Lecture 13: Pharmacology and Clinical Uses of Diuretics Flashcards
What is a diuretic?
A drug that increases urine volume
What is natriuresis?
Loss of Na+ only in the urine
What are the clinical uses of diuretics?
- salt excretion
- alteration of urinary K, Ca handling
- alteration in acid-base balance
- Treatment of HTN
- Shifting water between body compartments
What is the diuretic paradigm?
- Poison the ability of the tubules to reabsorb something (often sodium)
- increase excretion of that thing
- Increased osms in the urine leads to increased urinary volume
- perturb homeostasis
How much sodium is filtered daily in an individual with a GFR of 100 ml/min and a sodium concentration of 140 meq/L?
463,680 mg/day or 20,160 mEq/day
100 ml/min = 144,000 ml/day = 144 L/day
144 L/day * 140 mEq/L = 20,160 mEq/day
20,160 * 23 mg/mEq = 463680 mg/day
A medical student consumes a diet of 3000 mg of sodium daily. His weight is stable. What is his daily sodium excretion? What happens if you partially inhibit kidney’s ability to reabsorb sodium?
3000 mg
He will excrete more than 3000 mg of sodium, weight will decrease, TBW will decrease and ECF will decrease (all of the above)
What are the 6 classes of diuretics?
- Carbonic Anhydrase Inhibitors (proximal tubule)
- Loop diuretics (LoH)
- Thiazide diuretics (DCT)
- Potassium sparing diuretics (collecting duct)
- Osmotic diuretics (everywhere)
- Antidiuretic antagonists (collecting duct)
What mechanism do most diuretics depend upon to exert its pharmacological influence?
SECRETION, and not filtration…diuretics don’t get filtrated in the GFR because they are bound to large proteins
How do most diuretics get delivered to the site of action?
- diuretics are protein bound and are therefore concentrated in the plasma that is not part of ultrafiltrate
- Travel in blood through peritubular capillaries to the cell of action and require renal blood flow (RBF) for delivery
- Require secretion by active movement into the target cell through specialized transporters
- therefore dependent on tubular secretion rather than GFR
What are the receptors located on the apical membrane of the proximal tubule that pertain to salt reabsorption?
- Na/glucose symporter
- Na/amino acid symporter
- Na/H+ antiport
What are the key characteristics of carbonic anhydrase inhibitors?
Act at the proximal tubule
Blocks carbonic anhydrase, thereby inhibiting 85% of HCO3- absorption that occurs in proximal tubule
Does NOT promote natriuresis since distal sodium reabsorption sites compensate
Also will decrease water reabsorption (because water gets absorbed with CO2 after H2CO3 is broken by apical carbonic anhydrase)
If HCO3- is delivered to the distal nephron, what will happen to potassium?
Potassium secretion will increase (because of ROMK channel in principal cell)
-more negative charges in lumen (bicarb), the more K is secreted in prinicipal cell
What are the clinical uses of carbonic anhydrase?
Don’t use as a natriuretic agent
- Correction of metabolic alkalosis (since you have increased urinary loss of HCO3- as a result of a dysfunctional Carbonic anhydrase that won’t bicarb reaction to occur)
- Altitude sickness
- Glaucoma
- last ditch effort to fix hyperkalemia
What are the downsides of using carbonic anhydrase inhibitors?
Most of the excess fluid delivered out of prox tubule is reclaimed distally
Ineffective natriuretic agent
Thus clinical use centers on non-natriuretic properties
Can also lead to potassium wasting! (as seen from question above)
What are the key characteristics of loop diuretics?
Act at the thick ascending limb of the LoH (ThickAscendingLimb, TAL)
Blocks NKCC2 symporter
Example: Furosemide (Lasix)
Since you need NKCC2 in order for apical ROMK to work (and create a positive electric gradient), blocking NKCC2 will destroy positive electric gradient
Thus, TAL can no longer reabsorb Na, Ca and Mg!!!
So leads to calcium, magnesium and Na wasting
What are examples of loop diuretics?
Furosemide
Bumetanide
Torsemide
Ethacrynic Acid
What are clinical uses of loop diuretics?
- Correction of pathophysiological states of Na retention and intravascular volume overload (edematous disorders) such as
i. CHF
ii. pulm edema
iii. nephrotic syndrome
iv. renal failure - Correction of hyperkalemia
- Correction of hypercalcemia
What are the side effects of loop diuretics?
- Hypokalemia
- Hypocalcemia or hypercalciuria
- Hypomagnesemia
- Hyperuricemia which leads to gout
- Ototoxicity, reversible
- worse with ethacrynic acid
- Sulfa allergy
- but not with ethacrynic acid (non-sulfa loop)
What is one structural component that all loop diuretics share? Significance?
They all have a sulfa moiety
Thus can induce sulfa allergy
Significance: That’s why there is a need to use the more toxic ethacrynic acid in cases of severe sulfa allergy, since ethacrynic acid doesn’t have a sulfa moiety
What is the braking phenomenon?
Day 1 of loop diuretic therapy = a lot of urine
Day 5 of loop diuretic therapy = decrease in net Na excretion
What is braking phenomenon of loop diuretic therapy caused by?
Increased reabsorption of Na at other sites along the nephron in response to kidney’s perception of Na depletion
Increased Na uptake at proximal tubule, DCT and collecting tubules
What can happen when loop diuretic is chronically administered?
Hypertrophy of the sodium reabsorption sites distally to the loop
Can lead to diminished net sodium excretion and “diuretic resistance”
How can we explain the paradox of chronic loop diuretic administration in which one’s input is the same as one’s output of salt?
Chronically, when you have input = output, it means your body is at a steady state, but this steady state is DIFFERENT from what you started out with at the beginning of administration
New steady state = lower TBW and TBNa so input = output is no big deal
Also, if your output was constantly greater than your output, you would die of volume depletion
This explains why loop diuretics are still working in spite of braking phenomena
What are the key characteristics of thiazides?
Inhibitor of luminal NaCl cotransporter in DCL
Less filtrate reabsorbed here (5-10%)
Increase Ca reabsorption
Increase K secretion
Example: HCTZ (hydrochlorothiazide)
Also have a sulfa moiety like loop diuretics
What are examples of thiazides?
- HCTz
- Chlorthalidone
- Metolazone
Chlorthalidone and metolazone are “thiazide-like” because they inhibit Na/Cl symporter but don’t have thiazide moiety
What are the clinical uses of thiazide diuretics?
- first line therapy of HTN
- Combination with loop diuretics to prevent braking phenomenon in edematous states
- Anticalciuric properties helpful in diopathic hypercalciuric stone disease
- used to treat hyperkalemia
Often used to reduce calcium loss in urine for both reduction in formation of Ca-containing stones and as potential treatment for osteoporosis
How does thiazide increase calcium REABSORPTION?
Blocking Na-Cl symporter = less Na into the cell
There exists a Na/Ca on basolateral membrane
Less Na into the cell increased basolateral Na/Ca cotransporter (Na into cell and Ca into blood) activity to compensate
Thus, activation of Na/Ca cotransporter = less Ca into the cell
Less Ca in the cell = more Ca goes from lumen into the cell through apical Ca channel
What are the clinical uses of thiazide diuretics?
- first line therapy of HTN
- Combination with loop diuretics to prevent braking phenomenon in edematous states
- Anticalciuric properties helpful in diopathic hypercalciuric stone disease
- used to treat hyperkalemia
Often used to reduce calcium loss in urine for both reduction in formation of Ca-containing stones and as potential treatment for osteoporosis
What is the clinical use of thiazides with blood pressure?
Although it is a mild natriuretic agent, thiazides have marked BP lowering effects when combined with Na restricted diet
When using thiazides with loop diuretics, what does one need to watch out for?
Mg and K levels must be monitored to guard against profound K and Mg losses
What are the side effects of thiazide diuretics?
- Kaliuretic hypokalemia
- Hyponatremia
- Hyperuricemia
- Increase Ca reabsorption
- Carbohydrate intolerance
-impaired insulin release and diminished utilization of glucose - Rarely can produce sulfa allergies
Most of side effects can be avoided or minimized with modest doses
What are the differences between loop diuretics and thiazides?
Loops increase Ca excretion whereas thiazide Decrease Ca excretion (as shown by Ca transporter in the luminal side of the DCT)
Loops inhibit ability to concentrate urine, but thiazides DON’T inhibit ability to concentrate urine
-that is because loops act at TAL (thick ascending limb) which is a concentrating segment that is only permeable to electrolytes
Which diuretic class is more likely to result in hyponatremia, loop or thiazide?
Thiazide
What are K+ sparing diuretics?
Act at the principal cells of collecting ducts
Principal cells = portion sensitive to aldosterone
Two categories
i. Na channel blockers
ii. Aldosterone receptor antagonists
Net effect = inhibition of Na reabsorption and reduction in K+ secretion
What is the MoA of Na channel blockers?
1 category of K+ sparing diuretics
Block ENaC (epithelial Na channels) to inhibit Na uptake in collecting duct
Examples: Amiloride and triameterene
What is Amiloride?
A K+ sparing diuretic
What are examples of Na channel blocking K+ sparing diuretics?
- Amiloride
2. Triameterene
What are the characteristics of aldosterone receptor antagonists?
Inhibits the mineralocorticoid receptor from binding to aldosterone
Thereby prevents Na channels from being activated
Example: spironolactone and eplerenone
What are examples of aldosterone receptor antagonists?
- Spironolactone
2. Eplerenone
What are the clinical uses of K+ sparing diuretics?
Natriuretic activity limited since only 3-5% of filtered load is reabsorbed
Used in combination with more potent natriuretic diuretics
K+ sparing = K is reabsorbed or spared from being excreted in body
What are the special uses of spironolactone?
- does not require tubular secretion and works at relatively low EABV
- impact mortality in CHF
- Used in cirrhosis
- has anti-proteinuric effects
What are the side effects of K+ sparing diuretics?
- potentially dangerous in patients with propensity for elevated K+ levels (since it retains K)
- examples include chronic kidney disease and CHF
- painful gyencomastia = spironolactone side effect
What are the characteristics of osmotic diuretics?
- Nonreabsorbable substances that inhibt sodium and water reabsorption by osmotic forces
- acts at proximal tubule and LoH
- Does not directly affect Na transport
-indirectly inhibits movementof Na out of lumen by their effect on water reabsorption - Leads to water losses in excess of Na loss and can lead to hyperosmolality and hypernatremia
Examples: glucose in hyperglycemic diabetic patient
What is the sequence of events that an osmotic diuretic brings about?
Osmotic diuretic is freely filtered by glomerulus sits in lumen at high concentration increases osmotic pressure and induces osmotic gradient excretion of water > Na
What are the characteristics of the antidiuretic antagonists?
They antagonize the effects of ADH
Examples: Demeclocycline, Vaptans
What are the key characteristics of Demcloclycline?
A tetracycline antibiotic
Used for acne
Also antagonizes effect of ADH
What are the key charactreistics of vaptans?
Includes conivaptan (IV) and tolvaptan (PO)
Both ADH receptor antagonissts
Used in hyponatremic states
-especially in SIADH, heart failure, liver failure
Mortality benefit not yet demonstrated
What is the only water impermeable membrane in the body?
Collecting duct lumen if there is no ADH
