DIURETICS
Diuretics are drugs that increase the rate of urine flow by acting on the kidney & producing a net loss of Na+ and water
NEPHRON
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Appr. 120 ml of ultrafiltrate is formed each minute, yet only 1 ml/min of urine is produced Greater than 99% of the glomerular ultrafiltrate is reabsorbed Appr. 65% of filtered solutes are reabsorbed in the proximal tubule The descending thin limb is highly permeable to water, yet its permeability to NaCl and urea is low
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The ascending thin limb (ATL) is permeable to NaCl and urea but impermeable to water The thick ascending limb actively reabsorbs NaCl but is impermeable to water and urea
Approximately 25% of filtered solutes are reabsorbed in the loop of Henle, mostly in the thick ascending limb, which has a large reabsorptive capacity
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The hypertonicity of the medullary interstitium plays a vital role to concentrate urine and is therefore a key adaptation necessary for living in a terrestrial environment
In the presence of ADH, the collecting duct system is permeable to water Final adjustments in electrolyte composition are made, by the adrenal steroid, aldosterone in the collecting duct system
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RENAL PHYSIOLOGY
Classification of diuretics
A. High efficacy/high-ceiling/Loop diuretics/ Inhibitors of Na+K+2Cl - symport Furosemide, bumetanide, ethacrynic acid, torsemide
B. Medium efficacy diuretics/ Inhibitors of Na+Clsymport
Thiazides : chlorothiazide, hydrochlorothiazide
Thiazide – like : chlorthalidone, metalazone, xipamide
C. Low efficacy/weak diuretics
Carbonic anhydrase Inhibitors K+ sparing diuretics Osmotic diuretics Xanthines : theophylline
CARBONIC ANHYDRASE INHIBITORS
Acetazolamide, Dorzolamide, Brinzolamide inhibit both the membrane – bound and cytoplasmic forms of carbonic anhydrase ↓
complete abolition of NaHCO3 reabsorption in the proximal tubule & collecting duct ↓ rapid rise in urinary HCO3- excretion
Mechanism of Action
Mechanism of Action
Other Actions
Decreases the rate of formation of aqueous humor and consequently reduces intraocular pressure Decreases the rate of formation of CSF
Adverse effects
Acidosis Hypokalemia Calculus formation due to precipitation of calcium phosphate salts in an alkaline urine Drowsiness, paresthesia
Contraindications Hepatic cirrhosis Hyperchloremic acidosis or severe chronic obstructive pulmonary disease
Therapeutic Uses
Glaucoma Acute mountain sickness Familial periodic paralysis - hyperkalemia Metabolic alkalosis Epilepsy – H2CO3 is split into water and co2. this CO2 decreases the threshold of seizures
OSMOTIC DIURETICS
Freely filtered at the glomerulus Undergo limited reabsorption by renal tubule Relatively inert pharmacologically Non – metabolizable Increase plasma osmolarity
Four currently available osmotic diuretics Mannitol, glycerin, isosorbide, urea
Site of action: proximal tubule , loop of Henle collecting tubule
MECHANISM OF ACTION acts by an osmotic effect in the tubules As non-reabsorbable solutes ↓ limits the osmosis of water into the interstitial space → ↑s urine volume
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↑s RBF → reduces medullary hypertonicity → reduced salt reabsorption
In general, osmotic diuretics increase the urinary excretion of nearly all electrolytes including Na+, K+, Ca 2+, Mg2+, Cl-, HCO3& phosphate
extracts water from intracellular compartments, and the extracellular fluid volume becomes expanded
Therapeutic Uses In impending renal failure (e.g shock ) Acute attacks of glaucoma For short - term reductions in IOP (both preoperatively and postoperatively)
To reduce cerebral edema and brain mass (before and after neurosurgery) Head injury with d intracranial pressure To produce forced diuresis in poisoning
Adverse Effects
Headache, nausea, vomiting Loss of water in excess of electrolytes can cause hypernatremia and dehydration
Contraindicated in Anuria due to severe renal disease/ATN Heart failure / acute LVF Active cranial bleeding
LOOP DIURETICS
High-ceiling diuretics Furosemide, bumetanide, ethacrynic acid, torsemide
Mechanism of action: Blocks the Na+ - K+ - 2Cl - symporter in the thick ascending limb of the loop of Henle
MECHANISM OF ACTION
MECHANISM OF ACTION
Abolition of the transepithelial potential difference results in marked increase in the excretion of Ca2+ and Mg2+
Increases systemic venous capacitance and thereby decrease left ventricular filling pressure (before diuresis ensues) NSAIDs attenuate the diuretic response to loop diuretics, by preventing PG mediated increases in RBF
Adverse Effects
Hyponatremia,hypokalemia,hypomagnesemia hypocalcemia Ototoxicity (esp. ethacrynic acid) Hyperuricemia,hyperglycemia,hyperlipedemia Skin rashes, photosensitivity, paresthesias, bone marrow depression & g. i disturbances Dilutional hyponatremia
Contraindications
Severe Na+ and volume depletion Hypersensitivity to sulfonamides Anuria
Drug interactions
Aminoglycosides Digitalis glycosides NSAIDs, cisplatin, lithium Propranolol, Probenecid
Therapeutic Uses
Acute pulmonary edema Chronic congestive heart failure Hypertension To induce a forced diuresis in drug overdose Hypercalcemia
Edema associated with chronic renal insufficiency
ARF
Cerebral edema Blood transfusion Edema and ascites of liver cirrhosis
THIAZIDES
Sulfonamides, benzothiadiazine derivatives Primary site of action : early part of DCT Inhibit the Na+ Cl - symporter Moderately efficacious Decrease Ca2+ excretion
Prototype drug : hydrochlorothiazide
MECHANISM OF ACTION
MECHANISM OF ACTION
Adverse Effects
Extracellular volume depletion, hypotension
Hypokalemia,hyponatremia,hypomagnesemia
Hypercalcemia,hyperuricemia,hyperlipedemia
Metabolic alkalosis
Decreased glucose tolerance
Therapeutic Uses Edema associated with Heart (congestive heart failure) Liver (hepatic cirrhosis) Renal (nephrotic syndrome chronic renal failure, acute glomerulonephritis) Hypertension Calcium nephrolithiasis
Nephrogenic diabetes insipidus !
K+ SPARING DIURETICS
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Triamterene, Amiloride, Spironolactone
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Site of action: principal cells in the late distal tubule and collecting duct Blocks renal epithelial Na+ channels
Decreases cation secretion
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MECHANISM OF ACTION
MECHANISM OF ACTION
Adverse Effects o Hyperkalemia o Nausea, vomiting, diarrhea, headache, leg cramps, and dizziness Contraindicated in patients with / on o Renal failure o ACE inhibitors
Therapeutic Uses Major utility is in combination with other diuretics to o Prevent hypokalemia & o To augment the diuretic & antihypertensive response Amiloride – Li+ - induced nephrogenic diabetes Insipidus Improves mucociliary clearance in cystic fibrosis
Spironolactone : Aldosterone antagonist Site of action : epithelial cells in the late distal tubule and collecting duct Mechanism of Action competitively inhibit the binding of aldosterone to the mineralocorticoid receptor ↓ Inactivaton of the Na+ channels
Adverse Effects
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Life - threatening hyperkalemia
gynecomastia, impotence, decreased libido, hirsutism, deepening of the voice & menstrual irregularities
GI effects - diarrhea, gastritis, gastric bleeding, peptic ulcers
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CNS - drowsiness,lethargy,ataxia,confusion, headache
Therapeutic Uses
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Edema and hypertension (with thiazide / loop diuretics)
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Refractory edema associated with secondary aldosteronism (cardiac failure, hepatic cirrhosis, nephrotic syndrome, severe ascites) (diuretic of choice in patients with hepatic cirrhosis)
Primary hyperaldosteronism (adrenal adenomas or bilateral adrenal hyperplasia)
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