Question

Identify two classes of diuretics with regard to mechanism of action, indications, dosage, routes of administration, adverse effects, toxicity, cautions, contraindications, and drug interactions. Using a minimum of two scholarly article to support it, describe how these diuretics work in the kidney and how they lower blood pressure in individuals as well as why they are the drug of choice out of many diuretic medications (pathophysiological correlation).

Answer 1

Answer :-Diuretics, also called water pills, are medications designed to increase the amount of water and salt expelled from the body as urine. There are three types of prescription diuretics. They’re often prescribed to help treat high blood pressure, but they’re used for other conditions as well.

The three types of diuretic medications are called thiazide, loop, and potassium-sparing diuretics. All of them make your body excrete more fluids as urine.

Loop diuretics inhibit the sodium-potassium-chloride cotransporter in the thick ascending limb (see above figure). This transporter normally reabsorbs about 25% of the sodium load; therefore, inhibition of this pump can lead to a significant increase in the distal tubular concentration of sodium, reduced hypertonicity of the surrounding interstitium, and less water reabsorption in the collecting duct. This altered handling of sodium and water leads to both diuresis (increased water loss) and natriuresis (increased sodium loss). By acting on the thick ascending limb, which handles a significant fraction of sodium reabsorption, loop diuretics are very powerful diuretics. These drugs also induce renal synthesis of prostaglandins, which contributes to their renal action including the increase in renal blood flow and redistribution of renal cortical blood flow.

Because loop and thiazide diuretics increase sodium delivery to the distal segment of the distal tubule, this increases potassium loss (potentially causing hypokalaemia ) because the increase in distal tubular sodium concentration stimulates the aldosterone-sensitive sodium pump to increase sodium reabsorption in exchange for potassium and hydrogen ion, which are lost to the urine. The increased hydrogen ion loss can lead to metabolic alkalosis. Part of the loss of potassium and hydrogen ion by loop and thiazide diuretics results from activation of the renin-angiotensin-aldosterone system that occurs because of reduced blood volume and arterial pressure. Increased aldosterone stimulates sodium reabsorption and increases potassium and hydrogen ion excretion into the urine.

Indication (loop diuretics )=

Loop diuretics are principally used in the following indications:

• Heart failure - Giving 2.5 times of previous oral dose twice daily for those with acute decompensated heart failure is a reasonable strategy. ...
• Edema associated with liver cirrhosis, and nephrotic syndrome.

  Several loop diuretics come in IV and oral forms.

• Furosemide comes in oral tablet form in 20, 40, and 80 mg dosages. Injectable solutions come in 10 mg/mL doses. Oral solutions come in either 8 or 10 mg/mL doses.
• Torsemide comes in a tablet form in 5, 10, 20, or 100 mg doses. Injectable solution is 10 mg/mL dosing.
• Bumetanide comes in oral tablets of 0.5, 1 and 2 mg doses. IV solution is 0.25 mg/mL.
• Ethacrynic acid is available with oral tablets of 25 mg and in a powder form for injections at 50 mg.

  Adverse Effects

  Adverse effects for loops diuretics typically occur from electrolyte imbalances secondary to the diuresis effects which include: hyponatremia, hypokalemia, hypochloremia, hypomagnesemia, metabolic alkalosis, prerenal azotemia, dehydration, hypertriglyceridemia, hypercholesterolemia, hyperuricemia, gout, restlessness, headache, dizziness, vertigo, postural hypotension, and syncope. Other adverse reactions include skin photosensitivity, interstitial nephritis, tinnitus, ototoxicity, deafness, and in patients with renal failure who receive high doses, myalgias, and muscle soreness.

  Contraindications

  Contraindications to loop diuretics include:

• Anuria
• History of hypersensitivity to furosemide, bumetanide or torsemide (or sulfonamides) Toxicity :-Severe states of electrolyte depletion Diuretic toxicity can present in the form of electrolyte imbalances (hyponatremia, hypokalemia, hypocalcemia), acid/base disturbances (hypochloremic alkalosis), and dehydration secondary to excessive diuresis.Care is necessary to check electrolytes while the patient is on a diuretic periodically

Cautions:-There is a black box warning that states each loop diuretic is a potentdiuretic and, at higher dosages, could lead to a profound diuresis with water and electrolyte depletion. Careful medical supervision is necessary as adjustments to these drugs should be according to the patient's needs.

indications:

• Heart failure - Giving 2.5 times of previous oral dose twice daily for those with acute decompensated heart failure is a reasonable strategy. ...
• Edema associated with liver cirrhosis, and nephrotic syndrome.

Drug interaction :=Loop diuretics may also increase the risk of kidney damage from cisplatin. Cyclosporine - Loop diuretics and cyclosporine both increase the risk of gout. When taken together, the risk may be compounded. Ethacrynic acid -Loop diuretics and ethacrynic acid both have the potential to cause ototoxicity (hearing loss).

THIAZIDE DIURETICS

Mechanism of action

Thiazide diuretics control hypertension in part by inhibiting reabsorption of sodium (Na+) and chloride (Cl−) ions from the distal convoluted tubules in the kidneys by blocking the thiazide-sensitive Na+-Cl− symporter.

Administration

Thiazide diuretics are administered orally as tablets. Patients should take these agents in the morning with food. HCTZ and chlorthalidone have different dosing requirements for their indicated FDA uses listed above. Generally, for hypertension treatment, both drugs require a lower dosage starting at 25 mg daily and may be increased to 50 mg or 100 mg, respectively. The dosage should be increased based on the individual therapeutic needs of the patient. For patients suffering from fluid buildup and edema, dosing starts at 50 mg to 100 mg and 50 mg to 200 mg, respectively.

Adverse Effects

Adverse effects of thiazide diuretics stem from the ionic imbalance caused due to the initial Na loss in the DCT.

• Hypokalemia. Most widely recognized, the first adverse effect of thiazide diuretics is hypokalemia. As discussed above, hypokalemia is a sequela of the aldosterone-mediated actions of the Na/K pump in the CT. Hypokalemia can be life-threatening and requires monitored during the first 2-3 weeks of HCTZ therapy.
• Hyponatremia. The MOA of thiazide diuretics is to decrease sodium reabsorption and therefore decreased fluid reabsorption; this directly causes decreased levels of circulating sodium. If hyponatremia were to occur, it would happen during the first 2 to 3 weeks of therapy; after this time, the patient is in a new steady state in which further sodium and water losses do not occur.
• Metabolic alkalosis. Patients on thiazide diuretics may experience a hypokalemic metabolic acidosis due to the increase in aldosterone-mediated K and H ions excretion in the intercalated cells of the CT.
• Hypercalcemia. By increasing calcium reabsorption from the luminal membrane into the interstitium in exchange for sodium, thiazides reduce urine calcium levels and increase blood calcium. However, if indicated, this effect of thiazide diuretics makes thiazides useful for nephrolithiasis and osteoporosis treatment. Decreased urinary calcium decreases stone development in the kidney, and increased blood calcium is beneficial for patients with osteoporosis and promotes bone health.
• Hyperglycemia. Thiazide diuretics cause hypokalemia; at the level of the pancreatic B cells, this hypokalemia causes hyperpolarization of the B cell and decreases insulin secretion. Decreased K in the interstitium keeps the K channels open for an extended time, which causes the hyperpolarization of the cell. This hyperpolarization does not allow the voltage-gated calcium channels to open. When intracellular calcium does not increase through calcium influx via the voltage-gated calcium channels, exocytosis of insulin granules does not occur in the pancreatic B cells.
• Hyperuricemia. Thiazide diuretics cause hyperuricemia and increase the risk of developing gout. Thiazides directly increase urate reabsorption in the proximal tubule by using the OAT 1 anion exchanger on the basolateral membrane and the OAT 4 urate anion exchanger on the luminal membrane. At the OAT 1 exchanger, thiazides enter the proximal convoluted tubule, in replacement of urate, for an anion, increasing urate in the interstitium. The OAT 4 exchanger exchanges thiazides for urate in the lumen, causing increased urate in the proximal convoluted tubule that then crosses the basolateral membrane and therefore increases urate in the interstitium.
• Hyperlipidemia. The mechanism of hyperlipidemia with thiazide treatment is unclear. However, it appears to be an acute response to high dose thiazide treatment.
• Sulfonamide allergy. Thiazide diuretics are sulfa-containing drugs. Patients with sulfa allergies taking thiazides may experience headache, rash, hives, swelling of the mouth and lips, wheezing or trouble breathing, asthma attack, and anaphylaxis.  

Contraindications

Thiazide diuretics are contraindicated for use in patients with anuria and sulfonamide allergies.

TOXICITY:-Most widely recognized, the first adverse effect of thiazide diuretics is hypokalemia. , hypokalemia is a sequela of the aldosterone-mediated actions of the Na/K pump in the CT. Hypokalemia can be life-threatening and requires monitored during the first 2-3 weeks of HCTZ therapy. Hyponatremia.

Cautions:=Owing to their ability to increase the production of urine, these drugs may lower levels in the body of potassium and magnesium which also are present in urine. Thiazide diuretics may increase uric acid levels in blood. Like other antihypertensive medications, thiazides cause sexual dysfunction.

Drug interaction :- Thazide diuretics interact pharmacodynamically with drugs, such as digoxin, flecainide, and dofetilide through thiazide-induced hypokalemia, hyponatremia, and hypovolemia respectively.

how thr diuretics work in the kidney and how they lower blood pressure in individuals :=

As blood flows through the kidney, it passes into glomerular capillaries located within the cortex (outer zone of the kidney). These glomerular capillaries are highly permeable to water and electrolytes. Glomerular capillary hydrostatic pressure drives (filters) water and electrolytes into Bowman's space and into the proximal convoluting tubule (PCT). About 20% of the plasma that enters the glomerular capillaries is filtered (termed filtration fraction). The PCT, which lies within the cortex , is the site of sodium, water and bicarbonate transport from the filtrate (urine), across the tubule wall, and into the interstitium of the cortex. About 65-70% of the filtered sodium is removed from the urine found within the PCT (this is termed sodium reabsorption). This sodium is reabsorbed isosmotically, meaning that every molecule of sodium that is reabsorbed is accompanied by a molecule of water. As the tubule dives into the medulla, or middle zone of the kidney, the tubule becomes narrower and forms a loop (Loop of Henle) that reenters the cortex as the thick ascending limb (TAL) that travels back to near the glomerulus. Because the interstitium of the medulla is very hyperosmotic and the Loop of Henle is permeable to water, water is reabsorbed from the Loop of Henle and into the medullary interstitium. This loss of water concentrates the urine within the Loop of Henle.

The TAL, which is impermeable to water, has a cotransport system that reabsorbs sodium, potassium and chloride at a ratio of 1:1:2. Approximately 25% of the sodium load of the original filtrate is reabsorbed at the TAL. From the TAL, the urine flows into the distal convoluting tubule (DCT), which is another site of sodium transport (~5% via a sodium-chloride cotransporter) into the cortical interstitium (the DCT is also impermeable to water). Finally, the tubule dives back into the medulla as the collecting duct and then into the renal pelvis where it joins with other collecting ducts to exit the kidney as the ureter. The distal segment of the DCT and the upper collecting duct has a transporter that reabsorbs sodium (about 1-2% of filtered load) in exchange for potassium and hydrogen ion, which are excreted into the urine. It is important to note two things about this transporter. First, its activity is dependent on the tubular concentration of sodium, so that when sodium is high, more sodium is reabsorbed and more potassium and hydrogen ion are excreted. Second, this transporter is regulated by aldosterone, which is a mineralocorticoid hormone secreted by the adrenal cortex. Increased aldosterone stimulates the reabsorption of sodium, which also increases the loss of potassium and hydrogen ion to the urine. Finally, water is reabsorbed in the collected duct through special pores that are regulated by antidiuretic hormone, which is released by the posterior pituitary. ADH increases the permeability of the collecting duct to water, which leads to increased water reabsorption, a more concentrated urine and reduced urine outflow (antidiuresis). Nearly all of the sodium originally filtered is reabsorbed by the kidney, so that less than 1% of originally filtered sodium remains in the final urine.