01. Drug Kidney

7/27/2019 01. Drug Kidney

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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


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Diuretics increase the rate of urine flow

and sodium excretion

used to adjust the volume and/or

composition of body fluids in a variety ofclinical situations, including hypertension,

heart failure, renal failure, nephrotic

syndrome, and cirrhosis.


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The basic urine-forming unit of the

kidney is the nephron, whichconsists of a filtering apparatus, the

glomerulus, connected to a long

tubular portion that reabsorbs andconditions the glomerular

ultrafiltrate. Each human kidney is

composed of approximately onemillion nephrons.


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Glomerular Filtration. In the glomerular capillaries, a portion

of the plasma water is forced through a filter that has threebasic 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


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kidney is designed to filter large quantities of

plasma, reabsorb substances that the body must

conserve, and leave behind and/or secretesubstances 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 intakedespite the fact that the kidneys make up only

0.5% of body weight.


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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.

Seven basic mechanisms for t ransmembrane transpo r t of so lutes.


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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.


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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 epithelialtransporters, and perhaps alterations in natriuretic hormones such as

atrial natriuretic peptide


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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.


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OSMOTIC DIURETICS

Osmotic diuretics are agents that are freely filtered at the glomerulus, undergolimited 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 onlysecondary importance and that the major site of action of osmotic diuretics is the

loop of Henle.


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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 actingpredominantly 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.


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Mechanism and Site of Action. Inhibitors of Na+-K+-2Cl-symport 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 vitromicroperfusion 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


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INHIBITORS OF NA+-CL- SYMPORT (THIAZIDE AND THIAZIDELIKE

DIURETICS)

The benzothiadiazides were synthesized in an effort to enhance thepotency 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 andstationary-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. TheDCT 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.


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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 theeffects of other diuretics that increase K+ excretion. Consequently, triamterene

and amiloride, along with spironolactone (see next section), often are classified

aspotassium (K+)-

Mechanism and Site of Action. Available data suggest that triamterene andamiloride have similar mechanisms of action. Of the two, amiloride has been

studied much more extensively, so its mechanism of action is known with a

, principal cells in the late8-28Figurehigher degree of certainty. As illustrated in

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


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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).7-28Tableelsewhere (

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

). Aldosterone enters the1Chapterseehormones, vitamin D, and retinoids (epithelial cell from the basolateral membrane and binds to MRs; the MR-

aldosterone 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).


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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. Themost 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 beremediable. 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.


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Drug induced kidney disease

nephrotoxicity


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infeksi pada jaringan ginjal

penyakit imunologis

iskemia ginjal

batu obstruksi saluran gnjalobat bahan kimia

Penyakit sistemik

hiprertensi

diabetes

SLE

dll

Penyakit ginjal akut

Penyakit ginjal kronis

Gagal ginjal

Perubahan sruktur

Perubahan fungsi

Perubahan pada homeostais

Perubahan fungsi eskresi

Perubahan dosis obat

Anaemia


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Nephrotoxiity akibat obat tergantung pada

dosis

Interaksi dengan obat lain

Penyakit dan kondisi penderita

Pre-existing renal insufficiencyIncreased age

Poor nutrition

Shock

Gram-negative bacteremia

Liver disease

HypoalbuminemiaObstructive jaundice

Dehydration

Potassium or magnesium deficiencies


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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 inthe 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.

Diagnostic and therapeutic agents

Drug-induced kidney disease or nephrotoxicity (DIN)


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Aminoglycoside antibiotics,radiocontrast media,

nonsteroidal antiinflammatory drugs (NSAIDs),

amphotericin B, and

angiotensinconverting enzyme inhibitors (ACEIs) are frequently implicated.

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 acuterenal 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.


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Drug-Induced Renal

StructuralFunctional

Alterations and Examples

Tubular epithelial cell damage

Acute tubular necrosis

Aminoglycoside antibiotics

Radiographic contrast media

Cisplatin/carboplatin

Amphotericin B

Osmotic nephrosisMannitol

Dextran

Intravenous immunoglobulin

Hemodynamically-mediated

renal failureAngiotensin-converting

enzyme inhibitors

Angiotensin II receptor

antagonists

Nonsteroidal anti-inflammatory

drugs

Tubulointerstitial disease

Acute allergic interstitial nephritis

Penicillins

Ciprofloxacin

Nonsteroidal anti-inflammatory

drugs

Omeprazole

FurosemideChronic interstitial nephritis

Cyclosporine

Lithium

Aristolochic acid

Papillary necrosis

Combined phenacetin, aspirin,and caffeine analgesics


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Obstructive nephropathy

Intratubular obstruction

Acyclovir

SulfadiazineIndinavir

Foscarnet

Methotrexate

Extrarenal obstruction

Tricyclic antidepressants

IndinavirNephrolithiasis

Triamterene

Indinavir

Glomerular Disease

GoldNonsteroidal anti-inflammatory

drugs

Pamidronate

Renal vasculitis, thrombosis, and

cholesterol emboli

Vasculitis and thrombosis

HydralazinePropylthiouracil

Allopurinol

Penicillamine

Gemcitabine

Mitomycin C

Methamphetamines

Cholesterol emboli

Warfarin

Thrombolytic agents

Pseudo-renal failure

Corticosteroids

Trimethoprim

Cimetidine


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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 thosecontaining 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


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EFEK SAMPING OBAT PADA FUNGSI GINJAL

HEMODINAMIK ACE INHB, NSAID, CYCLOSPORIN

GLOMERULUS

TOKSIK NSAID GOLD, PENICILINAMIN

IMUNOLOGIS SULFONAMIDE,DRUG INDUCED LUPUS

PELARUT ORGANIK

INTERSTITIALTOKSIK 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


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NEPHROTIC SYNDROM


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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, orbe 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.


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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 alsoaddress 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 renaldisease.

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)


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DRUG THERAPY INDIVIDUALIZATION FORPATIENTS WITH RENAL INSUFFICIENCY


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Gagal ginjal

acute renal failure (hemodimik)

diuretik

chronic renal failure

pembatasan intake protein

eritropoetin

dialisapengaturan elektrolit


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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 isbased 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


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Absorbtion : tidak ada data lengkap oleh karenaEvaluasi 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


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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 ionYang masuk ke cns akibatnya timbul keracunan pada CNS


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Obat masuk tubuh

Metabolisme diusus/ hepar

Diconjugasi

Metabolit polar

Ekskresi ginjal

Ekskresi ginjal utuh

Gagal ginjal akumulasi

metabolit polar dan obat utuh

Dala tubuh

efek toksik


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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


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Gagal ginjal

Penurunan fungsi

Metablisme di ginjal Tubulus proksimalis

Glukoronyl transferse

Sulfo transferaseCytochrome p 450 ksidase

Eliminasi obat berkurang

Insulin metabolisme diginjalKebutuhan insulin berkurang


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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

(Variableinterval regimen)

Dosis dikurangi interval sama(vaiable-dose regimen)

Sebaiknya menggunakan infus apabila interval pendek


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Erythropoietic Therapy

Pharmacology and Mechanism of Action.

Erythropoietic growth factors are required to stimulate division and differentiationof 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 patientsdependent on transfusions for management of anemia.


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Dosing and Administration.

Starting doses of epoetin alfa are 80to 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.


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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 toleratehemodialysis 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.


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Disadvantages

1. Protein and amino acid losses through peritoneum and reducedappetite 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 areemployed.

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.


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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

Documents

01. Drug Kidney