Q:1. Why loop diuretics are often called as high ceiling diuretics?
Ans: They are often called as high ceiling diuretics because they are highly effective in inhibition of coupled transport of Na+/K+/2Cl- through luminal membrane of thick ascending limb of Henle’s loop as ascending limb results in reabsorption of 20-30 percent of NaCl which has already been filtered.
Q:2. Compare loop diuretics and thiazide diuretics.
Ans:
Differences between loop diuretics and thiazide diuretics:
1. Loop diuretics are more effective than thiazide diuretics.
2. The onset of action and duration of action of loop diuretics is shorter than the thiazide diuretics.
3. Loop diuretics show efficacy even in the presence of electrolyte and acid base disturbance unlike thiazide siuretics.
4. Loop diuretics are not good than thiazide diuretics against uncomplicated mild to moderate hypertension.
5. Loop diuretics increase renal blood flow whereas thiazide diuretics have the ability of lessening renal flow of blood.
6. Loop diuretics tend to increase Ca2+ in urine whereas thiazide diuretics cause a decrease in Ca2+ in urine.
Similarities between loop diuretics and thiazide diuretics:
1. They have almost identical side effects.
Monday, April 25, 2011
Loop diuretics
These diuretics act on the medullary and cortical (thick) ascending limb of Henle’s loop, although to some extent they also act on the proximal and distal tubules. They are more effective than thiazide diuretics.
Mechanism of action:
They inhibit Na+/K+/2Cl- symport on luminal membrane of thick ascending limb of Henle’s loop causes
a. Decreased reabsorption of NaCl
b. Lessen the normal lumen positive potential that derives from K+ recycling resulting in increased excretion of Mg2+ and Ca2+
They tend to decrease renal vascular resistance and resulting in increased renal blood flow.
They also promote prostaglandin synthesis. Prostaglandins also have some role as diuretic.
They produce large amount of urine.
1. Acute pulmonary edema of heart failure
2. Acute pulmonary edema (When given IV)
3. Impaired renal function
4. Hypercalcemia
They causes an increased tub ular Ca2+ excretion.
5. Hyperkalemia
6. Increased intracranial pressure
7. Diabetic nephropathy
8. Hypertensive situations
Pharmacokinetics:
They have short duration of action of approximately 2-4.5 hours. They are eliminated by glomerular filtration and tubular secretion. Their half life depends on the renal function. They are excreted through urine.
Adverse effects:
They have almost similar adverse effects as those of thiazide diuretics. But they may cause severe electrolytic imbalances and water depletion.
• Hypersensitivity reactions:
Skin rash, interstitial nephritis
• Water, electrolytes and acid-base balance:
Voiding of extra water, Hypercalcemia, hyponatremia, Hypomagnesemia,
Hypokalemic metabolic alkalosis:
More Na+ at the collecting tubule results in more K+ exchange with Na+ in the tubule. This results in hypokalemia.
More K+ loss results in more H+, resulting in hypokalemic alkalosis.
This can be reduced by the use of potassium sparing diuretics or potassium rich foods.
• Blood:
Transient granulocytopenia and thrombocytopenia
• Muscles:
Severe pain and tenderness in patients with renal failure
• Miscellaneous:
Ototoxicity:
Affect on hearing.
Hyperuricemia:
Blocks secretion of uric acid by competitively working at renal and biliary secretary systems. This results in gouty attacks.
Acute hypovolemia:
They cause a reduction in blood volume. This results in hypotension, shock and cardiac arrhythmias.
Contraindications:
It is contraindicated in patients with hepatic coma, hypokalemia, hypotension and hypersensitivity to sulfonamides.
Interaction:
Indomethacin interferes with the production of prostaglandin synthesis, so that is why causes some inhibitory effects on diuretic action of loop diuretics.
Mechanism of action:
They inhibit Na+/K+/2Cl- symport on luminal membrane of thick ascending limb of Henle’s loop causes
a. Decreased reabsorption of NaCl
b. Lessen the normal lumen positive potential that derives from K+ recycling resulting in increased excretion of Mg2+ and Ca2+
They also promote prostaglandin synthesis. Prostaglandins also have some role as diuretic.
Therapeutic uses:
They produce large amount of urine.
1. Acute pulmonary edema of heart failure
2. Acute pulmonary edema (When given IV)
3. Impaired renal function
4. Hypercalcemia
They causes an increased tub ular Ca2+ excretion.
5. Hyperkalemia
6. Increased intracranial pressure
7. Diabetic nephropathy
8. Hypertensive situations
Pharmacokinetics:
They have short duration of action of approximately 2-4.5 hours. They are eliminated by glomerular filtration and tubular secretion. Their half life depends on the renal function. They are excreted through urine.
Adverse effects:
They have almost similar adverse effects as those of thiazide diuretics. But they may cause severe electrolytic imbalances and water depletion.
• Hypersensitivity reactions:
Skin rash, interstitial nephritis
• Water, electrolytes and acid-base balance:
Voiding of extra water, Hypercalcemia, hyponatremia, Hypomagnesemia,
Hypokalemic metabolic alkalosis:
More Na+ at the collecting tubule results in more K+ exchange with Na+ in the tubule. This results in hypokalemia.
More K+ loss results in more H+, resulting in hypokalemic alkalosis.
This can be reduced by the use of potassium sparing diuretics or potassium rich foods.
• Blood:
Transient granulocytopenia and thrombocytopenia
• Muscles:
Severe pain and tenderness in patients with renal failure
• Miscellaneous:
Ototoxicity:
Affect on hearing.
Hyperuricemia:
Blocks secretion of uric acid by competitively working at renal and biliary secretary systems. This results in gouty attacks.
Acute hypovolemia:
They cause a reduction in blood volume. This results in hypotension, shock and cardiac arrhythmias.
Contraindications:
It is contraindicated in patients with hepatic coma, hypokalemia, hypotension and hypersensitivity to sulfonamides.
Interaction:
Indomethacin interferes with the production of prostaglandin synthesis, so that is why causes some inhibitory effects on diuretic action of loop diuretics.
Chlorothiazides
Chlorothiazed is the prototype of thiazide diuretics. This is used widely, orally effective and well tolerated.
They are effective in edema of hepatic cirrhosis and heart failure.
Pharmacokinetics:
Onset of action is 2 hours after oral administration and 10-15 minutes after IV administration. Its duration of action is about 4-12 hours.
They are effective in edema of hepatic cirrhosis and heart failure.
Pharmacokinetics:
Onset of action is 2 hours after oral administration and 10-15 minutes after IV administration. Its duration of action is about 4-12 hours.
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.
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:
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.
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:
Classification of Diuretics
Classification according to different groups:
Antidiuretic (ADH) hormone antagonists:
Lithium salts, demeclocycline, conivaptan
Carbonic anhydrase inhibitors:
Acetazolamide, Acetazolamide sodium
Loop (High ceiling) diuretics:
Bumetanide, Ethacrynic acid, Ethacrynate sodium, Furosemide, Torsemide, Umetanide, Piretanide
Mercurial diuretics:
Mercaptomerin, Calomel, Mercuhydrin, Meralluride, Mercumatilin, Mersalyl
Methylxanthine diuretics:
Aminophylline, Theobromine, caffeine, Theophylline, Oxtriphylline (A salt of theophylline)
Osmotic diuretics:
1. Osmotic electrolytes:
Sodium and potassium salts
2. Osmotic non-electrolytes:
Mannitol, Urea, Isosorbide, Sucrose, Glycerin
3. Acid-forming salts:
Ammonium chloride
Plant products:
Taraxacum, Cornsilk, Allium (Syn. Garlic), Buchu (dried leaves of Barosma betulina), Oleander, Turpentine oil
Potassium sparing diuretics:
Amiloride hydrochloride, Triamterene
Aldosterone antagonist:
Spironolactone, Aldadiene (A metabolite of apironolactone)
Thiazide diuretics:
Buthiazide, Chlorothiazide, Chlorthalidone, Hydrochlorothiazide, Indapamide, Metolazone, Cyclothiazide
Uracil derivatives:
Aminometramide
Miscellaneous diuretics:
Dextran, Ammonium benzoate, Dimethylpiperazine tartarate
Classification according to site of action:
Direct diuretics
1. Drugs acting on proximal tubule
Osmotic diuretics, Carbonic anhydrase inhibitors, Methylxanthine diuretics
2. Drugs acting on ascending limb of loop of henle
Loop (high ceiling) diuretics, Mercurial diuretics
3. Drugs acting on distal tubule
Thiazide diuretics
4. Drugs acting on collecting tubule
Potassium sparing diuretics, ADH antagonists, Aldosterone antagonists
Indirect diuretics
Cardiac diuretics
Antidiuretic (ADH) hormone antagonists:
Lithium salts, demeclocycline, conivaptan
Carbonic anhydrase inhibitors:
Acetazolamide, Acetazolamide sodium
Loop (High ceiling) diuretics:
Bumetanide, Ethacrynic acid, Ethacrynate sodium, Furosemide, Torsemide, Umetanide, Piretanide
Mercurial diuretics:
Mercaptomerin, Calomel, Mercuhydrin, Meralluride, Mercumatilin, Mersalyl
Methylxanthine diuretics:
Aminophylline, Theobromine, caffeine, Theophylline, Oxtriphylline (A salt of theophylline)
Osmotic diuretics:
1. Osmotic electrolytes:
Sodium and potassium salts
2. Osmotic non-electrolytes:
Mannitol, Urea, Isosorbide, Sucrose, Glycerin
3. Acid-forming salts:
Ammonium chloride
Plant products:
Taraxacum, Cornsilk, Allium (Syn. Garlic), Buchu (dried leaves of Barosma betulina), Oleander, Turpentine oil
Potassium sparing diuretics:
Amiloride hydrochloride, Triamterene
Aldosterone antagonist:
Spironolactone, Aldadiene (A metabolite of apironolactone)
Thiazide diuretics:
Buthiazide, Chlorothiazide, Chlorthalidone, Hydrochlorothiazide, Indapamide, Metolazone, Cyclothiazide
Uracil derivatives:
Aminometramide
Miscellaneous diuretics:
Dextran, Ammonium benzoate, Dimethylpiperazine tartarate
Classification according to site of action:
Direct diuretics
1. Drugs acting on proximal tubule
Osmotic diuretics, Carbonic anhydrase inhibitors, Methylxanthine diuretics
2. Drugs acting on ascending limb of loop of henle
Loop (high ceiling) diuretics, Mercurial diuretics
3. Drugs acting on distal tubule
Thiazide diuretics
4. Drugs acting on collecting tubule
Potassium sparing diuretics, ADH antagonists, Aldosterone antagonists
Indirect diuretics
Cardiac diuretics
Diuretics
Introduction:
Diuretics are the drugs that cause the increased outflow of urine.
General action of diuretics:
Many types of diuretics
1. Decrease that amount of fluid which is reabsorbed by the renal tubules, from where the fluid returns to the blood
2. Increase glomerular filtration
General uses of diuretics:
They are used to remove excess water from the body which may contain some salts, toxins and other accumulated waste products such as urea.
They have the ability of getting rid of excess fluid from the body which may cause edema, which contains an abnormal accumulation of fluid from serum resulting in some of the disease.
Diuretics are the drugs that cause the increased outflow of urine.
General action of diuretics:
Many types of diuretics
1. Decrease that amount of fluid which is reabsorbed by the renal tubules, from where the fluid returns to the blood
2. Increase glomerular filtration
General uses of diuretics:
They are used to remove excess water from the body which may contain some salts, toxins and other accumulated waste products such as urea.
They have the ability of getting rid of excess fluid from the body which may cause edema, which contains an abnormal accumulation of fluid from serum resulting in some of the disease.
Aprotinin
It is inhibitor of proteolytic enzymes.
It causes blockage of plasmin resulting in stoppage of bleeding.
It can cause inhibition of streptokinase.
It is used prophylactically for reducing blood loss around the time of operation. It is also used for hyperplasminaemia developed as a result of fibrinolytic drug overdosage.
It may start certain inflammatory conditions.
It causes blockage of plasmin resulting in stoppage of bleeding.
It can cause inhibition of streptokinase.
It is used prophylactically for reducing blood loss around the time of operation. It is also used for hyperplasminaemia developed as a result of fibrinolytic drug overdosage.
It may start certain inflammatory conditions.
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