Drug Use and Dosing in Chronic Kidney Disease2

Drug Use and Dosing in Chronic Kidney Disease : 

Drug Use and Dosing in Chronic Kidney Disease By: lubna riahi

Introduction : 

Introduction Chronic kidney disease (CKD) is an important therapeutic problem. There is an increasing realization that renal impairment is under-diagnosed, and this has led to attempts to improve both the detection and management of patients with impaired renal function.

Chronic Kidney Disease Staging and Clinical Action Plan : 

Chronic Kidney Disease Staging and Clinical Action Plan

Effect of Chronic Kidney Disease on Drug Pharmacokinetics : 

Effect of Chronic Kidney Disease on Drug Pharmacokinetics Patients with renal impairment often have alterations in their pharmacokinetic parameters include: 1) Absorption 2)Distribution. 3)Metabolism 4)Elimination

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Elimination of many drugs is dependent on :renal filtration, secretion and reabsorption. Glomerular filtration is impaired by renal disease or ageing. Therefore, the clearance of drugs eliminated primarily by this mechanism is decreased, and this should be considered when these drugs are prescribed to patients with impaired renal functions.

Effects on Absorption : 

Effects on Absorption For medications that are best absorbed in an acidic environment, drug dissolution and ionization are often reduced by increased gastric pH, resulting in reduced bioavailability, Examples include: furosemide, ketoconazole and ferrous sulfate.

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Conversely, it has been shown that the administration of magnesium hydroxide and sodium bicarbonate, can enhance the absorption of some weakly acidic molecules (e.g., ibuprofen, glipizide, glyburide, tolbutamide) by increasing their water solubility and subsequent absorption. Also, the ingestion of cation-containing antacids (e.g., calcium, magnesium, aluminum hydroxide, sodium polystyrene sulfonate and iron ) may reduce drug absorption because of chelation with other medications, resulting in the formation of insoluble compounds. The fluoroquinolones and tetracycline are 2 medication classes that are highly susceptible to chelate formation in patients with renal insufficiency.

Effects on Distribution : 

Effects on Distribution CKD-induced alterations in protein binding are associated with many clinical implication. Medications that are acidic, such as barbiturates, cephalosporin, furosemide, salicylates, valproate and warfarin are most severely affected by reduced protein binding. Acidic drugs are bound to albumin, plasma concentrations of which are often decreased in uremic patients.

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Hypoalbuminemia and altered plasma protein binding due to the competition for binding sites by other drugs, metabolites, and accumulating endogenous substances may displace medications from plasma protein binding sites leading to increased levels of free concentrations of drugs. Conversely, alkaline drugs (e.g., propranolol, morphine , oxazepam, vancomycin) bind primarily to non-albumin plasma proteins, such as α1-acid glycoprotein. α1-acid glycoprotein is an acute-phase protein whose plasma concentrations are often elevated in renal dysfunction. For this reason, concentrations of alkaline drugs, in CKD patients may be reduced (e.g., propranolol). For most medications, changes in tissue binding are probably irrelevant. The major exception is digoxin, Digoxin’s Vd is reduced by half in patients with stage 5 CKD. This reduction in Vd results in increased digoxin serum concentrations if the loading dose is not reduced. CKD-induced changes in body composition, such as increased total-body water and adipose tissue and decreased muscle mass, can have a profound effect on hydrophilic drugs (e.g., pravastatin, fluvastatin, morphine, codeine). Oedema and ascites is expected to increase the Vd of hydrophilic compounds such as vancomycin

Effects on Metabolism : 

Effects on Metabolism In general, phase I hydrolysis and reduction reactions are slowed in CKD. Phase II metabolic reactions are also affected by renal dysfunction Acetylating (e.g., dapsone, hydralazine, isoniazid, procainamide), glucuronidation (e.g., acetaminophen, morphine, lorazepam, oxazepam naproxen), sulfation (e.g., acetaminophen, minoxidil, dopamine, albuterol), and methylation (e.g., dobutamine, dopamine, 6-mercaptopurine) are all slowed in patients with CKD. Slowed phase I and II metabolic reactions result in increased serum drug concentration

Renal metabolism is obviouslyreduced during cases of renal insufficiency. : 

Renal metabolism is obviouslyreduced during cases of renal insufficiency.

Effects on Elimination : 

Effects on Elimination Renal excretion of medications is dependent on glomerular filtration rate, renal tubular secretion and reabsorption. The glomerular elimination of drugs depends on several factors, including the molecular weight and protein binding. In CKD, medication elimination by glomerular filtration is decreased, resulting in a prolonged free drug elimination half-life.

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Although protein binding decreases the glomerular filtration of some drugs, the renal tubular secretion of these medications may be increased. Highly protein-bound medications are actively secreted into the proximal convoluted tubules, ensuring they are excreted. In CKD, however, the secretion of drugs eliminated by this active transport system is reduced. Another factor affecting active tubular secretion of drugs is that this is a transport-mediated process and, with higher drug levels, the secretion reaches a limit leading to an increased elimination half-life. Also, competition between drugs for secretion can reduce their excretion Example: (co administration of penicillin and probenecid).

Reductions in medication reabsorption are observed in patients with CKD, resulting in increased urinary concentrations of renallyeliminated medications, such as aspirin and lithium. : 

Reductions in medication reabsorption are observed in patients with CKD, resulting in increased urinary concentrations of renallyeliminated medications, such as aspirin and lithium.

Drug-related Problems in CKD Population : 

Drug-related Problems in CKD Population Drug-related problems are common in patients with renal insufficiency and hemodialysis patients. Such patients are at higher risk as they require complex therapeutic Regimens with 5 or more medications and 12 or more medication doses per day that require frequent monitoring and dosage adjustment, and they usually have other concurrent diseases including : (diabetes mellitus, hypertension, coronary artery diseases and infections ). Drug-related problems can result in an increase in morbidity and mortality, as well as an increase in the cost of healthcare.

Dosage Adjustment According to Renal Function : 

Dosage Adjustment According to Renal Function 1) adequate renal function is important to avoid toxicity. 2) The proper dosing of medications for patients with renal impairment can maximize therapeutic efficacy and minimize toxicity. 3) Proper dosing can also have an economic on the health system. 4) Dosage adjustment can result in avoidance of costs associated with drug-related toxicity and in cost savings in terms of drug costs 5) A major reason for inappropriate dosage adjustment is the underestimation of potential adverse consequences.

How to address this problem to improve the quality of healthcare delivered to patients? : 

How to address this problem to improve the quality of healthcare delivered to patients?

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By two strategies have been suggested to assist practitioners in monitoring and adjusting drug therapy in patients: 1)computerized dosing programmes 2)clinical pharmacist dosing services

Computerized Dosing Programmes : 

Computerized Dosing Programmes reduce the number of medication orders and administration of medications that are contraindicated due to renal insufficiency. Computerized guided medication dosing for inpatients with renal insufficiency has shown improved dose and frequency choices.

Clinical Pharmacist Dosing Services : 

Clinical Pharmacist Dosing Services 1) Clinical pharmacy interventions and involvement in disease management by community pharmacists have the potential to provide a valuable contribution to healthcare and decrease the overall Healthcare cost. 2) Clinical pharmacy services provided to hospitalized patients have demonstrated an economic impact with improved patient health outcomes. 3) Having a pharmacist in a rounding team in the intensive care unit (ICU) and general medicine units have been shown to reduce preventable adverse drug events.

Stepwise approach for adjusting drug dosages for patients with renalimpairment : 

Stepwise approach for adjusting drug dosages for patients with renalimpairment 1)have detailed initial assessment ex:(Previous drugs, allergeis,current medications including OTC drugs, body weight,height,laboratory data for renal functions parameters…etc) 2)evaluate the degree of renal impairment (calculate eGFR using MDRD4 equation to determine CKD stage, calculate clearance) 3)Review the medication list. ensure that all drugs have specific indications, evaluate for potential drug interaction, and adverse drug interactions). 4) choose the drug that has no or minimal nephrotoxicity. 5) select loading doses( usually the same as in patients with normal renal functions). 6)select maintenance regimen (make dose adjustment based on CL if needed ). 7)monitor drug level ( if monitoring drug level is available to guide therapy, it should be done (ex: digoxin,aminoglycoside) the dose of certain drug maybe titrated based on pharmacodynamic response (ex: antihypertensive drugs) ).

Examples of Drugs that Require Dosage Adjustment or Betterto be Avoided in Renal Impairment : 

Examples of Drugs that Require Dosage Adjustment or Betterto be Avoided in Renal Impairment ACE inhibitors: captopril, enalapril, lisinopril, perindopril, ramipril Analgesics: aspirin, morphine, meperidine, NSAIDs, tramadol Antiarrhythmic agents: N-acetylprocainamide, procainamide Antibiotics: aminoglycosides, aztreonam, cephalosporins, fluoroquinolones, imipenem, meropenem, nitrofurantoin, penicillins, sulfonamides, vancomycin Anticoagulants: enoxaparin, tirofi ban Antiepileptics: gabapentin, topiramate, vigabatrin Antifungals: fluconazole, flucytosine Itraconazole, terbinafi ne Anti-gout drugs: allopurinol, colchicine Antihistamines (H1- blockers): acrivastine, cetirizine, loratidine Antihistamines (H2-blockers): cimetidine, famotidine, ranitidine Antineoplastic agents: bleomycin, carboplatin, etoposide, fludarabine, hydroxyurea, methotrexate, nitrosourea Antiviral drugs: acyclovir, amantadine, didanosine, famciclovir, foscarnet, ganciclovir, lamivudine Beta-blockers: acebutolol, atenolol, nadolol, sotalol Diuretics: acetazolamide, amiloride, mannitol, spironolactone, thiazides, triamterene Fibrates: bezafi brate, clofi brate Hypoglycemic agents: acarbose, insulin, metformin, sulfonylurea Muscle relaxants: alcuronium, metocurine, tubocurarine Others: digoxin, metoclopramide, pentoxifylline, tranexamic acid.

conclusion : 

conclusion 1)most important drug-related problems in patients with chronic kidney disease (CKD) is medication dosing errors. 2)adequate renal function is important to avoid toxicity. 3) The clearance of drugs eliminated primarily by renal filtration is decreased by renal disease. 4) special consideration should be taken when these drugs are prescribed to patients with impaired renal function. 5) Physicians and pharmacists can work together to accomplish safe drug prescribing.

The end : 

The end Thank you