Diuretic agents thiazides

The sites of action within the kidney and the pharmacokinetics of various diuretic drugs are discussed in Chapter 15 Diuretic Agents. Thiazide diuretics are appropriate for most patients with mild or moderate hypertension and normal renal and cardiac function. More powerful diuretics (eg, those acting on the loop of Henle) are necessary in severe hypertension, when multiple drugs with sodium-retaining properties are used in renal insufficiency, when glomerular filtration rate is less than 30 or 40 mL/min and in cardiac failure or cirrhosis, where sodium retention is marked. 

Chlorthalidone (49) is another thiazide-like diuretic agent that formally contains an isoindole ring. Transformation of the amine in benzophenone, 47, to a sulfonamide group by essentially the same process as was outlined for chlorexolone (46) affords Intermediate 43. This product cyclizes to the desired pseudoacid 1-ketoisoindole (49) on successive treatments with thionyl... 

The answer is c. (Hardman, pp 704-706J Triamterene produces retention of the K ion by inhibiting in the collecting duct the reabsorption of Na, which is accompanied by the excretion of K ions. The loop diuretics furosemide and bumetanide cause as a possible adverse action the development of hypokalemia. In addition, thiazides (e g, hydrochlorothiazide) and the thiazide-related agents (e.g., metolazone) can cause the loss of K ions with the consequences of hypokalemia. Triamterene can be given with a loop diuretic or thiazide to prevent or correct the condition of hypokalemia. 

The answers are 373-d, 374-c, 375-a. (Kut ung, pp 253— 254, 256-257.) The urinary excretion pattern of electrolytes for the thiazide diuretic agents (e.g., hydrochlorothiazide) shown in the table that accompanies the question is represented by choice a. These drugs block the reabsorption of Na and Cl at the early distal convoluted tubule of the nephron. In addition, they promote the excretion of K and Mg. At high doses, the thiazide diuretics (especially hydrochlorothiazide) may cause a... 

These potent diuretic agents interact with almost the entire nephron, including Henle s loop (Fig. 7). Their primary effect is probably the inhibition of the active reabsorption of chloride ions, which then leads to the enhanced excretion of sodium ions and water. Plasma volume is reduced as a result of these effects, whereas in the long-term both cardiac preload and afterload will diminish. The metabolic side-effects of the loop diuretics are globally the same as those of the thiazides, with some incidental differences. Plasma renin activity increases by loop diuretic treatment and it can be well imagined that this effect is noxious in the long-term management of heart failure. The loop diuretics provoke a clearly... 

The availability of this extremely well tolerated potent diuretic agent led clinicians to investigate the possibility that elevated blood pressure could be relieved by decreasing blood volume. The drug, now better known by its initials HCTZ, was in fact formd to be effective in lowering blood pressirre in close to half of all h) per-tensive patients. The mechanism by which this and other thiazide diuretics make this happen is now known to be more complex than simply decreasing volume. 

Only about 10% of the Na-i- filtered by the glomerulus is reabsorbed by the distal convoluted tubule (DCT) and therefore the capacity of the thiazide group of diuretics to influence the elimination of Na-H in the urine is limited compared to the loop agents. Thiazides can prevent the reabsorption of up to 5% of the total filtered Na+, whereas the equivalent figure for loop diuretics is about 20%. Thiazides can still produce a moderate naturesis and diuresis compared to carbonic anhydrase inhibitors and the K+-sparing agents. Most thiazides are ineffective at low glomerular filtration rates. They also hinder the ability of the kidneys to produce a dilute urine. 

See Table 15-5. The major indications for thiazide diuretics are (1) hypertension, (2) heart failure, (3) nephrolithiasis due to idiopathic hypercalciuria, and (4) nephrogenic diabetes insipidus. Use of the thiazides in each of these conditions is described in Clinical Pharmacology of Diuretic Agents. 

The combination of loop diuretics and thiazides can mobilize large amounts of fluid, even in patients who have not responded to single agents. Therefore, close hemodynamic monitoring is essential. Routine outpatient use is not recommended. Furthermore, K+-wasting is extremely common and may require parenteral K+ administration with careful monitoring of fluid and electrolyte status. 

Various thiazide, loop, or potassium-sparing diuretics can be used depending on the needs of each patient see Chapter 21, Table 21-3 for specific diuretic agents. 

Many diuretic agents (loop diuretics, thiazides, amiloride, and triamterene) exert their effects on specific membrane transport proteins in renal tubular epithelial cells. Other diuretics exert osmotic effects that prevent water reabsorption (mannitol), inhibit enzymes (acetazolamide), or interfere with hormone receptors in renal epithelial cells (spironolactone). 

These agents are most useful in states of mineralocorticoid excess, due either to primary hypersecretion (Conn s syndrome, ectopic ACTH production) or to secondary aldosteronism (from heart failure, hepatic cirrhosis, nephrotic syndrome, and other conditions associated with diminished effective intravascular volume) (Table 15-4). Use of other diuretics, like thiazides or loop agents, can cause or exacerbate volume contraction and thus intensify secondary aldosteronism. In the setting of enhanced mineralocorticoid secretion and continuing delivery of Na+ to distal nephron sites, renal K+ wasting occurs. Potassium-sparing diuretics of either type may be used in this setting to blunt the K+ secretory response. 

Q6 Thiazide diuretics are moderately powerful diuretic agents acting on the distal tubule of the nephron. They reduce reabsorption of sodium chloride and water by blocking the electroneutral sodium chloride (NaCl) transporter system at the luminal border of the distal tubular cells. In addition there are direct relaxant effects on vascular smooth muscle which reduces BP. Diuretics help patients in heart failure by reducing peripheral oedema and decreasing blood volume, which in turn reduces BP. In this way both preload and afterload are decreased and the work of the heart is diminished. 

In the absence of ADH or when the nephron is unresponsive to ADH, only hypotonic urine can be produced. Large volumes of dilute urine are produced, a condition called diabetes insipidus. This condition can be treated with thiazide diuretic agents. 

Drug interactions May decrease antihypertensive effects of ACE inhibitors and angiotensin II antagonists decrease of antihypertensive and diuretic effects of thiazides and loop diuretics Agents are CYP2C9 substrates may decease effects of ACE inhibitors, thiazides, and loop diuretics fluconazole Increases levels of celecoxib may increase INR when added to warfarin... 

Chlortalidone is a thiazide-like diuretic agent which essentially contains an isoindole ring. 

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