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Congestive Heart Failure Case B

Congestive Heart Failure Case B. Mr CC. 70 years old Digoxin 250 g Daily Frusemide 40mg 3 mane Naproxen 250mg 1 tds. Concerns. Electrolyte abnormalities which can predispose Mr CC to Digoxin toxicity. Medications taken by Mr CC can affect electrolyte levels.

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Congestive Heart Failure Case B

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  1. Congestive Heart FailureCase B

  2. Mr CC • 70 years old • Digoxin 250g Daily • Frusemide 40mg 3 mane • Naproxen 250mg 1 tds

  3. Concerns • Electrolyte abnormalities which can predispose Mr CC to Digoxin toxicity. • Medications taken by Mr CC can affect electrolyte levels. • Treatment of Digoxin toxicity. • Mode of action of digibind. • How treatment with Digibind might affect the monitoring of Digoxin levels by immunoassay.

  4. Na+/K+ ATPase • Na+/K+ ATPase pumps K+ in and Na+ out. • The Na+/Ca2+ exchanger allows Ca2+ to exit cell and Na+ to enter Ca2+ Na+ Na+/Ca2+ exchanger Cardiac muscle cell Na+/K+ ATPase K+ Na+

  5. Mechanism of action of Digoxin • Digoxin binds to and inhibit Na+/K+ ATPase. • Increases Na+ in the cell. • Decreases Ca2+ flowing out causing • increase force of contraction (+ve ionotropic) • decrease heart rate (-ve chronotropic) Ca2+ Na+ Na+/Ca2+ exchanger Cardiac muscle cell Na+/K+ ATPase K+ Na+ Digoxin binding to Na+/K+ ATPase

  6. Hypokalaemia Ca2+ • If plasma K+ decreases:decrease competition between K+ and Digoxin to bind to Na+/K+ ATPase. • more Digoxin binds as cell becomes more sensitive to high Digoxin concentration • Digoxin toxicity • eg. arrythmia, sinus bradycardia, depression, anorexia, blurred vision,confusion, dizziness Na+ Na+/Ca2+ exchanger Cardiac muscle cell K+ Na+/K+ ATPase K+ K+ Digoxin

  7. Hypercalcaemia Ca2+ Ca2+ • Increase extracellular Ca2+ Affects Ca2+ concentration gradient • Increases intracellular Ca2+ • Ca2+ needed for muscle contraction thus causes coupled heart beat • tachycardia, ventricular fibrillation Ca2+ Ca2+ Ca2+ Na+ Na+/Ca2+ exchanger Ca2+ Ca2+ Cardiac muscle cell Na+/K+ ATPase K+ Na+

  8. Hypomagnesaemia • Hypomagnesaemia results in digoxin toxicity due to sustained depolarisation. • Symptoms from hypomagnesaemia include weakness, disorientation and dysphagia (swallowing problems).

  9. Digoxin and Frusemide • Concurrent use of Digoxin and Frusemide can increase risk of Digoxin toxicity • Due to reduced potassium or magnesium levels. • Use combination with extreme caution. • Monitor and control serum potassium and magnesium.

  10. Digoxin and Naproxen • Possible elevation of Digoxin levels when given concomitantly with Naproxen (NSAIDs) • Monitor Digoxin level for toxicity.

  11. Other factors that may predispose to digoxin toxicity • Age • Renal impairment • Disease states • Hypothyroidism • Hyperthyroidism • Hypokalaemia, hypomagnesaemia, hyperacalcaemia, acidosis, hypoxia • Other • Medications, Vitamins, Herbs and Foods

  12. Digibind • Antidote for treatment of digoxin toxicity. • A lyophilised powder of antigen binding Fab fragments. • Derived from specific anti-digoxin antibodies raised in sheep.

  13. Digibind Digoxin Cell How does Digibind work?

  14. Digibind Digoxin Cell How does Digibind work?

  15. What happens to Digoxin levels after giving the patient Digibind? • Immunoassays used to measure Digoxin levels may produce misleading results following the administration of Digibind. • Immunoassays such as STRATUS and EMIT quantify free serum Digoxin concentrations with Digoxin-immune antibody (Fab). • Both assays depend on the amount of Fab present. • Higher amount of Fab results in greater binding to Digoxin and lower free serum Digoxin levels.

  16. What’s the difference between measuring free and total Digoxin levels? • The STRATUS assay produced elevated Digoxin measurements since it also measures total Digoxin. • Including albumin bound Digoxin as well as Digoxin bound to Digibind. • Total Digoxin levels would be misleading. • Total Digoxin does not indicate toxicity • Antibody-bound Digoxin molecules are inactive. • Therefore while levels of Digoxin seems to increase with the administration of Digibind, there is mainly an increase in inactive antibody-bound Digoxin.

  17. What can we do about it? • In STRATUS, ultrafiltration of serum samples to remove serum proteins may correct the discrepancies between free and total levels of Digoxin. • Also seen with the ULTRA-FPIA assay. • Employs a semipermeable membrane to remove large molecules such as Fab prior to immunoassay. • Elimination of Fab also involves removal of Digoxin bound to it. • Quantitation of free Digoxin levels can then be made. • Consequently, more clinically valid results may be obtained after elimination of Digibind.

  18. What could we do if such methods weren’t possible? • Measure the levels of Digoxin before taking Digibind. • Difficult as have to wait at least 5 to 6 hours (since taking the last dose of Digoxin) before Digoxin levels would equilibrate between serum and tissue.

  19. What if we can’t wait? • Difficult to wait 5 to 6 hours while a patient is suffering from Digoxin toxicity. • Patient is likely to need the dose of Digibind right away. • If the dose of Digibind was given before serum Digoxin levels could be taken • would have to wait for several days before Digoxin bound Fab would be removed. • This delay would be magnified in a patient with renal impairment. • A week or longer would have to pass before reliable Digoxin levels are given.

  20. What to do if can’t wait for serum levels? • Monitor for other signs of Digoxin poisoning. • Eg. temperature, blood pressure, ECG, serum potassium levels before and after treatment with Digibind. • Early sign of Digoxin toxicity is the occurrence of premature ventricular contractions. • Proceed to bigeminy or trigeminy. • Atrial tachycardia. • Characteristic of Digoxin toxicity or intolerance. • Extra beats on the ECG, prolonged PR intervals. • Serum potassium levels increased. • Reversed when a patient is given Digibind and significant hypokalaemia would result. • Can be monitored on the ECG.

  21. References • Allen N.M., Dunham G.D. Treatment of digitalis intoxication with emphasis on the clinical use of digoxin immune Fab. DICP, The Annals of Pharmacotherapy. (1990) 24: 991-997. • Australian Medicines Handbook. Finsbury press, Thebarton, South Australia. (2004) • EMIMS February 2004. Havas Media International, Australia 2004. • Hansell J.R. Effect of therapeutic dogoxin antibodies on digoxin assays. Arch Pathol Lab Med. (1989) 113: 1259-1262. • Jortani S.A., Pinar A., Johnson N.A., Valdes R. Jr. Validity of unbound digoxin measurements by immunoassays in presence of antidote (Digibind). Clinica Chimica Acta (1999) 283: 159-169. • Kaplan A., Jack R., Opheim K., Toivola B., Lyon A. Clinical Chemistry: Interpretation and Techniques. Williams and Wilkins (1995) pg.356-412. • Ujhelyi M.R., Cummings D.M., Green P., Ellison M.J., Vlasses P.H. Effect of digoxin Fab antibodies on five digoxin immunoassays. Therapeutic Drug Monitoring (1990) 12(3): 288-292.

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