therapeutics

• By saidi wazir (pharmacist)• Soroti pharmaceutical trainning college• Uganda

Physiological principles of the renalsystem

The kidney is both structurally and functionally complex, and plays a central role in homeostasis. Thus, many possible forms of renal malfunction can cause a wide range of clinical conditions. Manifestations of renal disorder include fluid, electrolyte and pH imbalances, haemodynamic imbalance, the accumulation of drugs, toxins and waste metabolic products, loss of essential metabolites, and endocrine abnormalities such as anaemia and bone disease.

Pathological processes such as infection, inflammation, auto-immunity, neoplasia and toxins can cause structural damage to the glomeruli, the tubules or the urinary tract.

Systemic or local circulatory insufficiency can also seriously compromise renal function. The most common pathologies are glomerular inflammation, urinary-tract infection and drug induced nephrotoxicity.

In this section we review the physiological principles of normal renal function, so that abnormalities of the renal system may be better understood.

FUNCTIONS OF THE KIDNEYEliminationof waste/surplus

Carbohydrate-derived, Nitrogenous and others.

Water, carbondioxide . Urea creatinine, uric acid, guanidine, amines, etc. Sulphate, phosphate, exogenous toxins

Regulationof fluid and electrolytebalance

Total body water Plasma osmotic pressure, pH,

Na, K, Ca, Mg, etc.Chloride, bicarbonate, phosphate, etc.

Endocrinehomeostasis

Blood pressure Calcium and bone metabolism RBC production

In certain less common renal diseases, e.g. polycystic kidney and renal tumour, there is erythropoietin over-production,with consequent polycythaemia.

Acute Renal Failure

• Acute renal failure (ARF) is broadly defined as a decrease in glomerular filtration rate (GFR) occurring over hours to weeks that is associated with an accumulation of waste products, including urea and creatinine.

PATHOPHYSIOLOGY

• ARF can be categorized as prerenal (resulting from decreased renal perfusion), intrinsic (resulting from structural damage to the kidney), postrenal (resulting from obstruction of urine flow from the renal tubule to the urethra), and functional (resulting from hemodynamic changes at the glomerulus independent of decreased perfusion or structural damage

CLINICAL PRESENTATION

• The presentation can be subtle and depends on the setting. Outpatients often are not in acute distress; hospitalized patients may develop ARF after a catastrophic event.

• Symptoms in the outpatient setting include change in urinary habits, weight gain, or flank pain. Clinicians typically notice symptoms of ARF before they are detected by inpatients.

• Signs include edema, colored or foamy urine, and, in volume-depleted patients, orthostatic hypotension.

RIFLE classification for acute renal failure (ARF). (ESRD, end-stage renal disease; GFR, glomerular

filtration rate; Scr, serum creatinine.)

DESIRED OUTCOME

• The primary goal of therapy is to prevent ARF. If ARF develops, the goal are to avoid or minimize further renal insults that would delay recovery and to provide supportive measures until kidney function returns.

TREATMENT

PREVENTION OF ACUTE RENAL FAILURE• Risk factors for ARF include advanced age,

acute infection, preexisting chronic respiratory or cardiovascular disease, dehydration, and chronic kidney disease (CKD). Decreased renal perfusion secondary to abdominal or coronary bypass surgery, acute blood loss in trauma, and uric acid nephropathy also increase risk.

• Nephrotoxin administration (e.g., radiocontrast dye) should be avoided whenever possible. When patients require contrast dye and are at risk of contrast dye–induced nephropathy, renal perfusion should be maximized through strategies such as assuring adequate hydration with normal saline or sodium bicarbonate solutions and administration of oral acetylcysteine 600 mg every 12 hours for four doses. Strict glycemic control with insulin in diabetics has also reduced the development of ARF.

• Nephrotoxin administration (e.g., radiocontrast dye) should be avoided whenever possible. When patients require contrast dye and are at risk of contrast dye–induced nephropathy, renal perfusion should be maximizedm through strategies such as assuring adequate hydration with normal saline or sodium bicarbonate solutions and administration of oral acetylcysteine 600 mg every 12 hours for four doses. Strict glycemic control with insulin in diabetics has also reduced the development of ARF.

MANAGEMENT OF ESTABLISHED ACUTE RENAL FAILURE

• No drugs have been found to accelerate ARF recovery. Therefore, patients with established ARF should be supported with nonpharmacologic and pharmacologic approaches through the period of ARF.

Nonpharmacologic Approaches• Supportive care goals include maintenance of adequate cardiac output and

blood pressure to optimize tissue perfusion while restoring renal function to pre-ARF baseline.

• Medications associated with diminished renal blood flow should be stopped. Appropriate fluid replacement should be initiated. Avoidance of nephrotoxins is essential in the management of patients with ARF.

• Renal replacement therapy (RRT), such as hemodialysis and peritoneal dialysis, maintains fluid and electrolyte balance while removing waste products. See Table 75-4 for indications for RRT in ARF. Intermittent and continuous options have different advantages (and disadvantages) but, after correcting for severity of illness, have similar outcomes. Consequently, hybrid approaches (e.g., sustained low-efficiency dialysis and extended daily dialysis) are being developed to provide the advantages of both.

• Intermittent RRT (e.g., hemodialysis) has the advantage of widespread availability and the convenience of lasting only 3 to 4 hours. Disadvantages include difficult venous dialysis access in hypotensive patients and hypotension due to rapid removal of large amounts of fluid.

• Several continuous renal replacement therapy (CRRT) variants have been developed. CRRT, performed as continuous hemodialysis, continuous hemofiltration, or both, is becoming increasingly popular. CRRT gradually removes solute resulting in better tolerability by critically ill patients. Disadvantages include limited availability, need for 24-hour nursing care, high expense, and incomplete guidelines for drug dosing (see Chap. 77).

Pharmacologic Approaches

• Loop diuretics have not been shown to accelerate ARF recovery or improve patient outcome; however, diuretics can facilitate managementof fluid overload. The most effective diuretics are mannitol and loop diuretics.

• Mannitol 20% is typically started at a dose of 12.5 to 25 g IV over 3 to 5 minutes. Disadvantages include IV administration, hyperosmolality risk, and need for monitoring because mannitol can contribute to ARF.

• Equipotent doses of loop diuretics (furosemide, bumetanide, torsemide, ethacrynic acid) have similar efficacy. Ethacrynic acid is reserved for sulfa-allergic patients. Continuous infusions of loop diuretics appear to be more effective and to have fewer adverse effects than intermittent boluses. An initial IV loading dose (equivalent to furosemide 40 to 80 mg) should be administered before starting a continuous infusion (equivalent to furosemide 10 to 20 mg/hour).

ELECTROLYTE MANAGEMENT AND NUTRITION THERAPY

• Hyperkalemia is the most common and serious electrolyte abnormality in ARF. Potassium must be restricted to less than 3 g/day and monitored daily.

• Hypernatremia and fluid retention commonly occur, necessitating restricting daily sodium intake to no more than 3 g. All sources of sodium, including antibiotics, need to be considered when calculating daily sodium intake.

• Phosphorus and magnesium should be monitored; neither is efficiently removed by dialysis.

• No parenteral nutrition has been shown to improve patient outcomes.

DRUG-DOSING CONSIDERATIONS

• Drug therapy optimization in ARF is a challenge. Confounding variables include residual drug clearance, fluid accumulation, and use of RRTs.

• Volume of distribution for water-soluble drugs is significantly increased due to edema. Use of dosing guidelines for CKD does not reflect the clearance and volume of distribution in critically ill ARF patients.

• ARF patients may have a higher residual nonrenal clearance than CKD patients with similar creatinine clearances; this complicates drug therapy individualization, especially with RRTs.

• The mode of CRRT determines the rate of drug removal, further complicating individualization of drug therapy. The rates of ultrafiltration, blood flow, and dialysate flow influence drug clearance during CRRT.

Other renal disease

• Pyelo nephritis• Nephrotic syndrome• Poly cystic disease