Lecture 2: Diuretics Pharm Flashcards
What’s a diuretic vs. natriuretic vs. aquaretic?
- Diuretic = substance that promotes excretion of urine
- Natriuretic = substance that promotes renal excretions of sodium
- Aquaretic = substance that produces free water clearance = Vaptans
What 2 types of diuretics act at the proximal tubule?
- Osmotic diuretics
- Carbonic anhydrase inhibitors
Which class of diuretics act at the Thin descending limb of Henle?
Osmotic diuretics
What are the 4 classes of K+-losing diuretics?
- Thiazides
- Loop diuretics
- Carbonic anhydrase inhibitors
- Osmotic diuretics
Major effects of hyperkalemia on the heart?
- Tall T waves
- Arrhythmias including bradycardia
Major effects of Hypokalemia on the heart?
- Tall U waves
- Atrial arrhythmias
- VTAC or VFIB
Explain why some diuretics are potassium-losing and others are potassium-sparing?
- K+-losing diuretics block Na+ reabsorption causing an increased delivery to the distal segments of the nephron, which activates aldosterone-sensitive Na+ pumps, which exchange Na+ for K+
- K+-sparing either block Na+ channels or the aldosterone sensitive pumps in the distal segments form working so that no Na+ is exchanged for K+
Where do Loop Diuretics exert their effects in the nephron?
MOA?
- Thick ascending limb of Henle
- Block the Na+-K+-2Cl- co-transporter = inhibit reabsorption of Na+ and Cl-
What is the prototypical loop diuretic?
Others in this class?
- Furosemide = most frequently prescribed
- Torsemide
- Bumetanide
- Ethacrynic acid
What are loop diuretics used for?
- Use when rapid and massive fluid removal is needed
- Management of edema in HF, hepatic and renal dz
- Acute pulmonary edema, by decreasing preload
- Tx of HTN that is unresponsive to other diuretics
If a patient has a sulfa allergey, which loop diuretic can you use?
Ethacrynic acid
What distinguishes the loop diuretics torsemide and bumetanide?
- Torsemide = longer t1/2, better oral absorption, and may work better in HF
- Bumetanide = has more predictable oral absorption
Which diuretic class can work in patients with low GFR and RBF?
Loop diuretics
Major adverse effects of Loop Diuretics?
Which toxicity?
- HYPOmagnesemia
- HYPOcalcemia –> increased kidney stone risk (opposite of thiazides!)
- Ototoxicity
How powerful are Loop Diuretics and what kind of urine is produced?
- Greatest amount of diuresis
- Max doses –> Larg volume of isotonic urine; irrespective of whether urine was dilute or concentrated
What are 3 drug interactions you must be aware of when using Loop Diuretics?
- Digoxin
- Ototoxic drugs
- K+-sparing diuretics
What is the most commonly used Thiazide diuretic?
Hydrochlorothiazide (HCTZ)
Where is the site of action for Thiazides in the nephron?
MOA?
- Distal convoluted tubule (DCT)
- Block Na+-Cl- cotransporter
What are the major therapeutic uses of Thiazide diuretics?
Decreases risk of?
- Primary HTN (often in combo w/ other drugs) and edema
- Nephrogenic diabetes insipidus (if NOT due to lithium toxicity)
- Decreases Ca2+ excretion, can decrease risk of kidney stones (opposite of loop diuretics)
What are 4 major adverse effects of Thiazides?
- HYPOvolemia
- K+-losing diuretic
- Hypochloremic metabolic alkalosis
- HYPOmagnesemia (may be severe!)
What are some drug interactions (good/bad) of Thiazides?
- Often combined w/ antihypertensive meds from other classes to potentiate BP lowering effects
- Increased risk of digoxin and lithium toxicity!
What are the 2 classes of K+ sparing diuretics and drugs in each?
- Na+ channel blockers –> amiloride and triamterene
- Aldosterone antagonists –> spironolactone and eplerenone
Where do the K+-sparing diuretics, amiloride and triamterene, exert their effects?
MOA?
- Directly block the Na+ channels (ENaC) in the collecting ducts and adjacent upstream nephron region known as “connecting tubule”
- ↑ urinary Na+ excretion
- ↓ urinary K+ excretion
What are the therapeutic uses of the K+-sparing diuretics (amiloride and triamterene)?
Off label uses?
- HTN and edema, often in combo w/ loop or thiazide diuretics
- Counteracts K+ loss induced by the other diuretics
- Sometimes used off label: ascites and pediatric HTN
Adverse effects associated with the K+-sparing diuretics: amiloride and triamterene?
- Hyperkalemia (boxed warning)
- N/V, leg cramps, and dizziness are common
Where do the K+-sparing diuretics, spironolactone and eplerenone, exert their effects and what is their MOA?
Which 2 receptors do they act on?
- Competitive antagonists of aldosterone receptors in the collecting duct —> ↑ Na+ excretion and ↓ K+ excretion
- Also partial agonists at andogen receptors
Why is the pharmacokinetics of the K+-sparing diuretics, spironolactone and eplerenone, significant?
Can take 48 hours to work!
What are the therapeutic used for the K+-sparing diuretics, spironolactone and eplerenone?
Known to greatly reduce mortality rate in which pts?
- Tx of HTN and edema, often in combo w/ loop or thiazide diuretics
- Primary hyperaldosteronism
- Also known to greatly reduce mortality rate in pts w/ severe heart failure… decrease myocardial fibrosis, reduced early morning rise in HR
What are 2 major adverse effects associated with the K+-sparing diuretics, spironolactone and eplerenone?
- HYPERkalemia
- Endocrine effects –> gynecomastia, impotence, menstrual irregularites, hirsutism, and deeping voice
What is the MOA and site of action for the Vaptans?
- Block the ADH receptor in the collecting duct
- Prevent ADH-mediated insertion of the aquaporin H2O channels into luminal membrane of principle cells of collecting duct
- Increases H2O excretion –> ↓ plasma volume and ↑ plasma osmolality
What is special about the aquaretic, Tolvaptan?
When is it used for hyponatremia and what must you be careful about?
- Selective V2 recpetor antagonist administered orally
- Only used in hospital and MUST use ≤ 30 days for hyponatremia, due to potential for fatal hepatotoxicitiy
What are the therapeutic uses for the Vaptans?
- Hypervolemic or Euvolemic HYPOnatremia in pts who are hostpitalized, symptomatic, or not responsive to fluid restriction
- Autosomal dominant polycystic kidney dz (slows progression)
What are the adverse effects associated with the Vaptans?
- Orthostatic HTN
- Fatigure
- Thirst
- Polyuria, bedwetting
Vaptans are metabolized by what, so there is potential for drug interactions?
- CYP3A4
- Inhibitors and inducers of this enzyme can alter its 1/2 life and potential for toxicity
Which 2 diuretics are sulfonamide drugs so must be careful with people that have sulfa allergies?
- Thiazides
- Loop diuretics (except ethacrynic acid)
What is the prototypical carbonic anhydrase inhibtor of the diuretic class?
Acetazolamide
What are the pharmacologic effects of the carbonic anhydrase inhibitor, acetazolamide?
Acts where?
- Acts at proximal tubule
- Sodium bicarbonate diuresis
- Hyperchloremic acidosis
Use of carbonic anhydrase inhibitors is now quite limited, but what are 4 things its still used for?
- Urinary alkalinization
- Metabolic alkalosis
- Glaucoma
- Acute mountain sickness
What is the prototype osmotic diuretic and what is its MOA both in the kidney and throughout the body?
Net effect?
- Mannitol
- Minimally reabsorbed and the inability to reabsorb this solute keeps H2O in the prox. tubule lumen –> excreted
- Mannitol acts throughout body to pull H2O out of cells
- Net effect = excrete total body water in excess of plasma electrolytes
Adverse effects of Osmotic Diuretics?
- Extracellular volume is acutely increased, which can exacerbate heart failure
- HA, N/V, and fluid/electrolyte imbalances can occur
What are/were 3 therapeutic uses of osmotic diuretics?
- Prophylaxis of renal failure –> prevents renal tubule collapse when GFR is low
- Reduction of ICP (no longer the best choice)
- Reduction of intraolcular pressure –> Tx of glaucoma when pts haven’t responded to other therapy
The loss of what ion tends to be greater with thiazides than loop diuretics?
Mg2+
Drug of choice for treating central/neurogenic diabetes insipidus?
Desmopressin (synthetic V2 agonist)
Drug of choice for treating nephrogenic diabetes insipidus?
Thiazide diuretic (unless caused by Li+)
Treatment of choice for Li-induced Diabetes Insipidus?
Amiloride —> blocks Li+ influx into principal cells, allowing ADH to work
Appearance of what 3 clinical findings is suggestive of bilateral renovascular HTN rather than primary HTN?
- Flash pulmonary edema
- Progressive renal failure
- Refractory congestive cardiac failure
