Clinical Pharmacokinetics (PPD-106) Clinical Pharmacy Diploma
TDM Digoxin
Mechanism of Action:
Digoxin inhibits sodium-potassium 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.
Digoxin increases the contractility of myocardial contraction - Heart failure patient
C.O.P): decrease heart size, venous pressure, and blood volume
Diuresis - relief of edema
Slow the ventricular rate in atrial fibrillation or flutter
The effects of digoxin in heart failure is mediated by its positive inotropic whereas
the effects of the drug in atrial arrhythmias are related to its vagomimetic actions
(=Ach)
Therapeutic Uses:
1. Congestive heart failure: used regardless of whether the failure is predominantly of
left or right ventricle or both (because of its chronotropic effects)
2. Atrial fibrillation & in Atrial flutter because of its chronotropic effects (that mediated
via increased parasympathetic activity and vagal tone on the electrophysiological
system of the heart. It is also possible to use digoxin in combination with a β-blocker
or a calcium channel blocker
3. Paroxysmal tachycardia
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Clinical Pharmacokinetics (PPD-106) Clinical Pharmacy Diploma
THERAPEUTIC AND TOXIC CONCENTRATIONS
Two - Three compartmental models, linear PK within the therapeutic range
Absorption:
Variable depending upon the formulation used: Following oral administration,
peak serum concentrations of digoxin occur at 1 - 3 hr.
Absorption of digoxin from Digoxin Tablets has been demonstrated to be 60% to
80% complete compared to an identical intravenous dose of digoxin
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.
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.
Therapeutic Range: 0.8 to 2.0 ng/ml (0.5 -1 ng/ml could be effective with less toxicity
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Clinical Pharmacokinetics (PPD-106) Clinical Pharmacy Diploma
in CHF: inotropic effect)
For Atrial Fibrillation: Chronotropic effects usually require higher digoxin steady-
state serum concentrations of 0.8–1.5 ng/mL.
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.
Contraindications: V-fibrillation; hypokalemia; WPW syndrome with wide complex.
In the case of life-threatening digoxin overdose, digoxin antigen binding fragments
or digoxin immune Fab (Digibind) are portions of digoxin-specific antibodies that can
be used to rapidly reverse the adverse
CLINICAL MONITORING PARAMETERS
In patients receiving digoxin for heart failure, the common signs and symptoms of
CHF should be routinely monitored; left-sided failure—dyspnea on exertion,
paroxysmal nocturnal dyspnea, orthopnea, tachypnea, cough, hemoptysis,
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Clinical Pharmacokinetics (PPD-106) Clinical Pharmacy Diploma
pulmonary rales/edema, S3 gallop, pleural effusion, Cheyne-Stokes respiration;
right-sided failure—abdominal pain, anorexia, nausea, bloating, constipation,
ascites, peripheral edema, jugular venous distention, hepatojugular reflux,
hepatomegaly; general symptoms—fatigue, weakness, nocturia, CNS symptoms,
tachycardia, pallor, digital cyanosis, cardiomegaly.
Digoxin & atrial fibrillation
When used for the treatment of atrial fibrillation, digoxin will not stop the atrial
arrhythmia but is used to decrease, or control, the ventricular rate to an acceptable
value (usually <100 beats/min). The patient’s pulse or ventricular rate should be
monitored using electrodiagram
Atrial fibrillation is characterized by 400–600 nonuniform atrial beats/min. Sinus
rhythum will not be restored with the use of digoxin alone although atrial fibrillation
can spontaneously remit. Depending on the symptomatology experienced by the
patient, cardioversion can be attempted by using direct electrical current or by the
use of an antiarrhythmic agent such as flecainide, dofetilide, propafenone,
amiodarone, or ibutilide.
Adequate anticoagulation to prevent thromboembolism is needed before
cardioversion if atrial fibrillation has occurred for longer than 48 hours
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Clinical Pharmacokinetics (PPD-106) Clinical Pharmacy Diploma
Digoxin & cornary artery disease
Patients with severe heart disease such as cornary artery disease (angina,
myocardial infarction) can have increased pharmacodynamic sensitivity to cardiac
glycosides, so should be monitored closely for adverse drug effects.
Digoxin & Electrolytes
(Augmented pharmacologic responses to digitalis derivatives occur with serum
electrolyte disturbances such as hypokalemia, hypomagnesemia, and
hypercalcemia even though steady-state digoxin serum concentrations are in the
therapeutic range)
Serum potassium concentrations should be routinely monitored in patients
receiving digoxin and potassium-wasting diuretics. Potassium supplementation may
be necessary in some of these patients.
Also, many patients receiving digoxin and diuretics will be receiving angiotensin I
converting enzyme (ACE) inhibitors which can cause potassium retention.
When receiving all three drugs, it can be difficult to reasonably ascertain what the
patient’s serum potassium status is without measuring it.
As an adjunct to the patient’s clinical response, post-distribution (8–12 hours)
steady-state digoxin serum concentrations can be measured 3–5 half-lives after a
stable dose is initiated. Serum creatinine measurements can be used to detect
changes in renal function which may result in digoxin clearance and concentration
alterations. Hospitalized patients with severe or acute heart failure may need to
have serum creatinine determinations 2–3 times weekly to monitor renal function,
while ambulatory patients with stable heart failure may only need yearly serum
creatinine measurements.
BASIC CLINICAL PHARMACOKINETIC PARAMETERS
The primary route of digoxin elimination from the body is by the kidney via
glomerular filtration and active tubular secretion of unchanged drug (~75%). The
remainder of a digoxin dose (~25%) is removed by hepatic metabolism or biliary
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Clinical Pharmacokinetics (PPD-106) Clinical Pharmacy Diploma
excretion. The primary transporter involved in active tubular secretion and biliary
excretion is p-glycoprotein (PGP).
Digoxin is not usually administered intramuscularly due to erratic absorption and
severe pain at the injection site.
Plasma protein binding is ~25% for digoxin.
Usual digoxin doses for adults are 250 μg/d, (range: 125–500 μg/d) in patients with
good renal function (creatinine clearance ≥80 mL/min) and 125 μg every 2–3 days
in patients with renal dysfunction (creatinine clearnace ≤15 mL/min).
EFFECTS OF DISEASE STATES AND CONDITIONS ON DIGOXIN
PHARMACOKINETICS AND DOSING
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Clinical Pharmacokinetics (PPD-106) Clinical Pharmacy Diploma
Elimination:
Follows first-order kinetics
Because digoxin is principally eliminated by the kidney, renal dysfunction is the most
important disease state that effects digoxin pharmacokinetics.
Digoxin clearance is proportional to creatinine
clearance for patients with moderate-severe
(NYHA class III or IV) heart failure [circles with
solid line: Cl = 1.303 (CrCl) + 20]
and without [squares with dashed line:
Cl = 1.303 (CrCl) + 40]
Non-renal clearance is lower for patients with
moderate-severe heart failure because reduced
cardiac output results in decreased renal blood
flow and digoxin renal clearance.
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Clinical Pharmacokinetics (PPD-106) Clinical Pharmacy Diploma
t1/2 depends upon the renal function - CrCl, age
* In normal renal function, digoxin has a half-life of 1.5 to 2.0 days.
* The half-life in anuric patients is prolonged to 3.5 to 5 days.
Distribution:
Two–C model
Distributed slowly in the body, it has a large Vd & is widely distributed to leantissues,
including the heart, brain, erythrocytes and skeletal muscles.
Tissue concentrations > 60 -100 times plasma conc.
Digoxin crosses both the blood-brain barrier and the placenta.
Vd Decreased in patients with renal impairment! Why? Therefore, the loading dose
should be decreased.
Digoxin is not significantly eliminated by hemodialysis or peritoneal dialysis, or
exchange transfusion or during cardiopulmonary bypass because most of the drug
is bound to tissue and does not circulate in the blood.
Hemofiltration does remove digoxin with a typical sieving coefficient of 0.7
Thyroid hormone & Digoxin kinetics
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), kidney (renal blood flow and glomerular filtration rate).
Patients who are hypothyroid will have slower metabolic rates and eliminate digoxin
more slowly than euthryoid 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
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Clinical Pharmacokinetics (PPD-106) Clinical Pharmacy Diploma
digoxin. Generally, these patients require higher digoxin doses to control ventricular
rate because of the increase in digoxin clearance.
Digoxin & neonates
Similar to other drugs, digoxin clearance is lower in neonates and premature infants
because renal and hepatic function are not completely developed.
Premature infants and neonates have average digoxin half-lives equal to 60 hours
and 45 hours, respectively.
In older babies and young children (6 months to 8 years old) renal and hepatic
function are fully developed and half-lives can be as short as 18 hours.
Older children (≥12 years old) have mean digoxin half-lives (t1/2 = 36 hours) that
are similar to those found in adults.
Also, volume of distribution is larger in infants and children compared to adults
Digoxin & Malabsorption
Malabsorption of oral digoxin has been reported in patients with severe diarrhea,
radiation treatments to the abdomen and gastrointestinal hypermotility.
In these cases, steady-state digoxin serum concentrations decrease due to poor
bioavailability of the drug.
Drug Interactions:
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Clinical Pharmacokinetics (PPD-106) Clinical Pharmacy Diploma
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.
Quinidine decreases both the renal and non-renal clearance of digoxin through
Inhibition of P-glycoprotein. This complex interaction results in that quindine
therapy increases the average steady-state digoxin concentration by 30–70%.
Calcium channel blockers like Verapamil & diltiazem inhibit digoxin clearance and
increase mean digoxin steady-state concentrations by various degrees. Verapamil is
the most potent inhibitor of digoxin clearance, and increases digoxin steady state
serum concentrations up to 70% while Diltiazem therapy each increase average
digoxin steady-state serum concentrations by about 30%. Amiodarone as
antiarrhythmic agent decreases digoxin clearance.
Aminodarone also simultaneously increases digoxin oral bioavailability, and it is
likely that P-glycoprotein inhibition is involved in the drug interaction between
these two drugs. Digoxin steady-state serum concentrations increase 2–3 times over
baseline values with concomitant amiodarone therapy.
Cyclosporine therapy has been reported to increase average steady-state digoxin
concentrations up to 50%. P-glycoprotein inhibition by cyclosporine is the primary
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Clinical Pharmacokinetics (PPD-106) Clinical Pharmacy Diploma
mechanism for this drug interaction.
Erythromycin, clarithromycin, and tetracycline are antibiotics that can kill
Eubacterium letum that metabolizes orally administered digoxin before it can be
absorbed so Digoxin steady-state serum concentrations increase with 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.
Aluminum-containing antacids and kaolin-pectin physically adsorb digoxin rending
it un-absorbable (These compounds should be administered no closer than 2 hours
to an oral digoxin). Similarly, cholestyramine also reduces digoxin oral bioavailability
by binding it in the gastrointestinal tract and should be given no closer than 8 hours
to a digoxin oral dose.
Propantheline increases oral digoxin bioavailability by prolonging gastrointestinal
transit time, while metoclopramide and cisapride decreases oral digoxin
bioavailability by decreasing gastrointestinal transit time
Problems
Example 1: MJ is a 50-year-old, 70-kg (5 ft 10 in) 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
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Clinical Pharmacokinetics (PPD-106) Clinical Pharmacy Diploma
Example 2: Same patient profile as in example 1, but serum creatinine is 3.5 mg/dL
indicating renal impairment.
Example 3: Same patient profile as in example 1, but serum creatinine is 3.5 mg/dL
indicating renal impairment. Additionally, the patient is being treated for NYHA class
III moderate heart failure, not atrial fibrillation. Compute an oral digoxin tablet
maintenance dose for this patient.
Example 4: OI is a 65-year-old, 170-kg (5 ft 5 in) 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.
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Clinical Pharmacokinetics (PPD-106) Clinical Pharmacy Diploma
Linear Pharmacokinetics Method problems:
MJ is a 50-year-old, 70-kg (5 ft 10 in) male with moderate heart failure. His current
serum creatinine is 0.9 mg/dL, and it has been stable over the last 6 months. A
digoxin dose of 250 μg/d using oral tablets was prescribed and expected to
achieve steady-state concentrations equal to 0.8 ng/mL. After a week of
treatment, a steady-state digoxin concentration was measured and equaled 0.6
ng/mL. Calculate a new digoxin dose that would provide a steady-state
concentration of 0.9 ng/mL
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