(See also Hypertension, Ch. 23)
Thiazides depress sodium reabsorption at site 3 which is just proximal to the region of sodium-potassium exchange. These drugs thus raise potassium excretion to an important extent. Thiazides lower blood pressure, initially due to reduction in intravascular volume but chronically by a reduction in peripheral vascular resistance. The latter is accompanied by diminished responsiveness of vascular smooth muscle to noradrenaline (norepinephrine); they may also have a direct action on vascular smooth muscle membranes, acting on an as yet unidentified ion channel.
Uses. Thiazides are used for mild cardiac failure, and mild hypertension, or for more severe degrees of hypertension, in combination with other drugs.
Pharmacokinetics. Thiazides are generally well absorbed when taken by mouth and most begin to act within an hour. There are numerous derivatives and differences amongst them lie principally in their duration of action. The relatively water soluble, e.g. cyclopenthiazide, chlorothiazide, hydrochlorothiazide, are most rapidly eliminated, their peak effect occurring within 4-6 h and passing off by 10-12 h. They are excreted unchanged in the urine and active secretion by the proximal renal tubule contributes to their high renal clearance and t'/2 of < 4 h. The relatively lipid-soluble members of the group, e.g. polythiazide, hydroflumethiazide, distribute more widely into body tissues and act for over 24 h, which can be objectionable if the drug is used for diuresis, though useful for hypertension. With the exception of metolazone, thiazides are not effective when renal function is moderately impaired, because they are not filtered in sufficient concentration to inhibit the NCCT.
Adverse effects in general are discussed below. Rashes (sometimes photosensitive), thrombocytopenia and agranulocytosis occur. Treatment with thiazide-type drugs causes an increase in total serum cholesterol, but on long-term usage even of high doses this is less than 5%. The questions about the appropriateness of use of these drugs for mild hypertension, of which ischaemic heart disease is a common complication, have been laid to rest by their proven success rates in randomised outcome comparisons.
Bendrofluazide (bendroflumethiazide) is a satisfactory member for routine use.
• For a diuretic effect the oral dose is 5-10 mg which usually lasts less than 12 h so that it should be given in the morning. It may be given daily for the first few days then, say, 3 days a week.
• As an antihypertensive 1.25-2.5 mg is given daily; in the absence of a diuresis clinically important potassium depletion is uncommon, but plasma potassium concentration should be checked in potentially vulnerable groups such as the elderly (see Ch. 24).
Hydrochlorothiazide is a satisfactory alternative. Other members of the group include: benzthiazide, chlorothiazide, cyclopenthiazide, hydroflumethiazide, polythiazide.
Diuretics related to the thiazides. Several compounds, although strictly not thiazides, share structural similarities with them and probably act at the same site on the nephron; they therefore exhibit moderate therapeutic efficacy. Overall, these substances have a longer duration of action, are used for oedema and hypertension and their profile of adverse effects is similar to that of the thiazides. They are listed below.
Chlortalidone acts for 48-72 h after a single oral dose.
lndapamide is structurally related to chlortalidone but lowers blood pressure at subdiuretic doses, perhaps by altering calcium flux in vascular smooth muscle. It has less apparent effect on potassium, glucose or uric acid excretion (see below).
Metolazone is effective when renal function is impaired. It potentiates the diuresis produced by frusemide and the combination can be effective in resistant oedema, provided the patient's fluid and electrolyte loss are carefully monitored.
Xipamide is structurally related to chlortalidone and to frusemide. It induces a diuresis for about 12 h that is brisker than with thiazides, which may trouble the elderly.
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