Principles of Drug Dosing in Renal Impairment



Principles of Drug Dosing in Renal Impairment


Bethany Tellor

Jennifer Hagopian



Introduction



  • One of the most significant drug-related errors in patients with renal impairment is inappropriate medication dosing leading to toxicity or ineffective therapy.1


  • Drugs with renally eliminated active metabolites require special dosing consideration as the consequences of accumulation can be particularly dangerous.


  • High degrees of precision are required when dosing medications with a narrow therapeutic index (e.g., aminoglycosides, digoxin) that rely on renal elimination.


  • Deciding on the appropriate dosing strategy of medications in patients with chronic kidney disease (CKD) or acute kidney injury (AKI) requires an understanding of the basic principles of pharmacokinetics, including absorption, protein binding, metabolism, and elimination.


  • Renal impairment affects glomerular blood flow and filtration, tubular secretion, reabsorption, renal bioactivation, and metabolism.


  • Nonrenal drug clearance, through mechanisms that are poorly understood, may also be impaired by kidney injury.1


  • Dosing for medications that undergo renal elimination is based primarily on an estimate of glomerular filtration rate (GFR). The Modification of Diet in Renal Disease (MDRD) study and Cockcroft–Gault equations provide useful estimates of GFR in adults. Patient-specific dosages calculated using these equations should be conducted in the presence of stable renal function and in patients not on renal replacement therapy (RRT).


  • Patients who are treated with different forms of dialysis may require supplemental dosing. The ability of dialysis to remove drugs is influenced by a variety of factors discussed elsewhere in this chapter.


  • Drugs that can further impair renal function in high-risk patients (heart failure [HF], liver disease, hypoperfusion) should be used with caution or avoided altogether in preference for safer alternatives.


  • Nephrotoxic medications have been linked to >20% episodes of AKI. Clinicians must recognize commonly used agents in order to ensure safety of medication administration in the setting of renal dysfunction.


  • Table 24-1 lists common medications that are potentially nephrotoxic.


General Dosing and Pharmacokinetic Principles



  • In general, renal insufficiency makes it difficult to predict whether a medication dose will produce an adequate, supratherapeutic, or subtherapeutic effect.2


  • Loading doses are often used to rapidly achieve a therapeutic drug concentration; they depend on the urgency with which a pharmacologic effect is needed against the half-life of the drug.



    • The time needed to reach 90% of the plateau drug concentration is 3.3 times the half-life. If this time is too long relative to the clinical urgency of the situation, a loading dose is needed.










      TABLE 24-1 MECHANISMS OF NEPHROTOXICITY AND ALTERNATIVES TO SOME COMMON DRUGS
































































































      Drug Mechanism Alternatives/Comments
      ACE inhibitors Intraglomerular hemodynamic alteration β-Blockers, calcium channel blockers
      Acetaminophen Chronic interstitial nephropathy Avoid doses >4 g/day chronically
      Acyclovir (intravenous) Acute tubular injury Hydration, oral administration, dose adjustment
      Aminoglycosides Acute tubular injury Monitor serum concentration, alternative antibiotic
      Amphotericin Acute tubular injury Saline loading, lipid formulation
      β-Lactam antibiotics Interstitial nephritis Alternative antibiotic
      Carboplatin Tubular injury Hydration, alternative chemotherapy agents
      Ciprofloxacin Interstitial nephritis Alternative antibiotic
      Cisplatin Tubular injury Hydration, alternative chemotherapy agents
      Cyclosporine Chronic interstitial nephritis, intraglomerular hemodynamic alteration Monitor serum concentrations, belatacept
      Foscarnet Tubular injury, crystal nephropathy Dose adjustment, ganciclovir
      Hydralazine ANCA-associated vasculitis Alternative antihypertensive
      Lithium Interstitial disease, hypercalcemia, CKD Monitor serum concentrations, alternative mood stabilizer
      Loop diuretics Interstitial nephritis Non–sulfa-containing diuretics
      Methotrexate Tubular injury Adjust dosage, urinary alkalinization, allopurinol
      NSAIDs Chronic interstitial nephropathy, intraglomerular hemodynamic alteration Acetaminophen, opiate analgesic
      Phenytoin Interstitial nephritis Alternative anticonvulsant
      Phenobarbital Interstitial nephritis Alternative anticonvulsant
      Proton pump inhibitors Interstitial nephritis, CKD H2 blockers
      Sulfonamides Tubular obstruction, interstitial nephritis Non–sulfa-containing antibiotic
      Tacrolimus Interstitial nephritis, intraglomerular hemodynamic alteration Monitor serum concentrations, belatacept
      Vancomycin Tubular and interstitial injuries Monitor serum concentrations, alternative antibiotic
      ACE, angiotensin-converting enzyme; CKD, chronic kidney disease.


    • Physiologic determinants affecting loading doses, such as an increase in total body water (e.g., edema, ascites), may warrant a higher than normal loading dose to account for change in volume of distribution (Vd), whereas dehydration may require a loading dose reduction.


    • The loading dose is a function of the Vd and the initial target blood concentration.

      Loading dose = Vd × Cp

      Vd = volume of distribution in L/kg

      Cp = desired plasma concentration in mg/L


  • Maintenance doses are used to achieve steady-state concentrations.



    • Dose reduction, increasing the interval, or both can be used to avoid the accumulation of renally eliminated drugs or their metabolites.


    • The best dosing option to employ depends on the properties of the medication and the disease state being treated.


    • Regimens with closer dosing frequencies and small individual doses result in less fluctuations between peak and trough concentrations. This may be particularly helpful for medications that need to be maintained within a narrow concentration range for optimal efficacy (e.g., anticonvulsants, antiarrhythmics).


  • Pharmacokinetics refers to the action of drugs in the body over time, and is used to understand drug handling as a means to optimize efficacy and minimize toxicity. As noted in Table 24-2, it involves four parameters of drug activity: absorption, distribution, metabolism, and clearance.1


  • It is important to identify how the pharmacokinetic profile of medications can be altered in patients with renal impairment (Table 24-2).


  • Accumulation of renally excreted active metabolites may occur (Table 24-3).


Dosage Adjustments of Commonly Used Drugs


Anticoagulants


Vitamin K Antagonists



  • Warfarin metabolism and elimination is not significantly altered in renal insufficiency, however CKD is a known risk factor associated with warfarin-related hemorrhage. This is likely due to platelet dysfunction and concomitant drug interactions.


  • Reduced doses should be used in patients with significant renal impairment.


Heparins



  • Unfractionated heparin (IV, SC) is primarily metabolized in the liver and endothelium; however, there is limited evidence to ensure safety of this agent in GFRs <30 mL/min.


  • Low–molecular-weight heparins (e.g., enoxaparin, dalteparin) administrated SC have predictable pharmacokinetic profiles and dosing curves that justify the use of these agents without routine coagulation monitoring. However, they primarily undergo renal clearance and require dose adjustment in renal insufficiency.


  • Anti-Xa monitoring has been recommended for GFRs <30 mL/min.


  • Use in dialysis is contraindicated and not Food and Drug Administration (FDA) approved.


Anti-Xa Inhibitors



  • Fondaparinux (SC) is primarily excreted in the urine as unchanged drug. Use with caution for GFRs <50 mL/min. Do not use if GFR <30 mL/min.


  • Rivaroxaban, apixaban, and edoxaban are three of the new direct oral anticoagulant agents (DOACs).3


  • Rivaroxaban and apixaban are renally eliminated and require dose adjustments. Use is not recommended for GFRs <30 mL/min. Neither agent is dialyzable but recent




    pharmacokinetic studies suggest a dose reduction may be used safely. However, clinical efficacy and long-term safety data are lacking in this patient population. Extreme caution is advised.








    TABLE 24-2 EFFECT OF RENAL DISEASE ON VARIOUS PHASES OF PHARMACOKINETICS





























    Phases Characteristics Effects of Renal Disease Examples of Medications
    Absorption Bioavailability refers to the fraction of medication that reaches the systemic circulation after oral ingestion.
    Several factors and physiologic processes influence intestinal absorption and bioavailability.
    Patients with CKD and AKI exhibit changes in the gastrointestinal tract that affect bioavailability.
    Gastroparesis: Patients with CKD often suffer from gastroparesis. This results in delayed gastric emptying and prolongs the time to maximum drug concentrations, which can be important when rapid onset of action is desired.
    Gastric alkalinization: Common use of medications such as phosphate binders, antacids, H2-receptor antagonists, and proton pump inhibitors in patients with CKD reduces the absorption of many medications requiring an acidic environment.
    Cationic chelation: Ingestion of common cation-containing antacids (e.g., calcium, magnesium, aluminum hydroxide, sodium polystyrene sulfonate) in patients with renal dysfunction decreases the absorption of many coadministered medications because of chelation.
    Examples of medications affected by gastric alkalinization:


    • Furosemide
    • Ferrous sulfate

    Examples of drugs affected by chelation:


    • Quinolones
    • Warfarin
    • Levothyroxine
    • Tetracycline
    Distribution Drug distribution or volume of distribution (Vd) is the total amount of drug present in the body, divided by the plasma concentration, expressed in liters.
    The Vd determines peak concentrations. Plasma protein binding, tissue binding, active transport, and body composition affect the Vd.
    Albumin and other plasma proteins bind most drugs to varying degrees. Plasma drug concentrations are representative of both bound and unbound drug, but only free drug is capable of crossing cellular membranes and exerting pharmacologic effects.
    Several drugs have shown changes in Vd in patients with renal dysfunction and this may mandate a change in a loading dose of a medication.
    Hypoalbuminemia due to the nephrotic syndrome often leads to an increase in the free drug fraction of medications that are highly bound to albumin.
    An increase in α-1-acid glycoprotein (an acute phase protein) associated with renal dysfunction will lead to increase in protein binding of medications bound to nonalbumin proteins.
    In addition, accumulation of metabolites and endogenous substances increase competition for binding sites.
    Digoxin: Vd that is one-half that in a patient with normal renal function.
    β-Lactams: They have increased Vd and may need higher dosing in in renal dysfunction.
    Examples of acidic drugs that are usually protein bound, and have higher free drug levels with decreased albumin:


    • Penicillins
    • Cephalosporins
    • Phenytoin
    • Furosemide
    • Salicylates

    Examples of alkaline drugs affected by increased protein binding in CKD:


    • Propranolol
    • Morphine
    • Vancomycin
    Metabolism The majority of drugs in the clinical setting undergo first-order kinetics (i.e., drug concentrations decline logarithmically over time) and rates are proportional to the total body concentration of the drug present.
    Biotransformation at numerous sites in the body happens through phase reactions.
    Phase I reactions include hydrolysis, reduction, and oxidation (cytochrome P450 reactions). These serve to increase drug hydrophilicity to prepare for excretion or further phase II metabolism.
    Phase II reactions or conjugation reactions include glucuronidation, sulfation, glutathione conjugation, acetylation, and methylation.
    Hepatic metabolism of medications is inhibited in both CKD and AKI.
    Renal dysfunction significantly slows both phase I and phase II reactions.
    Renal dysfunction reduces P-glycoprotein activity, resulting in increased bioavailability of some medications.
    Changes to oxidation reactions result in reduced activity of several of the CYP450 isoenzymes (2C9, 2C19, 2D6, 3A4).
    All phase II reactions are slowed in renal dysfunction.
    Examples of medications with narrow therapeutic index affected by decreased P-glycoprotein activity:


    • Cyclosporine
    • Tacrolimus

    Examples of drugs affected by decreased phase II actions:


    • Acetylation: dapsone, hydralazine, isoniazid, procainamide
    • Glucuronidation: acetaminophen, morphine, lorazepam, naproxen
    • Sulfation: acetaminophen, minoxidil, dopamine, albuterol
    • Methylation: dobutamine, dopamine, 6-mercaptopurine
    Elimination Elimination is reported as a half-life (T½), or the time needed to reduce medication plasma concentrations by 50%.
    T½ is influenced by both Vd and clearance and can reflect a change in either or both of these parameters.
    T½ and clearance of a drug are different.
    Approximately 5 T½s are required to eliminate 97% of drug from the body.
    This parameter is especially useful for estimation of the time required to achieve steady state (approximately 4–5 T½s), and to estimate appropriate drug dosing intervals.
    The rate of renal elimination is dependent on GFR, renal tubular secretion, and reabsorption.
    Reduced GFR results in prolonged free drug elimination T½.
    Medication-specific characteristics (e.g., molecular weight, protein binding) determine glomerular filtration with filtration rate dependent on free fraction.
    Drugs that are highly protein bound are not filtered, but actively secreted into the proximal convoluted tubule through a saturable process.
    In the distal portion of the nephron substantial passive reabsorption occurs and this is affected by urine concentrating activities, pH, lipophilicity, and protein binding.
    Reduced GFR will decrease secretion by active transport.
    Examples of drugs affected by reduced active secretion:


    • Ampicillin
    • Furosemide
    • Penicillin G
    • Trimethoprim

    Examples of drugs affected by reduced passive absorption:


    • Aspirin
    • Lithium
    CKD, chronic kidney disease; AKI, acute kidney injury; Vd, volume of distribution; CYP450, cytochrome P450; GFR, glomerular filtration rate.








    TABLE 24-3 COMMON MEDICATIONS WITH ACTIVE METABOLITES










































    Drug Metabolite Cumulative Toxicity
    Acetaminophen N-acetyl-p-benzoquinoneimine Hepatotoxicity, tubular acute necrosis
    Allopurinol Oxypurinol Bone marrow suppression
    Glyburide 4-trans-hydroxyglibenclamide (M1)
    3-cis-hydroxyglibenclamide (M2)
    Hypoglycemia
    Meperidine Normeperidine Seizures
    Primidone Phenobarbital Oversedation, coma
    Procainamide N-acetyl-procainamide Arrhythmia, hypotension, respiratory failure
    Nitroprusside Thiocyanate Lactic hallucinations, coma, acidosis, tinnitus
    Morphine 6-Morphine glucuronide Oversedation, coma
    Tramadol O-desmethyltramadol Respiratory depression, seizures, increased serotonin


  • Edoxaban requires dose adjustments in renal insufficiency. Use is not recommended for GFRs <15 mL/min and is not dialyzable. In patients with nonvalvular atrial fibrillation, use is not recommended if GFR >95 mL/min as an increased risk of ischemic stroke compared to warfarin has been noted.


Direct Thrombin Inhibitors

Apr 17, 2020 | Posted by in NEPHROLOGY | Comments Off on Principles of Drug Dosing in Renal Impairment
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