Thiazide derivatives, diuretic drugs

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. 

The thiazides are the most widely used of the diuretic drugs. They are sulfonamide derivatives and are related in structure to the carbonic anhydrase inhibitors. The thiazides have significantly greater diuretic activity than acetazolamide, and they act on the kidney by different mechanisms. All thiazides affect the distal tubule, and all have equal maximum diuretic effect, differing only in potency, expressed on a per -milligram basis. 

Mechanism of action The thiazide derivatives act mainly in the distal tubule to decrease the reabsorption of Na+ by inhibition of a Na+/CI cotransporter on the luminal membrane (see Figure 23.2). They have a lesser effect in the proximal tubule. As a result, these drugs increase the concentration of Na+ and Cl- in the tubular fluid. The acid-base balance is not usually affected. [Note Because the site of action of the thiazide derivatives is on the luminal membrane, these drugs must be excreted into the tubular lumen to be effective. Therefore, with decreased renal function, thiazide diuretics lose efficacy.]... 

Lithium is also known to interact in a variety of ways with different classes of diuretic drugs. Thiazide diuretics increase serum lithium concentration by increasing reabsorption of lithium, along with that of sodium, in the proximal tubule. With potassium-sparing diuretics, conflicting results have been reported. Increased serum lithium concentrations may be seen after amiloride. However, the loop diuretic furosemide safely can be combined with lithium with no reduction in renal lithium clearance or consequent increase in serum lithium concentration (191, 192). Other diuretics, for example, carbonic anhydrase inhibitor and xanthine derivatives, decrease serum... 

The development of an acute interstitial inflammatory reaction in the kidney related to the administration of certain classes of drugs and leading to renal failure has been recognized for almost a century [42]. Antibiotics, in particular the sulfonamides [43] and semisynthetic penicillins [44, 45], were recognized as etio-logically associated in many instances. A retrospective review of 1068 kidney biopsies from 1%8 to 1997 by Schwarz et al. yielded acute interstitial nephritis in 6.5% of cases. In the majority of instances (85%) acute interstitial nephritis was drug related. Diuretics were implicated in 7.8 % of these cases [46]. Lyons et al. noted that four patients with proliferative glomerulonephritis and nephrotic syndrome treated with sulfonamide-derivative diuretics (furosemide or thiazides) developed severe renal failure, which reversed when the diuretic was withdrawn and prednisone was adminis-... 

The thiazide diuretics, also called sulfonamide or ben-zothiadiazide diuretics, vary in their actions. For instance, the potency of hydrochlorothiazide (Hydro-Diuril and Esidrix) is ten times greater than that of chlorothiazide (Diuril), but the drugs have equal efficacy. The duration of action of hydrochlorothiazide, which is 6 to 12 hours, equals that of chlorothiazide. On the other hand, chlorthalidone (Hygroton) has a duration of action lasting 48 hours. Some thiazide derivatives inhibit carbonic anhydrase, which is unrelated to their diuretic activity. Those that are active in this respect may, at sufficient doses, have the same effect on bicarbonate excretion as does acetazola-mide. They cause a moderate loss of sodium (5 to 10% of the filtered load), chloride, and water, and the clearance of free water is impaired. They may cause metabolic alkalosis (resorption of bicarbonate and loss of hydrogen ions), hyperuricemia (enhanced resorption of uric acid), or hyperglycemia (due to directly inhibited insulin release and to hypokalemia). 

The original inhibitors of Na -Ct symport were benzothiadiazine derivatives, hence this class of diuretics became known as thiazide diuretics. Subsequently, drugs that are pharmacologically similar to thiazide diuretics but are not thiazides were developed and are called thiazide-like diuretics. The term thiazide diuretics is used here to refer to all members of the class of inhibitors ofNa —Ct symport. 

Anuria renal decompensation hypersensitivity to thiazides or related diuretics or sulfonamide-derived drugs hepatic coma or precoma (metolazone). 

Diuretics are highly efficient drugs for the treatment of edema associated with congestive heart failure. They are also used to increase the volume of urine excreted by the kidneys [9]. For example, duranide, 81, a dichlorinated benzene disulfonamide, is an oral carbonic anhydrase inhibitor. Duranide reduces intraocular pressure by partially suppressing the secretion of aqueous humor [11]. Diuril, 82, has an antihypertensive activity and is issued to control blood pressure [9]. Edecrin, 83, is an unsaturated ketone derivative of an aryloxyacetic acid. Edecrin is used in the treatment of the edema associated with congestive heart failure, renal disease, and cirrhosis of the liver [11]. Amiloride, 84, is also used as an adjunctive treatment with thiazide diuretics in congestive heart failure hypertension. 

Exanthematic/maculopapular reactions are the most frequent unlike a viral exanthem the eruption typically starts on the trunk the face is relatively spared. Continued use of the drug may lead to erythroderma. They commonly occur at about the ninth day of treatment (or day 2-3 in previously exposed patients), although onset may be delayed until after treatment is completed causes include antimicrobials, especially ampicillin, sulphonamides and derivatives (sulphonylureas, frusemide (furosemide) and thiazide diuretics). Morbilliform (measles-like) eruptions typically recur on rechallenge. 

An interesting sulfonamide diuretic that has little resemblance structurally to the thiazides is chlorthalidone, a benzophenone derivative. On a dose basis, it has an activity comparable to hydrochlorothiazide but is a much stronger carbonic anhydrase inhibitor than the thiazides, approximately 40 times sulfanilamide. Physical data indicate this compound to have the isoindoline structure rather than the benzophenone structure, I. The outstanding feature of this drug is its long duration of action, up to 72 hours (22, 32, 66). 

Established interactions. The CSM in the UK advises that, as potentially serious hypokalaemia may result from beta2 agonist therapy, particular caution is required in severe asthma, as this effect may be potentiated by theophylline and its derivatives, corticosteroids, diuretics, and by hypoxia. Hypokalaemia with concurrent use of thiazide and loop diuretics may be reduced or even abolished by the addition of spironolactone or high-dose triamterene. Plasma potassium levels should therefore be monitored in patients with severe asthma. Hypokalaemia may result in cardiac arrhythmias in patients with ischaemic heart disease and may also affect the response of patients to drugs such as the digitalis glycosides and an-tiarrhythmics. 

In contrast to thiazides and benzoic acid derivatives, the pyrazine-based drug amiloride (Fig. 4.12, 4) represents a potassium-sparing diuretic agent, which is one of the few diuretics that are preferably analyzed as protonated species under ESI conditions. Assuming an initial protonation of 4 at the guanidine moiety, a precursor ion at m/z 230 is obtained, which predominantly eliminates guanidine (-59 Da) followed by the release of carbon dioxide (-28 Da) and HCN (-27 Da) to produce the diagnostic ions at m/z 171,143, and 116, respectively (Table 4.5), all of... 

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