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