Diuretics Flashcards
What are the four function regions of the nephron?
Glomerulus
PCT
Loop of Henle
DCT
What comprises the distal nephron?
Last portion of DCT along with the collecting duct
How are the nephrons oriented within the kidney?
Upper portion of Henle’s loop is in the cortex, and the lower part is in the medulla
What are the functions of the kidneys?
Cleansing the extracellular fluid
Maintainance of acid-base balance
Excretion of metabolic waste and foreign substances
What are the three basic renal processes?
Filtration
Reabsorption
Secretion
Where does filtration occur?
At the glomerulus
What is filtration?
Non-selective and passive process: virtually all small molecules are filtered, cells and large molecules remain in blood
What are the most abundant substances in the filtrate?
Na+ and Cl-
HCO3- and K+ are also present but in smaller amounts
Which substances undergo reabsorption?
> 99% of water, electrolytes, and nutrients that are filtered
How are solutes reabsorbed?
Active transport
How is water reabsorbed?
Follows solutes and is reabsorbed through passive diffusion
How do diuretics work?
Modulating the reabsorption
How many pumps do the kidneys have for active secretion?
Two: one for organic acids and one for organic bases
What is the role of the two major pumps on the kidneys?
Promote excretion of the molecules like waste, toxins and drugs
Where are the two major pumps of the kidneys located?
In the PCT
Why are Na+ and Cl- the ions of greatest interest when it comes to reabsorption?
They are the most abundant
What is the reabsorptive capacity of PCT?
Highly reabsorptive capacity
65% of Na+ and Cl- reabsorbed at the PCT
All of bicarbonate and potassium reabsorbed at PCT
How are substances reabsorbed at the PCT?
Sodium, chloride, and other solutes –> active reabsorption
Water follows through passive reabsorption
What is the descending loop of Henle like?
Freely permeable to H2O
H2O is drawn from the loop into the interstitial space
What is reabsorption in the ascending loop of Henle like?
20% of filtered Na and Cl is reabsorbed
It is NOT permeable to water; water remains in the loop as Na & Cl are reabsorbed
What is the reabsorption of the early segment of DCT like?
10% of filtered Na & Cl is reabsorbed, water follows passively
What is the distal nephron the site of?
Exchange of Na for K and is under the influence of aldosterone
Determination of the final concentration of urine and regulated by ADH
What stimulates the sodium-potassium exchange?
Aldosterone
What is the role of aldosterone in the sodium-potassim exchange process?
Aldosterone increases the expression of the pumps responsible for sodium and potassium transport
What is the purpose of diuretics?
They increase urine flow which is directly related to the amount of Na and Cl reabsorption which is blocked
How do diuretics work?
Most diuretics block Na & Cl reabsorption; they create an osmotic pressure within the nephron that prevents the passive reabsorption of water
What is the order of highest reabsorption to lowest, excluding PCT?
Highest in the loop, followed by early DCT, followed by late DCT and collecting duct (distal nephron)
Which drug would have a greater diuretic effect and why? Furosemide or Thiazides?
Furosemide because it blocks reabsorption in the loop, which is higher than the reabsorption in the early DCT, where Thiazides work
What is the adverse impact of diuretics on extracellular fluid?
Diuretics cause hypovolemia, acid-base imbalance, and altered electrolyte levels
How are the adverse effects of diuretics minimized?
By using short-acting diuretics and by timing drug administration such that the kidney is allowed to operate in a drug-free manner between periods of diuresis
What are the classifications of diuretics?
Loop diuretics
Thiazide diuretics
Potassium-sparing
Osmotic diuretics
Carbonic anhydrase inhibtors
What is the most effective kind of diuretic available?
Loop diuretics, they produce more loss of fluid and electrolytes than any other diuretic
What are examples of loop diuretics?
Furosemide
Butemanide
Torasemide
Ethacrynic acid
What cases is Furosemide used in?
HTN and edema caused by CHF
When is Bumetanide given/used?
Furosemide-unresponsive patients,
40 times more potent (rapid diuresis) than Furosemide
What is Torasemide?
More prolonged action than Furosemide, with less potassium loss
What is Ethacrynic acid? When is it used?
The only loop diuretic without a sulfonamide group; used with patients with sulfonamide intolerance
What is the MOA of Furosemide?
Inhibits the Na+ K+ 2Cl- cotransporter, if no Na+ transported, then no K+ which means no K+ in the blood (hypokalaemia)
Where does Furosemide act?
Thick ascending loop of Henle
What are the PK of Furosemide?
Oral administration, diuresis begins in 60 minutes and persists for about 8 hours
Furosemide undergoes hepatic metabolism followed by renal excretion
What are the therapeutic uses of Furosemide? (4)
- Pulmonary edema associated with CHF
- Edema (unresponsive to less efficacious diuretics)
- HTN that cannot be controlled with other diuretics
- Patients with severe renal impairment
What happens if Furosemide, on it own is insufficient?
Add a thiazide
What is the effect of adding another loop diuretic to Furosemide?
There is no added beneift
What are the adverse effects of Furosemide? (11)
Hyponatremia, hypochloremia and dehydration
Hypotension
Hypokalemia
Ototoxicity
Low Mg & Ca
Maternal death/abortion
Hyperuricemia
Hyperglycemia
Weakness/tiredness
What are signs of evolving dehydration with Furosemide?
Dry mouth, unusual thirst, and oliguria
How can the risk of dehydration be minimized (Furosemide)?
Initiating therapy with low doses, adjusting the dosage carefully, and monitoring loss every day
What causes hypotension (Furosemide)?
- Loss of volume
- Relaxation of venous smooth muscle
What are the signs of hypotension?
Dizziness, lightheadedness, fainting
What are the complications of Hypokalemia (Furosemide)?
Fatal dysrhythmias
When is hypokalemia a special concern?
When patients are on digoxin, heart failure drug
How is hypokalemia minimised?
Consuming potassium-rich foods, taking potassium supplements or using potassium-sparing diuretics
What are the effects of ototoxicity due to Furosemide?
Rare hearing impairment, deafness is transient
What is the concern wth hyperuricemia (Furosemide)?
Gout
What are the drug interactions between Furosemide and Digoxin?
Increased risk of digoxin-induced toxicity
To reduce the risk: monitor K levels and when indicated K+ supplements or K+ sparing diuretc
What are the drug interactions between Furosemide and Ototoxic drugs?
Increase risk of ototoxicity, especially aminoglycoside antibiotics (Gentamicin)
What are the drug interactions between Furosemide and potassium-sparing diretics?
Helpful; reduce risk of hypokalemia
What are the drug interactions between Furosemide and NSAIDs?
Attenuate effects of Furosemide
What are the drug interactions between Furosemide and Antihypertensive drugs?
Excessive reduction in BP
What are the drug interactions between Furosemide and Lithium?
Used in bipolar disorders
When Na levels are low, Li excretion is reduced
What are examples of Thiazide diuretics?
Hydrocholorothiazie and chlororthalidone
How do thiazide diuretics work?
They decrease reabsorption of NaCl by inhibiting Na+/Cl- co-transporter on the DCT
Which membrane do thiazide diuretics act upon?
The luminal membrane, which means they must be present in the tubular fluid to have an effect on the Na+/Cl- transporter
What is an example of patients that should not use thiazide diuretics?
Patients with inadequate kidney function should use loop diuretics
What are the uses of thiazide diuretics?
Useful as initial therapy unless compelling issues prevent that
What are the adverse effects of thiazide diuretics?
Hypokalemia
Hyperuricemia
Hyperglycemia
What is the most widely used thiazide diuretic?
Hydrochlorothiazide
What is the MOA of Hydrochlorothiazide?
Blocks reabsorption of Na & Cl in the early segment of the DCT
What are the PK of Hydrochlorothiazide?
Diuresis begins 2 hours after oral administration; effects peak within 4 to 6 hours
Where is Hydrochlorothiazide excreted?
Most of it excreted unchanged in the urine
What are the therapeutic uses of Hydrochlorothiazide? (4)
- Essential HTN
- Edema
- Hyper-calciurea
- Diabetes inspidus
What is the preferred drug for edema?
Thiazides; Hydrocholorothiazide
How do Thiazides help with hyper-calciurea?
They promote the reabsorption of Ca (which is good for osteoporosis and recurrent stone formation in the kidneys)
What are the adverse effects of Hydrochlorothiazide?
Similar to loop diuretics but no ototoxicity and hypocalcemia/hypomagnesemia
What are the drug interactions of Hydrochlorothiazide?
Identical to loop diuretics
CAN be combined with ototoxic agents, though, without an increased risk of hearing loss
What are other examples of thiazides?
Chlorothiazide & Methylclothiazide
Where do the K+ sparing diuretics act?
Act on late DCT and collecting tube
What are the two mechanisms of K+ sparing diuretics?
Non-aldosterone receptor blockers
Aldosterone receptor blockers
Which K+ sparing diuretics are non-aldosterone receptor blockers?
Amiloride, Triamterene
Which K+ sparing diuretics are aldosterone receptor blockers?
Spironolactone, Eplerenone
How are K+ sparing diuretics sometimes used?
With loop/thiazide diuretics to reduce K+ loss
What is the role of aldosterone?
Promotes Na uptake in exchange for K selection
What is the MOA of Spironolactone?
Blocks aldosterone –> retention of K and increased secretion of Na
How long do Spironolactone effects take to develop?
They are delayed effects, take up to 48 hours to develop
What are the therapeutic uses of Spironolactone? (6)
- HTN & Edema
- Heart Failure
- Primary Hyperaldosteronism
- PMS
- PCOS
- Acne in young women
What are the adverse effects of Spironolactone?
Hyperkalemia
Endocrine effects
What are examples of the endocrine effects that Spironolactone causes?
Gynecomastia
Menstrual irregularities
Impotence
Hirsutism
Deepening of the voice
What are the drug interactions of Spironolactone?
Thiazide and loop diuretics
Agents that raise K+ levels (should be used ONLY when CLEARLY necessary)
What are examples of agents that raise K+ levels?
ACE inhibitors
ARBs
Direct renin inhibitors
What is the MOA of Triamterene?
Directly inhibits exchange protein (ENaC)
Results in a net decrease in Na reabsorption and a reduction in K secretion
Does Triamterene act slowly or quickly? Why?
Quickly, because it directly blocks the exchange
Why should you be careful if Triamterene is used with ACEi, ARBs, and direct renin inhibitors?
They suppress aldosterone secretion and thus can elevate K levels
What are the therapeutic uses of Triamterene?
HTN & Edema (used in combination with loop/thiazide)
What are the adverse effects of Triamterene?
Nausea, vomiting, leg cramps and dizziness
Which drug is similar to Tramterene?
Amiloride
Which diuretic categories does Mannitol fall under?
Osmotic diuretic
What is the MOA of Mannitol?
Freely filtered in the glomerulus
Undergoes minimal reabsorption
Undergoes minimal metabolism
Pharmacologically inert
Why must Mannitol be given parenterally?
It does not diffuse across GI and cannot be transported by carriers/receptors
What are the therapeutic uses of Mannitol?
Prophylaxis for renal failure
Reduction of intracranial pressure
Reduction of intraocular pressure
What are the adverse effects of Mannitol?
Edema, careful with heart disease
Headache, nausea and vomiting
What is an example of a carbonic anhydrase inhibitor?
Acetazolamide
What tubule does Acetazolamide work on?
PCT
What is the purpose of Acetazolamide?
Mostly used for their other pharmacologic effects rather than than diuretic effect because they are MUCH less efficacious than other diuretics
What are the therapeutic uses of Acetazolamide?
Glaucoma and Altitude sickness
How does Acetazolamide help with Glaucoma?
Oral acetazolamide decreases the production of aqueous humor and reduces IOP with chronic open-angle glaucoma
What are the examples of topical carbonic anhydrase inhibitors that do not cause systemic effects?
Dorzolamide
Brinzolamide
How does Acetazolamide help with altitude sickness?
It prevents weakness, breathlessness, dizziness, nausea, and cerebral as well as pulmonary edema
What are the PK of Acetazolamide?
PO or IV
90% protein bound
Eliminated by kidney
What are the adverse effects of Acetazolamide?
Metabolic acidosis
Potassium depletion
Renal stone formation
What is the contraindication of Acetazolamide?
Liver cirrhosis because it could lead to decreased excretion of NH4+
