Drugs in kidney diseases

Drugs in kidney diseases

Drugs in kidney diseases DrNoushin Hashemi.M.D. Nephrologist Drugs and the Kidney 1- Renal Physiology and Pharmacokinetics 2- Drugs and the normal kidney 3- Effect of renal disease on drug metabolism 4- Drugs toxic to the kidney 5- Prescribing in kidney disease

Normal Kidney Function 1 Extra Cellular Fluid Volume control 2 Electrolyte balance

3 Waste product excretion 4 Drug and hormone elimination/metabolism 5 Blood pressure regulation 6 Regulation of haematocrit 7 regulation of calcium/phosphate balance (vitamin D3 metabolism) Clinical Estimation of renal function Clinical examination pallor, volume status, blood pressure measurement, urinalysis Blood tests

Routine Tests haemoglobin level electrolyte measurement (Na ,K , Ca, PO4) urea Serum Creatinine and GFR Muscle metabolite - concentration proportional to muscle mass High: muscular young men

Low: conditions with muscle wasting Elderly Muscular dystrophy Anorexia Malignancy women Normal range 70 to 140 mol/litremol/litre GFR Estimation Cockroft-Gault Formula

CrCl=Fx(140-age)xweight/CreaP F=1.04 F=1.23 MDRD Formula EPI(race,age,gender,cr) ESTIMATION OF GFR Creatinine Clearance Crt clearance

= Crt clearance (Cockcroft-Gault equation) Urine crt Urine volume Plasma crt (140-AGE) =

WEIGHT 72 Crt. Tests of renal function cont. 24h Urine sample-Creatinine clearance gold standard Inulin clearance urea understimate and cr overestimate GFR

Pharmacokinetics Absorption Distribution Metabolism Elimination filtration

secretion Farmacodynamic Complex interactions of other farmacologic factors including drugconcentration,receptor-drug interaction and effect on body chemistry and clinical factors such as concurrent disease and degree of organ dysfunction

Drugs and normal kidney Effects of renal disease on drugs Effect of uremia on drug disposition 1-Bioavalability : uremia decreases GI absorption of drugs

(dissolution ,alkalinization,first pass hepatic metabolism , impaire protein binding) 2-Distribution: -edema and ascites :increase volume of distribution -dehydration and muscle wasting :decrease volume of distribution -combination of decrease serum Alb concentration and reduction in Alb affinity reduce protein binding in uremia 3-Metabolism: -uremia slows the rate of

reduction and hydrolysis reactions . -uremia alter the deposition of drugs metabolize by liver through changes in plasma protein binding. TABLE 57-2 -- Drugs That Have Active or Toxic Metabolites in Dialysis Patients Acetaminophen Angiotensin-converting enzyme inhibitors Angiotensin receptor blockers

Adriamycin Allopurinol Amiodarone Amoxapine Azathioprine Benzodiazepines -Blockers Bupropion Buspirone Cardiac glycosides

Clorazepate Cephalosporins Chloral hydrate Clofibrate Desipramine Diltiazem Encainide Esmolol H2-blockers Hydroxyzine Imipramine

TABLE 57-2-- Drugs That Have Active or Toxic Metabolites in Dialysis Patients cont.. Isosorbide Levodopa Lorcainide Meperidine Metronidazole Methyldopa Miglitol Minoxidil Morphine

Nitrofurantoin Nitroprusside Procainamide Primidone Propoxyphene Pyrimethamine Quinidine Serotonin reuptake inhibitors Spironolactone Sulfonylureas

Sulindac Thiazolidinediones Triamterene Trimethadione Verapamil Vidarabine Effect of dialysis on drugs: Drug clearance during dialysis : -Adsorption -Convection -Diffusion

drugs that have small volume of distribution more effectively removed by dialysis Effect of dialysis on drugs Molecular weight Water solubility Degree of protein binding Membrane clearance Drugs with MW >500 daltons poorly cleared by

conventional HD membranes. Protein or tissue binding or lipid soluble are not dialyzed properly.(<90% proteinbound) For drugs not removed by HD, it is unusual to be removed by peritoneal dialysis. High-flux membranes (porous) are more permeable to drugs.(treatment time,BFR,DFR) Effect of dialysis on drugs Hemofiltration modalities are using in ICU

for management of acute renal failure significantly increase drug removal due to increase plasma protein loss.(treatment of theophylline and aspirin poisoning) A drug significantly removed by this modality if is not protein bound and distributed in plasma. Measurement of serum drug level may be helpful in guiding the need for supplemental dosing. Drug dosing in PD :

PD is less efficient in removing drugs than HD LMW drugs and small volume of distribution are more effectively removed Depends on number and volume exchange done daily and dwell time. Depends on residual kidney function. Factors favoring absorption include inflamation of membrane and concentration gradient.

Drug dosing in CRRT: Provide less of a challenge for drug dosing Continuous nature of clearance is analogous with drug removal by kidney Depends on MW,membrane characteristic, BFR,DFR .

Drug dosing recommendations: loading dose is equal to usual dose in normal kidney function. In HD many drugs are given only at the end of dialysis. Maintenance dose of most drugs should be given after dialysis. Drugs toxic to the

kidney Patient related risk factors for drug-induced nephrotoxicity Absolute or effective intravascular depletion Age older than 60 years Diabetes Exposure to multiple nephrotoxins

Heart failure Sepsis Underlying renal insufficiency (glumerular filtration rate <60 ml per minute per 1.73m2) Drug toxicity is responsible for 1827% of Acute Renal injury 6 major mechanisms are involved: 1. 2.

3. 4. 5. 6. Hemodymanic mediated Glomerulonephritis Acute tubular necrosis Interstitial nephritis Papillary necrosis Obstructive uropathy

GLOMERULUS 1- Hemodynamic mediated Effect Gradient pressure between afferent and efferent arterioles are responsible for glomerular filtration. Drug involved: a. b. c.

d. NSAID ACE inhibitors ARB Calcineurin inhibitor A- NSAID They are nephrotoxic in patients with borderline renal function,

spesis or haert failure COX inhibition will block PG synthesis (vasodialtor) and consequently, V.C will dominate and blood flow and GFR will decrease . PG also important for maintaining fluid and electrolyte hemostasis. NSAIDs (Non-steroidal anti inflammatory drugs) Commonly

used Interfere with prostaglandin production, disrupt regulation of renal medullary blood flow and salt water balance Naproxen have the least cardiovascular risk Antithrombotic effect of ASA antagonized by NSAID Chronic renal impairment

Habitual use Exacerbated by other drugs ( antihypertensives, ACE inhibitors) Nephrotoxic potential of Nsaid determine by potency, length of action,period of administration A hypersensivity reaction of Nsaid may provoke AKI associated with preuteinuria and nephrotic syndrome and allergic

interstitial nephritis B & C- ACEIs and ARB Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blocker (ARB) are inhibiting Renin system and decrease the blood hemodynamic: It produces VD and decrease perfusion pressure and decreases GFR At the start of the treatment a decrease of urine volume and increase of creatinine by 30% indicates

Damage is reversible Rehydration of patient is advisable It is contraindicated to prescribe it for patients with renal artery stenosis. Why??? D- Immunosuppressing agents Calcineurin inhibitors Cyclosporine and Tacrolimus forms

immunophillin complex which inhibits protein calcineurin and mediates T- cell response It produces VC of afferent arteriols by increasing endothelin and thromboxan A2, affecting renal perfusion Nephrotoxicity is the dose limiting toxicity It can cause also interstitial nephritis and produce nephritis in renal transplant Therapeutic drug monitor is essential to reduce dose when needed

Drug toxicity is responsible for 1827% of Acute Renal injury in USA 6 major mechanisms are involved: 1. 2. 3. 4. 5. 6. Hemodymanic mediated

Glomerulonephritis Acute tubular necrosis Interstitial nephritis Papillary necrosis Obstructive uropathy 2- Glomerulonephritis 4 Different immunological drug induced GN: 1. Minimal change syndrome: by:

NSAID, ampicillin, rifampicin 2. Focal segmental glomeruloscerosis (FSGS): lithium, heroin 3. Membranous nephropathy (MN): NSAID, gold therapy, mercury, penicillamine 4. Membranoproliferative: hydralazine Drug toxicity is responsible for 1827% of Acute Renal injury in USA 6 major mechanisms are involved:

1. 2. 3. 4. 5. 6. Hemodymanic mediated Glomerulonephritis Acute tubular necrosis Interstitial nephritis

Papillary necrosis Obstructive uropathy 3- Acute Tubular Necrosis Due to ischemia from exposure to toxin. Death of the tube, sloughing of Renal tubules. Caused by: 1. 2.

3. 4. Aminoglycosides Amphotericin B Radiocontrast dye Cisplatin Aminoglycosides Highly effective antimicrobials

Particularly useful in gram -ve sepsis bactericidal BUT Nephrotoxic Ototoxic Narrow therapeutic range Aminoglycisdes Gentamycin and Kanamycin Affecting PCT by binding of +ve charges of AG to phospholipids in

plasma, mitochondria and lysosomal membranes. It will interfere in the functions of organelles. Renal toxicity appears 5-10 days of treatment by monitoring serum creatinine. AKI is reversible Prescribing Aminoglycosides Once

daily regimen now recommended in patients with normal kidneys High peak concentration enhances efficacy long post dose effect Single daily dose less nephrotoxic Dose depends on size and renal function Measure levels! Amphotericin

B In 80% of patients after 3-4 grams Affecting PCT and DCT to increase permeability and increase O2 requirements, VC of blood vessels. Avoid co administration of other nephrotoxic agents especially: carbicillin and Ticarcillin Intravenous contrast

Used commonly CT scanning, IV urography, Angiography Unsafe in patients with pre-existing renal impairment Risk increased in diabetic nephropathy, heart failure & dehydration Can precipitate end-stage renal failure Cumulative effect on repeated administration

Radiocontrast Dye low osmolarity,nonionise,low dose Max dose BW multiply 5 devided by cr Affecting tubular cells, renal ischemia, renal VC Use NaHCO3 and N-acetyl cysteine Deterioration happens 2-3 days after radiocontrast injection,recover after 1 week Hydration is the most important and use

mannitol pre and post injection and diuretics not advised Cisplatin Chemotherapeutic agent binding to tubular cells Drug toxicity is responsible for 1827% of Acute Renal injury in USA 6 major mechanisms are involved: 1.

2. 3. 4. 5. 6. Hemodymanic mediated Glomerulonephritis Acute tubular necrosis Interstitial nephritis Papillary necrosis Obstructive uropathy

4- Acute Allergic Interstitial Nephritis Due to hypersensitivity to medications T- Cell mediated Antibiotics: penicillin, cephalosprorins and sulfonamides. Vancomycin (therapeutic drug monitoring is essential, 5% alone produce AKI and percentage increases to 35% when adding

other nephrotoxic drug). NSAID (fenoprofen) PPI: proton pump inhibitors (omeprazole) Calcineurin inhibitors: cyclosporin Drug toxicity is responsible for 1827% of Acute Renal injury in USA 6 major mechanisms are involved: 1. 2. 3.

4. 5. 6. Hemodymanic mediated Glomerulonephritis Acute tubular necrosis Interstitial nephritis Papillary necrosis Obstructive uropathy 5- Papillary Necrosis

Death of renal papillae due to Analgesics (aspirin, acetaminophen, phenacetin and NSAID),morphin is choice,avoid meperidine and propoxyphen Diabetic nephropathy Kidney infection Renal transplantation Sickle cell anemia

Drug toxicity is responsible for 1827% of Acute Renal injury in USA 6 major mechanisms are involved: 1. 2. 3. 4. 5. 6.

Hemodymanic mediated Glomerulonephritis Acute tubular necrosis Interstitial nephritis Papillary necrosis Obstructive uropathy 6- Obstructive nephropathy Due to mechanical obstruction

Mainly stone formation Acyclovir (hydration of patients is critical) Sulfadiazine Methotrexate Anticonvulsants: Generalized seizure occur in severe uremia

Phenytoin frequently used for treatment Phenytoin absorption is slow and erratic Hepatic metabolism is concentration dependent and saturable Concentration of active ,free drug is higher in uremia . Seizure is a manifestation of toxicity Free serum phenytoin concentration measurement should done Hypoglycemic drugs : 46%

of new dialysis patient have DM Kidney account for 30% elimination of insulin Initial drug dose should be low and titrate carefully Risk of metformin accumulation and lactic acidosis increase with age and renal failure

Antiplatelet and anticoagulant : Low dose Aspirin had no adverse effect on kidney function. In AKI and CKD have inhance bleeding risk UFH is prudent in advanced CKD LMWH is problematic due to absence of activated factor10 monitoring

Sedatives : Benzodiazepines are usually used in dialysis patients . Benzodiazepines are usually safe and effective BNZD have active metabolites Lorazepam and Alprazolam advised MAOI are avoided

Prescribing in Kidney Disease Patients with renal impairment Patients on Dialysis Patients with renal transplants Principles Establish type of kidney disease

Most patients with kidney failure will already be taking a number of drugs Interactions are common Care needed to avoid drug toxicity Patients with renal impairment and renal failure Antihypertensives Phosphate binders

Dosing in renal impairment Loading dose does not change (usually) Maintenance dose or dosing interval does T often prolonged Reduce dose OR Increase dosing interval

Some drugs have active metabolites that are themselves excreted renally Warfarin, diazepam,allopurinol dialysis indications Renal replacement therapy in AKI 1-absolute indications:

a-volume overload unresponsive to diuretic therapy b-hyperkalemia despite medical treatment c-persistant metabolic acidosis d-overt uremic syndroms: encephalopathy pericarditis uremic bleeding diathesis Renal replacement therapy in AKI

2-relative indications: a-progressive azotemia without uremic manifestations b-persistant oliguria Renal replacement therapy in CKD 1-complications

that prompt initiation of renal replacement therapy: a-intractable extracellular overload and or hypertension b-hyperkalemia refractory to dietary restriction and pharmacologic treatment c-metabolic acidosis refractory to bicarbonate treatment d-hyperphosphatemia refractory to dietary counselling and to treatment

to phosphate binder e-anemia refractory to EPO and iron f-otherwise unexplained decline in functioning or well-being g-recent weight loss or deteroriation of nutritional status,specialy if accompanied by nausea ,vomiting or evidence of gastrodeodenitis 2-urgent indications:

a-neurologic dysfunction(neuropathy, encephalopathy , psychiatric disturbance) b-pleuritis or pericarditis without any explanation c-bleeding diathesis manifested by

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