Drugs and Kidney Disease (Mansoura University)

NEPHROLOGY UNIT FACULTY OF MEDICINE MANSOURA UNIVERSITY CHAPTER 5 SAFE PRESECRIPTION IN RENAL DISEASE  CHAPTER 5 THERAPEUTIC AND SAFE PRESCRIPTION IN RENAL PATIENTS DRUGS AND KIDNEY DISEASE (BIDIRECTIO...

NEPHROLOGY UNIT FACULTY OF MEDICINE MANSOURA UNIVERSITY CHAPTER 5 SAFE PRESECRIPTION IN RENAL DISEASE  CHAPTER 5 THERAPEUTIC AND SAFE PRESCRIPTION IN RENAL PATIENTS DRUGS AND KIDNEY DISEASE (BIDIRECTIONAL RELATIONSHIP) 1 (ABSORPTION – DISTRIBUTION – METABOLISM – ELIMINATION) ❶ ABSORPTION  Medications bioavailability: 1 FOR IV DRUGS ▪ 100% bioavailability. Not affected by kidney disease 2 FOR ORAL DRUGS ▪ ⮇ bioavailability due to ⮇ drug absorption. ❷ DISTRIBUTION  Kidney disease can alter the distribution of drugs within the body due to changes in plasma protein binding: ① Uremic toxins displace drugs from binding sites. Normal CKD patient ② ⮇ Serum albumin levels (As in nephrotic syndrome). Leading to ⮅ the drugs free (active) concentration → Which can lead to enhanced drug effects or toxicity.  ❸ METABOLISIM  Both hepatic and renal metabolism of the drugs is altered in patient with CKD. ❹ ELIMINATION  The kidney is the most important organ for drug and metabolite elimination:  SO… ⮇ Renal function → Drug accumulation and toxicity. 2  Mechanisms of medication-induced nephrotoxicity: ① Functional/Hemodynamic effect: Afferent VC or Efferent VD. ② Glomerular injury. ③ Tubulointerstitial injury: AIN + Analgesic nephropathy + Crystal Nephropathy ❶ Functional/Hemodynamic effect  Mechanisms: These drugs alter renal blood flow → ⮇ GFR  Examples: DRUGS THAT ⮇ AFFERENT ARTERIOLAR VD DRUGS THAT ⮇ EFFERENT ARTERIOLAR VC - Calcineurin inhibitor - RAAS blocker (ACEI & ARB) - NSAIDs 1  ❷ Medication-induced glomerular disease AFFECTED CELL PATHOLOGY DRUG -Minimal change -INF Epithelial disease -Lithium (Podocyte) -Focal segmental -NSAIDs GN -CNIs -Thrombotic Endothelial -Anti- microangiopathy DRUG platelets -Nodular A. Immune complex diseases Mesangial --- glomerulosclerosis - Hydralazine ① Lupus like GN - Penicillamine Membranous - Procainamide ② nephropathy - NSAIDs B. Small vessel vasculitis (ANCA related) - Infliximab Segmental - - Propylthiouracil necrotizing GN - various antibiotics ❸ Tubulointerstitial injury 1) AIN → Idiosyncratic (Dose & Time independent) ▪ Penicillins ▪ Isoniazid 1. ANTIBIOTICS ▪ Cephalosporins ▪ Rifampin ▪ Sulfonamides 2. ANALGESICS ▪ NSAIDs 3. DIURETICS & ▪ Furosemide ▪ Amlodipine ANTI- ▪ Thiazides Diltiazem HYPERTENSIVES ▪ Triamterene 4. PPI Omeprazole 5. H2 BLOCKERS ▪ Famotidine ▪ Ranitidine 6. ANTICONVULSANTS ▪ Phenytoin ▪ Carbamazepine ▪ Allopurinol 7. OTHER ▪ Immune Checkpoint Inhibitors (i.e., PD-L1 inhibitors) 2 2) Analgesic nephropathy → Dose & Time dependent ▪ A kidney disease characterized by papillary necrosis & chronic DEFINITION interstitial nephritis. ▪ When combination analgesics (e.g., NSAIDs + Paracetamol) are used in ETIOLOGY large cumulative doses. ▪ ⮇ Prostacyclin synthesis → VC of the medullary blood vessels → PATHOGENESIS papillary ischemia & papillary necrosis 3) Crystal Nephropathy: ▪ There are chemical agents & medications that cause kidney damage by forming crystalline deposits, resulting in: DEFINITION 1. Tubular injury 2. Interstitial inflammation 3. Obstruction ◈ Caused by: EXCESS VIT D 1. HYPERCALCEMIA ◈ Results in: Calcium phosphate is deposited. ◈ Vit c is converted to oxalate & excreted in the 2. EXCESS VIT C urine → allows calcium oxalate crystals to form. ETIOLOGY ◈ Caused by:  Medications: thiazide diuretics, cyclosporine, furosemide, cisplatin. 3. HYPERURICEMIA  Tumor lysis syndrome triggered by chemotherapeutic agents ◈ Results in: uric acid nephropathy ▪ Conditions favoring nucleation (crystal formation): 1. Urine supersaturation with crystal-forming substances. 2. Urine volume depletion (Dehydration). CONTRIBUTING 3. Lack of urinary inhibitors of stone formation: FACTORS  Citrates → inhibit calcium complexes  Magnesium → inhibit oxalate complexes 4. Other factors… 3  MEDCATION USAGE IN RENAL DISEASE ① Medications commonly used in renal patients. ② Medications that should be deprescribed in renal patients. ③ Medications that should be monitored closely in renal patients. 1  Patients with CKD are susceptible to adverse effects with agents routinely used in the management of CKD & comorbid conditions.  For example: ① Diuretics. ② RAAS blocker. ③ Anti-hyperglycemic agents. ❶ DIURITICS Benefits For natriuresis & BP control with a reduced GFR. ① Injudicious diuretic use can ⮅ the risk of AKI LOOP AND THIAZIDE DIURETICS: ② A range of electrolyte disturbances including ⮇ k+ & ⮇ Mg2+ ③ Hypochloremic metabolic alkalosis Risks ④ Hyperuricemia ⑤ At higher doses of thiazides → glucose intolerance, and hyperlipidemia K+ SPARING DIURETICS: (MRA, Amiloride) ⑥ Hyperkalemia 4  ❷ RAAS BLOCKERS  Include: ① Angiotensin-converting enzyme inhibitors (ACE inhibitors). ② Angiotensin-receptor blocker (ARBs). 5  RAAS blockers Double-Edged Sword: ◈ Essential to CKD treatment: ◈ Under certain clinical circumstances ① ⮇ Proteinuria can have the potential for harm: ② Control HTN (1st Line) ① Hyperkalemia ③ Retard CKD progression ② AKI. ④ Heart Benefits. A HYPERKALEMIA Mechanism  ⮇ Aldosterone secretion → ⮇ Potassium excretion in the kidney. The risk is higher when… ① Two RAAS blockers are used in combination (ACEI + ARBs) not recommended ② RAAS blockers are used with other drugs, such as: Risk factors ▪ K+ sparing diuretics ▪ NSAIDs ▪ TMP-SMX (Trimethoprim-sulfamethoxazole) ▪ Heparin. less commonly B AKI Mechanism  ⮇ Angiotensin II → Efferent VD → ⮇ Potassium excretion in the kidney. ① High summer temperatures ② Volume depletion ③ Renal artery stenosis (bilateral or unilateral with a solitary kidney) ④ Triple whammy = simultaneous use of NSAID + RAAS blocker + Diuretic Risk factors 6  ❸ ANTI-HYPERGLYCEMIC AGENTS  Treatment of hyperglycemia in patients with T2D & impaired renal function represents a major challenge for several reasons one of them is… ▪ ⮇ kidney function → ⮇ drug metabolism & excretion → ⮅ circulating levels of the drug → adverse effects including hypoglycemia. 2  Deprescribing is the systematic process of identifying and discontinuing drugs in instances in which existing or potential harms outweigh existing or potential benefits.  Examples: ① NSAIDs ② Iodinated contrast media ③ Others ❶ NSAIDs ① Acute kidney injury via hemodynamic and acute tubular injury ② Acute interstitial nephritis ③ Acute or chronic papillary necrosis ④ Progression of chronic kidney disease Risks ⑤ Nephrotic syndrome: Membranous nephropathy or Minimal change disease. ⑥ Hyperkalemia ⑦ Metabolic acidosis ⑧ Fluid retention ⑨ Exacerbation of hypertension ① Avoid with concomitant use of diuretics or RAAS inhibitors Cautions ② Maintain hydration to avoid AKI ③ Consider alternate analgesic as acetaminophen 7  ❷ IODINATED CONTRAST MEDIA Risks Contrast-induced nephrotoxicity ① Use the lowest dose. ② Maintain hydration with isotonic saline. ③ Consider N-acetylcysteine or sodium bicarbonate. Cautions ④ Avoid use of high-osmolarity agents. ⑤ Avoid concomitant nephrotoxins. ⑥ Avoid use of gadolinium-containing contrast media. ❸ OTHER ◈ Unneeded OTC medications & dietary supplements: ① Herbal supplements 1 OTC ② Non-herbal supplements ③ Vitamins 2 Licorice ◈ ⮅ Risk of sodium and water retention, hypokalemia. ◈ Growing evidence indicates potential kidney and non-kidney-related harm 3 PPI with prolonged usage. 8  3  For medications with narrow therapeutic index (Toxicity and side effects are common). Dose-Response Curves for wide Dose-Response Curves for Narrow Therapeutic Index Medications Therapeutic Index Medications Need monitoring ED50 Dose where 50% of the patients get the desired therapeutic effect. TD50 Dose where 50% of the patients get unwanted side-effect.  Example for drugs with narrow therapeutic index: DRUGS EFFECT OF TOXICITY ◈ Nephrotoxic (acute tubular necrosis, AKI). 1 Aminoglycosides ◈ Ototoxic 2 Digoxin ◈ Arrhythmias ◈ Diabetes insipidus 3 Lithium ◈ Interstitial disease 4 Warfarin ◈ Increased risk of bleeding APPROACH TO SAFE MEDICATION PRESCRIPTION IN RENAL PATIENTS ❶ Assess kidney function ❷ Medications list ❸ Prescribed Medication ❹ Adjust dose if needed ❺ Drug Monitoring 9  ❶ ASSESS KIDNEY FUNCTION  Glomerular filtration rate (GFR) should be the standard measure to evaluate kidney function for staging of CKD and drug dosing purposes.  Clinicians can use estimated GFR (Equations) or measured GFR (24 hours urinary collection) ❷ MEDICATION HISTORY  The medication list should include all prescriptions, OTC, and dietary supplements.  Ask for history of drug allergies/sensitivities. ❸ MEDICATION REVIEW  For each drug in the list check the following: ① Is the drug nephrotoxic or contraindicated in CKD? ② Is it contraindicated at a specific GFR level? ③ Is the risk of adverse effects increased in CKD? ④ Does this drug have a narrow therapeutic index? ❹ ADJUST REGIMEN  Adjust the dose based on patient’s eGFR and drug pharmacokinetics (Avoid renally cleared medications) ❺ DRUG THERAPY MONITORING  Monitor the following: ▪ Drug efficacy (Response). ▪ Drug toxicity. ▪ Drug level “If available/applicable” 10