Thiazide diuretics pharmacokinetics

Mechanism of Action A sulfonamide derivative that acts as a thiazide diuretic and antihypertensive. As a diuretic, blocks reabsorption of water, sodium, and potassium at the cortical diluting segment of the distal tubule. As an antihypertensive, reduces plasma, extracellular fluid volume, and peripheral vascular resistance by direct effect on blood vessels. Therapeutic Effect Promotes diuresis reduces BP. Pharmacokinetics ... 

The sites of action within the kidney and the pharmacokinetics of various diuretic drugs are discussed in Chapter 15. 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) such as furosemide 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, in which sodium retention is marked. 

Some pharmacokinetic characteristics and the initial and usual maintenance dosages of hydrochlorothiazide are listed in Table 11-2. Although thiazide diuretics are more natriuretic at higher doses (up to 100-200 mg of hydrochlorothiazide), when used as a single agent, lower doses (25-50 mg) exert as much antihypertensive effect as do higher doses. In contrast to thiazides, the blood pressure response to loop diuretics continues to increase at doses many times greater than the usual therapeutic dose. 

Pharmacokinetics Thiazide diuretics can be administered orally. They induce considerable disturbances in electrolyte balance. For example, blood levels of K+ and Mg++ are reduced, and Ca++ is retained by the body (see p. 229). 

The thiazide diuretics are weakiy acidic (see Appendix A for their pKa vaiues), with a behzothiadiazine 1,1-dioxide nucieus. The structure for the thiazide diuretics, reiative activities, and pharmacokinetic properties for the thiazides are shown in Tabie 27.3. Chiorothiazide is the simpiest member of this series, havihg a pKa of 6.7 and 9.5. The hydrogen atom at the 2-N is the most acidic because of the electron-withdrawing effects of the neighboring sulfone group. The sulfonamide group that is substituted at C-7 provides an additional point of acidity in the molecule but is less acidic than the 2-N proton. These acidic protons make possible the formation of a water-soluble sodium salt that can be used for intravenous administration of the diuretics. 

Table 27.3. Pharmacological and Pharmacokinetic Properties for the Thiazide Diuretics ...

Chlorthalidone has a long duration of action (48-72 hours) (see Table 27.3 for its other pharmacokinetic properties). Although quinethazone and metolazone are administered daily, chlorthalidone may be administered in doses of 25 to 100 mg three times a week. When chlorthalidone is formulated with the excipient povidone, the product. Thalitone. has greater bioavailability (>90%) and reaches peak plasma concentrations in a shorter time compared with its other products. Similar to the quinazolinones. it also is extensively bound to carbonic anhydrase in the erythrocytes. Chlorthalidone-induced effects on urine content and side effects are similar to those induced by thiazide diuretics. 

The chiorine and suifonamide substitutions are features aiso seen in previousiy discussed diuretics. Because the moiecuie possesses a free carboxyi group, furosemide is a stronger acid than the thiazide diuretics (pKa = 3.9). This drug is excreted primariiy unchanged. A smaii amount of metaboiism, however, can take piace on the furan ring, which is substituted on the aromatic amino group (see Tabie 27.2 for its other pharmacokinetic properties). 

There are no published reports on the pharmacokinetics of the thiazide-type diuretics in horses. A bolus dose of a combination of dexamethasone (5 mg) and trichlormethiazide (200 mg), a product commonly used for treatment of udder edema in periparturient cattle, is occasionally used to treat edema in horses and there are anecdotal reports that it is efficacious. Hydrochlorothiazide (0.5- 0.7mg/kg orally twice daily) has also been used to enhance urinary potassium excretion and thereby limit the increase in serum potassium concentrations during an episode of hyperkalemic periodic paralysis in horses (Beech Lindborg 1996, Spier et al 1990 see Ch. 8). However, hydrochlorothiazide was less effective than acetazolamide (see below) and phenytoin in controlling the clinical signs, but it did limit the increase in the serum potassium ion concentrations during an oral potassium chloride challenge test (Beech Lindborg 1996). 

In humans, spironolactone is absorbed readily and is metabolized in the liver to active compounds called canrenones. It is these metabolites that compete with aldosterone for its cytosolic receptor therefore, the maximal natriuretic effect is not observed until 24-48 h after treatment has been initiated. Spironolactone is indicated for the treatment of primary hyperaldosteronism but is also used in refractory edema and in secondary hyperaldosteronism consequent to use of loop or thiazide-type diuretics (Martinez-Maldonado Cordova 1990, Rose 1989, 1991, Wilcox 1991). In one study, the administration of spironolactone via nasogastric tube (1 and 2mg/kg) to ponies more than doubled the urinary excretion of sodium and reduced the urinary excretion of potassium for a period of 72 h, although there was no difference in the volume of urine produced (Alexander 1982). This suggests that spironolactone is a potassium-sparing agent in horses however, to date, no pharmacokinetic studies have been published. 

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.- ... 

Benzothiadiazines ( thiazides ) and related diuretics are the most frequently used class of antihypertensive agents in the U.S. Thiazides block the Na+-Q symporter and have the same pharmacological effects and are generally interchangeable with appropriate dose adjustment (see Chapter 28). Since their pharmacokinetics and pharmacodynamics differ, these drugs do not necessarily have the same clinical efficacy in treating hypertension. 

A. Pharmacokinetics Lithium is absorbed rapidly and completely from the gut. The dmg is distributed throughout the body water and excreted by the kidneys with a half-life of about 20 hours. Plasma levels should be monitored, especially during the first weeks of therapy, to establish an effective and safe dosage regimen. The therapeutic plasma concentration is 0.6-1.4 meq/L. Plasma levels of the drag may be altered by changes in body water. Thus, dehydration or treatment with diuretics (thiazides), may result in an increase of lithium in the blood to toxic levels. Theophylline increases the renal clearance of lithium. 

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