Thiazide

Patients having high plasma renin activity (PRA) (>8 ng/(mLh)) respond best to an ACE inhibitor or a -adrenoceptor blocker those having low PRA (<1 ng/(mLh)) usually elderly and black, respond best to a calcium channel blocker or a diuretic (184). -Adrenoceptor blockers should not be used in patients who have diabetes, asthma, bradycardia, or peripheral vascular diseases. The thiazide-type diuretics (qv) should be used with caution in patients having diabetes. Likewise, -adrenoceptor blockers should not be combined with verapamil or diltiazem because these dmgs slow the atrioventricular nodal conduction in the heart. Calcium channel blockers are preferred in patients having coronary insufficiency diseases because of the cardioprotective effects of these dmgs. 

Diuretics, such as those of the thiazide type, have been the cornerstone of first-line antihypertensive treatments for decades. However, popularity and use have eroded as a result of increases in sudden death in patients on diuretic therapy, and unfavorable effects on blood Hpids profile, ie, increasing cholesterol and triglyceride. These effects have been impHcated as possible causes for the lack of decrease in the mortaUty rate resulting from acute MI in patients treated with a diuretic (187,240,241). However, diuretics do protect against stroke and CHF. 

Diuretics are needed to return to normal the expanded extracellular volume that other antihypertensive agents produce, such as fluid retention and blood volume expansion, via compensatory mechanisms of the body. The loss of efficacy of antihypertensive agents can be restored if a diuretic is used concomitandy. In the treatment of hypertension, high ceiling or loop diuretics, such as furosemide, ethacrynic acid, and bumetanide, are no more efficacious than the thiazide-type of diuretics. In fact, these agents cause more side effects, such as dehydration, metaboHc alkalosis, etc, and therefore, should not be used except in situations where rapid elimination of duid volume is cleady indicated. 

Potassium Sparing Diuretics. Triamterene and amiloride, potassium sparing diuretics, by themselves produce only slight antihypertensive effects. The main use is to prevent or to treat the hypokalemia induced by thiazide-type and high ceiling loop diuretics, such as furosemide and bumetanide. 

Methyldopa is effective in mild, moderate, and severe hypertension but a thiazide-type diuretic is needed to overcome the fluid retaining side effect. Methyldopa has been shown to prevent and induce regression of ventricular hypertrophy in hypertensive patients. The principal side effects are sedation, drowsiness, nasal congestion, fluid retention, and in rare occasions, hemolytic anemia. 

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 efficacy of these diuretics led to their extensive use in the clinic, particularly in treatment of hypertension. In theory at least, reduction of the blood volume by diuresis should lead to a lowering of pressure (PV=RT). This expectation was in fact met in actual practice. Recent research does, however, seem to indicate that the thiazides have an antihypertensive effect beyond that explainable by a simple lowering of blood volume. 

In the preparation of the thiazides containing more highly functionalized side chains (183-185), an acetal of the aldehyde is usually used rather than the free carbonyl compound. Thus, trichlomethiazide (183) is prepared by reaction of 160 with the dimethyl acetal from dichloroacetaldehyde. In a similar vein, alkylation of the acetalthiol, 190, with allyl bromide affords 191. This yields altizide (184) on condensation with 160. Alkylation of 190 with 2,2,2-trifluoroethyl iodide gives 192. This leads to epithiazide (185) on condensation with 160. 

Each era of medicinal chemistry has been marked by intensive concentration on some structural type in a large number of laboratories. One need only look back in this book to the tables of sulfonamides, barbiturates, and thiazide diuretics, noting the small time span covered by the references to each list. The benzodiazepines have provided such a focus for the past decade. 

Thiazide diuretics have a venerable history as antihypertensive agents until the advent of the angiotensin-converting enzyme (ACE) inhibitors this class of drugs completely dominated first line therapy for hypertension. The size of thi.s market led until surprisingly recently to the syntheses of new sulfonamides related to the thiazides. Preparation of one of the last of these compounds starts by exhaustive reduction of the Diels-Alder adduct from cyclopentadiene and malei-mide (207). Nitrosation of the product (208), followed by reduction of the nitroso group of 209,... 

Agents acting in the proximal tubule are seldom used to treat hypertension. Treatment is usually initiated with a thiazide-type diuretic. Chlorthalidone and indapamide are structurally different from thiazides but are functionally related. If renal function is severely impaired (i.e., serum creatinine above 2.5 mg/dl), a loop diuretic is needed. A potassium-sparing agent may be given with the diuretic to reduce the likelihood of hypokalemia. 

ACE inhibitors - AT antagonists - Alpha blockers - Beta blockers Isolated syslolic hypertension (older patienls) - Diuretics preferred (generally Thiazides) - Long-acting dihydropyridine calcium channel blocker... 

Electroneutral NaCl transport in the distal convoluted tubule is inhibited by the class of thiazide diuretics (chlorothiazide, hydrochlorothiazide, metolazone, chlorthalidone, and others). Thiazides interfere with the Cl binding site of NCC, and cause a relatively small... 

The thiazide sensitive NaCI cotransporter (NCC) is the major pathway of NaCI entry in the distal convoluted tubule. Like NKCC2, NCC contains 12 putative transmembrane domains and long intracellular amino-and carboxy-tails. NCC and NKCC as well as the KC1 cotransporter KCC are members of the same gene family and have considerable homology. 

G protein p-3 subunit Truncated protein with increased signal transduction in carriers of the 825T allele. Associated with hypertension and with the response to thiazide diuretics. 

Tyrosine hydroxylase 1 Thiazide diuretics, a group of drugs with moderate diuretic activity, includes hydrochlorothiazide, chlorthalidone, and xipamide. They decrease active reabsorption of sodium and accompanying chloride by binding to the chloride site of the electroneutral Na+/CF cotransport system in the distal convoluted tubule and inhibiting its action. 

Fhtients taking a diuretic and a digitalis glycoside must be monitored closely. Thiazide and loop diuretics (see Chap. 46) may increase the risk and effects of toxicity. 

Diuretics are used in a variety of medical disorders. The primary health care provider selects the type of diuretic diat will most likely be effective for treatment of a specific disorder. In some instances, hypertension may be treated with the administration of an antihypertensive drug and a diuretic. The diuretics used for this combination tiierapy include the loop diuretics and the thiazides and related diuretics. The specific uses of each type of diuretic drug are discussed in the following sections. 

Figure 46-1. The nephron is the functional unit of the kidney. Note the various tubules, the site of most diuretic activity. The loop of Henle is the site of action for the loop diuretics. Thiazide diuretics ad at the ascending portion of the loop of Henle and the distal tube of the nephron.

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