Pharmacology - An Illustrated Review

19. Renal Pharmacology

19.1 Overview of Renal Physiology

The major activities of the kidney are eliminating metabolic waste and foreign substances from the body; controlling the excretion of water and electrolytes (salts) to maintain fluid volume, osmolality, and acid–base balance; producing hormones and renin; and aiding in the metabolism of glucose (Fig. 19.1).

Ultrafiltration and Starling forces

Ultrafiltration of plasma occurs as plasma moves from glomerular capillaries into Bowman's capsule under the influence of Starling forces. Glomerular filtration is the same mechanism as systemic capillary filtration, i.e., the balance between hydrostatic and oncotic forces across the glomerular membrane determines the direction of fluid movement. Glomerular capillary hydrostatic pressure is the main driving force for ultrafiltration across the glomerular membrane. This is opposed by the hydrostatic pressure in Bowman's capsule and glomerular capillary colloid oncotic pressure.

 

Glomerular versus systemic capillaries

The glomerular capillaries are much more permeable than average systemic capillaries. Approximately 180 L/day of fluid are filtered across glomerular capillaries, while only 4 L/day of fluid would have been filtered if these were systemic capillaries. The ultrafiltration coefficient (Kf: membrane permeability x surface area) for glomerular capillaries is about 40 to 50 times greater than for systemic capillaries.

 

Vasa recta

The vasa recta of the kidneys are vessels that branch off efferent arterioles of juxtamedullary nephrons and surround the loop of Henle. The vessels are composed of thin, fenestrated epithelial cells. Each of the vasa recta makes a U-shaped turn in the medulla, and the blood flow through them is very slow. This is fundamental to maintaining the ion gradients in the medulla that are ultimately responsible for the production of concentrated urine. The vasa recta eventually drain into the renal vein. Due to the slow blood flow, the vasa recta are potential sites for thrombosis in hyper-coagulable states.

 

Renal Transport Systems

The functional unit of the kidney is the nephron. Each section of the nephron and its effects on water and electrolyte excretion are explained in Table 19.1 and illustrated in Fig. 19.2.

  Table 19.1 image Effects on Water and Electrolyte Excretion at Different Sections of the Nephron

Section of the Nephron

Effects

 

Proximal convoluted tubule

Approximately 60 to 70% of the filtered Na+ and K+ ions are removed isotonically from the proximal tubule. After passing the length of the proximal tubule, the volume of the filtrate is reduced by 30 to 40% without altering Na+ or K+ ion concentrations. Actively transported species include Na+, K+, and HCO3. If Na+ and K+ ion reabsorption are inhibited at this site, the transport mechanisms remaining in the nephron (loop of Henle and distal convoluted tubule) can fully compensate, and the final urine composition is not altered. HCO3reabsorption and urine pH are primarily controlled in the proximal tubule.

 

Ascending loop of Henle

Approximately 15 to 20% of the total filtered Na+ and Cl– load are reabsorbed at this site by Na+–K+–2Cl− cotransporter.

 

Distal convoluted tubule

Approximately 8 to 10% of the Na+ and K+ load is reabsorbed in the distal convoluted tubule. Active transport mechanisms are present in the distal convoluted tubule for Na+, K+, and Cl–. Cotransport or exchange transport mechanisms exist in the distal convoluted tubule for both Na+− H+ exchange and Na+− K+ exchange.

 

Collecting tubule and duct

Na+− K+ exchange and, to some extent, Na+− H+ ion exchange are controlled by aldosterone and urine Na+ concentrations. When the Na+ concentrations increase in the distal tubule, Na+ ions are absorbed in exchange for K+ ion and H+ ion excretion. Increased aldosterone thus increases Na+ ion retention in the plasma and urinary K+ excretion. There is a resultant decrease in urine pH (H+ ion excretion in the urine).

 

Renin–Angiotensin−Aldosterone Relationship

Renin

Renin is an enzyme released by specialized cells in the proximal convoluted tubule. The enzyme cleaves the inactive peptide, angiotensinogen, into angiotensin I (Fig. 19.3). Angiotensin I is then further acted upon by angiotensin-converting enzyme (ACE) in the lung to produce angiotensin II. Angiotensin II is a vasoconstrictor and stimulates aldosterone release from the adrenal cortex. The renin–angiotensin mechanism for aldosterone release is dependent upon the actions of both renin and ACE for the activation of angiotensinogen. Increased quantities of renin are released by the kidneys into the systemic circulation under conditions of

– Low plasma [Na+]

– Increased sympathetic nervous system stimulation

Fig. 19.1 image Functions of the kidney.

The kidneys play an important role in excretion, homeostasis, hormone synthesis, and metabolism. (H, hormone; V, prohormone.)

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Fig. 19.2 image Urine formation.

Urine is formed by the ultrafiltration, secretion, and resorption of substances at different parts of the nephron. The relative quantities are regulated by the kidneys to maintain homeostasis.

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Fig. 19.3 image Renin–angiotensin system.

The kidneys produce renin in response to low blood pressure or low plasma Na+ concentration. Renin acts on angiotensinogen in plasma to form angiotensin I. Angiotensin I is converted to angiotensin II in the lungs by the action of angiotensin-converting enzyme (ACE). Angiotensin II acts as a hormone and a neurotransmitter on different organs to produce changes that help restore blood pressure and Na+

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Aldosterone

Aldosterone is secreted from the adrenal cortex and plays an important role in the control of renal Na+ excretion and extracellular electrolyte balance. The hormone acts to stimulate Na+ reabsorption, Na+−K+ exchange in the distal tubule, and H+ ion secretion in the proximal tubule. The net results of the actions of aldosterone are as follows:

– Na+ ion retention

– An increased K+ ion excretion

– Mild systemic alkalosis

19.2 Diuretics

Diuretics are the main class of drug used in renal pharmacology. They increase the production of urine by acting in the kidney to alter salt and water excretion. The major indications for use of diuretics are to decrease edema, to treat heart failure, and as antihypertensives.

Most diuretics increase urine flow by altering the reabsorption of Na+ ions, and, along with them, Cl and water, at different sites in the nephron (Fig. 19.4). Osmotic diuretics, however, increase urine flow directly. This capacity to increase urine flow is used to treat conditions such as hypertension and congestive heart failure (CHF).

Fig. 19.4 image Renal actions of diuretics.

Na+ ions are normally transported into cells from the lumen of the tubules by carrier molecules. They are then secreted into the interstitium by the Na+-K+ ATPase pump. Diuretics act at different parts of the nephron to inhibit Na+ reabsorption. The higher Na+ load in urine increases its osmolarity, which causes water to be drawn into it and excreted.

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Osmotic Diuretics

Mannitol

Mechanism of action. To be effective, an osmotic diuretic must be freely filtered by the glomerulus and not be reabsorbed from the glomerular filtrate. This increases urine osmolarity and draws water with it without directly affecting Na+ excretion, so excretion of edema fluid is not increased (Fig. 19.5).

Pharmacokinetics. Mannitol is available only as an intravenous (IV) administration dosage.

Uses

– Acute reduction of cerebrospinal or intraocular pressure

– Increased urine flow in cases of acute renal failure

– Dilute toxins in urine

Side effects. These agents can produce fluid overload in patients with inadequate glomerular filtration or dehydration in patients without adequate water replacement.

Fig. 19.5 image Sodium chloride (NaCl) reabsorption in the proximal tubule and the effect of mannitol.

Mannitol increases the osmolality of the glomerular filtrate. In the proximal tubule this causes reduced reabsorption of water relative to Na+. Overall this causes increased urine flow with little increase in Na+ excretion.

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Mannitol in head injury management

Mannitol is widely used to manage head injuries in which there is a need for the acute reduction of intracranial pressure, for example, if the patient shows signs of brain herniation. When given as a bolus, an osmotic gradient is set up such that fluid is drawn out of cells, thus decreasing edema (and intracranial pressure). As an extension of this, circulating blood volume increases, and blood viscosity decreases. This has the beneficial effects of increasing cerebral blood flow and oxygen delivery.

 

Osmotic diuresis with diabetes

Glucose is normally completely reabsorbed in the proximal tubule of the kidneys. In diabetes, however, high plasma glucose levels exceed the maximum tubular transport capacity (Tm), causing glucose to pass on to the loop of Henle and distal nephron where it causes an osmotic diuresis. Net re-absorption of Na+ is also reduced (causing hyponatremia), because the large amount of tubular water accompanying the glucose also contains large amounts of Na+. These factors explain polyuria (excessive urination), polydipsia (excessive thirst), and dehydration that are common presenting symptoms in diabetes.

 

Diabetic nephropathy

Diabetes mellitus is a leading cause of chronic renal failure. The main pathogenic feature is glomerular disease with thickening of the glomerular basement membrane and glomerulosclerosis. This causes protein-uria to develop and eventually the glomerular filtration rate is irreversibly reduced. Clinically, signs and symptoms include those seen with diabetes and its associated disorders, e.g., retinopathy, neuropathy, hypertension, peripheral vascular disease, coronary artery disease, non-healing ulcers, as well as frothy urine, proteinuria, and edema (if nephrotic syndrome develops [see call-out box page 187]). Diagnosis is made with albuminuria (<300 mg/dL) on two occasions, 3 to 6 months apart, decline in glomerular filtration rate and elevated arterial blood pressure. Treatment involves meticulous glycemic control and ACE inhibitors to slow progression to chronic renal failure. Ultimately dialysis or renal transplantation may be needed.

 

Carbonic Anhydrase Inhibitors

Acetazolamide

Mechanism of action. Carbonic anhydrase inhibitors act in the proximal convoluted tubule to reduce the absorption of HCO3 ions from the glomerular filtrate (Fig. 19.6). A 90% or greater inhibition of carbonic anhydrase activity must be observed before significant diuresis is observed. Both diuresis and natriuresis (excretion of Na+ in urine) are limited because the increased excretion of HCO3 in the urine quickly depletes plasma HCO3. This limits their use as diuretics.

Uses

– Treatment of glaucoma (inhibits aqueous humor formation and so reduces ocular pressure)

– Prophylaxis and treatment of acute mountain sickness (mechanism unknown)

– Metabolic alkalosis

Side effects. These include drowsiness and paresthesias (sensations of numbness or tingling of the skin). Serious side effects include metabolic acidosis and formation of kidney stones.

Contraindications

– Liver cirrhosis

Metabolic acidosis

Metabolic acidosis occurs when there is excess production of H+ in the body, causing blood pH to fall. One of the situations in which this occurs is diabetic ketoacidosis (DKA), when acidic ketone bodies (aceto- acetic acid, β hydroxybutyric acid, and acetone) are produced from the breakdown of fat. Bicarbonate ions (HCO3) buffer some of the excess H+ ions by binding to them, producing carbonic acid, which then dissociates to form carbon dioxide (CO2) and water. Centrally, the fall in blood pH stimulates the respiratory center in the medulla to initiate hyperventilation. This hyperventilation (known as Kussmaul respiration) “blows off” CO2, thus lowering partial pressure of CO2 (pCO2), causing blood pH to rise. Renal compensation involves virtually complete reabsorption of HCO3, which replenishes that used to buffer the excess acid and an i ncrease in the excretion of titratable acid and NH4+. The availability of titratable acid is very limited, but the kidneys can greatly increase production of NH4+.

 

Kidney stones

Kidney stones in the renal pelvis and ureters will increase hydrostatic pressure in the Bowman capsule and therefore greatly reduce the glomerular filtration rate. Uric acid kidney stones may sometimes be dissolved by alkalinizing the urine with potassium citrate. Kidney stones that are less than ½-inch in diameter can be fragmented by applying focused ultrasound waves (lithotripsy).

 

Loop (High-Ceiling) Diuretics

Furosemide, Bumetanide, and Ethacrynic Acid

Mechanism of action. The loop diuretics are actively secreted into the proximal convoluted tubule from plasma and act upon the ascending loop of Henle to inhibit the reabsorption of Cl− from the tubular lumen (Fig. 19.5) by inhibiting a Na+–K+–2Cl− cotransporter. These drugs also increase Na+, K+, and Ca2+ excretion, thereby increasing urine volume. Diuresis is independent of acid–base balance. The loop diuretics are the most effective natriuretic and diuretic agents available.

Fig. 19.6 image Action of thiazides, loop diuretics, and carbonic anhydrase inhibitors.

Thiazide diuretics inhibit the Na+–Cl− cotransporter on the luminal membrane of tubular cells. This leads to reduced reabsorption of NaCl and water. Loop diuretics produce a strong diuresis by inhibiting the Na+– K+–2Cl− cotransporter in the thick ascending loop of Henle. Carbonic anhydrase (CAH) inhibitors inhibit the production and absorption of bicarbonate in tubular cells. This causes less Na+ reabsorption because fewer H+ ions are available for the Na+–H+ antiporter.

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Pharmacokinetics. These agents have a rapid onset of action (within 10−20 min following IV administration).

Uses

– Pulmonary edema due to left ventricular failure

– Chronic congestive heart failure

– Acute oliguria (by maintaining urine formation)

– Hypertension

– Acute hypercalcemia

Pulmonary edema

Pulmonary edema is fluid accumulation in the lungs. Its acute formation constitutes a medical emergency. It is usually caused by left ventricular failure, which renders the heart unable to adequately drain fluid from the lung. Left ventricular failure may be caused by such conditions as myocardial infarction and hypertension. Other causes of pulmonary edema are direct injury to the lung parenchyma, pneumonia, toxins, and high altitude. Signs and symptoms include difficulty breathing, coughing up blood (hemoptysis), anxiety, sweating, pale skin, and pink, frothy sputum. Treatment involves sitting the patient up, oxygen therapy, administering a loop diuretic, nitrate administration, and treating the underlying cause.

 

Acute renal failure

Acute renal failure produces a sharp rise in urea, creatinine, K+ (hyperkalemia) and Na+ (hypernatremia) usually with oliguria (low urine output) or anuria (no urine output). There may also be vomiting, confusion, bruising, or GI bleeding. A metabolic acidosis (usually with a normal anion gap) will occur due to the failure to excrete H+ as titratable acid and NH4+. Acute renal failure may occur due to disease of the kidneys themselves, which may be vascular, septic, neoplastic, due to drugs, or due to pregnancy. Extra renal causes include burns, sepsis, trauma, heart failure, and obstruction. Treatment should be aimed at the underlying cause but hyperkalemia may require urgent correction to avoid cardiac complications (see call out box on page 188). Loop diuretics are given for oliguria/anuria.

 

Nephrotic syndrome

Nephrotic syndrome results in severe proteinuria (loss of proteins into the urine), hypoalbuminemia, and edema due to the decrease in capillary oncotic pressure. Causes of nephrotic syndrome include glomerulonephritis (inflammation of the glomerulus), diabetes, neoplasia, and drugs. Signs include peripheral edema, ascites, and swelling of the eyelids. Venous thrombosis and emboli may occur due to excretion of certain clotting factors and antithrombin III in the urine. Treatment involves addressing the underlying cause plus the administration of a loop diuretic with a K+-sparing agent, plasma protein replacement (without salt), and anticoagulation (if necessary).

 

Side effects. Loop diuretics are more potent than thiazides and thus have more potential for side effects, which may include

– Increased renin production

– Hyperglycemia (mechanism unknown)

– Allergic reactions (these drugs are related to the antibacterial sulfonamides)

– Hypokalemia and dehydration (this can lead to digitalis toxicity and may precipitate skeletal muscle weakness

– Hyperuricemia (excretion of drugs in the proximal convoluted tubules interferes with uric acid excretion and may precipitate gouty arthritis [see page 359 for discussion of gout])

Thiazide Diuretics

Hydrochlorothiazide, Chlorothiazide, and Chlorthalidone

Note: Chlorthalidone is not chemically a thiazide, but has the same mechanism of action.

Mechanism of action. The thiazide diuretics are actively secreted into the proximal convoluted tubule and inhibit Na+ ion reabsorption in the distal convoluted tubule by inhibiting the Na+–Cl− cotransporter. Ca2+ ion excretion in the urine is decreased (Fig. 19.5). The thiazide diuretics are weak inhibitors of carbonic anhydrase, but diuresis is not dependent upon an inhibition of carbonic anhydrase. Incomplete inhibition of carbonic anhydrase does produce a small increase in urine pH. All thiazide diuretics share a common mechanism of action and common side effects. They differ from each other in potency and duration of action.

Pharmacokinetics. Orally effective.

Uses

– Thiazide diuretics are the standard of therapy in mild to moderate hypertension. They are frequently given along with other antihypertensive medications and can potentiate the action of other antihypertensive drugs. Thiazides are more effective in lowering blood pressure than loop diuretics in patients without edema.

– They may also be used to increase urine flow to dissolve kidney stones.

– Diabetes insipidus (paradoxical antidiuretic effect [see call-out box page 189])

Side effects

– Renal failure due to a decreased glomerular filtration rate

– Hyperuricemia, which may precipitate gouty arthritis

– Hypokalemic alkalosis (due to K+ loss). This is rarely a problem in normal patients, but it may be problematic in patients with cardiac arrhythmias, especially if they are on digitalis or have severe liver disease.

– Hyperglycemia (decreased glucose tolerance)

– Hypercholesterolemia and hypertriglyceridemia (mild effect)

Potassium-sparing Diuretics

Spironolactone

Mechanism of action. Spironolactone is a competitive antagonist to aldosterone and thus inhibits the synthesis of Na+ channel proteins and Na+-K+-ATPases, which promotes the reabsorption of Na+, Cl−, and water.

Uses

– Hypertension: spironolactone is just as effective as thiazides in reducing blood pressure, but it has more side effects.

– Primary aldosteronism (overproduction of aldosterone)

– It may be useful in patients with hyperuricemia, hypokalemia, or glucose intolerance.

Side effects

– Hyperkalemia (high blood K+)

– Diarrhea, nausea, and vomiting

– Headaches, confusion, and somnolence

– Gynecosmastia

Hyperkalemia

Hyperkalemia (elevated potassium levels) usually occurs due to metabolic acidosis when K+ is taken up by tubular cells in exchange for H+ secretion via the H+-K+ ATPase antiporter. Hyperkalemia may also be caused by renal failure, severe tissue damage (e.g., rhabdomyolysis [see call-out box page 237]), massive blood transfusions, Addison disease, and potassium-sparing diuretics. Symptoms include palpitations, malaise, and muscle weakness. Severe hyperkalemia (>6.5mmol/L) is a medical emergency as it can cause ventricular fibrillation and sudden death. ECG findings in hyperkalemia include small P waves, widened QRS complexes, and peaked T waves. Treatment is aimed at the underlying cause. In an emergency, calcium gluconate is given intravenously to reduce myocardial excitability; insulin and 50% glucose are given intravenously to shift K+ into cells (via activity of Na+-K+-ATPase); and bicarbonate is given to correct acidosis. Hemodialysis may also be necessary to increase K+ elimination.

 

Triamterene and Amiloride

Mechanism of action. These drugs directly interfere with Na+ transport in the distal convoluted tubule (Fig. 19.7). Although the drugs do not act on the renin–angiotensin axis, the net effect on urinary composition is similar.

Uses. Triamterene and amiloride are used to treat hypertension. They are weak diuretics and have little hypotensive action when given alone. However, they are useful when given along with the thiazides to prevent K+ depletion.

Fig. 19.7 image Potassium-sparing diuretics.

These drugs inhibit Na+ reabsorption and K+ secretion in the tubules and proximal part of the collecting duct. This produces a mild diuresis without depleting potassium. Aldosterone increases the synthesis of Na+ channel proteins and Na+-K+-ATPases, which promotes the reabsorption of Na+, Cl−, and water. Spironolactone is an antagonist at the aldosterone receptor and inhibits the normal action of aldosterone.

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Side effects

– Hyperkalemia

Note: Do not use potassium-sparing diuretics and potassium supplements together.

Over-the-Counter Drugs as Diuretics

Most over-the-counter drugs promoted as diuretic agents contain caffeine (100 mg) and/or ammonium chloride (~500 mg). The drugs have, at best, only a mild diuretic action. Caffeine mildly inhibits Na+ reabsorption in renal tubules, and ammonium chloride metabolism results in urea formation and excretion of a Cl– ion. Na+ passively follows the increased Cl– load, resulting in mild diuresis.

19.3 Antidiuretic Drugs

Vasopressin

Vasopressin (8-arginine vasopressin), also known as antidiuretic hormone (ADH), is a peptide hormone composed of nine amino acids. It is synthesized in the hypothalamus and transported to its site of release in the posterior pituitary (see also page 142). The main stimuli for vasopressin release are hyperosmolality of the blood and volume depletion.

Two types of vasopressin receptors are known:

– V1 receptors stimulate contraction of vascular smooth muscles (Fig. 19.8).

– V2 receptors stimulate water reabsorption in the renal tubule through a cyclic adenosine monophosphate (cAMP)–dependent mechanism.

Vasopressin is found in other areas of the brain and may promote learning and improve long-term memory.

Fig. 19.8 image Vasopressin (antidiuretic hormone [ADH] and derivatives).

Vasopressin acts on V2 receptors to promote the reabsorption of water. This occurs due to an increased expression of aquaporins, which increases the permeability of collecting duct epithelium to water. Vasopressin also acts on V1 receptors on vascular smooth muscle, producing vasoconstriction. Desmopressin is an analogue of vasopressin that produces a varying amount of antidiuretic and vasoconstrictive effects. Nicotine increases and ethanol decreases vasopressin secretion.

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Desmopressin

Desmopressin (1-deamino-8-D-arginine vasopressin) is a synthetic arginine analogue of vasopressin with the highest ratio of antidiuretic:vasopressor activities and the longest duration of action.

Uses

– Diabetes insipidus of pituitary origin (neurogenic diabetes insipidous)

– Primary nocturnal enuresis (bedwetting) in children and adults

– Adjunct in hemophilia therapy (vasopressin increases circulating levels of blood clotting factor VIII)

Side effects

– Vasoconstriction (may be dangerous in patients with angina)

– Contraction and cramps of smooth muscles

– Water intoxication

19.4 Vasopressin Antagonists

Demeclocycline and Lithium Carbonate

Mechanism of action. Both demeclocycline and lithium antagonize the renal action of vasopressin.

Uses

– Treatment of syndrome of inappropriate secretion of antidiuretic hormone (SIADH)

Treatment of nephrogenic diabetes insipidus

In nephrogenic diabetes insipidus, the kidneys are unresponsive to vasopressin, and thiazide diuretics cause a paradoxical reduction in polyuria. The mechanism for this effect is uncertain, but it is usually attributed to changes in Na+ excretion. Thiazides inhibit NaCl reabsorption in the early segments of the distal tubule but have little effect in the thick ascending limb, which is involved in concentrating the urine. In the ascending limb, water is reabsorbed along with Na+. Although all thiazides share this effect, chlorothiazide is most commonly used to treat this condition.

 

Syndrome of inappropriate secretion of antidiuretic hormone

SIADH occurs when excessive amounts of ADH are secreted from the posterior pituitary gland. This leads to hyponatremia (low plasma Na+) and fluid overload. Causes include head injury, meningitis, infections (e.g., brain abscess), pneumonia, and cancer. Treatment involves addressing the cause and using demeclocycline or lithium carbonate for symptomatic control.