PART-II-DIURETICS

DIURETICS-Contd...

3.Benzothiazide Diuretics

Chemistry

These agents in the chemical structure having a thiazide moiety and benzene ring with various substitutions at the benzene ring at the 6th position. Chlorothiazide is the prototype of these groups with a chloride ion attached to the benzene ring in the 6th position. All thiazide compounds are having an unsubstituted sulphonamide group attached to the benzene ring in the 7th position.

The other drugs in this group included are hydrochlorothiazide,chlorothalidone indapamide,and quinethiazide and cyclothiazide.All are having a sulpha moiety and an aniline ring.

In hydrochlorothiazide, the 3 and 4 double are saturated with hydrogen ions and this may increase the activity. Hence hydrochlorothiazide exhibits better action than chlorothiazide.

Introducing an alkyl group at position 2, or 3 may increase the lipid solubility and thereby enhance better distribution in the body volume and effect.

Replacing the sulfonyl group at 1st position with a carbonyl group may enhance the activity as with quinethazone.

Indapamide and Chlorothalidone have diuretic effects similar to chlorothiazide.

In general, these sulpha compounds structurally related to carbonic anhydrase inhibitors but with different pharmacodynamics.

Pharmacology

The major pharmacological actions of these drugs in the early segment of the DCT through sodium is reabsorbed. These drugs inhibit reabsorption. The reabsorption is blocked by inhibiting sodium and chloride ion cotransporter.

The effects are moderate only as when the filtrate passes through the ascending LH most of the sodium ion is reabsorbed before it reaches DCT. 

Therapeutic Uses

1.Hypertension

2.Edema(Chronic)

3.As an adjunct to minimize edema in the treatment of CHF.

4.Nephrosis

5.Hypercalciuria(Formation of calcium stones)

6.Diabetes Insipidus(Nephrogenic) 

Side Effects

1.Headache, dizziness, paresthesias, drowsiness, and other CNS effects.

2.G.I.Distress

3.Postural hypotension

4.Venous thrombosis.

5.Blood dyscrasias

6.Leucopenia

7.Thrombocytopenia

8.Agranulocytosis

9.Aplastic and hemolytic anemia

10.Allergic rashes.

11.Hypokalemia

12.Hypercalcemia

13. Hyperuricemia leads to acute gout attacks.

14.Muscle cramps

15. Lipid dyscrasias such as elevated blood cholesterol and triglycerides.

4.LOOP DIURETICS

Loop diuretics are drugs that mainly act on the thick ascending loop of Henle through which a large chunk of sodium (nearly 35 to 45%) along with potassium, chloride, and water is reabsorbed and by blocking this which cannot be compensated by the following DCT and collecting duct these drugs cause effective diuresis but with a short duration.

The known prototype of these groups is Furosemide (Lasix), Bumetanide, and Ethacrynic acid are other compounds in this group.

Loop diuretics, unlike thiazide diuretics, causes increased calcium excretion

Chemistry

These are anthranilic acid derivative with a sulphonamide moiety with the exception of ethacrynic acid which is an aryloxy acetic acid without a sulphonamide group and hence it is suitable for those who are allergic to sulfites.

Therapeutic Indications

1.Pulmonary, and cardiac edemas due to hepatic cirrhosis and kidney failure.

2.Ascites-Abnormal collection of fluids over 25ml.in the stomach (peritoneal) cavity.

3.Acute hypercalcemia

4.Acute hyperkalemia

5.Kidney failure(Acute)

Route of Administration

1.By Oral 

2.By I.V.

Side Effects

1.Volume depletion in the blood

2.Potassium depletion (Hypokalemia)

3. Calcium depletion (Hypocalcemia), hypercalciuria leads to the formation of calcium stones.

4.Azotemia (High nitrogen wastes in the blood)

5.Dehydration

6.The elevated uric acid level in the blood

CNS effects are similar to thiazides.

7. Sulpha allergies.

8.Metabolic alkalosis

9.Interstitial nephritis.

5.POTASSIUM SPARING DIURETICS

This is based on all diuretics that are generally excreting potassium also which leads to heavy potassium loss from our body. Potassium depletion will produce serious cardiologic effects such as tachycardias and arrhythmias.

Chemistry

These are pteridine or pyrazine derivatives(Triamterene, amiloride) and steroidal derivatives of aldosterone antagonists (spironolactone)

Pharmacology

Spironolactone because of the structural similarity competitively inhibits the aldosterone receptors and thereby prevents potassium excretion through the DCT and collecting duct.

Triamterene and amiloride they without touching aldosterone receptors directly acting on the DCT and collecting duct by blocking the sodium, potassium, and hydrogen channels and thereby prevent the sodium reabsorption for potassium.

These drugs cause urine more alkaline by excreting bicarbonate ions.

These drugs are very weak and can be used only in conjunction with other diuretics.

Therapeutic Uses

1. Spironolactone is primarily used to block overactivity of aldosterone (Conn's Syndrome)

2.Edematous states due to secondary aldosteronism,

such as cardiac failure, liver cirrhosis, nephrosis, etc.

3.Hypokalemia

Side Effects

A.With Spironolactone

1.Hyperkalemia

2.G.I.Distress

3.Endocrine and steroidal effects such as gynecomastia, menstrual defects, and hair growth in women (Hirsutism)

4.CNS effects.

B.With Triamterene and Amiloride

Similar to the above except the steroidal effects.