Pharmacology of digoxin Clinical Uses Overview Introduction Toxicity and management 1 2 3 4 Digitalis Cardiac glycoside that occurs naturally in plants Its medical use dates back from the 18 ID: 1046019
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1. Digoxin toxicityAlex Battistini
2. Pharmacology of digoxinClinical UsesOverviewIntroductionToxicity and management1234
3. Digitalis: Cardiac glycoside that occurs naturally in plantsIts 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. IntroductionDigitoxinDigoxinOuabain
4. Steroid cyclopentenophenanthrene nucleusGlycone + aglycone portionsAglycone portion is pharmacologically activeGlycone portion anchors to the muscle cell membranePharmacology of digoxinStructure-activity relationships
5. 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
6. Varies according to the LV functionIn 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
7. NEUROHORMONALModulates maladaptive neuroendocrine activation (noradrenaline, renin and aldosterone)PNS tone and inhibits SNS activityImproves carotid baroreceptor sensitivity (dampened in HF)Other effectsELECTROPHYSIOLOGICALClosely related to effects on ANSPNS + SNS = automaticity + AV conduction (aka slow heart rate)Prolonged PR, short QTc,
8. Clinical UsesSymptomatic CHF
9. Clinical UsesRate-control for persistent and permanent AF
10. Incidence has decreased due to alternative CVS drugs and improved serum drug concentration monitoringIn the 70s: 20% of digitalised patients, mortality up to 40%.In the 90s: DIG trial showed 2% toxicity in inpatientsPredisposing conditions:AgingKidney diseaseDrug interactionsDigoxin toxicity
11. Drug interactions
12. Signs and symptomsDigoxin Toxicity
13. High level of suspicionSigns & Symptoms are non-specificAnorexia, N&V are early signs of toxicityECG changes are very variableOverall increased automaticity of all cardiac cells except SA nodeVF is commonest cause of death in digoxin toxicitySerum level concentrations:<0.5ng/mL likely non-toxic0.5 – 1.0ng/mL optimal (DIG trial)>2ng/mL usually associated with toxicityNB: Relationship between plasma concentrations and observed pharmacological effects is not always consistentDiagnosisDigoxin toxicity
14. Digoxin toxicity
15. Supportive care (ABCDE)Correction of predisposing causesHypokalaemia 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 correctionCalcium is contraindicatedHypoxaemiaAntiarrhythmic drugsPhenytoin: 0.5 – 1.5mg/kgLignocaine: 1 – 2mg/kgAtropine: 35 – 70mcg/kgTreatment
16. Fab fragments (e.g Digibind injections)Binds to digoxin, making it unavaliable to interact with the Na+-K+-ATPase pumpThe Fab-Digoxin complex gets excreted unchanged in urineDigoxin 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 hoursDigoxin binding therapyLife-threatening digitalis toxicity
17. Severe ventricular arrhythmias (e.g. VT or VF)Progressive bradyarrhythmias (e.g. severe sinus bradycardia or 2nd or complete heart block) not responsive to atropineCardiac arrestDigitalis-induced progressive elevation of serum K+ > 5mmol/LIngestion of more than 10mg (adults) or 4mg (children) or ingestions causing SDC > 10ng/mLIndications for Fab fragmentsLife-threatening digoxin toxicity
18. Dosage of Fab fragmentsLife-threatening digoxin toxicity
19. The Digitalis Investigation Group (DIG). The effect of digoxin on mortality and morbidity in patients with heart failure. N Eng J Med 1997; 336:525-33National 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.auNICE Guidelines (UK): Atrial Fibrillation: The Management of Atrial Fibrillation. June 2006. www.guidance.nice.org.ukRey P. Vivo et al: Digoxin: Current Use and Approach to Toxicity. The Am J Med Sci 2008; 336: 423-428Manyank K Mittal et al: Contemporary Indications and Therapeutic Implications for Digoxin Use. Am J Therap 2011; 18(4): 280-287Michael Ehle et al: Digoxin: Clinical Highlights: A Review of Digoxin and Its Use in Contemporary Medicine. Crit Path Cardio 2011; 10(2): 93-98MIMS OnlineReferences
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