DRUGS ACTING ON THE KIDNEY
PHYSIOLOGY OF URINE FORMATION
· Urine formation begins from glomerular filtration.
· Normally about 180 liters of fluid is filtrate every day.
· All blood constitutions are filtrated at the glomerulus.
· More than 99% of the glomerular filtrate is reabsorbed in the tubules.
· About 1.85 liters of urine is produced in 24 hours.
· The tubular reabsorption can be divided into following categories.
· Transport of Na+ and K+ coupled to active reabsorption of glucose, amino acid etc.
· PT cell secrete H+ with the help of Na+, H+ antiport at the luminal membrane (Na+, H+ exchanger).
· Na+ is reabsorbed inside the cell and exchange K+ through Na+, K+ ATPase.
· PT regulates acid, base balance, secrete H+ combine with HCO3– in the tubular fluid to form carbonic acid.
· This H2CO3 is broken into H2O and CO2 by the enzyme carbonic anhydrase (CAs).
· Both H2O and CO2 diffuse inside the cell and recombine to form H2CO3 by the enzyme CAs.
· The dissociated HCO3– in the cell is transported to basolateral membrane with Na+ (Na+, HCO3– symporter), resulting in net reabsorption of NaHCO3.
DESCENDING LIMB OF LOOP OF HENLE
· After reabsorbed from PTC, the remaining filtrate which is isotonic, enters the descending limb of loop of Henle and passes into the medulla of the kidney.
· In this portion the water reabsorption takes place due to increased osmolality.
ASCENDING LIMB OF LOOP OF HENLE
· The luminal membrane carrier transports ion in the stoichiometric ratio of Na+, K+, and 2Cl–.
· Na+ that enters the cell is pumped to extracellular fluid by Na+, K+ ATPase at the basolateral membrane.
DISTAL CONVOLUTED TUBULES
· The DCT are impermeable to water.
· A least amount of NaCl (nearly 10%) is reabsorbed through Na+/Cl– transporter.
· In this stage the Ca2+ are transported via Na+/Ca2+ exchanger into the intestinal fluid. This mechanism Ca2+ excretion is regulated by parathyroid hormone.
COLLECTING TUBULE AND DUCT
· The colleting tubule and duct are responsible for Na+, K+ and water transport, whereas the intercalated cells affect H+ secretion.
· Aldosterone influence increase in Na+ reabsorption and k+ secretion through the Na+, K+, ATPase pump.
· Antidiuretic hormone (Vasopressin) receptor promote the reabsorption of water from the collecting tubules and ducts.
· Diuretics promote the removal of excess water, salts, and metabolic products from the body.
· Diuretics increases osmolality and increase water excretion.
· Diuretics are the agents that increase the volume of urine output for the management of hypertension and for the edema.
1. High efficacy diuretics (Inhibition of Na+, K+, 2Cl– cotransporter)
a. Sulphamoyl derivatives
2. Medium efficacy diuretics (Inhibition of Na+, Cl– symport)
a. Benzothiadiazine (Thiazides)
b. Thiazide like
3. Weak or adjunctive diuretics
a. Carbonic anhydrase inhibitor
b. Potassium sparing diuretics
i. Aldosterone antagonist
ii. Inhibition of renal epithelial Na+ channel
c. Osmotic diuretics
HIGH CEILING (LOOP) DIURETICS
· The loop diuretics inhibit the Na+, K+, and 2Cl– cotransporter in the ascending loop of henle, resulting in retention of Na+, Cl–, and water in the tubule.
· Due to high Na+ concentration reaching in DT, K+ excretion is increased.
· Furosemide has weak carbonic anhydrase inhibitory action, so that increase HCO3– excretion, but acidosis does not develop due to predominant urinary anion is Cl–.
· The loop diuretics increase Ca2+ concentration of urine, DCT reabsorbed these Ca2+ so, hypocalcemia does not occur.
· Loop diuretics may enhance the prostaglandin synthesis (inhibit NSAIDs).
· Rapid oral absorption, but bioavailability is 60%.
· Administration orally or parenterally.
· Duration of action 2-4 hours.
· t ½ – 1-2 hours.
· Ototoxicity: Reversible or permanent hearing loss.
· Acute hypovolemia: Rapid reduction of blood volume.
· Hypomagnesemia: Chronic se of loop diuretics.
· Acute pulmonary edema
· Cerebral edema: Fluid buildup around the brain.
· Hypercalcemia of malignancy: Increase Ca2+ level.
MEDIUM EFFICACY DIURESIS (Inhibition of Na+, Cl– symport)
THIAZIDES & THIAZIDES LIKE
· The thiazide and thiazide-like diuretics act mainly in the cortical region of thick ascending limb of loop of henle and distal convoluted tubules.
· These drugs inhibit the reabsorption of Na+ by inhibition of Na+, Cl– cotransporter on the luminal membrane of the tubule, results increase concentration of Na+, Cl– in the tubular fluid.
· Thiazides and thiazides-like drugs increased Na+, Cl– excretion, which can results hyperosmolar urine (concentrated urine).
· The acid-base balance of the body and blood does not affect the diuretic action.
· Prolonged use of thiazide and thiazide-like drugs produce loss of K+ from the body, due to increase Na+ reaching at the distal convoluted tubule, more K+ is also exchanged.
· Continues use of these drugs leads to produce magnesium deficiency (the mechanism behind is not understood).
· Increase Ca2+ concentration by reabsorption in the DCT.
· Decrease blood volume leads to decrease cardiac output. Continued therapy, volume recovery occurs.
· Well absorbed orally.
· Onset of action within 1 hour.
· Duration of action 6-48 hours (Varies)
· The drugs are filtrated at glomerulus as well as secreted in the PT by organic anion transport.
· Reabsorption depends on lipid solubility: More lipophilic highly reabsorbed – prolonged duration of action.
· t ½ :
o Hydrochlorothiazide: 3-4 hours (persists 6-12 hours)
o Chlorthalidone: 40-50 hours
· Potassium depletion
· Hyponatremia: (Low Na+ concentration in the blood)
· Hyperuricemia: (increase serum uric acid)
· Volume depletion
· Hypertension: Combination with adrenergic blockers, ACE inhibitors, angiotensin receptor blockers etc.
· Heart failure: Reducing extracellular volume in heart failure.
· Diabetes insipidus
WEAK AND ADJUNCTIVE DIURETICS
CARBONIC ANHYDRASE INHIBITORS
· Carbonic anhydrase catalyze the reversible reaction H2O + CO2 ⇋ H2CO3.
· It transport CO2 and HCO3– and secrete H+ ion.
· This enzyme is found in renal tubular cell (PT), gastric mucosa, exocrine pancreas, ciliary body of eye, brain and RBCs etc.
· In presence of acetazolamide, it inhibit CAs which retards dehydration of H2CO3 in the tubular fluid so that less CO2 diffuses back into the cells.
· The decrease ability to exchange Na+ for H+ ion (Na+, K+ antiport), hence HCO3– is retained in the lumen.
· Acetazolamide produce alkaline urine.
· Continued action depletes body HCO3– and causes acidosis.
· Administered orally or i.v.
· 90% protein bound.
· Action of a single dose 8-12 hours.
· Metabolic acidosis
· K+ depletion
· Renal stone formation
· Drowsiness and paresthesia
· Avoided with hepatic cirrhosis: could leads to decrease excretion of NH4+.
· Mountain sickness
· Alkalinize urine: to promote excretion of acidic drugs or used in urinary tract infection.
· Cerebral and pulmonary edema
· Periodic paralysis.
POTASSIUM SPARING DIURETICS
· It is a steroid, chemically related to the mineralocorticoid aldosterone.
· Aldosterone penetrates the late DT and CD cells from the interstitial site and combine with mineralocorticoid receptor (MR).
· The complex (MR-Aldo) translocate to the nucleus and promotes gene mediated mRNA synthesis.
· The mRNA then directs towards the synthesis of aldosterone induce protein (AIPs).
· This protein activates the Na+, K+ ATPase and renal epithelial Na+ channels.
· AIPs activate Na+ channel and translocate from cytosolic site to luminal membrane, also translocate Na+, K+ ATPase to basolateral membrane.
· AIPs also increase ATP production by mitochondria.
· Promote Na+ reabsorption, more K+ and H+ secretions are take place.
· Spironolactone binds to MR, prevents the action of aldosterone and produce opposite effects.
· Amiloride blocks the Na+ channel from the luminal site – reducing the lumen –ve trans-epithelial potential difference which governs K+ and H+ secretion.
· Spironolactone antagonize the activity of aldosterone, resulting in retention of K+ and excretion of Na+.
· These action diminished by NSAIDs.
· Absorbed orally
· Significantly bound to plasma protein.
· Metabolized in liver and converted active metabolites.
· t ½ – 1-2 hours.
· Gastric upset
· Menstrual irregularities
· Mental confusion
· K+ supplement – Hyperkalemia.
· Aspirin block spironolactone action.
· Spironolactone increase plasma digoxin level.
· ACE-I / Angiotensin receptor blockers (ABRs) – Hyperkalemia.
· To counteract K+ loss due to thiazide and loop diuretics.
· Ascites: liver cirrhosis – fluid development in the abdomen.
· Polycystic ovary syndrome: a hormonal disorder causing enlarged ovaries with small cysts on the outer edges.
Hi….!! My name is Smrutiranjan Dash, From Odisha, India. Professionally I am Assistant Professor at The Pharmaceutical College, Barpali, Odisha, department of Pharmacology.