Lecture 2: Diuretics Pharm Flashcards
1
Q
What’s a diuretic vs. natriuretic vs. aquaretic?
A
- Diuretic = substance that promotes excretion of urine
- Natriuretic = substance that promotes renal excretions of sodium
- Aquaretic = substance that produces free water clearance = Vaptans
2
Q
What 2 types of diuretics act at the proximal tubule?
A
- Osmotic diuretics
- Carbonic anhydrase inhibitors
3
Q
Which class of diuretics act at the Thin descending limb of Henle?
A
Osmotic diuretics
4
Q
What are the 4 classes of K+-losing diuretics?
A
- Thiazides
- Loop diuretics
- Carbonic anhydrase inhibitors
- Osmotic diuretics
5
Q
Major effects of hyperkalemia on the heart?
A
- Tall T waves
- Arrhythmias including bradycardia
6
Q
Major effects of Hypokalemia on the heart?
A
- Tall U waves
- Atrial arrhythmias
- VTAC or VFIB
7
Q
Explain why some diuretics are potassium-losing and others are potassium-sparing?
A
- 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+
8
Q
Where do Loop Diuretics exert their effects in the nephron?
MOA?
A
- Thick ascending limb of Henle
- Block the Na+-K+-2Cl- co-transporter = inhibit reabsorption of Na+ and Cl-
9
Q
What is the prototypical loop diuretic?
Others in this class?
A
- Furosemide = most frequently prescribed
- Torsemide
- Bumetanide
- Ethacrynic acid
10
Q
What are loop diuretics used for?
A
- 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
11
Q
If a patient has a sulfa allergey, which loop diuretic can you use?
A
Ethacrynic acid
12
Q
What distinguishes the loop diuretics torsemide and bumetanide?
A
- Torsemide = longer t1/2, better oral absorption, and may work better in HF
- Bumetanide = has more predictable oral absorption
13
Q
Which diuretic class can work in patients with low GFR and RBF?
A
Loop diuretics
14
Q
Major adverse effects of Loop Diuretics?
Which toxicity?
A
- HYPOmagnesemia
- HYPOcalcemia –> increased kidney stone risk (opposite of thiazides!)
- Ototoxicity
15
Q
How powerful are Loop Diuretics and what kind of urine is produced?
A
- Greatest amount of diuresis
- Max doses –> Larg volume of isotonic urine; irrespective of whether urine was dilute or concentrated
16
Q
What are 3 drug interactions you must be aware of when using Loop Diuretics?
A
- Digoxin
- Ototoxic drugs
- K+-sparing diuretics
17
Q
What is the most commonly used Thiazide diuretic?
A
Hydrochlorothiazide (HCTZ)
18
Q
Where is the site of action for Thiazides in the nephron?
MOA?
A
- Distal convoluted tubule (DCT)
- Block Na+-Cl- cotransporter
19
Q
What are the major therapeutic uses of Thiazide diuretics?
Decreases risk of?
A
- 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)
20
Q
What are 4 major adverse effects of Thiazides?
A
- HYPOvolemia
- K+-losing diuretic
- Hypochloremic metabolic alkalosis
- HYPOmagnesemia (may be severe!)
21
Q
What are some drug interactions (good/bad) of Thiazides?
A
- Often combined w/ antihypertensive meds from other classes to potentiate BP lowering effects
- Increased risk of digoxin and lithium toxicity!
22
Q
What are the 2 classes of K+ sparing diuretics and drugs in each?
A
- Na+ channel blockers –> amiloride and triamterene
- Aldosterone antagonists –> spironolactone and eplerenone
23
Q
Where do the K+-sparing diuretics, amiloride and triamterene, exert their effects?
MOA?
A
- 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
24
Q
What are the therapeutic uses of the K+-sparing diuretics (amiloride and triamterene)?
Off label uses?
A
- 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
25
Adverse effects associated with the K+-sparing diuretics: amiloride and triamterene?
- **Hyperkalemia** (boxed warning)
- N/V, leg cramps, and dizziness are common
26
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**
27
Why is the pharmacokinetics of the K+-sparing diuretics, spironolactone and eplerenone, significant?
Can take **48 hours** to work!
28
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
29
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
30
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
31
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**
32
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)
33
What are the adverse effects associated with the Vaptans?
- Orthostatic HTN
- Fatigure
- Thirst
- Polyuria, bedwetting
34
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
35
Which 2 diuretics are **sulfonamide** drugs so must be careful with people that have sulfa allergies?
- Thiazides
- Loop diuretics (except ethacrynic acid)
36
What is the prototypical carbonic anhydrase inhibtor of the diuretic class?
Acetazolamide
37
What are the pharmacologic effects of the carbonic anhydrase inhibitor, acetazolamide?
Acts where?
- Acts at **proximal tubule**
- Sodium bicarbonate diuresis
- Hyperchloremic acidosis
38
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
39
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**
40
Adverse effects of Osmotic Diuretics?
- Extracellular volume is acutely **increased**, which can **exacerbate heart failure**
- HA, N/V, and fluid/electrolyte imbalances can occur
41
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
42
The loss of what ion tends to be greater with thiazides than loop diuretics?
Mg2+
43
Drug of choice for treating central/neurogenic diabetes insipidus?
Desmopressin (synthetic **V2** agonist)
44
Drug of choice for treating nephrogenic diabetes insipidus?
Thiazide diuretic (**unless caused by Li+)**
45
Treatment of choice for Li-induced Diabetes Insipidus?
**Amiloride** ---\> blocks Li+ influx into principal cells, allowing ADH to work
46
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
47
What channel reabsorbs Mg in the distal tubule?
TRPM6
48
What channel reabsorbs calcium in the DCT?
TRPV5
