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Thiazide Diuretics

Thiazide diuretics are also known as NaCl symporter inhibitors.

Thiazide diuretics act on the distal convoluted tubule. They were discovered accidentally when people were trying to increase the carbonic anhydrase property. They found compounds which instead of increasing NaHCO3 secretion increase NaCl excretion. The name thiazide diuretics was coined for these compounds.

 Chemistry

These are chemically sulphonamides and produce allergic manifestations.

As they act on luminal side, they reach the site of action through tubular secretion.

Pharmacokinetics

They are absorbed orally. Hydrochlorothiazide is the prototypical drug. Among others, Chlorothiazide can be given in large doses.

Chlorothiazide is slowly absorbed. Duration is 24-74 hours.

Metalazone is metabolized in liver, but enough drug reaches the kidneys in unchanged form.

Opposite to loop diuretics, these are given in a single dose. This is one reason why they are preferred in hypertension.

Duration Of Diuretic Action Of Thiazides

  Drug Oral Dose(mg/day) Duration(Hours)
Short Acting ChlorothiazideHydrochlorothiazideHydroflumethiazide

Benzofluazide

Cyclopenthiazide

500 – 200025 – 10025 – 200

2.5 – 15

0.5 – 1

6-12“   ““   “

“   “

“   “

Intermediate Acting MetolazoneCyclothiazideQuinethazone

Methyclothiazide

Trichlormethiazide

2.5 – 201 – 250 – 200

25 – 5

1 – 4

12 – 2418 – 2418 – 24

24 ———

“       “

Long Acting IndapamidePolythiazideChlor – Thalidone 2.5 – 51 – 425 – 200 24 – 3624 – 4824 – 74
Mechanism of Action

1. Site of action is distal convoluted tubule.

2. Reach the site of action by active tubular secretion

3. Normal physiology

Distal convoluted tubule is responsible for reabsorption of 8-10% NaCl, and is relatively impermeable to water. Thus dilution of urine occurs here.

4. Ionic Changes

Thiazide diuretics block NaCl pump on luminal side. As Na+K+ pump is working overtime, relative deficiency of Na+ occurs; this stimulates the Na+ Ca++ exchanger. Na+ moves in while Ca++ moves out, leading to deficiency of Ca++, but is reabsorbed under control of PTH.

Greater the load of Na+ entering the tubules, greater is K+, Cl- and H+ loss. Also Mg++ depletion occurs by some unknown mechanism.

Hypocalcemia does not occur, sometimes hypercalcemia might occur by:

After some time, volume depletion occurs leading to increased Ca++ reabsorption at proximal tubule.

5. Hemodynamic Changes

a. As thiazide diuretics are responsible for prostaglandin stimulation, they produce vasodilatation independent of diuretic effect.
b. Sodium is itself responsible for stiffness of blood vessels and increased neural activity of blood vessels. After 6-8 week therapy, sodium depletion occurs leading to decreased calcium, which helps in producing vasodilatation.

Clinical Indications

1. Hypertension

Thiazide diuretics are the most preferred in hypertension because:

  1. Once daily dose
  2. Are active as antihypertensives in low doses (hydrochlorothiazide 25mg once daily)
  3. PG mediated vasodilatation
  4. Contributed after 6-8 weeks by sodium depletion
  5. Action of diuretic (decreased blood volume and cardiac output) is blunted after some time (tolerance) but vasodilatation remains.
  6. Various studies show that these are as effective as the beta blockers or angiotensin converting enzyme inhibitors
  7. Are cost effective

Therefore, thiazide diuretics should be used as the 1st line of defense. They are also used in combination with others. As pseudo tolerance develops, they are combined with beta blockers, ACE inhibitors, vasodilators (hydrillazine) and other diuretics.

2. Congestive Heart Failure

When heart is failing, kidneys perceive hypovolemia, and stimulate renin-angiotensin-aldosterone mechanism. Although this is helpful but in the long term, causes extra load on heart, which goes into perpetual failure.

Loop diuretics are preferred as they increase the efficacy of sodium and water elimination mechanisms. Thiazide diuretics may be combined for long term management. Also ACE inhibitors may be used.

In acute left ventricular failure, loop diuretics are used because they:

  1. increase diuresis
  2. decrease pulmonary congestion
3. Nephrolithiasis –idiopathic hypercalciuria

Most of the stones in the kidney are calcium phosphate. Because diuretics lead to increased calcium reabsorption from nephron, calcium excretion in urine is decreased. Thus precipitation of calcium within kidneys is reduced. Thus these are helpful in reducing stone formation.

4. Diabetes insipidus

It occurs in two forms:

  1. Neurogenic –decreased ADH, increased dilute urine formation
  2. Nehprogenic –ADH is present but kidneys are not responding

Copious amounts of urine is produced, up to 20 liters/day. Specific gravity is less than 1.006.

Thiazide diuretics when given, after some time produce volume depletion, leading to decreased GFR and increased reabsorption of fluid in PCT. Less fluid enters the distal segment. Thus urine volume may be reduced by 50%.

5. Bromide intoxication

Bromide ion is excreted and reabsorbed similar to Cl-. In intoxication, increased excretion occurs like Cl-.

Side Effects

1. Hypokalemic Metabolic Alkalosis

Greater entry of sodium in collecting tubules leads to greater loss of water and sodium.

2. Hypochloremia
3. Hypomagnesemia

4. Hyponatremia

May be worsened when increased loss occurs with ADH increased. Because of loss of sodium thirst occurs and person drinks more water which adds to hyponatremia.

5. Hyperglycemia and hyperlipidemia

Increased total cholesterol, triglycerides, low density lipids, this can be partially reversed if hypokalemia is adjusted.

6. Blockage of release of insulin from pancreas
7.Decreased peripheral utilization

8. Hyperuricemia

Due to competitive inhibition in S2.

9. Allergic Reactions

Due to sulphonamide nature.

10. Other toxicities
  1. Weakness –due to K+ loss
  2. Paresthesias
  3. Fatigue
  4. Impotence

Which are carbonic anhydrase inhibitors like properties

K+ has a narrow normal range (3.5-5.5 mg/dl), which should be kept in mind when using diuretics. If hypokalemia is present, it must be corrected by K+ supplements given orally. KCl can be injected I/V if critical condition arises, 25 ml of which are diluted up to 500 ml. It is given slowly, otherwise instantaneous death might occur.

Caution:
  1. Cirrhosis –diuretics are used with caution, in case of overzealous treatment, problems might arise
  2. CHF –if venous return decreases, CHF may aggravate
  3. Renal –if blood flow is compromised, it is detrimental to renal functions
Interactions

With diuretics, loop and thiazide diuretics show synergism and potentiate each other’s effects.

Because thiazide diuretics produce hypokalemia, they are combined with K+ sparing diuretics.

Continue Reading

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