Diuretics

Question 1

Azetazolamide [Diamox]

Answer 1

MOA - Carbonic anhydrase inhibitor (proximal tubule)

Site 1 Diuretics

Mechanism of Action: Reversible inhibition of the enzyme carbonic anhydrase resulting in reduction of hydrogen ion secretion at renal tubule and an increased renal excretion of sodium, potassium, bicarbonate, and water.

Decreases production of aqueous humor and inhibits carbonic anhydrase in central nervous system to retard abnormal and excessive discharge from CNS neurons.

Question 2

Furosemide

Answer 2

Site 2 Diuretics (Loop/High ceiling diuretics)

25-30% Na reabsorption

Inhibition of Na+,K+,Cl2- pump

Only on tubular side of cell

Block high Na+ tubular absorption capacity.

Short t1/2 = 50min

Question 3

Ethacrynic acid

Answer 3

Furosemide - Me2

No sulfonamide group

Steeper dose response curve

GI disturbances

Lower incidence of hyperglycemia

Question 4

Bumetanide

Answer 4

Furosemide Me2

pts. with allergy to furosemide

Lower incidence of hyperglycemia, diabetic patients

Question 5

Toresmide

Answer 5

Furosemide Me2

2X greater bioavailability

Longer half life

Question 6

Chlorothiazide

Answer 6

Thiazide - Site 3 (15% of filtered Na+)

NCC channel, Ineffective when GFR<20mL/min

t1/2 - 1.5hrs

Inc excretion of Na+, K+ & H+(site 4 exchange)

Question 7

Hydrochlorothiazide

Question 8

Chlorthalidone

Answer 8

Site 3 Diuretic

Question 9

Metolazone

Answer 9

Site 3 Diuretic

Question 10

Indapamide

Answer 10

Site 3 Diuretic

Question 11

Spironolactone

Answer 11

Aldosterone Receptor Antagonist

Mechanism of action: receptor binding competitive antagonist of aldosterone, inhibits ability of aldosterone to increase Na+-K+ exchange.

Not specific for mineralocorticoid receptor (see below)

(ii) Pharmacokinetics
(1) Slow onset and offset due to mechanism of action (inhibition of steroid action)
(2) Parent drug and an active metabolite, canrenone, binds to androgen receptors
(3) T1/2: 10 to 35 hours
(4) Given p.o. (orally); best absorbed if given with food since bile acids aid absorption of this drug.

(iii) Effects

(1) Slight increase Na+ excretion, slight diuresis
(2) Greater effect to inhibit K+ loss (obvious potential side effect is hyperkalemia, which may be serious but is limited by compensatory changes in aldosterone )
(3) In patients with heart failure or in elderly patients, depressed liver function leads to elevated aldosterone levels. Effect of spironolactone is rapid and pronounced in these patients.
(4) Anti-androgenic effects (gynecomastia, impotence; menstrual irregularities in female)
(5) Contraindicated in patients with diabetes and impaired renal function due to increased risk of hyperkalemia

Question 12

Triamterene

Answer 12

triamterene [Dyrenium]: differences vs. amiloride

(i) Only oral administration
(ii) Shorter Tp (3 hrs)
(iii) Some hepatic metabolism
(iv) Reported (rare) nephrotoxicity in combination with indomethacin

See Amiloride - MOA, USE

Question 13

Amiloride

Answer 13

Mechanism of action: electrogenic (faster acting than spironolactone)

(i) Inhibition of Na+ influx through channel
(ii) Therefore less Na+ for Na-K ATPase
(iii) Therefore dissipates transepithelial -5 mV potential difference

(iv) Removes drive to transport K+ across cell

Pharmacokinetics

(1) T1/2= 6 to 9 hours
(2) unmetabolized - excreted unchanged by kidney (3) administered orally

(ii) Effects
(1) slight increase Na+ and H2O excretion
(2) decreased K+ excretion (hyperkalemia is possible - and potentially worse than with spironolactone because no compensatory mechanism exists)
(3) increased Li+ reabsorption (potentially dangerous)
(4) elevation of serum urate

Question 14

Epleronone

Answer 14

Specific antagonist of mineralocorticoid receptor. Does not bind to androgen or progesterone recepotors

Uses include anti-hypertensive and post-infarction (improves morbidity post MI by ~ 15%)

Major side effect is hyperkalemia.

Question 15

Dopamine/Caffiene

Answer 15

Mechanism of action - dopamine receptor and 􏰈1 receptor agonist

Renal vasodilator at low doses

Increases GFR

Increases renin production

Frequently combined with dobutamine in treating post-infarct patients with poor renal blood flow

Question 16

Mannitol/Isosorbide

Answer 16

MOA:

Inert, osmotically active, freely filtered but not reabsorbed, and are not metabolized. They “redistribute” water.

Increase renal perfusion by osmotically preventing water reabsorption countercurrent washout via increased renal blood flow, thus also increasing diuresis

Reduce intracranial and intraocular pressures osmotically; useful drugs do not partition into CSF or vitreous body quickly this effect is not mediated by the kidney but due to the presence of osmotic agent in plasma compartment. Re-distributed fluid then removed by kidney.

Major therapeutic uses

Reduction of intracranial or intraocular pressure prior to surgery

Prophylaxis of acute renal failure (but not in anuria). This treatment keeps some flow through kidney before anoxia sets in.

Side effects:

All agents will diffuse slowly into and out of CSF. Rapid peripheral removal of agent will lead to excess osmotic agent in CSF and thus excess CSF volume (cerebral edema).

Headache, nausea, vomiting due to increased CSF osmolarity.

Contraindications

Anuria (no urine production): no means to remove osmotic diuretic would exist

Peripheral edema: increased vascular volume can lead to pulmonary edema

Heart failure: osmotic diuretics increase circulating load

dehydration(obviously)