Pharmacology
Cardiovascular
Clinical features of digoxin toxicity include all of the following EXCEPT for:
Answer:
Digoxin has a narrow therapeutic index. Features of toxicity include gastrointestinal effects (nausea, vomiting, anorexia and diarrhea), visual disturbance (blurred or yellow vision), CNS effects (weakness, dizziness, confusion, headache, malaise, psychosis), hyperkalaemia, and conduction disorders and arrhythmias. Hypoglycaemia is not a typical adverse effect of digoxin toxicity. N.B. Hypoxia, hypercalcaemia, hypokalaemia and hypomagnesaemia predispose patients to digoxin toxicity. Digoxin toxicity causes hyperkalaemia.Digoxin
Pharmacology / Cardiovascular
Last Updated: 17th April 2019
Digoxin is a cardiac glycoside that increases the force of myocardial contraction (positive inotrope), and slows the heart rate (negative chronotrope). Digoxin has a narrow therapeutic index; digoxin toxicity can occur even when the serum digoxin concentration is within the therapeutic range (between 0.7 - 2.0 mcg/L).
Mechanism of Action
Inotropic effect:
Digoxin directly inhibits membrane Na+/K+ ATPase, which is responsible for Na+/K+ exchange across the myocyte cell membrane. This increases intracellular Na+ and produces a secondary increase in intracellular Ca2+ that increases the force of myocardial contraction. The increase in intracellular Ca2+ occurs because the decreased Na+ gradient across the membrane reduces the extrusion of Ca2+ by the Na+/Ca2+ exchanger that normally occurs during diastole. Digoxin and K+ ions compete for the receptor on the outside of the muscle cell membrane, and so the effects of digoxin may be dangerously increased in hypokalaemia.
Chronotropic effect:
Digoxin stimulates vagal activity , causing the release of ACh, which slows the heart rate, slows atrioventricular conduction and prolongs the refractory period in the AVN and bundle of His. By delaying AV conduction, digoxin increases the degree of block, and slows and strengthens the ventricular beat.
Indications
Digoxin is most useful for controlling the ventricular response in persistent and permanent atrial fibrillation and atrial flutter. Digoxin is usually only effective for controlling the ventricular rate at rest, and should therefore only be used as monotherapy in predominantly sedentary patients with non-paroxysmal atrial fibrillation. It is now rarely used for rapid control of heart rate, as even with intravenous administration, response may take many hours.
Digoxin also has a role in the management of heart failure; digoxin improves symptoms of heart failure and exercise tolerance and reduces hospitalisation due to acute exacerbations but it does not reduce mortality. Digoxin is reserved for patients with worsening or severe heart failure due to left ventricular systolic dysfunction refractory to combination therapy with first-line agents.
Contraindications
Digoxin is contraindicated in:
- Supraventricular arrhythmias associated with accessory conduction pathways e.g. Wolff-Parkinson-White syndrome
- Ventricular tachycardia or fibrillation
- Heart conduction problems e.g. second degree or intermittent complete heart block
- Hypertrophic cardiomyopathy (unless concomitant atrial fibrillation and heart failure but should be used with caution)
Cautions
Digoxin should be used with caution in:
- Hypercalcaemia (risk of digitalis toxicity)
- Hypokalaemia (risk of digitalis toxicity; diuretics may predispose to hypokalaemia)
- Hypomagnesaemia (risk of digitalis toxicity)
- Hypoxia (risk of digitalis toxicity)
- Recent myocardial infarction
- Severe respiratory disease
- Sick sinus syndrome
- Thyroid disease
- Constrictive pericarditis
- Renal impairment (reduce dose and monitor plasma-digoxin concentration; toxicity increased by electrolyte disturbances)
- Elderly people (reduce dose)
- Concomitant drug therapy with drugs which may increase plasma concentration of digoxin e.g. amiodarone, antimicrobials, calcium-channel blockers, spironolactone
Side Effects
The adverse effects of digoxin are frequently due to its narrow therapeutic window and include:
- Cardiac adverse effects
- Sinoatrial and atrioventricular block
- Premature ventricular contractions
- PR prolongation and ST-segment depression
- Nausea, vomiting and diarrhoea
- Blurred or yellow vision
- CNS effects
- weakness, dizziness, confusion, apathy, malaise, headache, depression, psychosis
- Thrombocytopenia and agranulocytosis (rare)
- Gynaecomastia in men in prolonged administration
Digoxin Toxicity
Unwanted effects of digoxin depend on both the plasma concentration of digoxin (increasing risk of toxicity through the range 1.5 - 3 mcg/L) and on the sensitivity of the conducting system or of the myocardium, which is often increased in heart disease. Hypoxia, hypercalcaemia, hypokalaemia and hypomagnesaemia predispose to digoxin toxicity. Care should also be taken in the elderly who are particularly susceptible to digoxin toxicity.
If toxicity occurs, digoxin should be withdrawn. Digoxin-specific antibody fragments are indicated for the treatment of known or strongly suspected life-threatening digoxin toxicity associated with ventricular arrhythmias or bradyarrhythmias unresponsive to atropine sulfate and when measures beyond the withdrawal of digoxin and correction of any electrolyte abnormalities are considered necessary.
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- Biochemistry
- Blood Gases
- Haematology
| Biochemistry | Normal Value |
|---|---|
| Sodium | 135 – 145 mmol/l |
| Potassium | 3.0 – 4.5 mmol/l |
| Urea | 2.5 – 7.5 mmol/l |
| Glucose | 3.5 – 5.0 mmol/l |
| Creatinine | 35 – 135 μmol/l |
| Alanine Aminotransferase (ALT) | 5 – 35 U/l |
| Gamma-glutamyl Transferase (GGT) | < 65 U/l |
| Alkaline Phosphatase (ALP) | 30 – 135 U/l |
| Aspartate Aminotransferase (AST) | < 40 U/l |
| Total Protein | 60 – 80 g/l |
| Albumin | 35 – 50 g/l |
| Globulin | 2.4 – 3.5 g/dl |
| Amylase | < 70 U/l |
| Total Bilirubin | 3 – 17 μmol/l |
| Calcium | 2.1 – 2.5 mmol/l |
| Chloride | 95 – 105 mmol/l |
| Phosphate | 0.8 – 1.4 mmol/l |
| Haematology | Normal Value |
|---|---|
| Haemoglobin | 11.5 – 16.6 g/dl |
| White Blood Cells | 4.0 – 11.0 x 109/l |
| Platelets | 150 – 450 x 109/l |
| MCV | 80 – 96 fl |
| MCHC | 32 – 36 g/dl |
| Neutrophils | 2.0 – 7.5 x 109/l |
| Lymphocytes | 1.5 – 4.0 x 109/l |
| Monocytes | 0.3 – 1.0 x 109/l |
| Eosinophils | 0.1 – 0.5 x 109/l |
| Basophils | < 0.2 x 109/l |
| Reticulocytes | < 2% |
| Haematocrit | 0.35 – 0.49 |
| Red Cell Distribution Width | 11 – 15% |
| Blood Gases | Normal Value |
|---|---|
| pH | 7.35 – 7.45 |
| pO2 | 11 – 14 kPa |
| pCO2 | 4.5 – 6.0 kPa |
| Base Excess | -2 – +2 mmol/l |
| Bicarbonate | 24 – 30 mmol/l |
| Lactate | < 2 mmol/l |
