Thiazide-like diuretics

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... 

Which electrolyte imbalance would the patient receiving a loop or thiazide diuretic most likely develop ... 

Thiazide diuretics (e.g., hydrochlorothiazide) are relatively weak diuretics and are used alone infrequently in HF. However, thiazides or the thiazide-like diuretic metolazone can be used in combination with a loop diuretic to promote effective diuresis. Thiazides may be preferred over loop diuretics in patients with only mild fluid retention and elevated blood pressure because of their more persistent antihypertensive effects. 

Renal function impairment Use with caution in severe renal disease because these agents may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function. Monitor renal function periodically. Metolazone is the only thiazide-like diuretic that may produce diuresis in patients with GFR less than 20 mL/min. Indapamide may also be useful in patients with impaired renal function. 

Low-dose thiazide-like diuretic and ACE-I or ARB ACE-I OR ARB - usually in combination with a diuretic... 

Diuretics, specifically the loop diuretics furose-mide or bumetanide, combined with the thiazide like diuretic metolazone are needed in hypertensive urgencies both to lower blood pressure by removing excess volume and to prevent loss of potency from tendency to cause fluid retention. Volume depletion should be watched in patients on diuretics. 

Mechanism of Action A thiazide-like diuretic that blocks reabsorption of water, sodium, and potassium at the cortical diluting segment of the distal tubule also reduces plasma and extracellular fluid volume and peripheral vascular resistance by direct effect on blood vessels. Therapeutic Effect Promotes diuresis and reduces BP. Pharmacokinetics Almost completely absorbed following PO administration. Protein binding 71%-79%. Extensively metabolized in liver. Excreted in urine. Half-life 14-15 hr. 

The benzothiadiazides and the newer thiazide-like diuretics antagonise the absorption of Na-i- and Cl- in the DCT by inhibition of the Na+/CI- symport mechanism in the luminal membrane (Figure 12.4). They do not have any effect on the LoH. Some of the thiazides are thought to have a minor action on the PCT but this is minimal and is not due to inhibition of the Na-i-/CI- symporter. It may be due to carbonic anhydrase inhibition which is a feature of sulphonamide-derived drugs. 

Thiazide and thiazide-like diuretics reduce the renal clearance of calcium by inhibiting the tubular secretion... 

The adverse effects of thiazide and thiazide-like diuretics on male sexual function include reduced libido, erectile dysfunction, and difficulty in ejaculating. The exact incidence of sexual dysfunction in patients taking diuretics is poorly documented, perhaps because of the personal nature of the problem and the reluctance of patients and/or physicians to discuss it. However, these abnormalities have been reported with incidence rates of 3-32%. The true incidence of sexual dysfunction probably lies closer to the lower end of this range (119). In a meta-analysis of 13 randomized, placebo-controlled trials conducted over a mean of 4 years the NNH (number needed to harm) for erectile impotence with thiazide diuretics in hypertension was 20 and the relative risk was 5.0 (120). 

Indapamide is a thiazide-like diuretic. Although it was introduced as a specific antihypertensive drug without appreciable diuretic action, the effects of indapamide are no different from those of bendroflume-thiazide. 

Although one thiazide diuretic may be 100 times more potent than another weight for weight, all these drugs have essentially the same properties. Their mechanism of action (inhibition of sodium and chloride reabsorption in the distal convoluted tubule of the kidney) is identical and they can therefore be dealt with as a group. Thiazidelike diuretics, structurally different from the thiazides, have similar actions. Thiazide and thiazide-like diuretics are listed in Table 1. 

Table 1 Thiazide and thiazide-like diuretics (rlNNs except where stated)...

Figure 18-5 Site 3 The Na transport systems responsible for the reabsorption of Na and Cl" in the water-impermeable distal convoluted tubule. Inhibitors of the luminal membrane-bound Na /CI cotransport system include the thiazide and thiazide-like diuretics.

Dkhlorphenamide. USP. Like the other CA inhibitors, dichlorphenamide. 4.S-dichloro-1.3-benzenedisulfonamide (Daranide) (Fig. 18-8). is seldom used as a diuretic. Little is known about its pharmacokinetics. Like other CA inhibitors. it reduces intraocular pressure and may be useful in the treatment of glaucoma. The importance of dichlorphenamide and chloraminophenamide is that (hey ultimately served as stepping stones away from the "pure" CA-inhibiting diuretics and toward the development of the thiazide and thiazide-like diuretics, which are effective natriuretic and chlorurctic agents with minimal CA-inhibitory activity.- ... 

Figure 18-10 Representatives from SIX classes of thiazide-like diuretics. These diuretics were developed as an outgrowth of the thiazide research that involved molecular modification of aromatic sulfamoyl

Mist of the thiazide and thiazide-like diuretics are aKsorbed dl alter oral administration, except ehlumthiazide (only. vt 10% of which is absorbed). Their on.sct of action sially occurs within I to 2 hours, and their peak diuretic. iket is expressed within. 1 to 6 hours. " Most diuretics in i ll class are bound extensively to plasma proteins (or to tdl ItsKicell CA for chlorthalidone and metolazone - ). 

The site of action of the thiazide and thiazide-like diuretics differs slightly from one species to another. In humans, however, it appears safe to conclude that all of these diuretics block the reabsorption of Na (and, thereby, the reabsorption of Cr) in the distal convoluted tubules by inhibiting the luminal membrane-bound Na /CI cotransport system (Fig. 18-5). Thus, all diuretics in this class arc responsible for the urinary loss of about 5 to 8% of the filtered load of Na. Although they differ in their potencies (i.c., the amount of drug needed to produce a given diuretic response), they are equally efficacious (i.c., they can all exert a similar maximal diuretic response).-"-As a result of their action at site 3, the thiazide and thia-zidc-like diuretics secondarily alter the renal excretion rate of important ions other than Na and Cl. Inhibition of Na ... 

Four of the adverse effects asscxiiated with the thiazide on thiazide-like diuretics are highly predictable because of Ibtir chemical makeup or their site of action along the nephiM... 

Some individuals with hypercalciuria (an elevated urinary concentration of calcium) are prune In the formation of Ca -enniaining. stnnes within the urinary tract. Becau.se Inng-temi use of thiazide and thiazide-like diuretics de-crea.ses the urinary excretion rate of Ca". they may help prevent Ca" -containing stone fnrmation. "... 

Furo.semide and bumetanide are similar to the CA inhibilm. thiazides, and thiazide-like diuretics in possessing a. sulfanHnl moiety. This functional group has been associated with h)pei. sensitivity reactions such as urtic-aria. drug fever, bloixldyvt. sios. and interstitial nephritis. 

Loop diuretics may be used fur (he treatment of certain nnncdemalous disorders. Symplomatie hypercalcemia may be (tcalcd with a loop diuretic, provided no reduction in pksma volume occurs and the fluid used for replacemcnl of ihc urinary losses is calcium free. In addition, furosemide has been used for (he treatment nf hypertensinn. Some inve.s-ligators believe, however, (hat because of its relatively short dunUion of action. i( may be le.ss effective than (he thiazide or thiazide-like diuretics. It has been suggested (hat furo.se-mide be reserved for hypertensive patients with fluid retention refractory (n thiazides or patients with impaired renal function. ... 

Ihladde and Thiazide-Like Diuretics iaimlhmiediiazlde, USP (Naturetln)... 

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