A Textbook of Clinical Pharmacology and Therapeutics

Drug interactions

Intravenousverapamilcan cause circulatory collapse in patients
treated concomitantly with β-adrenoceptor antagonists.

D DRUGS

DIURETICS

For more information, see Chapters 31 and 36.

Use in hypertension

A low dose of a thiazide, or related diuretic, e.g. chlortalidone,
remains the best first choice for treating older patients and Afro-
Caribbeans with uncomplicated mild essential hypertension,
unless contraindicated by some co-existent disease (e.g. gout).
They are also essential in more severe cases, combined with
other drugs. Diuretics reduced the risk of stroke in several large
clinical trials and in the Medical Research Council (MRC)
trial they did so significantly more effectively than did beta-
blockade.Chlortalidoneperformed at least as well as amlodip-
ineandlisinoprilin ALLHAT and thiazides are much less
expensive than all other antihypertensive drugs. The
dose–response curve of diuretics on blood pressure is remark-
ably flat. However, adverse metabolic effects (see below) are
dose related, so increasing the dose is seldom appropriate.
Thiazides (e.g. bendroflumethiazide) are preferred to loop
diuretics for uncomplicated essential hypertension. They are
given by mouth as a single morning dose. They begin to
act within one to two hours and work for 12–24 hours. Loop
diuretics are useful in hypertensive patients with moderate or
severe renal impairment, and in patients with hypertensive
heart failure.

Mechanism of action

Thiazide diuretics inhibit reabsorption of sodium and chloride
ions in the proximal part of the distal convoluted tubule.
Excessive salt intake or a low glomerular filtration rate interferes
with their antihypertensive effect. Natriuresis is therefore prob-
ably important in determining their hypotensive action.
However, it is not the whole story since although plasma
volume falls when treatment is started, it returns to normal
with continued treatment, despite a persistent effect on blood
pressure. During chronic treatment, total peripheral vascular
resistance falls slowly, suggesting an action on resistance
vessels. Responsiveness to pressors (including angiotensin II
andnoradrenaline) is reduced during chronic treatment with
thiazides.

Adverse effects

• Metabolic and electrolyte changes involve:
  
  
  • hyponatraemia – sometimes severe, especially in the
    elderly;
    
    
    • hypokalaemia – kaliuretis is a consequence of increased
      sodium ion delivery to the distal nephron where
      sodium and potassium ions are exchanged. Mild
      hypokalaemia is common but seldom clinically
      important in uncomplicated hypertension;
    
    
    • hypomagnesaemia;
    
    
    • hyperuricaemia – most diuretics reduce urate
      clearance, increase plasma urate and can precipitate
      gout;
    
    
    • hyperglycaemia – thiazides reduce glucose
      tolerance: high doses cause hyperglycaemia in
      type 2 diabetes;
    
    
    • hypercalcaemia – thiazides reduce urinary calcium ion
      clearance (unlike loop diuretics, which increase it) and
      can aggravate hypercalcaemia in hypertensive patients
      with hyperparathyroidism;
    
    
    • hypercholesterolaemia – high-dose thiazides cause
      a small increase in plasma LDL cholesterol
      concentration.
    
    
    
    
  
  
  
  


• Erectile dysfunction which is reversible on stopping
  the drug.


• Increased plasma renin, limiting the antihypertensive
  effect.


• Idiosyncratic reactions, including rashes (which may be
  photosensitive) and purpura, which may be
  thrombocytopenic or non-thrombocytopenic.

Contraindications

The effects of thiazide diuretics described above contraindi-

cate their use in patients with severe renal impairment (in

whom they are unlikely to be effective), and in patients with a

history of gout. They should not be used in pre-eclampsia,

which is associated with a contracted intravascular volume.

Diuretics should be avoided in men with prostatic symptoms.

It is prudent to discontinue diuretics temporarily in patients

who develop intercurrent diarrhoea and/or vomiting, to

avoid exacerbating fluid depletion.

Drug interactions

In addition to the non-specific adverse interaction with NSAIDs

(see above and Chapter 26), all diuretics interact with lithium.

Liis similar to Nain many respects, and is reabsorbed

mainly in the proximal convoluted tubule (Chapter 20).

Diuretics indirectly increase Lireabsorption in the proximal

tubule, by causing volume contraction. This results in an

increased plasma concentration of Liand increased toxicity.

Diuretic-induced hypokalaemia and hypomagnesaemia

increase the toxicity of digoxin (Chapters 31 and 32). Com-

binations of a thiazide with a potassium-sparing diuretic, such

asamiloride(co-amilozide),triamtereneorspironolactone

can prevent undue hypokalaemia, and are especially useful in

patients who require simultaneous treatment with digoxin,

sotalol(Chapter 32) or other drugs that prolong the electro-

cardiographic QT-interval.

192 HYPERTENSION