Lecture 1 - Diuretics Flashcards
What are the thiazide diuretics?
hydrochlorothiazide
chlorthalidone
metolazone
What are the loop diuretics?
furosemide
ethacynic acid
What is a potassium sparing diuretic?
spironolactone
Thiazide, loop, and potassium sparing diuretics are _______ diuretics
classic
Other than classic diuretics what is the other group of diuretics?
solute and/or water excretion altering (not clinically used as diuretics)
_____ = osmotic diuretic
mannitol
______ = carbonic anhydrase inhibitor
acetazolamide
_______ = vasopressin receptor antagonist
tolvaptan
_______ = sodium/glucose co-transport 2 inhibitor
dapagliflozin
Definition of a diuretic?
agents which increase urine flow
Clinically, what do diuretics do?
- renal solute excretion (sodium and water)
- block sodium reabsorption and water will follow later
Aim of therapy for diuretics?
- only need to decrease sodium reabsorption a few %
- change of 5% has a great effect
How much % of Na is reabsorbed?
99.6%
How many mmol/day of Na is excreted?
100
If Na reabsorption decreases to 95% then ____ mmol/day of Na is excreted
1250
Where does dapagliflozin work?
blocks glucose and sodium reabsorption (so it’s excreted, and then water will follow and be excreted as well)
Where does mannitol work?
increases H2O excretion
Where does acetazolamide work?
Increases excretion of HCO3
Where does hydrochlorothiazide and metolazone work?
increase NaCl excretion
Where does furosemide work?
Increases Na, Cl, and K excretion and Mg, Ca will follow
Where does spironolactone work?
blocks Na reabsorption
Where does tolvaptan work?
ADH (vasopressin receptor antagonist)
make fucking sense of slide 5 and 6
kay
Where do thiazide diuretics work?
In distal tubule (primary site of action) to:
- Increase NaCl excretion (decrease reabsorption)
- Decrease Ca excretion (increase reabsorption) - loop diuretics do the opposite
*they have some proximal tubular effect but it is not normally important (it is only important when combined with loop diuretic)
____ diuretics - may decrease blood pressure without a perceivable volume loss, low dose is usually effective (with decreased toxicity)
thiazide
For elderly patients, ____ diuretics are a problem
loop
*Because they increase the calcium excretion (decrease the Ca reabsorption) and can contribute to osteoporosis or other bone diseases
What is the formula for BP?
BP = CO x TPR
Describe how thiazide diuretics decrease blood pressure
- increase NaCl excretion
- decrease blood volume
- decreases cardiac output (which decreases BP - think of the BP formula)
- apparent tolerance = no diuresis?
- blood volume and CO returns to normal
- blood pressure stays down and may decrease further
Problems with thiazide diuretics?
- *in addition to electrolyte problems
- increased incidence of other risk factors for CV disease
- hyperglycemia (decreased insulin release, decreased tissue utilization)
- increased LDL levels (must monitor)
- increased incidence of ED
- plasma volume contraction due to increased urine loss
- increased proximal tubule reabsorption, response to fluid loss
- increased lithium; urea reabsorption
What are thiazide diuretics used for?
- edema
- hypertension
Advantages of thiazide diuretics?
- orally active, low toxicity, no postural hypotension
- potentiate other antihypertensive drugs
____ diuretics include furosemide, bumetanide, ethacrynic acid (non sulphonamide)
Loop
___ _____ diuretics are very potent and efficacious
high ceiling
Why are high ceiling diuretics dangerous?
up to 20% of filtered load excreted
Loop diuretics:
____ and ____ application
oral
IV
Loop diuretics:
Increase _____ production which results in vasodilation
prostaglandin
Where are loop diuretics useful?
in acute pulmonary edema - because it vasodilators veins
___ may decrease function of loop and thiazide diuretics
NSAIDs
MOA of loop diuretics?
- increases Na, Cl, and K excretion and Mg, Ca follow (excreted)
- inhibits renal diluting ability and abolishes the renal concentrating ability, urine becomes isotonic or slightly dilute
Problems with loop diuretics?
- in addition to electrolyte imbalances
- deafness - never combine with aminoglycoside antibiotics
- chronic dilution hyponatremia (due to excrete of an isotonic urine)
Uses of loop diuretics?
- good in renal insufficiency (GFR < 50 mL/min)
- edema (pulmonary); hypertension (not as sole medication); hypercalcemia (opposite to thiazides); heart failure
What do you need to caution if a patient is not responding to a loop diuretic? And how do you manage it?
- caution regarding circulating chloride concentration
- add a thiazide diuretic
- metolazone often used for this
What is the main electrolyte problem with thiazide and loop diuretics?
Potassium depletion
- not a problem in healthy patients
- more a problem if low potassium already a problem (heart failure, cirrhosis, etc.)
What are the two major causes of potassium depletion?
1) Secondary hyperaldosteronism (due to plasma volume depletion)
- increased renin
- increases angiotensin 2
- increased aldosterone
- Na reabsorption at expense of K (and H) loss
2) Increased Na delivery from distal tubule
- due to inhibition of Na reabsorption in loop and distal tubule
- collecting tubules therefore increase Na reabsorption - to conserve sodium
Describe the potassium depletion treatment
1) dietary intake - apricots and bananas
2) potassium chloride tablets - chloride salt - dilute solution
3) slow - potassium tablets - ulceration
4) emergencies require IV KCl - repeat cautiously until potassium rises
5) potassium sparing diuretics
- weak diuretics
- give with other diuretics to decrease K loss
- may cause hyperkalemia
Never coming potassium sparing diuretics with K supplements
List 3 potassium sparing diuretics
- spironolactone
- triamterene
- amiloride
How does spironolactone work?
- blocks aldosterone receptor
- prevents cardiac remodelling (fibrosis, cardiac collagen proliferation) - may delay progression of failure
How does triamterene and amiloride work?
-decreases sodium permeability
B-blockers, ACEi’s and ARB’s may also increase plasma _____ concentrations
potassium
B-blockers decrease potassium _____ cells
entering
ACEi’s and ARB’s decrease ______ concentrations
aldosterone
So potassium depletion is one electrolyte disturbance, what is another?
Extracellular Volume Depletion
- furosemide - kidney unable to concentrate or dilute
- excrete an isotonic urine
- inability to concentrate urine (save water)
- simply drink more water to excrete solutes
- inability to dilute urine (excrete excess water)
- ingest hypotonic solution - excrete isotonic urine
- net loss of electrolytes including plasma sodium
- chronic dilution hyponatremia
Describe calcium as an electrolyte disturbance
- Thiazides decrease calcium excretion, good for hypocalciuria
- Furosemide increases calcium excretion, good for hypercalcemia
Describe how volume depletion and increased proximal tubule reabsorption can be a problem.
1) uric acid excretion
- initially increased but decreased with chronic administration (gout?)
2) Lithium - increased proximal tubular reabsorption
- toxicity is a concern (same clinical concern for digoxin)
List the 4 uses of diuretics
- tissue edema
- hypertension
- hepatic cirrhosis
- cardiac failure
Describe how diuretics treat tissue edema
- fluid shift into the extracellular space has exceeded 3 to 4 L due to salt and water retention
- Loop diuretic (furosemide) preferred
- if no response to loop diuretic, check for low serum chloride concentration
- fluid excreted in urine is taken from the “vascular space”, allow time for this to be replaced by the interstitial (oedematous) fluid - go slow! otherwise CV collapse
Describe how diuretics treat hypertension
- 1st line single therapy (thiazide diuretic)
- but possible increase in LDL and plasma glucose (not metabolically neutral)
- good as second medication to treat sodium and water retention
- which is a common side effect of other anti-hypertensives
Describe how diuretics treat hepatic cirrhosis
- sodium/water accumulates in the abdomen and/or tissue
- abdominal fluid movement into vascular space may be a concern
- slower than fluid movement from interstitial to vascular space
- aggressive treatment will remove fluid faster from the vascular space than can be replaced fly the abdominal fluid
Describe how diuretics treat cardiac failure
- fluid retention increases vascular volume
- helps to increase preload and stimulate the heart
- as failure continues so does fluid retention
- preload increases to levels causing edema
- diuretics decrease vascular volume
- successful treatment of heart failure requires adequate control of vascular volume
What are osmotic diuretics?
osmotically active compounds in the plasma
List 4 properties for a perfect osmotic diuretic
- filtered
- not reabsorbed
- pharmacologically inert
- resistant to alteration
*osmotically active compounds “hold” onto water - high urine volume - little sodium
List 3 uses of mannitol (IV) and glycerol (oral)
- vascular surgery
- renal transplant
- ophthalmological procedures
Where do osmotic diuretics work?
they block water reabsorption so they increase water excretion
What is an example of a carbonic anhydrase inhibitor?
Acetazolamide (Diamox)
Describe carbonic anhydrase inhibitors (ex. acetazolamide)
- very weak diuretics
- inhibit carbonic anhydrase
- decreases reabsorption of bicarbonate in proximal tubular cells
- increase bicarbonate excretion (with some sodium)
Uses of carbonic anhydrase inhibitors (ex. acetazolamide)
- in severe alkalosis (increases renal excretion of bicarbonate)
- alkalinization of filtrate ionizes acidic drugs
- ionization increases renal excretion ex. salicylate
List 3 main uses of carbonic anhydrase inhibitors (ex. acetazolamide)
- acute mountain sickness
- increasing excretion of weak acids
- glaucoma - decreases aqueous humor formation
MOA of carbonic anhydrase inhibitors (ex. acetazolamide)
increase renal excretion of bicarbonate
Conivaptan is a ????
ADH Antagonist
ADH (vasopressin) increases water _____ (no effect on electrolytes)
reabsorption
How does conivaptan work?
Blocks the ADH receptor in the collecting tubules
*Increases water excretion without electrolytes
____ is increased in heart failure and syndrome of inappropriate ADH (SIADH) secretion. The chronic increased water reabsorption may produce ______.
vasopressin (ADH)
hyponatremia (diluted sodium)
What can ADH antagonists produce?
nephrogenic diabetes insipidus (increased urine flow due to lack of a renal effect of ADH)
Main uses of conivaptan (ADH antagonist)
SIADH (relatively new)
MOA of ADH antagonists
block ADH receptors, increase water excretion
Dapagliflozin is a ??
Sodium glucose Co-transport 2 (SGLT2) inhibitor
What is sodium glucose co-transport 2?
the major site of glucose reabsorption in the proximal tubule
90% is via the SGLT2
blockade of this transport increases urinary excretion of glucose
*associated with a small decrease in plasma glucose
SGLT2 inhibitors associated with?
a decrease in blood pressure and weight
