Field of pharmacy sciences

Bachelor of pharmacy Phram-D program (Clinical Pharmacy)

Clinical Pharmacokinetics
PPP 517
Autumn semester 2024

Dr : Haitham Saeed Date : 30 / 11 /2024

Digoxin
 Introduction
• Digoxin is an inotropic agent primarily used to treat
congestive heart failure (CHF) and atrial fibrillation (AF).

• It is incompletely absorbed and once absorbed, a

substantial fraction is cleared by the kidneys.
Introduction
 THERAPEUTIC PLASMA CONCENTRATIONS

• Therapeutic range of 0.5 to 0.9 mcg/L is indicated for patients

with CHF.

• Greater risk for toxicity occurs with digoxin concentrations ≥

1.2 mcg/L.

• For patients on digoxin for atrial fibrillation, the goal for

digoxin is rate control.

• Rate control is achieved by atrioventricular (AV) nodal blockade

and may require higher digoxin concentrations (0.5 -2 mcg/L).
 THERAPEUTIC PLASMA CONCENTRATIONS
90 free 10 bound

• Very little digoxin is bound to plasma proteins, only about 10%,

(FU=0.9)→ a change in the desired therapeutic plasma
concentration is unlikely to result from plasma protein
displacement.

• → It is important to note that dialysis can induce digitalis

toxicity by altering serum electrolyte concentrations and acid-
base balance.
 BIOAVAILABILITY (F)
correction is important

• The bioavailability of digoxin tablets ranges from 0.5 to

greater than 0.9. Many clinicians use a bioavailability of
0.7 to 0.8.

• Various antibiotics have also been reported to alter the

bioavailability of digoxin.
• →The most common class of antibiotics that have been
reported to increase digoxin concentrations are macrolides
(by decreasing normal flora)
 VOLUME OF DISTRIBUTION (V)

• The average volume of distribution for digoxin is ≈ 7.3 L/kg.

• This V is decreased in patients with renal disease and hypothyroid patients and
increased in hyperthyroid.
• Due to digoxin’s hydrophilic nature, it does not significantly distribute into adipose
tissue
• The volume of distribution for digoxin in obese subjects appears to be more closely
related to the non-obese or ideal body weight (IBW) than total body weight (TBW).
 VOLUME OF DISTRIBUTION (V)

Hyper-th

5 mg/L
Hypo-th
RF

20 mg/L
 VOLUME OF DISTRIBUTION (V)

• The distribution of digoxin follows a two-compartment model.

• Digoxin first distributes into a small initial volume of distribution, Vi,

consisting of plasma and other rapidly equilibrating tissues.
• Then distributes into a larger and more slowly equilibrating tissue
compartment (Vt).
• The myocardium responds pharmacologically as though it were
located in the larger more slowly equilibrating tissue compartment (Vt).
 VOLUME OF DISTRIBUTION (V)

• Since plasma samples are obtained from Vi, plasma digoxin levels do not
accurately reflect the drug’s pharmacologic effects until the digoxin is completely
distributed into both compartments.

• Serum concentrations of digoxin obtained before complete distribution are often

misleading.

• Plasma concentrations are only meaningful when obtained after equilibration is

complete (i.e., at least 4 hours after an IV dose or 6 hours after an oral dose).
 VOLUME OF DISTRIBUTION (V)
• The clinical effects of a dose, however, may be → observed much sooner than 4 to

6 hours → because the distribution half-life t1⁄2 is only about 35 minutes.

• After approximately two t1⁄2’s (i.e., 1 hour), the myocardium experiences the

effects of 75% of an IV dose.

• However, a plasma sample taken at this time would be misleadingly high because

the remaining 25% of the dose which is not yet distributed out of Vi would produce

a plasma concentration that is high relative to that which would be observed once

equilibrium between the two compartments is complete

VOLUME OF DISTRIBUTION (V)
 CLEARANCE (Cl)
• In healthy individuals,
– The metabolic clearance of digoxin is ≈ 0.57 to 0.86 mL/kg/min (15-20%)
– The renal clearance is approximately equal to or a little less than
creatinine clearance.

• In Congestive heart failure

▪ CHF reduces the metabolic clearance of digoxin to about → one-
half (50%) its usual value and may reduce the renal clearance
slightly as well.
 CLEARANCE (Cl)
• The total digoxin clearance in mL/kg/min can be calculated in patients
with and without CHF as follows:

• IBW should also be used to estimate digoxin clearance (renal and

metabolic) in obese patients.

• ClDigoxin (Patients with CHF) equation is the more conservative

approach and is recommended to use even in patients without a
diagnosis of heart failure.
 CLEARANCE (Cl)
Most Common Factors That Alter Digoxin
Volume of Distribution and Clearance
Volume of distribution Clearance
• Creatinine clearance • Creatinine clearance
• Obesity IBW • Obesity IBW
• Clinically hypothyroid 0.7 • Clinically hypothyroid 0.7
• Clinically hyperthyroid 1.3 • Clinically hyperthyroid 1.3
• Quinidine 0.7 • Congestive heart failure
• Quinidine 0.5
• Amiodarone 0.5
• Verapamil 0.75
CLEARANCE (Cl)
 CLEARANCE (Cl)

• The time course for the expected change in digoxin

concentrations will depend on whether the drug interaction
alters digoxin volume of distribution or clearance or both.

• When drugs are added to a patient’s therapy that can alter the disposition
of digoxin, the nature of the drug interaction and expected change in
half-life should provide some clues as to the time course and extent of
the expected change in the digoxin concentration.
 HALF-LIFE (t1⁄2)
• The half-life for digoxin is approximately 2 days in patients with normal
renal function.
• In a nephric patients, the half-life increases to approximately 4 to 6 days.
• 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 elminate digoxin
faster than euthyroid patients (t1/2 = 24 hours with normal renal function).
 HALF-LIFE (t1⁄2)
• Similar to other drugs, digoxin clearance is lower in neonates and
premature infants because renal and hepatic functions 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.
 HALF-LIFE (t1⁄2)

Dependent on organ function Dependent on clearance

Premature Neonates 6 months – >12 year - Hypothyroi Hyperthyro Renal

infant 8 years adult dism idism failure

60 hrs 45 hrs 18 hrs 36 hrs 48 hrs 24 hrs 4-6 days

 TIME TO SAMPLE

Note: There is a large overlap between toxic and therapeutic

levels. When interpreting serum digoxin levels, monitor
patient for efficacy and toxicity as → level alone may be
misleading.

→ Hence, digoxin levels are most useful when ordered in the

context of a patient's symptoms and clinical condition.
 TIME TO SAMPLE

• Digoxin Serum Levels-when to measure:

a) Concern about compliance, or inadequate digoxin history.
b) Suspected toxicity of such severity that → Digibind® may be
required for therapy.
c) Inadequate therapy despite high doses.
d) Drug interactions (e.g. amiodarone, verapamil)
Stable dose →An annual SDC measurement is sufficient.
 TIME TO SAMPLE

• Falsely elevated serum digoxin concentration (SDC) can

be caused by → endogenous digoxin-like substances
(EDLS) in patients with → renal or liver impairment,
pregnant and neonates.
 TIME TO SAMPLE
• Physical activity → increase binding of digoxin to
skeletal muscle. → So 2hr rest is required before
sample time.

• For out-patients → the appointment should be

scheduled to ensure that the daily dose has not been
taken.

• For hospitalized → patients trough concentration

should be scheduled 1-4 hrs before next dose.
 Dose adjustment
• Serum digoxin concentrations should be interpreted within the clinical context.

• It is generally accepted that when the concentration is above the therapeutic range,
the dose should be reduced even in the absence of obvious toxicity.
• → This is because the patient is at risk of arrhythmia and there is probably no
additional efficacy associated with a high concentration.

• On the other hand, toxicity can occur with concentrations within the therapeutic
range. → This may result from several known factors that change tissue sensitivity
to digoxin and alter the therapeutic index.
 Dose adjustment
Factors altering digoxin sensitivity and the
likelihood of toxicity
Increased sensitivity Decreased sensitivity

Hypokalaemia Hyperkalaemia
Hypercalcaemia Hypocalcaemia
Hypothyroidism Hyperthyroidism
Hypoxia/acidosis Neonates
 Digoxin Immune Fab (Ovine)
• Digoxin Immune Fab (Ovine) is the generic name for an
antidote for overdose of digitalis.
• Its brand names include Digibind and DigiFab.

• Digoxin conc. → in the presence of Digoxin immune fab is

increased by 10-20 fold in total serum digoxin.

• It works by binding to the digoxin, rendering them unable to

bind to their sites of action on target cells. →The complexes
accumulate in the blood and are expelled by the kidney.
 Antidote dosing
Condition Dose of Digoxin Dose of Digibind

Each vial of digoxin immune Fab 40 mg will bind ~0.5 mg of digoxin

Acute digoxin ingestion Known dose For each 0.5 mg of digoxin give 1 vial of
digibind

Unknown dose Initial: 10 vials; if needed, administer a

second dose of 10 vials

Chronic Toxicity Steady-state Digoxin Immune Fab Dose (vials) =

serum digoxin concentration (serum digoxin concentration [ng/mL] x
known weight [kg]) / 100
Unknown conc. 6 vials is adequate to reverse most cases
of toxicity.
 Summary.

• It must be emphasized that SDC do not predict efficacy

or toxicity.
• SDC should be use only to complement good clinical
judgment.
• Strict attention should be given to the time of last dose.
• Factors that could enhance digoxin toxicity should be
considered.
 KEY PARAMETERS
Therapeutic Range
CHF 0.5-0.9 mcg/L
Non CHF 0.5-2 mcg/L for atrial fibrillation and ventricular rate control
Bioavailability (F)
Tablets 0.7
Elixir 0.8
Soft gelatine capsule 1
S (Salt factor) 1
Volume of distribution V (L) 3.8 (Weight in kg) + 3.1 (ClCr in mL/min)
Cl (mL/min)
Non-CHF patients 0.8 mL/kg/min (Weight in kg) + (ClCr in mL/min)
Patients with CHF 0.33 mL/kg/min (Weight in kg) + 0.9 (ClCr in mL/min)
Half-life (t1/2) 2 days (in a nephric patient: 4-6 days)
Fraction unbounded in plasma (fu) 0.9