Thiazide diuretics diazoxide

The thiazide diuretics possess antihypertensive properties, in part consequent upon electrolyte and plasma-volume changes but mainly resulting from a direct cardiovascular depressant effect. This is clearly illustrated by the non-diuretic thiazide, diazoxide, which is an effective hypotensive [326b, c]. It is not therefore, surprising that both these properties should be found (in varying proportions) in other, structurally related, compounds. One particular line of research, aimed at modification of the thiazide heterocycle (the o-chlorobenzenesulphonamide moiety was untouched as it was believed essential to activity-the subsequent advent of ethacrynic acid questions this belieO examined first the corresponding... 

The electronic structures of hydrochlorothiazide 146 and related substances have been determined by the complete neglect of differential overlap (CNDO/2) method (83AF688). The calculation confirms that the diuretic thiazides are electron-accepting, whereas diazoxide 147, a non-... 

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. 

Cardiovascular Acetyldigosin, ajmaline, amiodarone, aprindine, bepridil, bezaflbrate, captopril, dinepazide, clopidogrel, coumarins, diazoxide, digoxin, dipyridamole, disopyramide, doxazosin, enalapril, flurbiprofen, fur-oxemide, hydralazine, lisinopril methyldopa, metolazone, nifedipine, phenindione, procainamide, propanolol, propafenone, quinidine, ramapril, spironolactone, thiazide diuretics, ticlopidine, vesnarinone... 

Diazoxide (Hyperstat) is chemically similar to the thiazide diuretics. It is devoid of diuretic activity and causes Na and water retention. Diazoxide is a very potent vasodilator and is available only for intravenous... 

Diazoxide is similar chemically to the thiazide diuretics but has no diuretic activity. It is bound extensively to serum albumin and to vascular tissue. Diazoxide is partially metabolized its metabolic pathways are not well characterized. The remainder is excreted unchanged. Its half-life is approximately 24 hours, but the relationship between blood concentration and hypotensive action is not well established. The blood pressure-lowering effect after a rapid injection is established within 5 minutes and lasts for 4-12 hours. 

In contrast to the structurally related thiazide diuretics, diazoxide causes renal salt and water retention. However, because the drug is used for short periods only, this is rarely a problem. 

The peripheral receptors activated by noradrenaline fall into at least two classes, a-receptors and /3-receptors, which differ in their function and in their response to drugs. The a-receptors cause constriction of blood vessels and compounds used to block them include indoramin (216), prazosin (217) and phentolamine (218). Another imidazoline, tolazoline (2-benzyl-2-imidazoline), is a useful vasodilator but is unsuitable for the treatment of hypertension since it stimulates the heart. Other drugs described as peripheral vasodilators are diazoxide (219), which is related to the thiazide diuretics, hydralazine (220) which also depresses the CNS, hydracarbazine (221) and minoxidil (222). The /3-receptors control the action of adrenaline on the heart (among other effects) and the agents that block them are mostly nonheterocyclic aromatic compounds with aminoethanol or 3-amino-2-hydroxypropoxy side-chains. They have proved effective in the treatment of hypertension. One heterocyclic compound of this class, timolol (223), is in use. 

Diazoxide is chemically a thiazide but has no appreciable diuretic effect indeed, like other potent arterial vasodilators it causes salt and water retention. It reduces peripheral arteriolar resistance through activation of the ATP-dependent potassium channel (c.f. nicorandil and minoxidil), with little effect on veins. The t) is 36 h. 

Diazoxide (see p. 470) is chemically similar to thiazide diuretics, but stimulates the ATP dependent K ... 

Desmopressin replacement therapy is the first choice. Thiazide diuretics (and chlortalidone) also have paradoxical antidiuretic effect in diabetes insipidus. That this is not due to sodium depletion is suggested by the fact that the nondiuretic thiazide, diazoxide (see Index), also has this effect. It is probable that changes in the proximal renal tubule result in increased reabsorption and in delivery of less sodium and water to the distal tubule, but the mechanism remains incompletely elucidated. Some cases of the nephrogenic form, which is not helped by antidiuretic hormone, may be benefited by a thiazide. 

Diazoxide is a potent vasodilator chemically resembling the thiazides, but it is not a diuretic. Diazoxide can be administered both parenterally and orally. Caution has been stressed when diazoxide is administered as an intravenous bolus into the pulmonary artery because the solution is highly alkaline (pH 11.6) and irritating to vascular tissue (Cotter and Honey, 1980). In one study with chronic oral diazoxide administration (300-600 mg/day), five of seven patients had important side effects including diabetes mellitus, fluid retention, nausea, vomiting, and postural hypertension that required discontinuation of the drug (Wise, 1983). 

Thiazide diuretics may diminish the effects of anticoagulants, uricosuric agents used to treat gout, sulfonylureas, and insulin and increase the effects of anesthetics, diazoxide, cardiac glycosides, hthium, loop diuretics, and vitamin D. The effectiveness of thiazide diuretics may be reduced by NSAlDs and bile acid sequestrants (reduced absorption of thiazides). Amphotericin B and corticosteroids increase the risk of hypokalemia induced by thiazide diuretics. 

Another example of how new chemical entities can be derived from compounds with unrelated biological effects is that of the development of the potassium channel agonist diazoxide (Fig. 2.29). This compound was developed as a result of the observation that the thiazide diuretics, such as chlorothiazide, not only had a diuretic component, because of inhibition of sodium absorption in the distal convoluted tubule, but also a direct effect on the renal vasculature. Structural modification to enhance this direct effect led to the development of diazoxide and related potassium channel agonists for the treatment of hypertension (see Chapter 29). 

The hypotensive, hyperglycaemic and hyperuricaemic effects of diazoxide are increased by the concurrent use of thiazide diuretics (105 ). 

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