1. Acute pulmonary edema 

2. Edema associated with heart failure, cirrhosis, renal failure
3. Hypertension (but thiazides more commonly used - more effective in patients with normal renal function, and thiazides decrease mortality and morbidity)

4. Hypercalcemia - a classic use, but minimal supporting evidence, bisphosphonates preferred

5. Acute renal failure - convert oliguria to nonoliguria (not supported by recent meta-analyses - furosemide does not improve mortality or decrease th eneed for transplant/dialysis, may cause ototoxicity)

1. enhanced Na retention in distal tubule - after chronic use

2. Post diuretic salt retention (between doses of short-acting agents) exacerbated by high sodium intake          3. Chronic renal failure - decreased RBF limits delivery of diuretic to kidney and accumulation of organic acids competes for transport
4. Nephrotic syndrome - urinary protein binds diuretics and decreases free concentration in urine

Na/Cl (@ DCT) symporter inhibitors (2)

Mechanism:

Compared to loops (2)

(2)

Drugs: 1) hydrochlorothiazide 2) chlorthalidone

Mechanism:

A. Effects Compared to Loops

1) because only 5-7% of Na is reabsorbed at this site, net natriuresis and diuresis is less than for loop diuretics.

2) Also because this symporter does not contribute to the medullary gradient, thiazides do not alter the ability to produce a maximally concentrated urine in the presence of ADH

B.  Increased Ca absorption (via Ca channel & Ca ATPase and 3Na/Ca exchanger)

C. Net effect: increase in Na, Cl, K, H, and Mg excretion and a decrease in Ca excretion (if drug has CA inhibitory activity, then HCO3 and PO4 excretion increase too)

1. All orally available
2. Half-lives vary from  hours (Hydrochlorothiazide, about 2.5 hrs) to about 2 days  (Chlorthalidone)

3. Protein binding varies, and drugs are secreted by the weak acid transporter (therefore probenecid interaction)

a. Volume depletion 
b. Hypotension

c. Hyponatremia (Na loss with no reduction in ability to reabsorb water in the CD)
d. Hypokalemia (Na+/K+ "exchange" in the CD)              
e. Metabolic alkalosis (Na+/H+ "exchange" in the CD)
f. Hypochloremia
g. Hypomagnesemia (mechanism unclear)
h. Hypercalcemia, (Ca may be high normal, frank hyperalcemia unlikely)

a. Hyperuricemia (with chronic administration)(gout?).

b. Decreased glucose tolerance (both reduced insulin secretion and altered glucose metabolism)--effect is reduced if K+ given along with diuretic.
c. Increase LDL and TGs, increase LDL/HDL ratio

1) erectile dysfxn

2) sulfonamide hypersensitivity

Drug interaction of Na/Cl symport inhibitors

Phkinetic (2)

Phdynamic (4)

Phkinetic:

1) Li

2) Probenecid (varies with fraction of diuretic that arrives in tubular fluid by transporter)

Phdynamic:

1) Digoxin

2) QT-prolonging agents

3) Loop diuretics (DCT NaCl  reabsorption up-regulate with chronic administration of loop diuretics

4) NSAIDs

1. Hypertension. --SE are dose related, use lowest possible doses.

2. Edema associated with CHF, hepatic cirrhosis, nephrotic syndrome, chronic renal failure (note, however, that with the exception of metolazone and indapamide, most of these drugs are ineffective if GFR decreases to < 30-40 ml/min)

3. Calcium nephrolithiasis (off label) and

4. Osteoporosis (off label)
5. Nephrogenic DI, reducing urine volume by up to 50%. Mechanism is unknown. Combination with amiloride more effective. (off label)

Drugs: 1) triamterene 2) amiloride

K-sparing diuretics - blockers of renal epithelial Na channels (Where?)

Mechanism (2)

Where? principal cells of late distal tubule and collecting tubule

Effect:

1) reduction of Na diffusion into principal cells which decreases the lumen's negative potential leading to decreased excretion of K, H, Ca, Mg

2) other diuretics increase K/H excretion by increasing delivery of Na to collecting duct and by evoking a compensatory response from the renin-angiotensin-aldosterone system

K-sparing diuretics - blockers of renal epithelial Na channels

Kinetics for each drug

(3)

(1)

1) triamterene

a.) half-life approximately 4 hrs

b.) active metabolite in addition to active parent compound

c.) elimination of active moieties is part renal, part biliary—thus t1/2  increases with either hepatic or renal failure

2. amiloride
a.) elimination is primarily renal, half-life about 20 hrs

 Adverse effects/Toxicity/ CI/ drug interactions of K-sparing drugs that block sodium channels on epithelial cells of kidney tubules

General (1)

Amiloride (4)

Triamterine (6)

1) Hyperkalemia

2) Amiloride - Nausea, vomiting, diarrhea, headache

3) Triamterine -

a.) weak folic acid antagonist

b.) photosensitization

c.) renal stones

d.) nausea/vomiting

e.) leg cramps

f.) dizziness

 1. In combination with other diuretics, to increase diuretic action while maintaining normal K (both are marketed in combination with hydrochlorothiazide)

2. Liddle's syndrome (pseudohyperaldosteroneism) - autosomal dominant mutations in Na channel subunits leading to increased basal inward Na current, producing low-renin, volume-expanded hypertension (off label)
3. Treatment of lithium-induced nephrogenic DI by blocking Li + entry into the cells of the collecting tubules. (off label)

Spironolactone

Eplerenone

 K-sparing diuretics--aldosterone antagonists

Mechanism

1)  competitive antagonists of aldosterone at the cytoplasmic mineralocorticoid receptor

2) Access to the cell is from the basolateral surface (the only diuretics that do not access their site of action from the renal tubule)

3.) The net effect of aldosterone in the kidney, is to increase activation of, migration of, and synthesis of luminal Na channels and basolateral Na/K-ATPase with a net increase in Na current from the tubule into the cell and net increase in Na transport from the renal epithelial cell to the interstitial fluid

4.) The net renal effect of spironolactone is similar to Na channel blockers but not as rapid in onset, and the magnitude of effect is dependent on basal aldosterone activity.

5.) Other physiological actions of aldosterone subject to blockade by these antagonists

a.) vasculature - fibrosis, endothelial dysfxn, inhibition of NO synthesis

b.) heart - fibrosis, LV hypertrophy, electrical excitability-arrythmias

Kinetics:

Spirinolactone

Eplerenone

1) Partially absorbed, converted to canrenone and other active metabolites - t1/2s are1.5 hrs (spironolactone) and 16 hrs (canrenone)

2) t1/2 5 hrs, primary clearance is via CYP3A4 conversion to inactive metabolites (caution when used with CYP3A4 inhibitors-dose decrease may be necessary)

K-sparing diuretics--aldosterone antagonists

Adverse effects/Toxicity/ CI/ drug interactions

Special spironolactone side effx (4)

1.) Similar to other K-sparing agents

2.) Special Txs with spironolactone - basis for  these effects includes spironolactone acting as an androgen receptor and progesterone receptor antagonist, and possibly alterations in sex steroid biosynthesis.

a.) gynecomastia,

b.) impotence,

c.) decreased libido,

d.) menstrual irregularities. 

3.) Eplerenone is a  more selective mineralocorticoid antagonist and appears to  have a better side-effect profile (time will tell)

4.) Metabolic acidosis in cirrhotic patients

5.) CI hyperkalemia, anuria

 Therapeutic utility for

K-sparing aldosterone antagonists

Spironolactone (5)

Eplerenone (2)

Spironolactone
a. Hypertension , commonly in combination with thiazides or loops to avoid hypokalemia

b.  Edema-nephrotic syndrome

c. Primary aldosteronism, secondary aldosteronism (cardiac failure, hepatic cirrhosis, severe ascites) --Spironolactone has been a diuretic of choice in patients with ascites
d. Reduces morbidity and mortality in pts with NYHA class III and class IV heart failure and ventricular arrhythmias (block of HERG K channels).

e. Used off-label to treat female hirsuitism.

2. Eplerenone
                  a. Hypertension
                  b. Heart failure post MI.

Diuretic "Braking"

Why (1)

Mechanisms (4)

* body cannot maintain chronic negative Na balance so it responds to retain more Na

1) Sympathetic activation

2) activation of renin-angiotensin-aldosterone system

3) decrease BP (decreases GFR)

4) hypertrophy of renal epithelial cells (increased expression of transporters)

1) Loops

2) DCT Diuretics

3) K-sparing

4) Osmotic Diuretics

5) CA Inhibitors

6) ADH effect blockers

bold = most popular

CA Inhibitors (2)

Molecular Effects (3)

Why are they not so effective (2)?

Drugs:

1.) Acetazolamide

2.) Dorzolamide

1.) block reabs of HCO3-

A. decrease H+ formation in cell

1. dec Na absorb (via Na/H antiporter)

2. dec Cl reabs (via Cl/Base antiporter)

B. inc HCO3 lumen

C. Inc Na/K/HCO3/PO4 Excretion

2.) Self Limiting Effx

A. CA inhibition --> metabolic acidosis and inc Na at macula densa

B. macula densa initiates tubulo-glomerular-feedback and decreases RBF/GFR

Acetazolamide

Kinetics:

F =

Cl = renal or hepatic?

t1/2 =

F = 100%

Cl = renal

t1/2 = 6-9 hours

Acetazolamide

Sulfonamide related rxns (3)

1) bone marrow supression

2) rash

3) interstitial nephritis

Acetazolomide

Contraindications/Preacautions (3)

1) hepatic cirrhosis

a. hepatic encephalopathy

b. ammonia retention bc of basic urine

2) Renal stones

a. CaPO4 precipitatones in high pH urine

3) Acidosis

a. gets worse when you cannot reabsorb HCO3

b. contraindicated in patients with hyperchloremic acidosis

Acetazolomide

Drug interactions (1)

CA Inhibitors (2)

Therapeutic uses (5)

Drugs: 1) Acetazolamide 2) Dorzolamide

Uses

1) Glaucoma - Dorzolamide topical & Acetazolamide oral

2) Metabolic alkalosis - from aggressive use of diuretics for CHF, these drugs increase excretion of HCO3

3) Acute Altitude Sickness - prophylaxis & sx relief

a. dec choroid plexus prodxn of CSF (required CA)

4) Epilepsy - induce metabolic acidosis which suppresses seizures, rapid tolerance

5) Edema - not 1st line; may be used in combination with other diuretics

Osmotic Diuretics (1)

Definition (1)

Mechanistic Effx (3)

Drugs: 1) Mannitol

Definition: 1) freely filterable substance that undergoes limited reabsorption in rena tubule and are given in lareg does to increas osmolality of plasma & urine

Effx:

1) increas solute load --> decreas water reabs in prox tubule/ DTL

2) water reabs at DTL is further reduced by dec in medullary osmotic gradient (mechanism?)

3) net increase in excretion of all electrolytes Na/K/Ca/Mg/Cl/HCO3/PO4

Mannitol

Kinetics

Administration?

Cl = renal or hepatic?

t1/2 =

IV

80% renal Cl

t1/2 = 0.3 -1.5 hrs (6-36 hrs in renal failure)

Mannitol

Adverse Effx/Toxicity/Cl/Drug interactions (3)

1) increas extracellular fluid

a. contraindicated in CHF & pulmonary congestion

2) hyponatremia (osmotic load extracts water w/Na from cells)

a. Sx: headache, nausea, vomiting

3) Overdiuresis

a. hypernatremia, dehydration

Osmotic Diuretics

Therapeutic Uses (5)

1) Inc Urine Volume - for pts w/ acute renal failure or acute tubular necrosis

2) Dec Intraocular Pressure - acute attack of inc pressure or pts undergoing eye surgery

3) Dec Intracranial Pressure

4) Tx dialysis disequilibrium - to correct hyposmolality of extracellular fluid caused by hemo/peritoneal dialysis

5) To estimate GFR

Loop Mechanism (1)

Molecular Effx (4)

Mechanism: 1) Blocks Na/K/2Cl Symporters in TAL

Molecular Effx:

1) normally lumen is more positive but + gradient decreases --> dec intercellular reabs of Ca/Mg --> inc Ca/Mg excretion

2) dec deposition of NaCl in medulla --> dec osmotic gradient --> can't concentrate urine w/ADH or dilute urine to excrete free water (since Na/K/2Cl symporters are also in part of diluting segment)

3) Macula densa does not "see" inc Na reaching it so GFR does not dec by TGF. RBF inc bc of prostaglandins. JGA may release renin since dec vol & inc Na are not inhibiting Macula Densa

4) Direct or indirect effx on vasculature - Furosemide acutely inc venous capacitance (via renal PG's?) --> dec preload

- can dec pulm edema before diuresis

Loop Diuretics

Kinetics

Administration =

t1/2 =

Excretion =

Administration: available orally

t1/2: all have short t1/2 0.5-2 hrs (torsemide 2-4 hrs)

Excretion = all excreted mostly by kidney (60-70%); torsemide is exception

Loop Diuretic Adverse Effx

related to diuretic effx (5)

1) volume dec --> hypotension, dec GFR

2) hyponatremia - rarer than with thiazides bc of reduced ability to retain free H2O w/ADH

3) Hypokalemia - secondary to inc Na at collecting duct

4) Metabolic alkalosis - bc of inc Na at collecting duct

5) HypoMg - Ca dec but copmensation in DCT prevents hypoCa

Ototoxicity - tinnitus, hearing loss, vertigo due to altered endolymph

- may add to other ototoxic drugs (e.g. aminoglycoside Ab)

1) hyperuricemia

2) inc LDL & TG, dec HDL

3) Impaired glucose tolerance

1) Phkinetic

a. Li - inc reabs at proximal tubule

b. Probenecid - dec access of diuretic to tubule

2) Phdynamic

a. inc chance of digoxin toxicity - bc of hypokalemia

b. NSAIDs

c. Thiazides - synergistic diuretic effect

1) severe Na or vol depletion

2) Hx of/ sulfonamide hypersensitivity

3) anuria unresponsive to a trial dose

4) post menopausal woman w/osteopenia