Clinical Pharmacokinetics of Digoxin

Dr. Muslim Suardi, MSi., Apt. Faculty of Pharmacy

University of Andalas

1998

Digoxin

The primary cardiac glycoside

Possesses a low therapeutic index dosage Individualization important

Uses

CHF

Because of its inotropic effects on the myocardium

Atrial fibrillation/tachycardia

Because of its chronotropic effects on the electrophysiological system of the heart

HEART FAILURE CLASS DESCRIPTION I. Patients with cardiac disease but without limitations of physical activity. Ordinary physical activity does not cause undue fatigue, dyspnea, or palpitation.

II. Patients with cardiac disease that results in slight limitations of physical activity. Ordinary physical activity results in fatigue, palpitation, dyspnea, or angina.

• III. Patients with cardiac disease that results in marked limitations of physical activity. Although patients are comfortable at rest, less than ordinary activity will lead to symptoms.

• IV Patients with cardiac disease that results in an inability to carry on physical activity without discomfort. Symptoms of CHF are present even at rest. With any physical activity, increased discomfort is experienced.

Absorption

• Not usually administered im-ly due to erratic absorption & severe pain at the injection site

• Oral BA, F, ranges from 0.5-0.9 ng/mL (Ẋ ~ 0.70ng/mL).

• Absorption of oral digoxin from the GIT is influenced by many different compounds

• Food decreased rate, but not extent, of absorption.

Absorption

F is decreased by:- Antacids- Charcoal - Cholestyramine- Kaolin-pectin- Metoclopramide

Vd

Vd is large due to the extensive tissue binding of digoxin in the body

510 L in normal renal function

330 L in patients with RI.

Best described by a 2-comp model

Distribution• The myocardium (target organ) behaves as

though it were in the tissue comp. Since plasma samples are obtained from Vi (or Vc), Cp of digoxin do not accurately reflect the drug’s pharmacological effects until it is completely distributed into both comp

• Digoxin levels obtained prior to complete distribution are often misleading. Because the initial Vd (Vi or Vc) is relatively small (~ 1/10 x V), high plasma levels are commonly reported soon after a dose is administered.

Distribution• Because the heart behaves as though it

were in the second (tissue) comp, these levels are not reflective of either therapeutic or toxic effects.

Distribution

• When given as oral or iv doses, the Cp digoxin–time curve follows a 2-comp model & exhibits a long & large distribution phase of 8-12h

• Therefore, plasma levels should be taken >6h post-dose

• 20-30% bound - no clinical significance.

Elimination

• Digoxin is primarily eliminated unchanged by the kidney ~75% in normal patient.

• So its Cl is predominately influenced by renal function.

• The remainder of a digoxin dose (~25%) is removed by hepatic metabolism or biliary excretion

Metabolism

• Each metabolic step decreases the cardioactivity of the molecule.

• Digoxin & its metabolites, are also present in bile & entero-hepatic cycling occurs

Metabolite Activity

Compared to Digoxin

• Dihydrodigoxin 2-6%

• Dihydrodigoxigenin 2%

• Digoxigenin 4-21%

• Digoxigenin mono-digitoxiside 66%

• Digoxigenin bis-digitoxiside 77%

Clearance

• Digoxin Cl rate decreases in proportion to CrCl, & this relationship will be utilized to aid in the computation of initial doses

• Metabolic Cl of digoxin is 40mL/min in normal patients.• The presence of CHF reduces Cl to 20mL/min.

Renal Excretion

• Digoxin undergoes GF as well as both tubular reabsorption & active secretion.

• ClCr approximates the renal Cl of Digoxin.• ClT = ClR + Clm• ClT = +40mL/min (without CHF)• ClT = +20mL/min (with CHF)

Terminal t½

• Normal renal 1.6 days

• RI 3.5 - 6.0 days

Elimination Half-Live

• t½ =  (0.693 X Vd)/Cl

• Because of the reduction in Vd in renal failure & the variability of Cl, relationship between renal function & t½ is not perfectly clear-cut.

Plasma Level Monitoring of Digoxin

Therapeutic range: 0.8 - 2.0ng/mL1. There is considerable overlap & inter-

patient variability ie. many patients with concentrations > 2ng/mL can tolerate more digoxin without toxicity, while others with concentrations below this may be either close to or already showing toxicity.

2. Many factors can influence myocardial sensitivity to digoxin

Monitoring

Hospitalized patients with severe or acute heart failure may need to have Scr determinations 2–3x weekly to monitor renal function, while ambulatory patients with stable heart failure may only need yearly Scr measurements

Factors can Influence Myocardial Sensitivity to Digoxin

1. Hypokalaemia, hypomagnesaemia, hypothyroidism–sensitivity

2. Successful treatment of arterial fibrillation may require digoxin level of 2.0-4.0ng/mL

Signs of Digitalis Intoxication

Cardiac

GI

Neurological

Vision

Psychiatric

Others

Digitalis Intoxication

Cardiac• Brady- & tachyarrhythmia• Worsening cardiac failureGI • Anorexia • Nausea, vomiting• Diarrhoea• Abdominal pain

Digitalis Intoxication

Neurological• Fatigue, malaise

• Headache, Neuralgic pain• Drowsiness, Convulsions

• Aphasia

Vision• Blurred vision

• Altered color vision• Amblyopia, diplopia

• Ascotomata

Digitalis Intoxication

Psychiatric• Confusion

• Delirium

• Hallucinations

Others • Gynaecomastia

• Skin rashes

Factors that Influence Myocardial Sensitivity to Digoxin 1. Hypo & hyper-kalemia2. Hypercalcemia3. Hypo & hyper-magnesemia4. Acid base disorders5. Myocardial ischemia6. Hypoxemia7. Underlying heart disease8. Automatic nervous system tone9. Pulmonary disease

Special Situations Requiring Care in Digoxin Dosage

1. Age (children, elderly)

2. RI

3. Electrolyte disturbance (K, Mg, Ca, Na)

4. Severe heart disease

5. Thyroid disease

6. Lung disease with hypoxaemia

7. Pregnancy

When should Digoxin levels be Monitored?

1. When standard doses would not be expected to produce satisfactory effect without toxicity, eg. RI, hypokalemia, hyper/hypo-thyroidism

2. When toxicity is suspected, eg. anorexia, nausea, vomiting, confusion in the elderly, visual disturbances or arrhythmias.

3. When compliance is in doubt.

4. When a digoxin-drug interaction is known or suspected.

Side EffectsMost digoxin side effects involve:

• GIT

• CNS

• Cardiovascular system

GI-related Adverse Effects

• Anorexia

• Nausea, vomiting

• Diarrhea, abdominal pain

• Constipation.

CNS Side Effects

Headache

Fatigue, insomnia

Confusion, vertigo

Visual disturbances are manifested as blurred vision & changes in color vision or colored halos around objects often times involving the yellow-green spectrum.

GI & CNS Side Effects of Digoxin

• Most of the GI & CNS side effects of digoxin are nonspecific & 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.

Cardiac Side Effects

Commonly include:

• Second/third degree atrioventricular block

• Atrioventricular dissociation

• Bradycardia

• Pemature ventricular contractions

• Ventricular tachycardia.

Toxic Effects of Digoxin1. GI: Anorexia, nausea, vomiting

2. CNS: Weakness, lethargy

3. Visual: Blurred vision, yellow/green tinting or halos, red-green color blindness.

4. Cardiac: PVC’s heart block, ventricular tachycardia.

Drug Interactions

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

Factors Influencing Digoxin Cl & Plasma Levels

Renal disease.

Age (via renal function).

Other drugs.

Reduced Digoxin Levels

1. Cholestyramine2. Antacid gels3. Kaolin, Pectin 4. Neomycin 5. Sulphasalazine6. PAS7. Vasodilators, eg. Hydralazine8. Rif9. Antineoplastic   

Increased Digoxin Levels

• Antibiotics (in certain individuals)• Quinidine, quinine, hydroxychloroquine• Amiodarone• Verapamil• Diltiazem• Frusemide, spironolactone• Triamterene• Amiloride• Indomethacin

Mechanism of Interaction

• Quinidine decreases both the renal & nonrenal Cl & also decreases the Vd of digoxin.

• Verapamil, diltiazem, & bepridil inhibit digoxin Cl & increase mean digoxin SS concentrations by various degrees

• Amiodarone & propafenone are antiarrhythmic agents that decrease digoxin Cl

Drugs that Alter Digoxin Cl

• Drug : Spironolactone• Effect on Cp: Increasing • Mechanism : Inhibition of tubular

secretion

• Drug : Verapamil • Effect on Cp: Increasing • Mechanism : Decreased renal &

extrarenal Cl

INITIAL DOSAGE DETERMINATION METHODS

• Pharmacokinetic dosing method: • CLEARANCE ESTIMATE• VOLUME OF DISTRIBUTION ESTIMATE• SELECTION OF APPROPRIATE

PHARMACOKINETIC MODEL AND EQUATIONS• STEADY-STATE CONCENTRATION SELECTION

BAYESIAN PHARMACOKINETIC• COMPUTER PROGRAMS

• Jelliffe method

Clinical Application of Pharmacokinetic Data

Estimation of

MD

LD

Estimation of MD

Css = (F x DC) / (Cl xד) D/ ד  = (Css x Cl) / F

Digoxin Cl can be estimated:

Cl = ClCR + 40 mL/min (without CHF)

Cl = ClCR + 20 mL/min (with CHF)

Use TDM to individualize dosage more accurately!

Estimation of LD

IV : LD = Vd x Cdesired

Oral : MD = LD (1 – e–k t)

• LD of digoxin are almost always administered in divided doses, so that the patient can be evaluated for toxicity & efficacy prior to receiving the total LD. Eg. 1/2 the calculated LD initially followed by 1/4 in 6 hrs & the remaining 1/4 after a further 6h.

Clinical Examples

A 50 year old male patient (70kg) with HF & RI (SCr 0.44 mmol/L) is to be commenced on digoxin

1. Estimate the oral daily dose that would maintain the average digoxin Cp at 1.5ng/mL

2. How long will it take to achieve SS levels?3. Suggest an oral LD protocol for this patient

Clinical Examples

A 62 year old woman weighing 45kg was admitted to the hospital for possible digoxin toxicity. Her SCr was 0.17mmol/L & her dosing regimen at home was 0.25mg digoxin daily for many months, for HF.Digoxin Cp on admission was reported to be 3.5ng/mL.

1. How long will it take for the digoxin level to fall from 3.5 to 2.0 ng/mL?

2. How do the patient’s actual & predicted Cl of digoxin compare?

3. What daily dose should she receive to maintain an average Cp of 1.5ng/mL.

Terminology

Lethargy = keadaan mengantuk/tdk peduli

Yellow/green tinting or halos =

PVC’s heart block =

Ventricular tachycardia

Delirium = gangguan mental

Hallucinations = persepsi sensorik tanpa adanya sumber dalam dunia luar

Gynaecomastia = perkembangan berlebihan kelenjar susu lelaki