Digoxin toxicityAlex Battistini

Pharmacology of digoxin

Clinical Uses

Overview

Introduction

Toxicity and management

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• Digitalis: Cardiac glycoside that occurs naturally in plants

• Its medical use dates back from the 18th century (usage of foxglove) to treat dropsy (oedematous state)

• In the 19th century digitalis strengthened the pulse when weak and slowed in down when it was strong…

• Nowadays digoxin is the only one available in the market.

Introduction

DigitoxinDigoxin Ouabain

• Steroid cyclopentenophenanthrene nucleus

• Glycone + aglycone portions• Aglycone portion is

pharmacologically active• Glycone portion anchors to the

muscle cell membrane

•Pharmacology of digoxinStructure-activity relationships

• Binds to the α-subunit of the Na+-K+-ATPase pump (competitive reversible inhibition)

• IC Na+ inhibits Ca+2 efflux by the Na+-Ca+2 exchanger

• IC Ca+2 increased myocardial contractility (positive inotropic effect)

•Pharmacology of digoxinMechanism of action

• Varies according to the LV function

• In normal subjects it increases contractility but also causes a reflex SVR (no change in cardiac output)

• In the failing heart it improves LVEF, PCWP, CO (increased renal perfusion and mobilisation of oedema)

•Haemodynamic effects

NEUROHORMONAL• Modulates

maladaptive neuroendocrine activation (noradrenaline, renin and aldosterone)

• PNS tone and inhibits SNS activity

• Improves carotid baroreceptor sensitivity (dampened in HF)

•Other effects

ELECTROPHYSIOLOGICAL• Closely related to

effects on ANS• PNS + SNS =

automaticity + AV conduction (aka slow heart rate)

• Prolonged PR, short QTc,

•Clinical UsesSymptomatic CHF

•Clinical UsesRate-control for persistent and permanent AF

• Incidence has decreased due to alternative CVS drugs and improved serum drug concentration monitoring

• In the 70s: 20% of digitalised patients, mortality up to 40%.

• In the 90s: DIG trial showed 2% toxicity in inpatients• Predisposing conditions:

• Aging• Kidney disease• Drug interactions

•Digoxin toxicity

•Drug interactions

• Signs and symptoms•Digoxin Toxicity

• High level of suspicion• Signs & Symptoms are non-specific

• Anorexia, N&V are early signs of toxicity• ECG changes are very variable

• Overall increased automaticity of all cardiac cells except SA node

• VF is commonest cause of death in digoxin toxicity• Serum level concentrations:

• <0.5ng/mL likely non-toxic• 0.5 – 1.0ng/mL optimal (DIG trial)• >2ng/mL usually associated with toxicity

• NB: Relationship between plasma concentrations and observed pharmacological effects is not always consistent

• Diagnosis•Digoxin toxicity

•Digoxin toxicity

• Supportive care (ABCDE)• Correction of predisposing causes

• Hypokalaemia and hypomagnesaemia require replacement with careful monitoring (supplemental K+ decreases binding of digoxin to cardiac myocytes)

• Hyperkalaemia (K+ > 5.0mmol/L) in the setting of digoxin toxicity has a high mortality rate and needs correction• Calcium is contraindicated

• Hypoxaemia• Antiarrhythmic drugs

• Phenytoin: 0.5 – 1.5mg/kg• Lignocaine: 1 – 2mg/kg• Atropine: 35 – 70mcg/kg

•Treatment

• Fab fragments (e.g Digibind injections)• Binds to digoxin, making it unavaliable to interact with the Na+-K+-ATPase pump

• The Fab-Digoxin complex gets excreted unchanged in urine

• Digoxin from peripheral tissues then gets redistributed to blood to maintain equilibrium, reducing digoxin concentration.

• 80 – 90% effectiveness in reversing symptoms of toxicity with complete reversal within 4 hours

• Digoxin binding therapy

•Life-threatening digitalis toxicity

• Severe ventricular arrhythmias (e.g. VT or VF)• Progressive bradyarrhythmias (e.g. severe sinus bradycardia or 2nd or complete heart block) not responsive to atropine

• Cardiac arrest• Digitalis-induced progressive elevation of serum K+ > 5mmol/L

• Ingestion of more than 10mg (adults) or 4mg (children) or ingestions causing SDC > 10ng/mL

• Indications for Fab fragments

•Life-threatening digoxin toxicity

• Dosage of Fab fragments

•Life-threatening digoxin toxicity

• The Digitalis Investigation Group (DIG). The effect of digoxin on mortality and morbidity in patients with heart failure. N Eng J Med 1997; 336:525-33

• National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand. Guidelines for the prevention, detection and management of chronic heart failure in Australia. Updated July 2011. www.csanz.edu.au

• NICE Guidelines (UK): Atrial Fibrillation: The Management of Atrial Fibrillation. June 2006. www.guidance.nice.org.uk

• Rey P. Vivo et al: Digoxin: Current Use and Approach to Toxicity. The Am J Med Sci 2008; 336: 423-428

• Manyank K Mittal et al: Contemporary Indications and Therapeutic Implications for Digoxin Use. Am J Therap 2011; 18(4): 280-287

• Michael Ehle et al: Digoxin: Clinical Highlights: A Review of Digoxin and Its Use in Contemporary Medicine. Crit Path Cardio 2011; 10(2): 93-98

• MIMS Online

•References

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