Thiazide diuretics

see also:

• diuretics
• gout
• hypertension

• 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

• 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 / renal stones / renal calculi 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;
    • ? via hypokalaemia → insulin decreased;
  • increased plasma [cholesterol] & [TG's];

• hypotension
• allergy to sulfur-containing medications
• gout
• hypokalaemia
• renal failure
• lithium carbonate therapy
• may worsen diabetes mellitus
• hepatic encephalopathy as increases ammonia levels
• pregnancy - can decrease placental perfusion and adversely affect the fetus
• lactation - pass into breast milk, and can decrease the flow of breast milk

• 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

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

• clinical toxicity rare but large short-term doses:
• decreased CNS function;