1. DRUG TREATMENT OF HEART FAILURE IN PATIENTS WITH CHRONIC RENAL DISEASE Presented by Ri

2. Introduction Cardiovascular disease is a common comorbidity and a major cause of mortality in patients with chronic renal disease. Drug regimens in patients with cardiovascular disease are frequently complex and can be significantly affected by alterations in renal function. Several cardiovascular drugs directly affect renal function and the management of patients with renal disease.

3. Subtitles Impact of renal dysfunction on the pharmacokinetics of cardiovascular drugs Dosing adjustments for cardiovascular drugs in dialysis Drug interactions involving cardiovascular agents and other drugs used in patients with renal disease Special consideration of each drug

4. Impact of renal dysfunction on the pharmacokinetics of cardiovascular drugs Absorption  the amount of drug that reaches the systemic circulation after extravascular drug administration  extent of absorption: bioavailability, percentage of the administered dose that reaches the circulation  Renal dysfunction has been shown to significantly alter the bioavailability of several cardiovascular drug  The bioavailability of propranolol is increased: due to decrease in the first-pass effect  Pindolol exhibits a decreased bioavailability

5. Impact of renal dysfunction on the pharmacokinetics of cardiovascular drugs Distribution(1)  Degree of plasma and tissue protein binding, solubility, and ionization of the drug compound  Volume of distribution 〈 Vd 〉 : altered in patients with renal dysfunction

6. Impact of renal dysfunction on the pharmacokinetics of cardiovascular drugs Distribution(2)  Potential causes for Vd alterations in renal dysfunction patients changes in plasma protein concentrations which bind drugs Accumulation of endogenous byproducts that compete for protein binding of drugs Alterations in the binding characteristics caused by specific changes in the protein binding site

7. Impact of renal dysfunction on the pharmacokinetics of cardiovascular drugs Distribution(3)  Examples: renal dysfunction produces significant reduction in the Vd of digoxin and produces an increase in the Vd of furosemide  Decreased Vd is clinically significant and require a reduction in loading dose of 30% to 50%

8. Impact of renal dysfunction on the pharmacokinetics of cardiovascular drugs Metabolism(1)  Renal insufficiency has been shown to significantly reduce the metabolic clearance of numerous drug  Although the majority of drug metabolism occurs in the liver, the kidney also contains these enzyme  Renal tissue has approximately one-third of the enzyme activity of the liver and these enzymes can be impaired in experimental renal failure

9. Impact of renal dysfunction on the pharmacokinetics of cardiovascular drugs Metabolism(2)  Reduction in metabolic clearance: nicardipine, verapamil and captopril  Increased metabolic clearance: nifedipine  Although these clearance alterations in renal insufficiency are statistically significant they do not appear clinically important

10. Impact of renal dysfunction on the pharmacokinetics of cardiovascular drugs Metabolism(3)  Maintenance dose of nicardipine, verapamil, and nifedipine do not have to be adjusted in renal insufficiency  Captopril dose require a decrease in dosage: because of changes in the renal clearance rather rhan the metabolic clearance alterations

12. Impact of renal dysfunction on the pharmacokinetics of cardiovascular drugs Excretion  Depending on the solubility, ionization, and protein binding of the compound  Although most cardiovascular drugs are primarily eliminated via hepatic metabolism, many exhibit a large degree of renal clearance and are significantly affected by renal dysfunction

14. Dosing adjustments for cardiovascular drugs in dialysis Many factors are involved in the determination of the extent of drug removal during dialysis  Method of dialysis  The type of dialysis membrane  The duration of dialysis  The rate of ultrafiltration  Pharmacokinetic characteristics of the drug

15. Dosing adjustments for cardiovascular drugs in dialysis Pharmacokinetic characteristics of the drug(1)  Vd Directly correlated with the amount of drug that is bound to tissue Dialysis would significantly alter the clearance of drugs that have a small Vd and would have little effect on a drug with a large Vd

16. Dosing adjustments for cardiovascular drugs in dialysis Pharmacokinetic characteristics of the drug(2)  Protein binding Any drug bound to plasma proteins cannot be filtered because of the size of the drug-protein complex Drugs having a low degree of protein binding(<30%) would be more likely to have clinically significant removal by extracorporal methods

17. Dosing adjustments for cardiovascular drugs in dialysis Pharmacokinetic characteristics of the drug(3)  Drug molecular weight Conventional hemodialysis membrane: only allow the passage of drugs with a molecular weight of less than 500D High-flux membrane: can remove drugs in the molecular weight range of up to 5000 to 20000D The majority of cardiovascular drugs have a molecular weight less than 500D and therefore particle size is not a limiting factor digoxin: 780D. Because of its large volume of distribution, digoxin is not removed to a significant degree by dialysis with either conventional or high flux membranes

19. Drug interactions involving cardiovascular agents and other drugs used in patients with renal disease Mechanism  Alterations in hepatic metabolism  Alterations in protein binding  Alterations in renal excretion  Alterations in gut absorption  Pharmacodynamic alterations Synergistic Antagonistic additive

23. Special considerations of each drug

24. Diuretics (1) Therapeutic options in patients with renal dysfunction  Ccr<30 ml/min, thiazides will fail to provide effective diuresis  Loop diuretics Retain some efficacy even at low Ccr Increase renal blood flow and solute excretion in ARF Initiated at conventional doses and then increased until a desirable effect is established

25. Diuretics (2) Diuretic resistance(1)  The effectiveness of loop diuretics will decrease as renal function declines because of the reduced ability of the diuretic to reach its site of pharmacologic activity  Results in the need to administer larger than normal doses in order to produce an acceptable diuresis  May require the use of combination therapy

26. Diuretics (3) Diuretic resistance(2)  Additive and/or synergistic diuretic activity has been shown between loop diuretics and metolazone and furosemide and hydrochlorothiazide  When doses in the range of 400 to 600mg per day of furosemide(or equivalent doses of other loop diuretics) addition of metolazone 5 to 20 mg per day or hydrochlorothiazide 25 to 200mg per day

27. Diuretics (4) Spironolactone  Recently study: significantly reduce mortality in patients with advanced heart failure when added to standard therapy  Scr>2.5mg/dl were excluded from the study given the increased potential for hyperkalemia  It is unknown if spironolactone would be beneficial or even tolerated in the severe heart failure patients with renal insufficiency

28. Digitalis glycosides(1) Toxicity of digoxin in patients with renal dysfunction(1)  Therapeutic range of digoxin is narrow, at approximately 0.8 to 2 ng/ml  Digoxin is cleared by the kidney and serum levels should be followed closely in patietns with renal dysfunction  Clinical manifestations of digoxin toxicity include virtually al forms of cardiac arrythmias

29. Digitalis glycosides(2) Toxicity of digoxin in patients with renal dysfunction(2)  Of particular concern in the renal failure patient: impact of serum electrolyte concentrations  Hypokalemia and hypomagnesemia both increase the risk of digoxin cardiac toxicity  The presence of hyperkalemia increases the risk of AV nodal blockade with digoxin  Digoxin toxicity has been associated with refractory hyperkalemia in patients with renal failure through inhibition of the Na-K ATPase pump

30. Digitalis glycosides(3) Toxicity of digoxin in patients with renal dysfunction(3)  Despite withdrawal of the drug, patients with chronic renal failure are at prolonged risk of adverse events  In patients with renal failure experiencing life- threatening digoxin toxicity, administration of digoxin specific antibody fragments(Fab) is indicated

31. Digitalis glycosides(4) Therapeutic monitoring in patients with renal failure(1)  Serum digoxin concentrations may be useful in assessing appropriate dosing  In patients with renal failure, use of standard immunoassays may result in overestimation of serum digoxin concentrations Production of endogenous digitalis-like immunoreactive substances or factors in renal failure Produce measurable digoxin concentrations

32. Digitalis glycosides(5) Therapeutic monitoring in patients with renal failure(2)  Although newer immunoassays are less prone to interference, assessment of the patient and reanalysis of the blood should be perform to confirm digoxin toxicity  For therapeutic monitoring, blood samples should be drawn at least 6 to 8 hours after a dose to avoid the distribution phase of the drug and falsely elevated blood concentrations

33. Digitalis glycosides(6) Digitoxin  Insoluble, metabolized by the liver, its elimination is not affected by alterations in renal function  Although a potential alternative to digoxin for the treatment of supraventricular arrythmias or heart failure in patients with renal dysfunction, it has not been rigorously evaluated in clinical trials

34. ACEI(1) Beneficial effects of ACEI on renal function  Patients with diabetic or hypertensive nephropathy as well as patients with proteinuria are likely to benefit from the renoprotective effects~reduce the progression of renal disease

35. ACEI(2) Acute worsening of renal function with ACEI(1)  Acute decrease in glomerular filtration rate is often seen after the initiation of ACEI therapy  Although ACEI have been shown to reduce progression of renal disease, the clinical use of ACEI in patients with renal insufficiency may be limited by concern of acute increases in serum creatinine

36. ACEI(3) Acute worsening of renal function with ACEI(2)  In patients with baseline serum creatinine of >1.4mg/dL, there was a strong correlation between acute increases of serum creatinine of up to 30% that stabilized in the following 2 months and overall reduction in the progression of renal disease  More significant increases in serum creatinine after administration of ACEI may indicate presence of bilateral renal artery stenosis or unilateral stenosis of a solitary functioning kidney~ renal scan or angiogram

37. ACEI(4) Hyperkalemia associated with ACEI  The prevalence of hyperkalemia in patients receiving ACEI was approximately 11%  Renal insufficiency as indicated by a serum creatinine of >1.6 mg/dL was associated with 4.6-fold risk of hyperkalemia  Concurrent diuretic therapy was associated with a 60% risk reduction

38. ACEI(5) Anaphylactoid reactions in dilaysis patients  Patients receiving hemodialysis using synthetic membrane, in particular the high flux polyacrylonitrile(AN69)membrane, are at increased risk of developing an anaphylactoid reaction when they are given ACEI  Anaphylactoid reactions during hemodialysis are mediated by bradykinin  Although patients are not uniformly at risk of anaphylactoid reactions, hemodialysis with high flux AN69 membranes in patients receiving ACEI should be avoided if possible

39. Angiotensin II receptor antagonists Risk of anaphylactoid reactions in dialysis patient  Because they do not inhibit the destruction of bradykinin, A-II receptor antagonists should be less likely than ACEI to induce an anaphylactoid reactions to high flux AN69 dialysis memebranes