Obat pada ginjal

Prof M.A.Widodo PhD

THE KIDNEY IS A MAJOR ORGAN THAT DETERMINED DRUG KINETIS AND IS A MAJOR SITE OF DRUG ACTION RENAL FUNCTION MUST BE CONSIDERED IN THE DEVELOPMENT OF MOST THERAPEUTIC STATEGIES

Diuretics increase the rate of urine flow and sodium excretion used to adjust the volume and/or composition of body fluids in a variety of clinical situations, including hypertension, heart failure, renal failure, nephrotic syndrome, and cirrhosis.

The basic urine-forming unit of the kidney is the nephron, which consists of a filtering apparatus, the glomerulus, connected to a long tubular portion that reabsorbs and conditions the glomerular ultrafiltrate. Each human kidney is composed of approximately one million nephrons.

Glomerular Filtration. In the glomerular capillaries, a portion of the plasma water is forced through a filter that has three basic components: the fenestrated capillary endothelial cells, a basement membrane lying just beneath the endothelial cells, and the filtration slit diaphragms formed by the epithelial cells that cover the basement membrane on its urinary space side. Solutes of small size flow with filtered water (solvent drag) into the urinary (Bowman's) space, whereas formed elements and macromolecules are retained by the filtration barrier. For each nephron unit, the rate of filtration [single-nephron glomerular filtration rate (SNGFR)] is a function of the hydrostatic pressure in the glomerular capillaries the hydrostatic pressure in Bowman's space

kidney is designed to filter large quantities of plasma, reabsorb substances that the body must conserve, and leave behind and/or secrete substances that must be eliminated. The two kidneys in humans produce together approximately 120 ml of ultrafiltrate, yet only 1 ml/min of urine is produced. Therefore, greater than 99% of the glomerular ultrafiltrate is reabsorbed at a staggering energy cost. The kidneys consume 7% of total-body oxygen intake despite the fact that the kidneys make up only 0.5% of body weight.

Seven basic mechanisms for transmembrane transport of solutes.

1, convective flow in which dissolved solutes are "dragged" by bulk water flow; 2, simple diffusion of lipophilic solute across membrane; 3, diffusion of solute through a pore; 4, transport of solute by carrier protein down electrochemical gradient; 5, transport of solute by carrier protein against electrochemical gradient with ATP hydrolysis providing driving force; 6 and 7, cotransport and countertransport, respectively, of solutes, with one solute traveling uphill against an electrochemical gradient and the other solute traveling down an electrochemical gradient.

By definition, diuretics are drugs that increase the rate of urine flow; however, clinically useful diuretics also increase the rate of excretion of Na+ (natriuresis) and of an accompanying anion, usually Cl-. NaCl in the body is the major determinant of extracellular fluid volume, and most clinical applications of diuretics are directed toward reducing extracellular fluid volume by decreasing total-body NaCl content.

A sustained imbalance between dietary Na+ intake and Na+ loss is incompatible with life. A sustained positive Na+ balance would result in volume overload with pulmonary edema, and a sustained negative Na+ balance would result in volume depletion and cardiovascular collapse. Although continued administration of a diuretic causes a sustained net deficit in total-body Na+, the time course of natriuresis is finite because renal compensatory mechanisms bring Na+ excretion in line with Na+ intake, a phenomenon known as diuretic braking. These compensatory, or braking, mechanisms include activation of the sympathetic nervous system, activation of the renin-angiotensin-aldosterone axis, decreased arterial blood pressure (which reduces pressure natriuresis), hypertrophy of renal epithelial cells, increased expression of renal epithelial transporters, and perhaps alterations in natriuretic hormones such as atrial natriuretic peptide

INHIBITORS OF CARBONIC ANHYDRASE

Acetazolamide (DIAMOX) is the prototype of a class of agents that have limited usefulness as diuretics but have played a major role in the development of fundamental concepts of renal physiology and pharmacology

Mechanism and Site of Action. Proximal tubular epithelial cells are richly endowed with the zinc metalloenzyme carbonic anhydrase, which is found in the luminal and basolateral membranes (type IV carbonic anhydrase, an enzyme tethered to the membrane by a glycosylphosphatidylinositol linkage), as well as in the cytoplasm (type II carbonic anhydrase). Carbonic anhydrase plays a key role in NaHCO3 reabsorption and acid secretion.

OSMOTIC DIURETICS Osmotic diuretics are agents that are freely filtered at the glomerulus, undergo limited reabsorption by the renal tubule, and are relatively inert pharmacologically. Osmotic diuretics are administered in large enough doses to increase significantly the osmolality of plasma and tubular fluid. gives the molecular structures of the four currently available osmotic diuretics glycerin (OSMOGLYN), isosorbide (ISMOTIC), mannitol (OSMITROL), and urea (UREAPHIL). Mechanism and Site of Action. For many years it was thought that osmotic diuretics act primarily in the proximal tubule. By acting as nonreabsorbable solutes, it was reasoned that osmotic diuretics limit the osmosis of water into the interstitial space and thereby reduce luminal Na+ concentration to the point that net Na+ reabsorption ceases. Although early micropuncture studies supported this concept, subsequent studies suggested that this mechanism, while operative, may be of only secondary importance and that the major site of action of osmotic diuretics is the loop of Henle.

INHIBITORS OF NA+-K+-2CL- SYMPORT (LOOP DIURETICS, HIGH-CEILING DIURETICS) Drugs in this group of diuretics inhibit the activity of the Na+-K+-2Cl- symporter in the thick ascending limb of the loop of Henle; hence these diuretics also are referred to as loop diuretics. Although the proximal tubule reabsorbs approximately 65% of the filtered Na+, diuretics acting only in the proximal tubule have limited efficacy because the thick ascending limb has a great reabsorptive capacity and reabsorbs most of the rejectate from the proximal tubule. Diuretics acting predominantly at sites past the thick ascending limb also have limited efficacy because only a small percentage of the filtered Na+ load reaches these more distal sites. I In contrast, inhibitors of Na+-K+-2Cl-symport in the thick ascending limb are highly efficacious, and for this reason, they sometimes are called high-ceiling diuretics. The efficacy of inhibitors of Na+-K+-2Cl- symport in the thick ascending limb of the loop of Henle is due to a combination of two factors: (1) Approximately 25% of the filtered Na+ load normally is reabsorbed by the thick ascending limb, and (2) nephron segments past the thick ascending limb do not possess the reabsorptive capacity to rescue the flood of rejectate exiting the thick ascending limb.

Mechanism and Site of Action. Inhibitors of Na+-K+-2Clsymport act primarily in the thick ascending limb. Micropuncture of the DCT demonstrates that loop diuretics increase the delivery of solutes out of the loop of Henle. Also, in situ microperfusion of the loop of Henle and in vitro microperfusion of the CTAL indicate inhibition of transport by low concentrations of furosemide in the perfusate. Some inhibitors of Na+-K+-2Cl- symport may have additional effects in the proximal tubule; however, the significance of these effects is unclear

INHIBITORS OF NA+-CL- SYMPORT (THIAZIDE AND THIAZIDELIKE DIURETICS) The benzothiadiazides were synthesized in an effort to enhance the potency of inhibitors of carbonic anhydrase. However, unlike carbonic anhydrase inhibitors, which primarily increase NaHCO3 excretion, benzothiadiazides were found predominantly to increase NaCl excretion, an effect shown to be independent of carbonic anhydrase inhibition. Mechanism and Site of Action. Some studies using split-droplet and stationary-microperfusion techniques have described reductions in proximal tubule reabsorption by thiazide diuretics; however, free-flow micropuncture studies have not consistently demonstrated increased solute delivery out of the proximal tubule following administration of thiazides. In contrast, micropuncture and in situ microperfusion studies clearly indicate that thiazide diuretics inhibit NaCl transport in the DCT. The DCT expresses thiazide binding sites and is accepted as the primary site of action of thiazide diuretics; the proximal tubule may represent a secondary site of action.

INHIBITORS OF RENAL EPITHELIAL NA+ CHANNELS (K+-SPARING DIURETICS) Triamterene (DYRENIUM, MAXZIDE) and amiloride (MID-AMOR) are the only two drugs of this class in clinical use. Both drugs cause small increases in NaCl excretion and usually are employed for their antikaliuretic actions to offset the effects of other diuretics that increase K+ excretion. Consequently, triamterene and amiloride, along with spironolactone (see next section), often are classified as potassium (K +)Mechanism and Site of Action. Available data suggest that triamterene and amiloride have similar mechanisms of action. Of the two, amiloride has been studied much more extensively, so its mechanism of action is known with a higher degree of certainty. As illustrated in Figure 28-8, principal cells in the late distal tubule and collecting duct have, in their luminal membranes, epithelial Na+ channels that provide a conductive pathway for the entry of Na+ into the cell down the electrochemical gradient created by the basolateral Na+ pump

ANTAGONISTS OF MINERALOCORTICOID RECEPTORS (ALDOSTERONE ANTAGONISTS, K+-SPARING DIURETICS) Mineralocorticoids cause retention of salt and water and increase the excretion of K+ and H+ by binding to specific mineralocorticoid receptors. Early studies indicated that some spirolactones block the effects of mineralocorticoids; this finding led to the synthesis of specific antagonists for the mineralocorticoid receptor (MR). Currently, two MR antagonists are available in the United States, spironolactone (a 17-spirolactone) and eplerenone; two others are available elsewhere (Table 28-7). Mechanism and Site of Action. Epithelial cells in the late distal tubule and collecting duct contain cytosolic MRs that have a high affinity for aldosterone. This receptor is a member of the superfamily of receptors for steroid hormones, thyroid hormones, vitamin D, and retinoids (see Chapter 1). Aldosterone enters the epithelial cell from the basolateral membrane and binds to MRs; the MRaldosterone complex translocates to the nucleus, where it binds to specific sequences of DNA (hormone-responsive elements) and thereby regulates the expression of multiple gene products called aldosterone-induced proteins (AIPs).

The Role of Diuretics in Clinical Medicine. Another implication is that three fundamental strategies exist for mobilizing edema fluid: Correct the underlying disease, restrict Na+ intake, or administer diuretics. The most desirable course of action would be to correct the primary disease; however, this often is impossible. For instance, the increased hepatic sinusoidal pressure in cirrhosis of the liver and the urinary loss of protein in nephrotic syndrome are due to structural alterations in the portal circulation and glomeruli, respectively, that may not be remediable. Restriction of Na+ intake is the favored nonpharmacologic approach to the treatment of edema and hypertension and should be attempted; however, compliance is a major obstacle. Diuretics, therefore, remain the cornerstone for the treatment of edema or volume overload, particularly that owing to congestive heart failure, ascites, chronic renal failure, and nephrotic syndrome.

Drug induced kidney disease nephrotoxicity

infeksi pada jaringan ginjal penyakit imunologis iskemia ginjal batu obstruksi saluran gnjal obat bahan kimia Penyakit sistemik hiprertensi diabetes SLE dll Perubahan pada homeostais Perubahan fungsi eskresi Perubahan dosis obat Anaemia

Perubahan sruktur Perubahan fungsi

Penyakit ginjal akut Penyakit ginjal kronis Gagal ginjal

Nephrotoxiity akibat obat tergantung pada dosis Interaksi dengan obat lain Penyakit dan kondisi penderita
Pre-existing renal insufficiency Increased age Poor nutrition Shock Gram-negative bacteremia Liver disease Hypoalbuminemia Obstructive jaundice Dehydration Potassium or magnesium deficiencies

Diagnostic and therapeutic agents

Drug-induced kidney disease or nephrotoxicity (DIN)

Manifestations of DIN include acid-base abnormalities, electrolyte imbalances, urine sediment abnormalities, proteinuria, pyuria, and/or hematuria. However, the most common manifestation of DIN is a decline in the glomerular filtration rate (GFR), which results in a rise in the serum creatinine (Scr) and blood urea nitrogen (BUN). This is consistent with the qualitative definition of acute renal failure (ARF) or an abrupt and sustained decrease in glomerular filtration, urine output, or both.

EPIDEMIOLOGY Drug-induced nephrotoxicity occurs in all settings in which drugs are ingested or administered. It is a significant source of morbidity and mortality in the acute care hospital setting. DIN accounts for nearly 7% of all drug toxicity and from 18% to 27% of all cases of acute renal failure in hospitals. Overall, in-hospital drug use may contribute to 35% of all cases of acute tubular necrosis (ATN), most cases of allergic interstitial nephritis (AIN), as well as to nephropathy due to alterations in renal hemodynamics and postrenal obstruction.

Aminoglycoside antibiotics, radiocontrast media, nonsteroidal antiinflammatory drugs (NSAIDs), amphotericin B, and angiotensinconverting enzyme inhibitors (ACEIs) are frequently implicated.

Drug-Induced Renal StructuralFunctional Alterations and Examples Tubular epithelial cell damage Acute tubular necrosis Aminoglycoside antibiotics Radiographic contrast media Cisplatin/carboplatin Amphotericin B Osmotic nephrosis Mannitol Dextran Intravenous immunoglobulin Hemodynamically-mediated renal failure Angiotensin-converting enzyme inhibitors Angiotensin II receptor antagonists Nonsteroidal anti-inflammatory drugs Tubulointerstitial disease Acute allergic interstitial nephritis Penicillins Ciprofloxacin Nonsteroidal anti-inflammatory drugs Omeprazole Furosemide Chronic interstitial nephritis Cyclosporine Lithium Aristolochic acid Papillary necrosis Combined phenacetin, aspirin, and caffeine analgesics

Obstructive nephropathy Intratubular obstruction Acyclovir Sulfadiazine Indinavir Foscarnet Methotrexate Extrarenal obstruction Tricyclic antidepressants Indinavir Nephrolithiasis Triamterene Indinavir
Glomerular Disease Gold Nonsteroidal anti-inflammatory drugs Pamidronate

Renal vasculitis, thrombosis, and cholesterol emboli Vasculitis and thrombosis Hydralazine Propylthiouracil Allopurinol Penicillamine Gemcitabine Mitomycin C Methamphetamines Cholesterol emboli Warfarin Thrombolytic agents Pseudo-renal failure Corticosteroids Trimethoprim Cimetidine

NSAIDs have an overall favorable safety profile resulting in OTC availability in the United States of ibuprofen, naproxen, and ketoprofen for short-term therapy. While potential adverse renal effects from OTC NSAIDs have been a concern. NSAIDs are unlikely to impair renal function in the absence of renal ischemia or excess renal vasoconstrictor activity. Nevertheless,given the fact that 50 million U.S. citizens report NSAID use, it has been estimated that 500,000 to 2.5 million people will develop NSAID nephrotoxicity in this country annually

ANALGESIC NEPHROPATHY Classic analgesic nephropathy, characterized by chronic tubulointerstitial nephritis with papillary necrosis, was initially reported in 1953 and was subsequently recognized as a worldwide public health concern. Chronic excessive consumption of combination analgesics, particularly those containing phenacetin, was believed to be the major cause and led to the removal of phenacetin and phenacetin mixtures from mostworld markets. Itwas subsequently thought, however, that abuse of contemporary analgesics, aspirin, acetaminophen, and NSAIDs, alone or in combinations, also results in analgesic nephropathy regardless of phenacetin content

EFEK SAMPING OBAT PADA FUNGSI GINJAL HEMODINAMIK ACE INHB, NSAID, CYCLOSPORIN GLOMERULUS TOKSIK NSAID GOLD, PENICILINAMIN IMUNOLOGIS SULFONAMIDE,DRUG INDUCED LUPUS PELARUT ORGANIK INTERSTITIAL TOKSIK CYCLOSPORIN, ANALGESIK, LOGAM BERAT IMUNOLOGIS PENICILLIN, SULFONAMIDE COLLECTING SYSTEM SULFONAMIDE, OXYPURINOL, TRIAMTERENE, PENINGKATAN EKSKRESI ASAM URAT TUBULUS RENALIS BANYAKOBAT MEMPENGARUHI HOMEOSTASIS CAIRAN DAN ELEKTROLIT Na, K Ca Mg

NEPHROTIC SYNDROM

NEPHROTIC SYNDROME Nephrotic syndrome is characterized by proteinuria greater than 3.5 g/day per 1.73 m2, hypoproteinemia, edema, and hyperlipidemia. A hypercoagulable state may also be present in some patients. Thesyndrome may be the result of primary diseases of the glomerulus, or be associated with systemic diseases such as diabetes mellitus, lupus, amyloidosis, and preeclampsia. Hypoproteinemia, especially hypoalbuminemia, results from increased urinary loss of albumin and an increased rate of catabolism of filtered albumin by proximal tubular cells. The compensatory increase in hepatic synthesis of albumin is insufficient to replenish the protein loss, probably because of malnutrition.

Mempengaruhi distribusi obat lebih banyak obat bebas.

The management of patients with glomerulonephritis Specific pharmacologic therapy for the glomerular disease, and supportif measures to prevent and/or treat the pathophysiologic sequelae, namely hypertension, edema, and progression of renal disease. In patients with nephrotic syndrome, supportive therapy should also address the management of extrarenal complications of heavy proteinuria, namely hypoalbuminemia, hyperlipidemia, and thromboembolism. Patients with significant proteinuria tend to have a more rapid decline of renal function. Thus reduction of proteinuria becomes critical in delaying the rate of progression towards end-stage renal disease. Immunosuppressive agents, alone or in combination, are commonly used to alter the immune processes that are responsible for the glomerulonephritides.

Corticosteroids, in addition to their immunosuppressive effect, also possess anti-inflammatory activities. They reduce the production and/or release of many substances that mediate the inflammatory process, such as prostaglandins, leukotrienes,platelet-activating factors, tumor necrosis factors (TNFs), and interleukin-1 (IL-1)

DRUG THERAPY INDIVIDUALIZATION FOR PATIENTS WITH RENAL INSUFFICIENCY

Gagal ginjal
acute renal failure (hemodimik) diuretik chronic renal failure pembatasan intake protein eritropoetin dialisa pengaturan elektrolit

1.Chronic kidney disease can affect all aspects of drug disposition, including absorption, distribution, metabolism, and elimination. 2 Changes in protein binding induced by renal failure can alter the relationship between total drug concentration and response.

3 In addition to the expected changes in renal drug elimination, nonrenal drug clearance (i.e., hepatic drug metabolism) may also be decreased in patients with chronic kidney disease.
4 Individualization of a drug dosage regimen in a patient with renal disease is based on the pharmacokinetic characteristics of the drug and the patients level of renal function. 5 The effect of hemodialysis or chronic renal replacement therapy on drug elimination is dependent on the characteristics of the drug and the dialysis conditions. 6.Acute renal failure (ARF) and chronic kidney disease (CKD) are often accompanied by alterations in several other organ systems and results in the development of anemia, hyperparathyroidism, bleeding abnormalities, hyperlipidemia, hypertension, and changes in gastrointestinal tract integrity

Absorbtion : tidak ada data lengkap oleh karena

Evaluasi bioavailability dlakukan pada pasien dengan gagal ginjal staium 5 Atau pada end-stage kidney disease (ESKD). Penilaian bioavailability sulit oleh karena pasien menerima berbagai macam pengobatan dan sering drop out pada study. Peningkatan bioavailability terjadi akibat penurunan metabolisme obat di usus Dan herpar seperti obat -blockers (i.e., bufuralol,oxprenolol, propranolol, and tolamolol), dextropropoxyphene, dihydrocodeine. The volume of distribution of many drugs may be significantly increased or decreased in patients with renal insufficiency Alterations in distribution volume may result from increased or decreased protein binding; altered tissue binding; alterations in body composition in addition to the expected decrease in renal drug elimination, there is increasing evidence that CKD also alters other elimination pathways, most notably cytochrome P450 (CYP450)-mediated metabolism in the liver and other organ

Gagal ginjal

Perubahan keseimbangan asam basa

Perubahan rasio obat terion dan non ion

Mempengaruhi distribusi obat dari plasma kejaringan

Salisilat pada pH asam menyebabkan leih banyak salislat non ion Yang masuk ke cns akibatnya timbul keracunan pada CNS

Obat masuk tubuh

Ekskresi ginjal utuh

Metabolisme diusus/ hepar

Diconjugasi

Metabolit polar

Ekskresi ginjal

Gagal ginjal akumulasi metabolit polar dan obat utuh Dala tubuh efek toksik

Gagal ginjal

Penumpukan asam organik endogen

Menggantikan ikatan obat dengan protein

Penurunan ikatan protein dengan obat yang sifatnya asam

Obat bebas diplasma meningkat

Efek obat mengkat efek toksik

Gagal ginjal Penurunan fungsi Metablisme di ginjal

Tubulus proksimalis Glukoronyl transferse Sulfo transferase Cytochrome p 450 ksidase

Eliminasi obat berkurang Insulin metabolisme diginjal Kebutuhan insulin berkurang

Obat asam atau basa yang ekskresi oleh ginjall

Obat sifat nya asam Chepalosporin Loop diuretik Methotrexate NSAID/salisilat Penicilline Probenecide Sulfonamide Thiazide diuretik

obat yang sifatnya basa amiloride epedrin/pseudoepedrin cimetidine morphine procainamide quinine tetrahylamonium triamterene

Obat yang ekskresinya terganung pH Asam lemah meningkat (urine alkali) Chlorpropaide Methtrexate Phenobarbital Salisilate Derivat sulfonamide Trimethoprim

basa lemah meningkat (urine asam) ampheamine epedrine mexiletine pseudo epedrine Quinine toxainide

Dose regimen Pasien gagal ginjal Ancaman akumulasi obat

Toksik efek
Dosis perlu disesuaikan Terutama obat dengan terapeutik widow sempit Dosis sama namun interval lebih jarang (Variable interval regimen) Dosis dikurangi interval sama (vaiable-dose regimen) Sebaiknya menggunakan infus apabila interval pendek

Erythropoietic Therapy Pharmacology and Mechanism of Action. Erythropoietic growth factors are required to stimulate division and differentiation of erythroid progenitor cells and induce the release of reticulocytes from the bone marrow to the bloodstream where they mature into erythrocytes (red blood cells). Available erythropoietic agents include epoetin alfa and darbepoetin alfa and Epoetin beta These agents are glycoproteins manufactured by recombinant DNA technology that have the same biological activity as endogenous erythropoietin. The amino acid sequence of epoetin alfa is identical to the endogenous protein; however, the carbohydrate structure differs. Since 1989, epoetin alfa has been the mainstay of therapy for anemia of CKD and substantially reduced the percentage of patients dependent on transfusions for management of anemia.

Dosing and Administration.

Starting doses of epoetin alfa are 80 to 120 units/kg per week for SC administration and 120 to 180 units/ kg per week for IV administration divided in two to three doses per week (typically three times per week for hemodialysis patients receiving IV therapy).
If a patient is converted from IV to SC epoetin and is not at the target Hgb/Hct, the weekly SC dose should remain the same as the IV dose. The starting dose of darbepoetin alfa in patients not previously receiving erythropoietic therapy is 0.45 mcg/kg IV or SC administered once weekly.

TABLE 452. Advantages and Disadvantages of Peritoneal Dialysis Advantages 1. More hemodynamic stability (blood pressure) due to slow ultrafiltration rate. 2. Increased clearance of larger solutes, which may explain good clinical status in spite of lower urea clearance. 3. Better preservation of residual renal function. 4. Convenient intraperitoneal route of administration of drugs such as antibiotics and insulin. 5. Suitable for elderly and very young patients who may not tolerate hemodialysis well. 6. Freedom from the machine gives the patient a sense of independence (for continuous ambulatory peritoneal dialysis). 7. Less blood loss and iron deficiency, resulting in easier management of anemia or reduced requirements for erythropoietin and parenteral iron. 8. No systemic heparinization requirement. 9. Subcutaneous versus intravenous erythropoietin or darbepoetin is usual, which may reduce overall doses and be more physiologic.

Disadvantages 1. Protein and amino acid losses through peritoneum and reduced appetite owing to continuous glucose load and sense of abdominal fullness predispose to malnutrition. 2. Risk of peritonitis. 3. Catheter malfunction, exit site, and tunnel infection. 4. Inadequate ultrafiltration and solute dialysis in patients with a large body size, unless large volumes and frequent exchanges are employed. 5. Patient burnout and high rate of technique failure. 6. Risk of obesity with excessive glucose absorption. 7. Mechanical problems such as hernias, dialysate leaks, hemorrhoids, or back pain may occur. 8. Extensive abdominal surgery may preclude peritoneal dialysis. 9. No convenient access for intravenous iron administration.

THE KIDNEY IS A MAJOR ORGAN THAT DETERMINED DRUG KINETIS AND IS A MAJOR SITE OF DRUG ACTION RENAL FUNCTION MUST BE CONSIDERED IN THE DEVELOPMENT OF MOST THERAPEUTIC STATEGIES