Clinical Pathology

1. Clinical Pathology Cardiovascular-Topic A

2. Core Area 2: Cardiovascular – Topic A Mr BB, aged 64 years, takes the following medications on a regular basis: • Digoxin 125 mcg daily • Glipizide 5mg daily He has recently been prescribed spironolactone100mg daily.

3. Spironolactone • Spironolactone is a specific pharmacological antagonist of aldosterone (inhibits sodium reabsorption in the distal tubule). • Acting primarily through competitive binding of receptors at the aldosterone dependent sodium-potassium exchange site in the distal convoluted renal tubule and reduces urinary potassium excretion. • Common adverse effects ofspironolactone include:hyperkalaemia, hyponatraemia, hypochloraemia.

4. PK-Spironolactone • 25 to 30% of the dose administered is converted to Canrenone, which attains peak serum levels at two to four hours following single oral administration. • Both Spironolactone and Canrenone are more than 90% bound to plasma proteins.

5. Digoxin • Increases force of myocardial contraction (positive inotrope) and decreases AV nodal conduction, predominantly by its vagotonic effect on the heart which also results in a negative chronotropic effect. It can increase the excitability of cardiac muscle, particularly at higher doses. • Digoxin has a narrow therapeutic index • Adverse effects of digoxin are related to its plasma concentration

6. CONCERNED????

7. CONCERNED? • Digoxin has a narrow therapeutic index • Therapeutic serum concentration for digoxin is 1-2ng/mL • Digoxin toxicity may cause same symptoms as treated disease.

8. Drug/Drug Interactions • DIGOXIN -- SPIRONOLACTONE Severity: moderateOnset: delayed

9. Drug/Drug Interactions • Concomitant use of digoxin and spironolactone may result in increased digoxin plasma levels due to decreased digoxin renal clearance. • Spironolactone may displace digoxin from tissue binding sites by spironolactone or its metabolites; • Spironolactone and its metabolites can interfere with digoxin radioimmunoassay tests causing artificially high serum digoxin level results.

10. Drug/Lab Interferences • SPIRONOLACTONE -- DIGOXIN ASSAYSeverity: minor Onset: rapid

11. Drug/Lab Interferences • Spironolactone can interfere with assays for plasma digoxin concentrations • The mechanism behind this interaction is proposed to be the structural similarity between digoxin, spironolactone, and canrenone (a spironolactone metabolite), as well as lesser spironolactone metabolites. • It is also possible for spironolactone to inhibit tubular secretion of digoxin and reduce digoxin clearance, resulting in actual increases in serum digoxin levels.

12. Specific monitoring of clinical chemistry tests • Monitor potassium each week for the first month, then each month for 2 months, then every 3 months. • Sodium Levels • Chloride levels • Creatinine • urea

13. Other clinical chemistry tests • Glycated haemoglobin concentration (HbA1c) • Glucose

14. Upon commencement of Spironolactone: • When is the most appropriate time to sample Digoxin levels and why? • When should serum samples be taken with respect to the time of dosing and why? • Would this change if Mr BB had End-Stage Renal Disease (ESRD)?

15. Digoxin Clearance and Steady State Concentration: • Digoxin half-life (t1/2) ranges from 38-48 hrs in a patient with normal renal function. • A drug requires 4 half-lives to reach a steady state serum concentration. • Steady-state concentration is used to determine maintenance dose.

16. Digoxin Clearance and Steady State Concentration: • After initiation of Spironolactone by about 3 days (preferably 5-7 days) Digoxin levels should be drawn. This period would have allowed for a steady-state concentration to have been reached as 4 half-lives will have elapsed. • Assay results would otherwise be falsely low and would result in an inappropriate increase in maintenance dose.

17. Digoxin Distribution Phase: • Digoxin has a large volume of distribution (Vd) of 6-7 L/Kg in a patient with normal renal function. • This is due to extensive distribution to peripheral tissues including the liver, the kidneys, the intestine, the skeletal muscle, and the heart where Digoxin exerts its pharmacologic effects. • The distribution phase lasts for 6-8 hours resulting in delayed pharmacologic effects.

18. Digoxin Distribution Phase: • Pharmacologic effects do not correlate with serum concentrations unless the distribution phase has been completed. • ====>Serum samples should be drawn at least 8-12 hrs after the last oral dose, (optimally 12-24 hrs after the last oral dose). • Assay results would otherwise be falsely high and would result in an inappropriate reduction in maintenance dose.

19. What Is ESRD And What Are Its Implications: 1. Patients with ESRD are patients in whom the rate of Creatinine Clerance (Clcr ) has declined to levels below 10 mL/min. • 86% of Digoxin in the body is renally eliminated as unchanged drug. Any reduction in renal function would reduce the rate of Digoxin clearance and hence increase its half-life.

20. What Is ESRD And What Are Its Implications: • In patients with ESRD, Digoxin half-life is increased to 120 hrs and therefore steady-state serum concentration is reached in 10-14 days. • Although Vd is reduced in ESRD by up to 50% possibly as a result of decreased tissue binding caused by competition from endogenous or exogenous substances, time to complete the distribution phase does not change.

21. What Is ESRD And What Are Its Implications: • In ESRD, Digoxin half- life increases to 120 hrs and steady-state serum concentration is reached in 10-14 days. • ====>Digoxin samples should be drawn after 10-14 days following initiation of Spironolactone. • Assay results would otherwise be falsely low and would result in an inappropriate increase in maintenance dose. • In ESRD, time to complete the distribution phase does not change hence samples can still be drawn 8-12 hrs after the last oral dose (preferably12-24 hrs after the last oral dose).

22. Digoxin • Digoxin levels stable for 12 months • Routine check-up, digoxin conc =4.2 (v.high) 24 hrs after last dose, therefore admitted to hospital. • Digoxin and spironolactone stopped, but digoxin levels stayed elevated for more than 2 months • Possible explaination? Sources of any interfering substances---assay

23. Digoxin • In 1995 it was the drug most often monitored, and has potentially serious side effects. • There are many assays that may be used to monitor the concentrations of digoxin in serum. Some of these include: • TinaQUant, • the Emit asay, • Dimension, and • AxSYM & IMx microparticle enzyme immunoassays (MEIAs).

24. Falsely low results and potentially toxic concentrations of digoxin • Digoxin toxicity caused by negative interference by spironolactone and canrenone, an active metabolite of spironolactone. • Supposedly “NORMAL” therapeutic concentrations are measured when the true concentration is much higher

25. Falsely low results and potentially toxic concentrations of digoxin • Negative interferences very dangerous. Toxic concentrations may remain unidentified, leading to continuing standard doses or toxicity could occur if dosing is based on these misleading values. Increased dosing is therefore promoted by continual falsely low serum digoxin concentrations. • Unless the samples are cross-checked with other methods insensitive to the interference.

26. Spironolactone • increases the elimination half life of digoxin, which may result in increased serum digoxin levels and subsequent toxicity. • reduces renal tubular secretion of digoxin and attenuates its positive inotropic effect.

27. How does this relate to Mr BB? • Serum digoxin levels taken over the 12 month used an assay sensitive to the interference of spironolactone and its metabolites. • Routine examination revealed , a different assay may have been used, which is insensitive to spironolactone interference. Thus the true serum digoxin concentration was measured.

28. Is spironolactone is a major cause of the increased serum digoxin concentrations • EMIT assay are KNOWN NOT to be interfered with by spironolactone.

29. So how is this important in practice??? • Interference from spironolactone and its metabolites is a potential problem in a potentially high number of patients • The number of patients possibly affected by this limited inhibition is significant because spironolactone is used in severe heart failure and about 75% of patients in this category also use digoxin.

30. So how is this important in practice??? • serum levels of digoxin remaining elevated for the next two months after the last dose of digoxin. There are a few possible explanations of this, even though more data is needed to ascertain what is the cause.

31. Possible explanations • Renal failure • High half-life of spironolactone metabolites, resulting in a prolonged inhibition of digoxin renal tubular secretion • A herbal medicine the patient is taking which may give false results of the presence of digoxin, e.g. ginseng • Assays used were not reliable

32. Possible explanations • Canrenone can accumulate in the body. Both spironolactone and can are over 90% bound to plasma proteins. Metabolites of spironolactone are excreted in urine (32-53%) and biliary excretion ain the faeces ( 14-36%).

33. In conclusion • The negative interference from spironolactone definitely is a clinically significant problem. NOTE!!! • Several modern digoxin assays suffer from positive or, in particular, potentially dangerous negative interference from aldosterone inhibitors such as spironolactone. • Therefore assays insensitive to spironolactone and metabolite interference such as EMIT need to be used especially in patients with these drug regimens.