3. Plasma Level Monitoring of Digoxin:

Therapeutic range: 1.0 - 2.6nmol/L (0.8 - 2.0ng/ml).

NB 

(i) There is considerable overlap and inter-patient variability. Ie. many patients with concentrations greater than 2ng/ml can tolerate more Digoxin without toxicity, while others with concentrations below this may be either close to or already showing toxicity.

(ii) Many factors can influence myocardial sensitivity to Digoxin,

Eg:-

- Hypokalaemia, hypomagnesaemia, hypothyroidism - sensitivity.

- Successful treatment of arterial fibrillation may require Digoxin level of 2.0 - 4.0ng/ml.

 

Symptoms and signs of digitalis intoxication:

- Cardiac:

- Brady- and tachyarrhythmias
- Worsening cardiac failure

- Gastrointestinal:

- Anorexia
- Nausea, vomiting
- Diarrhoea
- Abdominal pain

- Neurological:

- Fatigue, malaise
- Headache
- Drowsiness
- Neuralgic pain
- Convulsions
- Aphasia

- Vision:

- Blurred vision
- Altered colour vision
- Amblyopia, diplopia
- Ascotomata

- Psychiatric:

- Confusion
- Delirium
- Hallucinations

- Other:

- Gynaecomastia
- Skin rashes

 

Factors that influence myocardial sensitivity to Digoxin:

1. Hypokalemia; hyperkalemia

2. Hypercalcemia

3. Hypomagnesemia, hypermagnesemia

4. Acid base disorders

5. Myocardial ischemia

6. Hypoxemia

7. Underlying heart disease

8. Automatic nervous system tone

9. Pulmonary disease

 

Special situations requiring care in Digoxin dosage:

- Age

- Children
- Elderly

- Renal impairment

- Electrolyte disturbance

- Potassium
- Magnesium
- Calcium
- Sodium

- Severe heart disease

- Thyroid disease

- Lung disease with hypoxaemia

- Pregnancy

 

When should Digoxin levels be monitored?

1. When standard doses would not be expected to produce satisfactory effect without toxicity, eg. renal insufficiency, hypokalaemia, hyper- or hypothyroidism.

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.

 

4. Toxic Effects of Digoxin:

- GI - Anorexia, nausea, vomiting.

- CNS - Weakness, lethargy.

- Visual - Blurred vision, yellow/green tinting or halos, red-green colour blindness.

- Cardiac - PVC’s heart block, ventricular tacchycardia.

 

5. Factors Influencing Digoxin Clearance and Plasma Levels:

- Renal disease.

- Age (via renal function).

- Other drugs.

Drugs that alter Digoxin clearance
Drug	Effect on Cp	Mechanism(s)
Spironolactone		Inhibition of tubular secretion.
Amiloride	?	Increased renal tubular secretion, decreased extrarenal clearance.
Nifedipine		?
Verapamil		Decreased renal and extrarenal clearance.
Aminodarone		?
Rifampin		? Enhanced Metabolism.
Diazepam		? Decreased renal clearance.
Quinidine		Reduced tissue binding, decreased clearance.
? Nonsteroidal Antiinflammatory agents		? Reduced renal clearance in canines.

Drugs that alter Digoxin levels
Reduced Digoxin levels	Increased Digoxin levels
Cholestyramine	Antibiotics (in certain individuals)
Antacid gels	Quinidine
Kaolin/pectin	Quinine
Neomycin	Hydroxychloroquine
Sulphasalazine	Aminocdarone
Para-aminosalicylic acid	Verapamil
Vasodilators, eg. Hydralazine	Diltiazem
Rifampicin	Frusemide
Antineoplastic	Spironolactone
	Triamterene
	Amiloride
	Indomethacin

 

Drugs which increase Digoxin levels
Drug	Expected increase in Digoxin level (%)
Antiarrhythmics Amiodarone Quinidine	100 100 - 120
Calcium antagonists Diltiazem Nifedipine Verapamil	20 - 60a 0 - 45b 70
Aldosterone antagonist Spironolactone	35
a This interaction is highly variable with a mean increase of 30% (Chaffman & Brogden 1985). b This interaction is controversial. The likelihood of clinically significant interaction is low (Freedman 1986).

6. Clinical Application of Pharmacokinetic Data:

(a) Estimation of maintenance dose:

		F x D
C	=	___________
		Cl x
	.
		Css X Cl
D/	=	___________
		F

 

Table 1 A guide to Digoxin Dosage¶
Loading dose (use only when urgent digitalisation is required)
Oral Intravenous	0.75 - 1.5mg 0.5 - 1.0mg
Average daily maintenance dose
Oral	0.125 - 0.5mg
Daily dose according to creatinine clearance (ml/min)§
50 - 100 25 - 50 < 25	75% 60% 30%
¶ Digoxin is available in 0.0625mg and 0.25mg tablets; 0.05mg/ml elixir; and 0.05mg/2ml and 0.5mg/2ml injection  § If Digoxin toxicity occurs despite a daily dose as low as 0.0625mg then increase dosage interval appropriately.

Where Digoxin clearance can be estimated:-

Cl	Cl + 40ml/min (without CHF)
	Cl + 20ml/min (with CHF)

NB Use TDM to individualise dosage more accurately.

 

(b) Estimation of loading dose:

(i) IV : LD = Vd x C

(ii) Oral : MD = LD (1 - e)

Loading doses of Digoxin are almost always administered in divided doses, so that the patient can be evaluated for toxicity and efficacy prior to receiving the total loading dose. Eg. one-half the calculated loading dose initially followed by one-fourth in six hours and the remaining one-fourth after a further six hours.

 

7. Clinical Examples:

(a) A 50 year old male patient (70kg) with heart failure and renal impairment (serum creatinine 0.44 mmol/L) is to be commenced on Digoxin:-

(i) Estimate the oral daily dose that would maintain the average Digoxin plasma concentration at 1.5ng/ml.

(ii) How long will it take to achieve steady-state levels?

Suggest an oral loading dose protocol for this patient.

 

(b) A 62 year old woman weighing 45kg was admitted to the hospital for possible Digoxin toxicity. Her serum creatinine was 0.17mmol/L and her dosing regimen at home was 0.25mg Digoxin daily for many months, for heart failure.

The Digoxin plasma concentration on admission was reported to be 3.5ng/ml.

(i) How long will it take for the Digoxin level to fall from 3.5 to 2.0 ng/ml?

(ii) How do the patient’s actual and predicted clearances of Digoxin compare?

(iii) What daily dose should she receive to maintain an average plasma level of 1.5ng/ml.