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Flashcards in Renal/Uro pharm Deck (40)
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1

Diuretic

Any substance that increases urine volume
- Inhibitors of renal ion transporters
- Decreases the reabsorption of sodium at different sites of the nephron
- Increase in urine flow is secondary to increase in sodium excretion
- Kidneys adjust the excretion of sodium and water to maintain extracellular fluid (ECF)
- In pathophysiologic states, this balance is altered

Used for:
1. Diseases causing edema: CHF, Cirrhosis, nephrotic syndrome, renal failure
2. HTN
3. Nephrolithiasis
4. Hypercalcemia (loop diuretics)
5. Diabetes insipidus

2

Natriuretic

Any substance increasing renal sodium excretion (same function as diuretci)

3

Acetazolamide

Carbonic anhydrase inhibitor

Site of action: proximal tubule

MOA:
- Inhibits carbonic anhydrase
- Decreases sodium bicarbonate reabsorption
- Cause bicarbonate diuresis (up to 85%) that may lead to metabolic acidosis
- Over time (several days), effectiveness decreases--> soon increase Na reabsorption (thus reversing diuresis)

Use: metabolic alkalosis (alkalinizes urine)
- Induces hyperchloremic metabolic acidosis after excessive use of other diuretics
- Prophylax acute mountain sickness (decreases CSF formation, pH--> increase minute ventilation--> decrease symptoms)
- Glaucoma (decreases rate of aqueous humor formation--> decreased IOP)

AEs:
- Metabolic acidosis
- Phosphaturia, hypercalciuria (can cause calcium stone formation)
- Potassium wasting
- Toxicity: drowsiness/fatigue (CNS carbonic anhydrase inhibition), parasthesis, avoid in liver disease (increases ammonia--> hepatic encephalopathy)

4

Dichlorphenamide

Carbonic anhydrase inhibitor

Site of action: proximal tubule

MOA:
- Inhibits carbonic anhydrase
- Decreases sodium bicarbonate reabsorption
- Cause bicarbonate diuresis (up to 85%) that may lead to metabolic acidosis
- Over time (several days), effectiveness decreases--> soon increase Na reabsorption (thus reversing diuresis)

Use: metabolic alkalosis (alkalinizes urine)
- Induces hyperchloremic metabolic acidosis after excessive use of other diuretics
- Prophylax acute mountain sickness (decreases CSF formation, pH--> increase minute ventilation--> decrease symptoms)
- Glaucoma- topical use (decreases rate of aqueous humor formation--> decreased IOP)

AEs:
- Metabolic acidosis
- Phosphaturia, hypercalciuria (can cause calcium stone formation)
- Potassium wasting
- Toxicity: drowsiness/fatigue (CNS carbonic anhydrase inhibition), parasthesis, avoid in liver disease (increases ammonia--> hepatic encephalopathy)

5

Methazolamide

Carbonic anhydrase inhibitor

Site of action: proximal tubule

MOA:
- Inhibits carbonic anhydrase
- Decreases sodium bicarbonate reabsorption
- Cause bicarbonate diuresis (up to 85%) that may lead to metabolic acidosis
- Over time (several days), effectiveness decreases--> soon increase Na reabsorption (thus reversing diuresis)

Use: metabolic alkalosis (alkalinizes urine)
- Induces hyperchloremic metabolic acidosis after excessive use of other diuretics
- Prophylax acute mountain sickness (decreases CSF formation, pH--> increase minute ventilation--> decrease symptoms)
- Glaucoma (decreases rate of aqueous humor formation--> decreased IOP)

AEs:
- Metabolic acidosis
- Phosphaturia, hypercalciuria (can cause calcium stone formation)
- Potassium wasting
- Toxicity: drowsiness/fatigue (CNS carbonic anhydrase inhibition), parasthesis, avoid in liver disease (increases ammonia--> hepatic encephalopathy)

6

Furosemide

Loop diuretic

Site of action: cortical and medullary TAL of loop of Henle

MOA: inhibits Na+-K+-2Cl- transporter

Clinical:
- Rapid onset of action (first line in pulmonary edema)
- Stimulates prostaglandin synthesis in lung, kidneys (NSAIDs--> decreased prostaglandins--> decreased diuresis)
- CHF (decrease ECF volume)
- Excretion of: K+, Mg+2 and Ca+2 (Ca reabsorbed later in DCT, but can be used in hypercalcemia)
- Blocks reabsorption of bromide, fluoride, iodide (poisoning)
- Used 2nd line or with thiazide diuretics for HTN
- Edema of nephrotic syndrome (refractory to other diuretics)

Side effects:
- hypokalemia, hypomagnesemia
- hyperuricemia (gouty attack)
- hypochloremic metabolic alkalosis (increased excretion of H+)
- Dose-related irreversible hearing loss (alters membranous labyrinth in inner ear)
- Cross-reactivity with sulfonamide allergy
- Dehydration
- Increased LDL, triglycerides, decreased HDL

7

Bumetanide

Loop diuretic

8

Torsemide

Loop diuretic

9

Ethacrynic acid

Loop diuretic

10

Hydrochlorothiazide

Thiazide diuretics

Site of action: distal convoluted tubule

MOA: inhibits luminal co-transport of Na, Cl
- Contraction of ECF volume--> decrease in CO--> decrease peripheral vascular resistance

Clinical use:
- Augment production of vasodilatory prostaglandins (NSAID interaction)
- Use in HTN, mild CHF
- Edema due to liver/renal disease
- Only moderately efficacious in decreasing Na+ reabsorption (most reabsorbed before DCT)
- Increased K, H excretion
- Decreased renal Ca+2 excretion (good with urinary stone treatment)

Conditions:
- Nephrogenic DI: paradoxical decrease in urine output

AEs:
- Avoid in low GFR
- "Ceiling diuretics": increasing dose does not promote further diuresis
- hypokalemia, hypomagnesemia
- hyperuricemia (gouty attack)
- hypochloremic metabolic alkalosis
- Sulfa allergy interaction: photosensitivity, generalized dermatitis (rare)
- Hyperglycemia (impair pancreatic insulin release, tissue utilization of glucose)
- Hyperlipidemia

11

Chlorothalidone

Thiazide diuretics

12

Metolazone

Thiazide diuretics

13

Spironolactone, eplerenone

Potassium-sparing diuretic

MOA: competitive antagonist of aldosterone receptors on collecting tubule (Na-H exchanger)

SIte of action:
- Cortical collecting tubule

Clinical:
- Most effective in primary/secondary hyperaldosteronism (Conn syndrome) - prevents binding of aldosterone to its receptor
- Secondary hyperaldosteronism seen in: CHF, hepatic cirrhosis, nephrotic syndrome
- Ascites
- HTN
- Loop/thiazide-induced hypokalemia

AEs:
- Hyperkalemia (if not on another diuretic)
- Hyperchloremic metabolic acidosis= blocks collecting duct Na-H exchange (aldosterone receptor)--> can't excrete H+
- Endocrine abnormalities: gynecomastia, hirsutism, impotence, benign prostatic hyperplasia, menstrual irregularities

14

Triamterene, amiloride

Postassium-sparing diuretic

MOA: interferes with Na+ influx thru epithelial Na ion channels in luminal membrane (Na-H exchanger in collecting duct)
- K+ secretion coupled with Na+ entry (therefore spare K+ secretion by blocking Na entry)

Clinical use:
- HTN
- Loop/thiazide-induced hypokalemia

AEs:
- Hyperkalemia (if not on another diuretic)
- Hyperchloremic metabolic acidosis= blocks collecting duct Na-H exchange (aldosterone receptor)--> can't excrete H+

15

Eplerenone

Spironolactone with greater selectivity to mineralocorticoid receptor
- Less activity on androgen, progesterone receptors (decreased side effects)
- Blocks fibrosis/inflammation caused by aldosterone--> slows albuminuria in diabetes

16

Mannitol

Osmotic diuretic

Not reabsorbed, causing water to be retained initially, then diuresis

Site of action:
- Proximal tubule: decreased Na reabsorption by osmotic gradient--> increased urine volume
- Descending loop of Henle: increased medullary blood flow, inhibit reabsorption of water
- Collecting duct: opposes action of ADH

Clinical:
- Prevents acute renal failure after severe trauma, complicated surgical procedures (hemolysis, rhabdomyolysis)
- Toxin excretion
- Reduces intracranial, intraocular pressure--> fluid (not Na) leaves cells
- Does not increase Na excretion (only water)
- Must be given IV (only effects colon if given orally)

AEs:
- Rapidly distributes to ECF--> extracts water from cells
- Causes acute increase in ECF/hyponatremia (can't use in CHF, pulmonary edema)
- N/V, headache
- Severe dehydration, hypernatremia
- Hyperkalemia

17

Conivaptan

Antidiuretic hormone antagonist

MOA: inhibits effects of ADH

Site of action: collecting duct

Clinical use:
- Hypervolemic, euvolemic hyponatremia not corrected by fluid restriction
- SIADH (with failure of water restriction)
- CHF, cirrhosis (diminished circulating blood volume)--> increased ADH
- Conivaptan= IV

AEs:
- Severe hypernatremia
- Too rapid correction can cause seizures/death

18

Tolvaptan

Antidiuretic hormone antagonist

Can be administered PO

19

Edema and diuretics

NaCl reabsorption too high in many disease states leading to:
- Water retention
- increased blood volume
- Expansion of ECF compartment

20

CHF and diuretics

Diuretic of choice: Loop diuretic

CO continues to deteriorate--> kidney retains sodium, water
- Water leaks from vasculature--> interstitial--> pulmonary edema

Diuretics:
- Improve exercise tolerance, quality of life
- Reduce fluid retention symptoms
- Reduce hospitalizations

Do not:
- alter disease progression

Clinical:
- Change in body weight is sensitive marker of fluid retention due to CHF

21

Kidney disease and diuretics

Cause retention of sodium, water
- Milder renal insufficiency, diuretics beneficial
- Need larger doses as GFR declines (risk hearing loss)
- Continuous infusion dosing best

Does not:
- reverse clinical disease, help with renal function
- minimally beneficial in severe insufficiency

* avoid acetazolamide (worsening acidosis) and potassium-sparing diuretics (hyperkalemia)

22

Diuretic resistance in renal failure

1. Excessive sodium intake
2. Inadequate diuretic dose
3. Reduced oral bioavailability (double dose IV to oral)
4. Nephrotic syndrome: glomerulus allows plasma protein loss--> decreased osmotic pressure and increased aldosterone--> edema/Na/water retention
5. Reduced renal blood flow:
- NSAIDs, ACE-I, Vasodilators
- Hypotension (Intravascular volume expansion, vasopressors)
- Intravascular depletion (volume expansion)
6. Heart failure
7. Nephrotic adaptation
8. Cirrhosis (tx: paracentesis)
9. Acute tubular necrosis
10. Some patients with resistance respond to continuous infusions

23

Cirrhosis and diuretics

Liver disease--> obstructed portal blood flow--> increased portal pressure
- Decreased plasma protein synthesis--> decreased oncotic pressure
- Both cause fluid to leave portal vascular system--> collects in abdomen

Mechanism for Na retention:
- diminished renal perfusion
- Diminished plasma volume (+ ascites)
- Diminished oncotic pressure (low albumin)
- Primary sodium retention (elevated aldosterone)

24

HTN and diuretics

Thiazide= first line

Enhance other anti-hypertensives

25

Nephrolithiasis and diuretics

Thiazide diuretics: enhance calcium reabsorption (decrease urinary calcium concentration)

2/3 kidney stones have calcium phosphate or oxalate crystals (hypercalcuria)

26

Drug treatments for BPH

1. Alpha antagonists (-zosin)
- Old= terazosin, dexazosin (need to be titrated to avoid hypotension)
- Newer formulas target Alpha-1 receptors
- Decreased risk of postural hypotension

2. 5-alpha reductase inhibitors
- May take 6-12 months for maximal effect

27

Alpha-1 antagonists: AEs

- Postural hypotension (dizziness)
- Nasal congestion
- Headache
- Asthenia (weakness)
- Abnormal (retrograde) ejaculation)
- Erectile dysfunction (can cause or improve)
- Avoid with planned cataract surgery (Floppy Iris Syndrome)

28

5-alpha reductase inhibitors

Testosterone converted to 5-DHT in prostate by 5-alpha reductase
- 5DHT contributes to BPH
- Blocking 5-alpha reductase--> decreased DHT--> decreased BPH

Type 2= seen primarily in genitals vs Type 1 (liver and skin)

29

Finasteride

Inhibits Type II 5-AR

Side effects:
- Decreased libido
- Ejaculatory disorder
- Erectile dysfunction
- Breast tenderness
- Gynecomastia

30

Dutasteride

Inhibits Type I and II 5-AR

Side effects:
- Decreased libido
- Ejaculatory disorder
- Erectile dysfunction
- Breast tenderness
- Gynecomastia