Medicinal Chemistry and Pharmacology of Diuretics Flashcards
What are the functions of the kidneys
maintain homeostatic balance of electrolytes and water, excrete water-soluble end products of metabolism
What is the functional unit of the kidney
Nephron
What are the two important physical processes in urine formation
osmosis and active transport
What are the five parts of the Nephron
Glomerulus, Proximal Tubule, Loop of Henle, Distal Tubule, Collecting Duct
Filtrated plasma provided by glomerular capillary network into the Bowman’s capsule becomes what, what is a key difference
Luminal fluid, change in osmotic concentration
What are the most important molecules reabsorbed in the proximal tubule, what is the other important molecule absorbed
sodium chloride and bicarbonate, water
What enzyme is responsible for transcellular reabsorbption of sodium and bicarbonate
Carbonic anhydrase
How does carbonic anhydrase work
Water binds to the enzyme and grabs carbon dioxide to become carbonic acid, carbonic acid is unstable and dissociates to protons and bicarbonate, the protons and sodium are exchanged through an antiporter system to keep electrostatic equilibrium, bicarbonate and sodium are put into the interstitial fluid through a symporter system
What enzyme is the driving force to create an osmotic gradient, what is the result
Na+/K+ ATPase, creates Na+ deficit in luminal cell and draws sodium from luminal fluid
How are other ways sodium enters the cell or anti-luminal membrane
transcellular transport (passive to luminal membrane, active to anti-luminal membrane), paracellular transport (diffusion)
What part of the nephron is most responsible for absorbing Sodium, how much sodium does it reabsorb
proximal tubule, 60%
What are the two portions of the loop of Henle
Descending limb, ascending limb
Which part of the Loop of Henle water permeable, is it active or passive
Descending limb, osmosis (passive)
Which part of the Loop of Henle is water impermeable, what is usually reabsorbed at what ratio
Ascending limb, NaCL (1:2)
What percentage of the reabsorbed sodium is reabsorbed by the loop of Henle, which part
30%, Ascending Limb
How does sodium and chloride get into the cell in the ascending limb
symporter system
What part of the nephron is hormone driven, what hormones drive it
Distal Tubule,ADH and Renin
Where is potassium is more likely to enter the urine
Collecting duct
How does the nephron react to hypovolemia/ dehydration
decreased renal blood flow and GFR, increased renin secretion, increased secretion of ADH, increased water re-absorption
How do diuretic agents work
promote urination by increasing the rate of renal excretion of water and electrolytes
T/F: Most diuretics work by inhibitng Na+ transport at one or more of the four mayjor anatomical sites
True
What will influence how much diuretic enters the luminal fluid by the filtration process
GFR. plasma concentration of diuretic agent, fraction of the drug that is bound to unfiltrable plasma proteins
How do the diuretics get to their site of action
travel through the blood stream and bind to OATs (acids) or OCTs (bases) where they are secreted
What is the driving force of the glomerular filtration process
hydraulic pressure (pumping heart)
What is the role of the Na+/K+ ATPase in the anti-luminal membrane
driving force of sodium re-absorption and creates a sodium deficit in the luminal cell
T/F: Water is reabsorbed throughout the entire Loop of Henle
False- the ascending Loop of Henle is not water-permeable
Where is the salt (osmotic) concentration is higher
Medulla
What are the classes of diuretics
osmotics, carbonic anhydrase inhibitors, thiazides, loop, potassium sparing
What are properties of osmotic dieuretics
highly water soluble, with minimal re-absorption by the renal tubule that are freely filtered through the Bowman’s capsule into the renal tubules
What are the osmotic diurectics
Mannitol, isosorbide, and sorbitol
What is MOA of osmotic diuretics
artificially concentrate the urine causing less sodium absorption and water reabsorption
Where do the osmotics usually work at
Proximal tubule and descending limb
Where do carbonic anhydrase inhibitors do most of the action at
Proximal tubule
What is the MOA of carbonic anhydrase
inhibiton of renal carbonic anhydrase decreases sodium carbonate reabsorption leading to increased volume of luminal fluid
What do all carbonic anhydrase drugs have in common
Sulfanilamide lead compound (unsubstituted sulfamoyl group and aromatic system)
T/F: Carbonic anhydrase are competitive inhibitors that block the binding of water and carbon dioxide
True
What are carbonic anhydrase usually used for
Glaucoma
Where do thiazide diuretics work
Distal tubule
T/F: Thiazide have a strictly diuretic activity
False: Thiazide diuretics posses a diuretic activity along with CA inhibitory activity due to its sulanilamide moeiry
What occurs in the distal tubule, how do thiazides change this
Symporter system that carries sodium and chloride in the luminal cells, inhibit the sodium and chloride symporter leading to an increase in water excretion
What is basic in thiazide structure in order for them to work
Six membered aromatic phenyl ring attached to a cyclic six membered ring, a free sulfonilmide and one in the cyclic ring
What is essential for diuretic activity in thiazides
an electron withdrawing group at C-6, free sulfonamide at C-7
T/F: Substituation with a lipophilic group at C-3 increases diuretic potency and/or its duration of action
True
What is the most apparent adverse effect of using thiazide diuretics, why
Hypokalemia, Due to high Sodium in lumen due to thiazide there is increased K+ secretion in the collecting duct when sodium is reabsorbed
What is another electrolyte disorder caused by thiazide diuretics, why
hypercalcemia, long-term thiazide treatment is known to trigger an increase in proximal tubule reabsorption of fluid, uric acid, and electrolytes (such as calcium)
How do thiazides lead to hyperuricemia
Both thiazides and uric acid are weak organic acids that compete for OATs
Which diuretics are used in emergencies, where do they work
Loop diuretics, thick ascending loop
What is the most potent Loop diuretic, which is mostly prescribed to patients, which lacks the CA inhibitor activity due to lacking the sulfamoyl group
Bumetanide, Furosemide, Torsemide
Which Loop diuretics not only inhibit the luminal Na+/K+/2Cl- symporter system but also the Na+/K+ATPase, what do they lack from other Loop diuretics
Etacrynic acid and Indacrinone, Lack CA inhibition due to no sulfamoyl group
What is MOA of potassium sparing diuretics
competitive inhibition of aldosterone receptor or blockade of sodium channels at the luminal membrane
What are potassium sparing diuretics that selectively block sodium channels, where do they work, what is their ionic state
Amiloride and Triamterene, collecting duct, positive (basic)
What is aldosterone, what does it do
endogenous mineralocoricoid with antidiuretic hormone action through binding mineralocorticoid receptor leading to more Na+/K+ATPase and more Na+ channels
What are potassium sparine diuretics that are aldosterone receptor antagonists,
spironolactone, canrenone, and eplerenone
Which aldosterone receptor antagonists is a active metabolite of spironolactone, which is more selective for the aldosterone receptor
canrenone and eplerenone
T/F: Both potassium sparing diuretics bind to Na channels directly leading to potassium sparing
False: Amiloride and triamterene block these channels directly while spironolactone, canrenone, eplerenone are used to reduce the concentration of these channels
What is the mutual effect of all diuretics
increase in osmotic concentration of the luminal fluid and resulting in reduced water re-absorption
How do diuretics increase the risk of gout
Uric acid is built up in the body and crystallizes, this happens because Uric acid must now competes with diuretics that also use the enzyme OATs in order to get to the urine
Which class diuretics work on the proximal tubule and descending loop of henle, which work on just the proximal tubule, which work on the ascending loop of henle, which work on the distal tubule
osmotic, carbonic anhydrase, Loop, thiazides and potassium sparing
