Thiazides and related agents

They are developed in efforts to develop more potent carbonic anhydrase inhibitors. So, that is why they are structurally similar to the carbonic anhydrase inhibitors.

Mechanism of action:
1. They cause the inhibition of Na+/Cl- cotransporter reabsorption from luminal side of epithelial cells in
    a. early distal convoluted tubule and also
    b. in late proximal tubule but not to a lesser degree.

This causes an increase in the concentration of NaCl in the tubular fluid resulting in urinary excretion of sodium and water.
2. They also cause an increase in Ca2+ reabsorption in distal convoluted tubule that may be due to lowering of cell Na+.
3. They also increase excretion of chloride, potassium and to some extent bicarbonate ions.

The excretion of Na+ and Cl- result in a very hyperosmolar urine.

4. They also directly relax arteriolar smooth muscle and cause a decrease in peripheral vascular resistance, resulting in continued hypotensive effect.

The hypotensive effect is also attributed to the decreased sodium level and as a result in the reduction of plasma volume which leads to decreased cardiac output.

5. They also decrease glomerular filtration rate.
Thiazide diuretics interfere with the dilution of the urine but not with the concentration of the urine due to the site of action.

Therapeutic uses:
1. Mild to moderate cases of Hypertension:
Three to seven days of continued treatment leads to lower peripheral resistance resulting in the stabilization of blood pressure.

2. Congestive cardiac failure:
They have the ability of reducing plasma volume helping in mild to moderate heart failure.

3. Diabetic nephropathy

4. Edema which may be due to congestive heart failure, renal dysfunction or corticosteroid therapy

5. Nephrosis

6. Prevent the formation of calcium stones in hypercalciuric and normal calciuric patients. As thiazide diuretics have the ability of inhibiting urinary Ca2+ excretion

Pharmacokinetics:
They are effective orally. There half life is about 35-42 hours. They are excreted by the kidney by organic acid secretary system of proximal tubule.

Adverse effects:
1. Gastrointestinal
Gastric irritation, anorexia, nausea, vomiting, diarrhea, constipation

2. Central nervous system
Weakness, fatigability, dizziness, vertigo, headache

3. Hematological
Leukopenia, agronulocytosis, aplsatic anemia

4. Cardiovascular
Orthostatic hypotension can be caused by volume depletion.

5. Hypersensitivity
Generalized dermatitis, hemolytic anemia, photosensitivity, rash, purpura

6. Hypercalcemia

7. Hypokalemia
Decreased intravascular volume activates rennin angiotensin aldosterone system resulting in K+ loss with urine.

This potassium loss can be decreased by spironolactone which interferes with aldosterone action or by giving triamterene. This can also be done by in creasing the intake of citrus fruits and bananas which are rich in potassium.


8. Hyponatremia:
This can be decreased by less water intake and decreasing the dose of thiazide diuretics.


9. Muscle spasm.

10. Hyperglycemia:
This may be due to impaired release of insulin and the uptake of glucose by the tissues.

11. Hyperuricemia:
Thiazide diuretics decrease the amount of acid excretion from the organic acid excretory system resulting in increased uric acid in the serum. This results in the gouty attacks.

Contraindications:
It is contraindicated in patients who are hypersensitive to thiazide or sulfonamides. It is also contraindicated in anuria, healthy pregnant women and hepatic cirrhosis.

Precautions:
It should be used with caution in patients of renal disease, gout or diabetes. In patients of renal disease it may initiate azotemia.

Drug Interaction: