg (height = 6 ft 2 in) male with atrial fibrillation who is receiving therapy with intravenous digoxin. He has normal liver and renal function. After receiving an initial loading dose of digoxin (1000 μg) and a maintenance dose of 250 μg/d of digoxin for 5 days, his digoxin concentration is measured at 0.6 ng/mL immediately after pulse rate increased to 200 beats/min. Compute a booster dose of digoxin to achieve a digoxin concentration equal to 1.5 ng/mL. EXAMPLE 5 1. Estimate the volume of distribution: V = 7 L/kg *BW ➔ 7*85 kg = 595 L. 2. Compute booster dose. The booster dose is computed using the following equation: BD = [(Cdesired . Cactual)V]/F ➔ BD= [(1.5 mcg/L - 0.6 mcg/L) * 595 L]/1 = 536 mcg, rounded to 500 mcg of digoxin ❖This booster dose could be split into two equal doses and given 4-6 hours apart with appropriate monitoring to avoid adverse side effects. If the maintenance dose was also increased, it will take additional time for new steady-state conditions to be achieved. Digoxin serum concentrations should be measured at this time CONVERSION OF PATIENT DOSES BETWEEN DOSAGE FORMS ❖When patients are switched between digoxin dosage forms, differences in bioavailability should be accounted for within the limits of available oral dosage forms using the following equation: DIV = DPO*F ❖where DIV is the equivalent digoxin intravenous dose in μg, DPO is the equivalent digoxin oral dose, and F is the bioavailability fraction appropriate for the oral dosage form (F = 0.7 for tablets, 0.8 for oral solution). Where possible, digoxin tablet doses should be rounded to the nearest 125 μg to avoid the necessity of breaking tablets in half. Also, it is best to avoid mixing tablet dosage strengths so that patients do not become confused with multiple prescription vials and take the wrong dose of medication. ❖For example, if it were necessary to prescribe 375 μg/d of digoxin tablets, it would be preferable to have the patient take three 125 μg tablets daily rather than 1½ 250 μg tablets daily or a 125 μg and 250 μg tablet each day. EXAMPLE 6 ❖YT is a 67 year-old, 60kg male (height = 165 cm) with atrial fibrillation receiving 200 μg of intravenous digoxin daily which produces a steady-state digoxin concentration of 1.3 ng/mL. ❖Compute an oral tablet dose that will maintain steadystate digoxin concentrations at approximately the same level. EXAMPLE 5 ❖1. Convert the current digoxin dose to the equivalent amount for the new dosage form/route (tablet/oral). ❖DPO = DIV/F ❖DPO= 200/0.7 ➔ 286 mcg rounded to 250 mcg ❖2. Estimate change in digoxin steady-state concentration due to rounding of dose. ❖The oral tablet dose of 286 μg would have produced a steady-state concentration similar to the intravenous dose of 200 μg. However, the dose had to be rounded to a dose that could be given as a tablet. The expected digoxin steady-state concentration from the rounded dose would be proportional to the ratio of the rounded dose and the actual computed dose: ❖Cssnew = (Cssold/Dcomputed)Drounded➔ 1.3 *250/286= 1.1mcg/mL EXAMPLE 5 ❖The steady-state digoxin concentration after the dosage form change may not be exactly the value calculated due to a variety of causes. Because of interindividual variations in digoxin bioavailability, the patient’s actual bioavailability constant for oral tablets may be different than the average population bioavailability constant used to convert the dose. Also, there are day to day intrasubject variations in the rate and extent of digoxin absorption that will affect the actual steady-state digoxin concentration obtained while taking the drug orally. Finally, other oral drug therapy that did not influence digoxin pharmacokinetics when given intravenously may alter the expected digoxin concentration. EXAMPLE 6 ❖B.G., a 62-year-old, 50-kg 175 cm woman, with heart failure (severe symptoms) was admitted to the hospital for possible digoxin toxicity. Her serum creatinine was 3 mg/dL, and her dosing regimen at home had been 0.25 mg of digoxin tablet daily for many months. The digoxin plasma concentration on admission was 3 mcg/L. How long will it take for the digoxin concentration to fall from 3 to 1 mcg/L? EXAMPLE 6 ❖The answer to this question requires knowledge of the digoxin half-life (t½) or the elimination rate constant (K), both of which are dependent on the clearance and volume of distribution for digoxin in B.G. The relationship between these parameters is described by ❖K=CL/V Crcl=18 ml/min ❖Digoxin clearance (based on average steady state concentration): 58.3 L/day ❖Digoxin volume of distribution: 243 ❖T0.5 =2.89 days ❖Time =Ln(C2/C1)/K➔Ln(3/1)/0.24➔4.6 days EXAMPLE 7 ❖Do patients receiving hemodialysis require additional digoxin following dialysis? EXAMPLE 7 ❖One should first determine whether digoxin is expected to be significantly removed by dialysis. To evaluate digoxin’s unbound volume in a dialysis patient, we need to calculate digoxin’s volume. Assuming a ClCr of 5 mL/min and a weight of 70 kg, and using ❖V=270 L ❖Based on unbound fraction of 0.9 ❖Vu=270/0.9=300 L➔ 300/70➔ 4.3 L/kg EXAMPLE 7 ❖This assessment of digoxin not being significantly removed by dialysis is further supported by the literature. ❖Digoxin has a molecular weight of about 500 Da and will pass through the dialysis membrane; however, most of the digoxin is in the deeper, more slowly equilibrating tissue compartment and is difficult to remove by any intermittent hemofiltration process. EXAMPLE 7 ❖This assessment of digoxin not being significantly removed by dialysis is further supported by the literature. ❖Digoxin has a molecular weight of about 500 Da and will pass through the dialysis membrane; however, most of the digoxin is in the deeper, more slowly equilibrating tissue compartment and is difficult to remove by any intermittent hemofiltration process. EXAMPLE 8 ❖C.B. is a patient with atrial fibrillation who was given digoxin for ventricular rate control. He is taking a maintenance dose of 0.25 mg/day of digoxin. Now, however, amiodarone will be added to C.B.’s drug regimen in an attempt to further control his ventricular response and, it is hoped, to convert him to normal sinus rhythm. What are the pharmacokinetic considerations with regard to the amiodarone–digoxin drug interaction? EXAMPLE 8 ❖Amiodarone is well recognized to decrease both the metabolic and renal clearance of digoxin. Although estimates vary, most patients have about a 50% reduction in digoxin clearance when amiodarone is added to their regimen. ❖While the digoxin volume of distribution may also decrease slightly, the change is small. ❖In addition, amiodarone has a very long t½ and accumulates slowly in the body. As a result, following the initiation of amiodarone, digoxin concentrations rise slowly over a 1- to 2-week period. ❖Given that the change in digoxin disposition is primarily a 50% reduction in clearance, we would expect to reduce the patient’s digoxin maintenance dose by 50% if our goal was to maintain the same steady-state digoxin concentration after the initiation of amiodarone. ❖Although the change in digoxin occurs slowly, most clinicians reduce the digoxin maintenance dose at the time of starting amiodarone to ensure that the change in the digoxin regimen is not forgotten. If the digoxin steady-state concentration was very low at the time of initiating amiodarone, no change in digoxin may be necessary if the goal was to approximately double the digoxin concentration.