Companion 2nd Year MBBS :Diuretics

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Q)what are diuretics?

A)Drugs inducing a state of increased urine flow are called diuretics.

Q) Classify Diuretics

A) Refer image above

Q)Write a short note on Loop Diuretics / Write a short note on Furosemide

A)The site of action – Thick Asc. loop of Henle (TAScLH). 

Mechanism of action – Loop diuretics inhibit the cotransport of Na+/K+/2Cl in the luminal membrane in the thick medullary part of ascending limb of the loop of Henle where it reaches after being secreted by organic anion transporter in PCT. Therefore, the reabsorption of these ions is decreased.T he loop diuretics are the most efficacious of the diuretic drugs because the ascending limb accounts for the reabsorption of 25 to 30 percent of filtered NaCl. Na+/K+/2Clco-transporter inhibition resulting in retention of sodium, chloride ions, and water. 

Actions– (1)Increased urinary excretion of sodium,potassium,chloride,calcium and magnesium

             (2)loop diuretics cause decreased renal vascular resistance and transient increase in renal blood flow 

(3) Increase prostaglandin synthesis (4) volume of urine increases

(4) GFR remains the same due to compensatory mechanisms.

(5) Increased uric acid level as furosemide competes with its PCT excretion through organic anion transporter. 

Pharmacokinetics of Furosemide – (1)rapid oral absorption 

(2) bioavailability -60% 

(3) reduction in bioavailability in case of Congestive cardiac failure

(4) Low lipid solubility and high affinity to plasma proteins 

(5) Excreted unchanged by glomerular filtration and tubular secretion. 

(6) Plasma half-life – 1-2 hrs

 (7) Increase in plasma half-life in patients suffering from hepatic, renal insufficiency or with pulmonary edema

 (8) Loop diuretics are administered orally or parenterally

Uses -(1) loop diuretics are the drugs of choice for reducing the acute pulmonary edema of heart failure

(2) Used to treat edema arising from cardiac failure, hepatic or renal insufficiency, chronic renal failure 

(3) Used in cerebral edema alongside osmotic diuretics to lower intracranial pressure. 

(4) Hypertension 

(5) Hypercalcemia of malignancy

Adverse effects – 

Ototoxicity – Hearing can be affected adversely by the loop diuretics, particularly when used in conjunction with the aminoglycoside antibiotics. Permanent damage may result with continued treatment. Ethacrynic acid is the most likely to cause deafness. Vestibular function is less likely to be disturbed, but it, too, may be affected by combined treatment with the antibiotic.

Hyperuricemia – Furosemide and ethacrynic acid compete with uric acid for the renal and biliary secretory systems, thus blocking its secretion and, thereby, causing or exacerbating gouty attacks.

Acute hypovolemia –Loop diuretics can cause a severe and rapid reduction in blood volume, with the possibility of hypotension, shock, and cardiac arrhythmias. Hypercalcemia may occur under these conditions.

Potassium depletion –The heavy load of Na+presented to the collecting tubule results in an increased exchange of tubular Na+for Kwith the possibility of inducing hypokalemia. The loss of Kfrom cells in exchange for H+leads to hypokalemic alkalosis. Potassium depletion can be averted by use of potassium-sparing diuretics or dietary supplementation with K+.

Hypomagnesemia – A combination of chronic use of loop diuretics and low dietary intake of Mg2+can lead to hypomagnesemia, particularly in the elderly. This can be corrected by oral supplementation.

Q) Write a short note on Thiazide diuretics OR

Q) Give uses and adverse effects of Chlorothiazide  OR

Q) write mechanism of action, uses and adverse effects for Hydrochlorothiazide.

A)Thiazides are sulfonamides derivative diuretics and are most widely used of all diuretics. They are medium efficacy diuretics since 90% of the glomerular filtrate has already been absorbed in PCT before it reaches the early DCT.

The site of Action– Early DCT 

Mechanism of action– These drugs inhibit  Na+/Cl– co-transporter (glycoprotein) on the luminal membrane of the distal convoluted tubule. These drugs get excreted via the organic acid transporter located in the middle 1/3rd of the PCT.

[Note: Because the site of action of the thiazide derivatives is on the luminal membrane, these drugs must be excreted into the tubular lumen to be effective. Therefore, with decreased renal function, thiazide diuretics lose efficacy.]

Actions–

Increased excretion of Naand Cl: Chlorothiazide causes diuresis with increased Na+and Clexcretion, which can result in the excretion of very hyperosmolar urine. This latter effect is unique; the other diuretic classes are unlikely to produce hyperosmolar urine. The diuretic action is not affected by the acid-base status of the body, nor does chlorothiazide change the acid-base status of the blood.

Loss of K+: Because thiazides increase the Nain the filtrate arriving at the distal tubule, more K+is also exchanged for Na+, resulting in a continual loss of Kfrom the body with prolonged use of these drugs. Therefore, it is imperative to measure serum K+ to assure that hypokalemia does not develop during therapy.

Loss of Mg2+: Magnesium deficiency requiring supplementation can occur with chronic use of thiazide diuretics, particularly in the elderly. The mechanism for the magnesuria is not understood.

Decreased urinary calcium excretion: Thiazide diuretics decrease the Ca2+content of urine by promoting the reabsorption of Ca2+. This contrasts with the loop diuretics, which increase the Ca2+concentration of the urine. 

[Note: thiazides preserve bone mineral density at the hip and spine and that the risk for hip fracture is reduced by a third.]

Reduced peripheral vascular resistance:  An initial reduction in blood pressure results from a decrease in blood volume and, therefore, a decrease in cardiac output. Continued hypotensive effects, results from reduced peripheral vascular resistance caused by relaxation of arteriolar smooth muscle. 

Reduction in G.F.R 

Uses– 

1.Edema- used for maintenance therapy 

2. Hypertension -Thiazides have long been the mainstay of antihypertensive medication because they are inexpensive, convenient to administer, and well tolerated

                 They are effective in reducing systolic and diastolic blood pressure for extended periods in the majority of patients with mild to moderate essential hypertension. After 3 to 7 days of treatment, the blood pressure stabilizes at a lower level and can be maintained indefinitely by a daily-dosage level of the drug, which causes lower peripheral resistance without having a major diuretic effect

3)Diabetes insipidus – Thiazides have the unique ability to produce hyperosmolar urine. Thiazides can substitute for the antidiuretic hormone in the treatment of nephrogenic diabetes insipidus. The urine volume of such individuals may drop from 11 L/day to about 3 L/day when treated with the drug.

 4) Hypercalciuria –beneficial for patients with calcium oxalate stones in the urinary tract.

Adverse effects–

1)Potassium depletion/ Hypokalemia – is the most frequent problem encountered with the thiazide diuretics due to activation of the renin-angiotensin-aldosterone system by the decrease in intravascular volume which contributes significantly to urinary Klosses and it can predispose patients who are taking digitalis to ventricular arrhythmias. 

How to restore Klevels?

(1)supplementation by diets alone such as by increasing the intake of citrus fruits, bananas, and prunes.

(2) K+deficiency can be overcome by spironolactone (potassium-sparing diuretics) which interferes with aldosterone action/ by administering triamterene, which acts to retain K+.

 (3) Low sodium containing diet

2)Hyponatremia:  due to an elevation of ADH as a result of hypovolemia, as well as a diminished diluting capacity of the kidney and increased thirst. Limiting water intake and lowering the dose of diuretic can prevent this condition.

3)Hyperuricemia: Thiazides increase serum uric acid by decreasing the amount of acid excreted by the organic acid secretory system. Being insoluble, the uric acid deposits in the joints and a full-blown attack of gout may result in individuals who are predisposed to gouty attacks. 

It is important, therefore, to perform periodic blood tests for uric acid levels. 

[Note: Probenecid, a drug sometimes used in the treatment of gout, can interfere in the excretion of the thiazides and increase serum uric acid levels.]. 

Alkalosis– may occur with hypokalemia as more H exchanges with Na in DT when less K is available for exchange with Na.

4)Volume depletion: This can cause orthostatic hypotension(decrease in systolic blood pressure of 20 mm Hg or a decrease in diastolic blood pressure of 10 mm Hg within three minutes of standing when compared with blood pressure from the sitting or supine) or light-headedness.

5)Hypercalcemia

6)Hyperglycemia: due to impaired release of insulin and tissue uptake of glucose.

7)Hyperlipidemia

8)Hypersensitivity: Individuals who are hypersensitive to sulfa drugs may also be allergic to the thiazide diuretics. Rashes, photosensitivity occurs.

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