Drug Dosing in CKD and Dialysis PDF

formu -ge Goh Drug dosing in CKD and Dialysis Dr.Razan Alsheikh, PharmD 1 Drug dosing in CKD and Dialysis The dosages of many drugs will require adjustment to...

formu -ge Goh Drug dosing in CKD and Dialysis Dr.Razan Alsheikh, PharmD 1 Drug dosing in CKD and Dialysis The dosages of many drugs will require adjustment to prevent toxicity in patients with CKD. Adjustment strategies vary depending on whether the patient is receiving RRT and, if so, which type. 2  Pharmacokinetic Changes in CKD 1. Absorption: Gastrointestinal (GI) Changes: CKD can cause alterations in the GI tract, such as changes in gastric pH, delayed > - gastric emptying, and edema of the intestinal mucosa, which may affect drug absorption. Drug Interactions: Use of phosphate binders and other medications in CKD patients can bind with certain drugs in the gut, reducing their absorption. - 2. Distribution: Volume of Distribution (Vd): CKD can alter the Vd of drugs due to changes in fluid status (e.g., edema, fluid retention, or dehydration). Protein Binding: Reduced serum albumin levels (common in CKD) can decrease the binding of highly protein- bound drugs (e.g., phenytoin, warfarin), leading to an increased free (active) drug concentration. This can enhance drug efficacy but also raises the risk of toxicity. Tissue Binding: Accumulation of uremic toxins may compete with drug binding sites on plasma proteins, = further altering drug distribution. 3  Pharmacokinetic Changes in CKD 3. Metabolism: Hepatic Metabolism Changes: CKD can lead to altered activity of hepatic cytochrome& P450 enzymes, reducing or altering the metabolism of certain drugs. Metabolite Accumulation: Some drugs have active or toxic metabolites that are renally excreted. In CKD, these metabolites may accumulate, increasing the risk of adverse effects (e.g., morphine-6-glucuronide from morphine). Non-Renal Clearance: CKD can influence non-renal elimination pathways, such as biliary excretion and hepatic metabolism, potentially leading to - altered drug clearance. 4. Excretion: ↑ T2/2 Reduced Renal Clearance: The primary pharmacokinetic change in CKD is the reduction in renal drug elimination due to decreased glomerular filtration rate (GFR). This prolongs the half-life of renally cleared drugs, leading to - & potential accumulation and toxicity. Tubular Secretion and Reabsorption Changes: CKD can impair active tubular secretion and reabsorption e processes, further affecting the excretion of certain drugs. 4 Dosage Adjustment Strategies in CKD Dose Reduction: Lowering the dose while maintaining the standard dosing interval. Interval Extension: Maintaining the dose but increasing the time between doses. = Combination Approach: Adjusting both the dose and the dosing interval. The choice among these strategies depends on the drug's pharmacodynamics and the degree of renal impairment. 5 X 99 & - - - - - -- 6 Case A 65-year-old male with Stage· 4 CKD is prescribed a medication that is primarily renally cleared. Which action would you take to avoid drug accumulation? a) Maintain the same dose as for a healthy patient b) Increase the dose but shorten the interval c) Decrease the dose and extend the dosing interval d) Prescribe a different drug with no renal clearance 7 Case A 70-year-old patient with CKD has hypoalbuminemia. He is taking a drug that is 90% protein-bound. How might his condition affect the pharmacokinetics of the drug? a) The drug will have a lower free (active) concentration b) The drug's efficacy and toxicity will be reduced c) The free (active) concentration of the drug will increase - d) No effect; protein binding is unrelated to CKD status 8 Case A 72-year-old male with CKD stage 4 (estimated GFR of 20 mL/min/1.73 m²) is prescribed② gabapentin for neuropathic pain. Gabapentin is primarily renally excreted. What is the appropriate dosing strategy? a) Continue at the standard dose with normal frequency b) Increase the dose due to reduced clearance c) Reduce the dose and/or extend the dosing interval d) No dose adjustment necessary since it is not metabolized 9 Case A 60-year-old female patient with CKD stage 3b (eGFR 35 mL/min/1.73 m²) is started on Eenoxaparin for deep vein thrombosis prophylaxis. What adjustment is required? a) No dose adjustment is necessary b) Increase the dose to ensure efficacy c) Reduce the dose or switch to[ J unfractionated heparin d) Switch to an oral anticoagulant without adjustment 0 4 normal as just 36 10 Drug Dosing in dialysis 1.Molecular Weight: Smaller molecules are more likely to be dialyzed. 2.Water Solubility: Water-soluble drugs are more readily removed by dialysis. 3.Protein Binding: Drugs with low protein binding (free form in plasma) are more likely to be dialyzed. 4.Volume of Distribution (Vd): Drugs with a small volume of distribution (limited to extracellular fluid) are more likely to be dialyzed. 5. Dialysis Modality: Hemodialysis tends to clear drugs more effectively than peritoneal dialysis due to differences in membrane permeability and blood flow rates. ord Ant Teriatric 11 Procedure-related factors affecting drug removal a. Type of dialyzer: High flux, widely used now b. Blood flow rate: Elevated rates increase delivery and maintain gradient across membrane. ↑ a removal c. Duration of dialysis session d. Dialysate flow rate. High rates of flow increase removal by maintaining the gradient across membranes. 12 Examples of dialyzable and non-dialyzable drugs Dialyzable drugs Antibiotics: Vancomycin (partially), gentamicin, ampicillin, cephalexin. Antifungal Agents: Amphotericin B (liposomal forms are less dialyzable). Anticonvulsants: Gabapentin, levetiracetam (partial dialysis clearance). Analgesics/Antipyretics: Acetaminophen. E Cardiovascular Drugs: Atenolol (significantly dialyzable), enalaprilat. Lithium: This drug is highly dialyzable, and special caution is needed for patients on dialysis. Non-Dialyzable Drugs: Some drugs are not significantly removed by dialysis due to high protein binding, large molecular size, or a high volume of distribution. Examples include: Digoxin Amiodarone Phenytoin (due to high protein binding) 13 14 low vs-remove high Ude not remove 15 Dialysis Considerations: 1.Post-Dialysis Dosing: If a drug is significantly dialyzed, it may be necessary to administer a supplementary dose after dialysis to maintain therapeutic levels. 2.Monitoring Levels: For drugs with a narrow therapeutic index, monitoring plasma levels and adjusting dosages accordingly is critical. 3.Timing of Administration: For some dialyzable drugs, timing doses relative to dialysis sessions can be important to maximize effectiveness and minimize toxicity. 16 17  Case Properties of four drugs are described in the table that follows. Drug 1: 98% protein bound g) Drug 2 : Molecular weight = 485 Da - I · Drug 3: Vd = 180 L 300 Drug 4: High lipid solubility Which one of these drugs, if administered to a patient weighing 70 kg, would most likely require supplementation after a high-flux IHD session? her miters 52 A. Drug 1 2 180. = B. Drug 2 ⑨ 78 C. Drug 3 D. Drug 4 18 Case Which type of dialysis is known to have a lower clearance for many large molecule drugs? a) Peritoneal dialysis b) Hemodialysis Intermerent - c) Continuous renal replacement therapy (CRRT) d) Ultrafiltration dialysis 19 Case When considering drug administration in a hemodialysis patient, which timing strategy is often recommended for dialyzable medications? a) Administer the drug just before dialysis b) Administer the drug during dialysis c) Administer the drug immediately after dialysis d) No specific timing considerations are needed 20 Case Which of the following is true regarding dialysis clearance of drugs? a) All drugs are effectively removed by dialysis b) Drugs with a high volume of distribution are typically removed easily c) Small, water-soluble, non-protein-bound drugs are most easily cleared d) Lipophilic drugs are more efficiently cleared than hydrophilic ones 21 Case A 45-year-old woman on hemodialysis is being treated with a drug that is partially removed by dialysis. What is the most appropriate strategy to ensure therapeutic efficacy? sand end my ne a) Administer an extra dose after each dialysis session b) Increase the daily dose but give no special consideration for dialysis timing c) Switch to a drug that is completely dialyzed d) No adjustment needed as dialysis minimally affects drug levels 22 Case A patient with CKD is taking a medication that has a high volume of distribution (Vd) and low protein binding. How might this affect dialysis clearance? a) The drug is likely to be easily removed by dialysis nigh vJ b) The drug will not be removed efficiently by dialysis c) The drug will bind to dialysis membranes and accumulate in tissue d) The drug's removal will be dependent solely on its half-life 23  Thank you! [email protected] 24