DIURETICSFor BSc Nursing

Dr. Pravin PrasadMD Resident, 1st Yr

Maharajgunj Medical Campus12th Shrawan, 2072 (31st July, 2015), Friday

Preliminaries

Nephron: The Functional Unit of Renal System

Renal Physiology: Pharmacological Aspect

Site I:Movement of Na+ is by:• Direct Entry of Na+

• Coupled to active reabsorption of organic anions via specific symporters

• Exchange with H+ ions• Diffusion through paracellular

pathways (along with Cl- ions)

Site II:Medullary Portion:• Na+K+2Cl- and Na+ K+ ATPase;• Na+-Cl- symporter

Renal Physiology: Pharmacological Aspect

Site III:• Na+ -Cl- symporter• Impermeable to water• Dilution of luminal/tubular fluid

Site IV:• Na+ actively reabsorbed (Amiloride

sensitive Na+ channels)• Cation-anion balance maintained

by:• Passive Cl- diffusion• Secretion of K+ (aldosterone

dependent) and H+

Net Movement of Potassium

• Movement of Potassium:• Reabsorbed in Proximal Tubule (PT) and thick ascending limb of Loop of Henle

(Asc LH)• Secreted in the Distal Tubule (DT) and Collecting Duct (CD)

• Net K+ loss depends on:• Na+ load delivered to DT and CD• Presence or Absence of Aldosterone• Availability of H+

• Intracellular K+ stores

Role of Anti Diuretic Hormone (ADH)

• Cells lining CD are sensitive to ADH• ADH absent:• Hypotonic fluid entering CD passes as such: dilute urine passed.

• High ADH levels:• CD cells fully permeable to water• Tubular fluid gets equilibrate with hyperosmotic medulla• Concentrated urine passed

DiureticsDrugs that cause net loss of Na+ and water in urine

ClassificationHigh Efficacy Diuretics (Na+K+2Cl- cotransport inhibitors)

• Sulphamoyl Derivatives: Furosemide, Bumetanide, Torasemide

Medium Efficacy Diuretics (Na+ Cl- symport)

• Thiazides (Benzothiadiazines): Hydrochlorthiazide, Benzthiazide, Hydroflumethiazide, Bendroflumethiazide

• Thiazide Like (related heterocyclics): Chlorthalidone, Metolazone, Xipamide, Indapamide, Clopamide

Weak/ Adjunctive Diuretics

• Carbonic Anhydrase Inhibitors: Acetazolamide• Potassium Sparing Diuretics(Aldosterone antagonist): Spironolactone, Eplerenone• Potassium Sparing Diuretics(renal epithelial Na+ channel): Triamterene, Amiloride• Osmotic Diuretics: Mannitol, Isosorbide, Glycerol

High Ceiling Diuretics(Loop Diuretics): Furosemide

Mechanism Of Action: Inhibits Na+K+2Cl- cotransport in thick

ascending limb of loop of Henle decreased Na+ and Cl- absorption increased urine passed

Weak Carbonic Anhydrase inhibitory action Changes in systemic and renal blood flow:

resulting in decreased reabsorption at Proximal tubules

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High Ceiling Diuretics: Uses

• Edema• Preferred in CHF• Nephrotic syndrome, chronic renal failure, resistant edema• Impending acute renal failure

• Acute pulmonary edema (acute Left Ventricular Failure, following Myocardial Infarction)• Hypertension

• Co-existing renal insufficiency, CHF, resistant cases, hypertensive emergencies

• Along with Blood Transfusion• Hypercalcemia of malignancy• Cerebral edema

• Combined with osmotic diuretics to improve efficacy

Medium Efficacy Diuretics: Thiazide and Thiazide like diuretics

Mechanism Of Action: Inhibits Na+-Cl- symport in early Distal Tubule

decreased Na+ and Cl- absorption increased urine passed

Additional carbonic anhydrase inhibitory action: generally weak

Well absorbed orally, no injectable preparationsOnset of Action within 1hr, duration 6-48 hrs

Thiazide and Thiazide like diuretics: Uses

• Hypertension• One of the First line drugs (Chlorthalidone)

• Edema• Diabetes Insipidus (DI)• Nephrogenic DI

• Hypercalciuria with recurrent calcium stones in the kidney

Adverse Drug Reaction of Loop Diuretics, Thiazide and Thiazide like

DrugsLoop Diuretics Thiazide

Hypokalemia• Brisk Diuresis• Low Dietary K+ intake

Less common than thiazides More common than Loop Diuretics

Acute Saline Depletion• Dehydration• Fall in BP (erect)• Hemoconcentration – venous thrombosis

Seen with overuse of Loop Diuretics Not So Common

Dilutional Hyponatremia After vigorous use of Loop diuretics in CHF Rare with thiazides

GIT and CNS Disturbances Nausea/Vomiting, diarrhoea, headache, giddiness, weakness, paresthesias, impotence

Hearing Loss Only with Loop diuretics

Allergic manifestation Rahses photosensitivity, blood dyscrasias rare, especially in pts hypersensitive to sulfonamides

Loop Diuretics Thiazide

Hyperuricemia Avoid probenecid Long term use of high dose thiazides

Hyperglycaemia and hyperlipidemia

Minimal with low dose thiazides used these days

Hypocalcemia Seen on chronic administration Raises serum Ca2+ levels, may cause hypercalcemia

Magnesium depletion Seen after prolonged use

Renal insufficiency Can be used in renal insufficiency Aggravated due to decreased GFR

• Brisk diuresis in cirrhotics may lead to mental disturbances and hepatic coma: may be due to hypokalemia, increased blood NH3 levels

• Avoided in toxaemia of pregnancy

Adverse Drug Reaction of Loop Diuretics, Thiazide and Thiazide like

Drugs

Loop Diuretics and Thiazides: Interactions• Potentiates all other Hypertensives• As it induces Hypokalemia:• Enhances digitalis toxicity• Increased risk of Cardiac arrhythmia• Reduces sulfonylurea action (oral hypoglycaemics)

• Additive ototoxicity and nephrotoxicity of aminoglycosides• Higher incidence of thrombocytopenia when combined with co-

trimoxazole• Actions reduced when used with indomethacin and other NSAIDs• Probenecid and diuretics reduces each other’s actions• Serum Lithium level rises

Carbonic Anhydrase (CAse) inhibitors: Acetazolamide

Reversibly inhibits CAse (type II) in PT cells decreased H2CO3 formation decreased H+ concentration Na+-H+ antiport cannot function: Mild alkaline diuresis

Secretion of H+ in DT and CD also interfered Causes marked kaliuresis

Acetazolamide

UsesGlaucoma: as an adjuvantAcute Mountain SicknessOther uses:• Periodic Paralysis• Alkalinise urine• Epilepsy: adjuvant

Adverse Effects• Acidosis• Hypokalemia• Drowsiness• Paresthesias• Fatigue• Abdominal Discomfort• Hypersensitivity reactions• Bone marrow depression (rare)

Contraindicated in liver disease: potential to induce hepatic coma

Potassium Sparing Diuretics

Aldosterone Antagonist• Spironolactone, Eplerenone• Mechanism of Action:• Blocks aldosterone activity by

blocking mineralocorticoid receptor, Aldosterone Induced Protein / Na+ channels not expressed decreased absorption of Na+ and water• Acts from the interstitial side• No aldosterone = no effect

Inhibitors of renal epithelial Na+

channels• Triamterene, Amiloride• Mechanism of Action:• Blocks Amiloride sensitive Na+

channels at DT and CD entry of Na+ ions blocked transepithelial potential not generated excretion of K+ decreased

• Due to decreased transepithelial potential, H+ ion secretion (via H+ ATPase pump) is decreased predisposes to acidosis

Uses

Aldosterone Antagonist• Weak diuretic, always used in

combination1. Hypertension: adjuvant to

thiazide2. Edema (cirrhotic/nephrotic,

refractory)3. Congestive Heart Failure

Inhibitors of renal epithelial Na+

channels• Used in conjunction with other

diuretics1. Hypertension: prevent

hypokalemia, increase natriuretic response

Aldosterone Antagonist: Spironolactone• Interactions• K+ supplements: dangerous hyperkalemia• Aspirin: decreases potency of Spironolactone• ACE inhibitors/ARB: pronounced hyperkalemia• Digoxin: increased levels of plasma digoxin

• Adverse Effects• Hyperkalemia• Drowsiness, mental confusion, ataxia, epigastric discomfort, loose motions• Gynaecomastia, erectile dysfunction, loss of libido• Breast tenderness, menstrual irregularities• Acidosis in cirrhotics

Contraindicated in Peptic ulcer patient : may aggravate ulcers

Inhibitors of renal epithelial Na+

channels: Amiloride• Adverse Effects• Hyperkalemia

• Should not be given with K+ supplements• More likely in patients receiving ACE inhibitors/ARBs, β- blockers, NSAIDs,• More likely in patients with renal impairment

• Elevated Plasma Digoxin levels• Nausea, Dizziness, Muscle cramps, rise in blood urea• Impaired glucose tolerance, photosensitivity

Osmotic Diuretics: Mannitol

• Pharmacologically inert• Mechanism of Action:• Retains water isoosmotically in PT• Inhibits transport process in thick Asc LH• Expands extracellular fluid volume• Increased renal blood flow

• Increases urinary output, excretion of all cations and anions also enhanced• Given as intravenous drip

Osmotic Diuretics: Mannitol

• Uses• Increased intracranial and intraocular tension• To maintain glomerular filtration rate and urine flow in impending acute renal

failure: prognostic benefits not proven• Counteract low osmolality of plasma/e.c.f.

• Contraindications• Acute tubular necrosis• Anuria• Pulmonary Edema, acute left ventricular failure, CHF, cerebral haemorrhage

• Side Effects• Headache, nausea/vomiting, hypersensitive reactions

Thank you!!!