Pharm - Chapter 25

Acetazolamide

Acetazolamide is approved for the treatment of acute mountain sickness.

Antidiuretic hormone (ADH)

Antidiuretic hormone (ADH) is a substance that regulates water balance in the body by controlling water loss in the urine.

Carbonic anhydrase inhibitors

Carbonic anhydrase inhibitors potentiate potassium depletion in the presence of corticosteroids and increase the excretion of acidic drugs. Alcohol, antihypertensive drugs, barbiturates, and opioid analgesics increase the possibility of orthostatic hypotension when taken with the potent diuretics such as thiazides and organic acids. Aminoglycoside antibiotics potentiate otoxicity with organic acid diuretics. Vaptans should not be given with midazolam or simvastatin. Increased blood levels of midazolam and simvastain result from this interaction.

Carbonic anhydrase inhibitors

Carbonic anhydrase inhibitors such as acetazolamide (Diamox) and methazolamide are used to assist the treatment of CHF or drug-induced edema. The drugs are capable of reducing edema caused by open-angle or angle-closure glaucoma. They inhibit the production of aqueous humor and reduce painful pressure. Carbonic anhydrase inhibitors are also useful in the treatment of epilepsy.

Carbonic anhydrous inhibitors

Carbonic anhydrous inhibitors are used in glaucoma, edema with alkalosis, and mountain sickness.

Diuretics classes

Diuretics are divided into classes such as osmotic agents, carbonic anhydrase inhibitors, thiazide and thiazide-like compounds, organic acids, potassium-sparing diuretics, and ADH antagonists.

Diuretics usage

Diuretics are primarily used in the management of anuria, hypertension, and edema. These are conditions in which the kidneys have stopped making urine (anuria), or there is an accumulation of fluid in other tissues (edema). Some diuretics stimulate urine production by increasing glomerular filtration. Other diuretics reduce the excess fluid associated with hypertension and edema by decreasing renal sodium and water reabsorption.

hypokalemia, hyperuricemia, and hyperglycemia.

Diuretics can also produce hypokalemia, hyperuricemia, and hyperglycemia. Hyperglycemia may be due to decreased glucose utilization. This effect can upset the blood sugar level in individuals with diabetes mellitus. Muscle spasms or cramps may occur due to the excretion of electrolyte

nephron

Each nephron is composed of several segments: the glomerulus, the proximal convoluted tubule (PCT), the loop of Henle, the distal convoluted tubule (DCT), and the collecting duct. Urine is produced in the nephrons through the processes of filtration, reabsorption, and secretion

How do diuretics work?

Each of these classes of diuretics produces diuresis by inhibiting water and/or sodium ion reabsorption in the kidneys. Because these drugs inhibit water reabsorption at different sites along the nephrons, the intensity of the diuresis varies with each class of drugs. In general, the intensity of dieresis is dependent upon the extent to which sodium ions are excreted into the urine.

Ethacrynic acid

Ethacrynic acid helps in the short-term management of ascites due to malignancy and lymphedema. The drug is administered parenterally when a rapid response is required or when GI absorption is impaired.

Hypokalemia

Hypokalemia can produce muscle weakness, fatigue, and cardiac arrhythmias. Patients are encouraged to follow a supplementation schedule to avoid hypokalemia.

hypertonic effects on ADH

If there is too much sodium in the blood (hypertonic), ADH will be secreted from the posterior pituitary gland. The target organs for ADH are the kidneys, where ADH binds to receptors in the collecting ducts of the renal tubules. ADH increases the reabsorption of water into the blood by causing the collecting duct cells to synthesize specialized proteins called water channels. Free water (without sodium) flows out of the urine into the blood through channels known as aquaporins. While water is reabsorbed, the urine becomes more concentrated because less water and more ions/sodium are excreted. ADH levels are reduced when the osmolarity of the plasma compartment decreases.

severe edema

In severe edema, oral potassium salt supplements (K-Lyte or Slow-K) may be required. These potassium supplements often produce GI irritation, which reduces patient compliance

process of tubular reabsorption

In the process of tubular reabsorption, the renal tubules absorb most of the nutrients filtered at the glomerulus. About 99 percent of the filtered sodium is reabsorbed. Sodium is an important component in the extracellular fluid as well as in the renal mechanism of water conservation. Sodium ions are reabsorbed by two mechanisms: cation exchange and chloride ion transport.

In the proximal and distal convoluted tubules

In the proximal and distal convoluted tubules, sodium ions (Na+) are reabsorbed in exchange for hydrogen ions (H+). Hydrogen ions are produced in the tubular cells through the action of the enzyme carbonic anhydrase (CAH). Carbon dioxide and water combine to form carbonic acid in the presence of the enzyme carbonic anhydrase (CAH), and carbonic acid rapidly breaks down into hydrogen ions and bicarbonate ions. The sodium and bicarbonate ions are transported into the blood at the peritubular capillary.

uremia

In uremia (toxemia) nitrogenous waste products accumulate in the blood due to impaired renal filtration. Inefficient clearance of sodium may cause water retention in the circulatory system which can cause edema and hypertension.

Loop diuretics are contraindicated in....

Loop diuretics are contraindicated in patients who are unable to make urine (anuria) or have severe electrolyte depletion.

Loop diuretics

Loop diuretics are used in pulmonary edema, peripheral edema, hypertension, acute hypercalcemia, or hyperkalemia, and acute renal failure.

Loop diuretics for cardiac conditions

Loop diuretics can also be used to provide relief to a certain extent in some cardiac conditions; they can reduce cardiac workload by increasing the removal of water. All of the drugs are metabolized to some extent in the liver and excreted in the urine.

Sodium ions are present in the blood

More sodium ions are present in the blood, and fewer sodium ions are present inside the renal tubules. Therefore, water molecules migrate toward the sodium ions and into the blood (water reabsorption) and are reabsorbed within the proximal convoluted tubules and the collecting ducts. Under the influence of the pituitary hormone antidiuretic hormone (ADH), the pores (aquaporins) of the collecting ducts open, and water rushes toward the sodium ions. This results in removal of water from the urine, and the volume of urine decreases. The renal reabsorption of sodium and water maintains the plasma volume and water balance.

Nephrons also regulate blood pressure

Nephrons also regulate blood pressure by reabsorbing water and sodium ions into the blood as part of the reabsorption and secretion mechanisms and through the activity of the juxtaglomerular cells located in every nephron near the glomerulus.

Orthostatic hypotension

Orthostatic hypotension is caused by removal of salt and water from the circulation by diuretics, which can cause contraction of the plasma volume. The vital signs should be monitored periodically in order to follow effects on circulation and blood pressure. Patients receiving diuretics may have to restrict their dietary sodium intake.

Osmoreceptors

Osmoreceptors in the hypothalamus detect changes in the salt (sodium) concentration in the plasma that indicate whether more or less water needs to be conserved.

Osmotic diuretics

Osmotic diuretics are compounds that can be filtered by the glomerulus but not reabsorbed by the renal tubules. The drugs cannot penetrate cell membranes, therefore they are provided intravenously. Once inside the circulation, the drugs act osmotically, attracting fluid from edematous tissues. Since these drugs cannot cross tubular membranes, osmotic diuretics become trapped in the tubular lumen and create an osmotic gradient within the renal tubule lumen. Although water reabsorption is inhibited, there is no major alteration of sodium reabsorption. This class of diuretics produces a mild diuresis with no alteration in electrolyte or acid-base balance.

Osmotic diuretics

Osmotic diuretics are used to improve renal failure due to increased load (rhabdomyolysis, chemotherapy), reduce increased intracranial pressure and remove fluid and reduce pressure in glaucoma.

orthostatic hypotension

Patients receiving thiazide and thiazide-like diuretics often experience orthostatic hypotension, which is a sudden drop in blood pressure when they quickly change from a sitting position to a standing position.

Diuretics overdose

Plasma volume depletion contributes to hypotension, dizziness, and drowsiness. Electrolyte deficiency produces confusion, muscle weakness, and gastrointestinal disturbances. There is no antidote for any diuretic. Gastric lavage and vomiting may be necessary while maintaining hydration and electrolyte balance parenterally, and supporting respiration as necessary.

Potassium-sparing diuretics

Potassium-sparing diuretics are used for hypokalemia due to other diuretics and postmyocardial infarction. Spironolactone is specific for the treatment of aldosteronism from any cause.

Potent diuretics

Potent diuretics produce changes in electrolyte and acid-base balance with chronic use. Changes in serum potassium level should be monitored as changes in potassium can alter cardiovascular and skeletal muscle function

Renal function may be altered

Renal function may be altered by renal disease or cardiovascular dysfunction. Infection or inflammation in the renal tissues (nephritis), glomerulonephritis, and pylonephritis can reduce renal function. Circulatory problems associated with chronic heart failure (CHF), hypertension, and shock decrease renal function by reducing blood flow to the kidneys. This can often produce renal failure.

hypokalemia

Since the hydrogen ion exchange is blocked, the distal convoluted tubules attempt to reabsorb sodium ions by increasing the potassium ion exchange. The increased secretion of potassium ions causes an increased loss of potassium in the urine. Eventually, this loss of potassium leads to hypokalemia (decreased potassium ions in the blood).

Where are sodium ions reabsorbed

Sodium ions are reabsorbed in the loop of Henle in conjunction with chloride ions (Cl-).

What does the distal convoluted tubules secrete

The distal convoluted tubules also secrete potassium ions (K+) in exchange for sodium. The secretion of potassium ions is controlled by the adrenal mineralocorticoid aldosterone.

diuretic action of acetazolamide

The diuretic action of acetazolamide involves the inhibition of carbonic anhydrase, which is responsible for the production of hydrogen ions and bicarbonate ions from CO2 and water. When carbonic anhydrase is hindered, there are lesser hydrogen ions available for the exchange of sodium ions. This leads to an increased excretion of sodium ions into the urine along with increased amounts of water.

glomerulus

The filtration of blood into the nephrons occurs in the glomerulus. The difference in blood pressure between the entrance of the glomerulus and its interior allows the passage of small molecules and fluid into the glomerular filtrate. Vitamins, amino acids, and electrolytes pass into the glomerular filtrate (which ultimately becomes urine), but large molecules like RBCs and plasma proteins do not.

inhibition of carbonic anhydrase

The inhibition of carbonic anhydrase also influences the acid-base balance. Sodium ions cannot be excreted alone. They are usually accompanied by bicarbonate ions. Due to inhibition of carbonic anhydrase, there is little to no bicarbonate produced. Bicarbonate ions make the urine alkaline and maintain a normal pH level. The lack or absence of bicarbonate ions results in metabolic acidosis as hydrogen and chloride ions get into the bloodstream. - This is called hyperchloremic metabolic acidosis.

organic acid diuretics

The organic acid diuretics, which have a greater diuretic action than do the thiazides, are often used to relieve edema in patients who have become resistant to the thiazide diuretics. The organic acid diuretics are also useful in severe peripheral edema and pulmonary edema where greater diuretic activity is needed. Otherwise, the primary use is reduction of edema associated with CHF, liver cirrhosis, and renal disease.

potent mobilization of sodium causes

The potent mobilization of sodium causes chloride and potassium excretion to increase. As a result, these drugs usually produce hypochloremic alkalosis and hypokalemia. As long as these drugs are continually administered, diuresis will occur even in the presence of alkalosis.

tubular reabsorption

The proximal tubule, loop of Henle (nephron loop), and distal tubule pull ions out of the tubule lumen and transport them back into the blood (tubular reabsorption). One of the most important tubular reabsorption mechanisms is the transport of sodium ions into the circulation.

renal tubules have specialized transport systems

The renal tubules have specialized transport systems that remove weak acids and bases from the blood as part of the excretory function. Weak acids and bases are produced through normal cell metabolism and passed on to the kidneys for excretion. The proximal convoluted tubules secrete weak acids and weak bases into the urine. Many drugs are also weak acids or weak bases, which also are secreted into the tubular fluid through the proximal convoluted tubules. Metabolic waste products compete for the same transport sites that excrete these drugs, which may result in altered drug excretion.

vaptans

The vaptans remove water through interactions with vasopressin (ADH) receptors. These drugs are also referred to as antidiuretic hormone (ADH) antagonists and vasopressin antagonists.

thiazide-like diuretics on calcium

These diuretics reduce the renal excretion of calcium ions. This leads to a mild elevation in serum calcium levels with chronic therapy.

Thiazide and thiazide-like diuretics work by

Thiazide and thiazide-like diuretics work by preventing the transport of sodium ions at the distal part of the nephron. This leads to a significant loss of water and sodium, producing intense diuresis.

Thiazide and thiazide-like drugs

Thiazide and thiazide-like drugs are the largest group of diuretics. These drugs are widely used in the treatment of edema with hypertension and can alleviate edema of any cause, including the chronic edema associated with CHF or renal disease. These diuretics are useful in the management of mild to moderate hypertension as they reduce the plasma volume and relax vascular smooth muscle instantly. Thiazide diuretics such as metolazone are added to the loop diuretic regimen in refractory heart failure due to systolic dysfunction. The thiazide diuretic in addition to the loop diuretic is able to stimulate diuresis, remove sodium and water, and reduce the volume workload on the heart in these patients.

hyponatremia

Thiazide-induced hyponatremia (low sodium level) has been reported to occur in elderly patients.

Thiazides

Thiazides are preferred therapy in hypertension, mild heart failure, nephrolithiasis, and nephrogenic diabetes insipidus.

Tubular secretion is comprised of what

Tubular secretion comprises of the secretion of hydrogen ions, potassium ions, weak acids, and weak bases. The acidification of urine plays an important role in the acid-base balance. Any condition that impairs the renal production of hydrogen and bicarbonate ions alters the acid-base balance of the body

Tubular secretion

Tubular secretion involves secretion of ions, acids, and bases by the segments to facilitate sodium ion reabsorption and to maintain acid-base balance.

Urine formation

Urine formation is essential for normal body function because it enables the blood to reabsorb necessary nutrients, water, and electrolytes. It also enables elimination of metabolic waste products from the body through the urine. These processes take place in the working units of the kidneys known as the nephrons

hypotonic effects on ADH

When the plasma compartment has a decreased osmolarity (hypotonic), ADH secretion is inhibited. Conditions associated with an increase in retained water include cirrhosis, cardiac failure, severe vomiting, and diarrhea and would inhibit ADH secretion.

osmotic gradient

When the renal tubules reabsorb sodium ions through these mechanisms, an osmotic gradient is established along the nephron.

oliguria and anuria

Whether the renal tissue is damaged or the blood flow is reduced, the ultimate result is decreased urine flow, decreased urine volume (oliguria), or no urine production at all (anuria). As a result, the blood is not adequately filtered, and toxic products and ions accumulate. Such an accumulation can lead to uremia, edema, and hypertension.

ADH antagonists

ADH antagonists are indicated for the clinical management of euvolemic and hypervolemic hyponatremia in hospitalized patients.