Diuretics above

Interactions. Hyperkalaemia can result from use with potassium-sparing diuretics. Renal clearance of lithium is reduced and toxic concentrations of plasma lithium may follow. Severe hypotension can occur with diuretics (above), and with chlorpro-mazine, and possibly other phenothiazines. 

The cyclized analog of meralluride is prepared by a similar synthesis. Thus, condensation of camphoric acid (42) (obtained by oxidation of camphor) with ammonia gives the bicyclic succinimide (44). Reaction with allyl isocyanate followed by ring opening and then reaction with mercuric acetate affords the mercury derivative (45) as the acetate rather than the hydroxide as above. Reaction with sodium chloride converts that acetate to the halide (46). Displacement on mercury with the disodium salt of thioglycollic acid affords the diuretic mercaptomerine (47). ... 

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. 

Often used to augment blood pressure lowering, CCBAs are most commonly used as add-on therapy for patients who are in need of further blood pressure lowering above and beyond that afforded by diuretics or other antihypertensives. Nonetheless, they have demonstrated their efficacy in select patient populations as very effective blood pressure lowering agents. 

This indoline derivative has antihypertensive and diuretic actions. Indapamide (233) in methanol under nitrogen was irradiated with a medium-pressure mercury lamp through a copper sulphate filter solution for 12 h. The filter removed wavelengths below 300 nm. Products were separated by preparative TLC and identified as 2-methylindoline (234), the formylhydrazide (235), the amide (237) and semicarbazide. The procedure was repeated under oxygen to give the above products plus the urethane (236), acid (238), ester (239) and TV-acetylanthranilic acid [146]. 

In face of the above discouraging results, recent innovative catalyst work has led to highly effective solutions for some otherwise very difficult and expensive problems. For example. Dolling and co-workers (Chapter 7) have shown that by careful choice of PTC catalyst and use of optimal reaction conditions one can obtain high chiral selectivity (greater than 90% enantiomeric excess) and have applied this chemistry to a commercial process for production of the diuretic drug candidate Indacrinone. 

The mechanism of action of this kappa mediated neuroprotective effect is under investigation. In addition to the diuretic effects mentioned above, it has been shown that CI-977 (11) is inactive in a model of focal brain ischaemia in Brattleboro rats which lack vasopressin and do not exhibit kappa-mediated water diureses [33c]. An alternative mechanism for which there is increasing evidence is an inhibition of excitatory amino-acid release. U-50488 (5) and PD 117302 (12) have been shown to block convulsions in-... 

Since the major part of this section was written, evidence has been published [326a] demonstrating that the above diuretics are possibly even more diabetogenic than the thiazides (judged by inhibition of C-labelled glucose utilization in adipose tissue), with a mechanism of action probably similar to that of the earlier drugs. This work seems more enlightening on this controversial point than any hitherto presented. 

There are a number of extremely important thiazide diuretics not listed above. These widely used drugs include hydroflumethiazid, trichlormethiazide, methylcyclothiazide, cyclothiazide, benzothiazide, diazoxide, and others, whose methods of synthesis and pharmacological action are practically identical to those listed above. 

Maintenance dosage - 20 to 40 mg/day as a single dose or 2 divided doses. A dose of 80 mg gives an increased response, but experience is limited. Total daily doses above 80 mg have not been evaluated. If blood pressure is not controlled with benazepril alone, add a diuretic. 

Use in concomitant diuretics - If BP is not adequately controlled with perindopril alone, a diuretic may be added. In patients currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of perindopril. To reduce likelihood of such reaction, the diuretic should, if possible, be discontinued 2 to 3 days prior to beginning perindopril therapy. Then, if BP is not controlled with perindopril alone, resume the diuretic. If the diuretic cannot be discontinued, use an initial dose of 2 to 4 mg daily in 1 or 2 divided doses with careful medical supervision for several hours and until BP has stabilized. Titrate the dosage as described above. 

In summary, black hypertensive patients respond well to thiazide diuretics, CCB, vasodilators like prazosin, doxazosin or the vasodilating /3-blocker la-betalol. It is suggested that in black hypertensive patients a thiazide diuretic should be routinely added when a /3-blocker or an ACE inhibitor is used. This above information is summarized in Table 10. 

During the peak effect of the loop diuretics, urine flow is greatly augmented, as is the excretion of Na+ and Cl, corresponding to as much as 20 to 30% of their filtered load. K+ loss also occurs as an indirect effect of the large Na+ load reaching the distal tubules and is 2 to 5 times above normal levels of excretion. With low or moderately effective doses, these drugs do not appreciably affect HCOj" or excretion. 

Hypertension (monotherapy) PO Initially, 5-lOmg/day. Range 20-40 mg/day. Hypertension (combination therapy) PO Discontinue diuretic 2-3 days prior to initiating benazepril, then dose as noted above. If unable to discontinue diuretic, begin benazepril at 5 mg/day. 

Because CBZ can cause hyponatremia, it should be used cautiously in patients on a salt-restricted diet ( 373). Hyponatremia is rarely clinically significant when sodium values are above 125 mmol/L. Low sodium levels, as well as concomitant diuretic and lithium users, may predispose to the development of the syndrome of inappropriate ADH. Since CBZ enhances the effects of ADH, it can lead to impairment of free water clearance from the body. Older patients are at higher risk and should be closely monitored for this adverse effect which can be managed by dose reduction of CBZ. More severe cases, however, usually require switching to... 

Figure 12.4 Mechanism of action of Na+/K+symport inhibitors (thiazides) on the distal convoluted tubule. As in the other parts of the nephron, Na+movement is powered by the energy-requiring sodium pump (P) in the basolateral membrane which exchanges intracellular Na+for K-i-in the extracellular fluid (ECF). The transport of Na-rand Cl- into the cell from the filtrate against the prevailing electrochemical gradient is facilitated by the symporter (S). The Na-Hons are then transported by the pump mechanism described above and the Cl- ions diffuse passively Into the ECF through ion channels in the basolateral membrane. Thiazide diuretics inhibit the symporter by disabling the Cl- binding site with the loss of Na-rand Cl- in the urine.

Many glomerular diseases, such as those associated with diabetes mellitus or systemic lupus erythematosus, exhibit renal retention of salt and water. The cause of this sodium retention is not precisely known, but it probably involves disordered regulation of the renal microcirculation and tubular function through release of vasoconstrictors, prostaglandins, cytokines, and other mediators. When edema or hypertension develops in these patients, diuretic therapy can be very effective. If heart failure is also present, see the warnings mentioned above. 

Other drugs of lesser therapeutic importance can be classified into a series of minor classes including the antifungals, -adrenergic agonists, corticosteroids, diuretics, dyes, nonsteroidal anti-inflammatories, sedatives and -blockers, and thyreostatics. It is important to note that some drugs within the classes mentioned have dual function and can properly be classified in more than one of the above classes. As a result, overlap between drug classes is not unusual. 

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