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diuretics_thiazides

Thiazide diuretics

Introduction

  • Benzothiadiazides were synthesised in attempt to enhance potency of carbonic anhydrase inhibitors but an unanticipated chemical reaction led to substances that increased chloride excretion & thus had a different effect to carbonic anhydrase inhibitors although many have mild non-clinical carbonic anhydrase inhibitors effects
  • Chlorothiazide was the 1st diuretic to seriously challenge the mercurials that had dominated diuretics for 30yrs prior;
  • Like many other organic acids, thiazides are actively secreted in proximal tubule & this is inhibited by Probenecid which seems to inhibit their diuretic effect

Diuretic mechanism

  • Site of action is at early distal tubule where they block electroneutral Na-Cl co-transport resulting in a modest increase in Na excretion (NB. 90% Na already reabsorbed!).
  • the increase in distal tubular sodium concentration stimulates the aldosterone-sensitive sodium pump to increase sodium reabsorption in exchange for potassium and hydrogen ion, which are lost to the urine and which may cause hypokalaemia, metabolic alkalosis and a more acid urine.
  • their mechanism depends on renal prostaglandin production
  • In addition:
    • may decrease GFR via direct renal vasc. effect esp. if IV or decreased renal reserve;
    • increased plasma [urate]: increase prox. tub. reabsorption due to increase fluid reabsorption as decrease ECFV;
    • decreased tubular secretion urate?
    • decreased Ca excretion direct effect on early distal tubule - may help reduce urolithiasis and osteoporosis
    • increased P excretion?
    • increased Mg excretion
    • increased Cl, I, Br excretion;
    • increased plasma serum ammonia levels if cirrhosis
    • hyperglycaemia due to decreased insulin secretion response, increased glycogenolysis and decreased glycogenesis;
    • increased plasma [cholesterol] & [TG's];

Contra-indications

Chlorothiazide:

  • the effect on lowering BP is dose related and usually amounts to a reduction of around 11mmHg systolic and 5mmHg diastolic at maximum dose of 50mg/day

P/K:

  • only 10% absorbed GIT → diuretic effect within 1hr, T1/2 = 1.5hrs, duration 6-12hrs;
  • renal excreted & metabolised → enterohepatic circulation;

OD:

  • clinical toxicity rare but large short-term doses:
  • decreased CNS function;
diuretics_thiazides.txt · Last modified: 2019/06/27 16:47 (external edit)