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Diuretics

most potent diuretic = loop diuretic

Dr. Yuri Clement,


Pharmacology Unit, FMS

Mr. R: A case of acute heart failure


Mr. R, a 70-year old male, is taken by ambulance to the ER
at 1am after waking up with shortness of breath for the 4th
night in a row.
Each time he felt tight in the chest and couldnt get a
breath; this discomfort was relieved somewhat by sitting up
in bed. He recalls previous episodes of shortness of breath
while climbing stairs.
Physical examination reveals tachycardia, mild
hypertension, pedal edema and bilateral pulmonary crackles
on inspiration. Serum troponin T level (a marker of
myocardial injury) is normal, but serum creatinine and BUN
are mildly elevated. Urinalysis is normal.

Mr. R: A case of acute heart failure

The ECG shows evidence of an old MI. Echocardiography


reveals diminished left ventricular ejection volume (the
fraction of blood in the ventricle at the end of diastole that is
ejected when the ventricle contracts) without ventricular
dilatation.
Based on the clinical findings of decreased cardiac output,
pulmonary congestion, and peripheral edema, Mr. R. is
diagnosed with acute heart failure. His increased
creatinine and BUN also indicate an element of renal
insufficiency.

Objectives

Compartmentalization of body water & regulation of intravascular


volume.
The kidney in regulating intravascular volume: review of renal
physiology of Na+ and H2O reabsorption.

Definition of a diuretic. Classes: Based on site of action.

Common indications for diuretic use.

Common adverse effects of and contra-indications for diuretic use.

Fluid compartmentalization
and body water distribution

Fluid movement between


compartments

Fluid filtration = Kf(Pc Pif) (IIc IIif)


Kf = capillary permeability; Pc = capillary hydrostatic pressure; Pif = interstitial fluid hydrostatic
pressure; IIc = capillary oncotic pressure; IIif = interstitial oncotic pressure
Hydrostatic and oncotic gradient terms have opposing vectors.

Volume regulation:
Feedback mechanisms

Low-pressure atria and pulmonary vasculature

ADH: released in volume depletion to induce water


retention.
Natriuretic peptides: released in volume overload to
induce water loss.

High-pressure baroreceptors

ADH
Sympathetic outflow

Neurohormonal volume
regulation (RAAS)

Altered Na+ reabsorption:


Edema

Peripheral edema
(initially in right HF)

Pulmonary edema
(initially in left HF)

Both interstitial and alveolar edema. Alveolar oedema manifests as ill-defined


nodular opacities tending to confluence. Interstitial oedema can be seen as
peripheral septal lines - Kerley B lines (arrowheads).

Ascites (in cirrhosis)

Diuretics

rate of urine formation by altering Na+ and H2O reabsorption.


Indicated in pathophysiological states with ECF volume. Ideally
volume without distorting electrolyte balance.

Edematous states: CHF, hepatic cirrhosis, nephrotic syndrome.

Non-edematous states: Hypertension, diabetes insipidus, nephrolithiasis,


hypercalcemia, glaucoma.

Diuretics: Points to know

Tightly bound to plasma proteins and undergo minimal filtration;


secreted across the proximal tubule by pumps.

Other drugs may compete for the secretory pump and reduce diuretic
efficacy eg. NSAIDS, probenecid for acidic (S2 segment) and cimetidine
for basic (S1 and S2 segment) .

Most diuretics must enter the tubular fluid to exert their effects
most of the channels
on the luminal side. since
are on the luminal side
renal blood flow or renal failure reduces therapeutic efficacy.

The kidney in regulating intravascular volume:


Na+ and H2O reabsorption

There are about 1 million per kidney and about 75 miles of tubular length
GFR ~ 180 L/day in 70kg male

Diuretics Classes

(Sites of action)

CARBONIC ANHYDRASE INHIBITORS

Generic name

Trade name(s)

Available doses

Acetazolamide

Diamox

Oral: 125, 250 mg


Oral sustained release: 500mg
Parenteral: 500mg

Methazolamide

Neptazane

Oral: 25, 50mg

Dichlorphenamide

Daranide

Oral: 50mg

Carbonic Anhydrase
Inhibitors

Site of action Proximal tubule

Most marked effect in the EYE and KIDNEY

Cause depletion of body stores of HCO3-

CA also found in ciliary processes in the eye, RBCs,


choroid plexus, intestine & pancreas

Proximal convoluted tubule

OVERALL EFFECT:

Reabsorption of HCO3- & Na+

Pharmacokinetics

Well absorbed, plasma protein bound, renal excretion.

Effect within 30 mins, maximal at 2hrs, persists for 12 hrs.

~30% of filtered bicarbonate appears in the urine.

Short-lived (few days) due to up-regulation of NaHCO3


reabsorption and increased NaCl reabsorption distally.

(Hyperchloremic metabolic acidosis renders subsequent doses ineffective.)

Indications

Glaucoma. Topical dorzolamide (Trusopt) and brinzolamide (Azopt).

Prophylaxis in acute mountain sickness, with increased CSF


pressure.

Urinary alkalinization to excretion of weak organic acids (eg.


Aspirin). Short-lived

Metabolic alkalosis (in HF patients treated with loop diuretics)

With oral bicarbonate, in uric acid nephropathy to prevent


precipitation

Toxicity

Mild-to-moderate METABOLIC ACIDOSIS (Limit use to 2-3 days).

K+-wasting: HCO3- exchange for K+ in collecting duct

Renal stone formation.

Drowsiness & paresthesia: large doses

Hypersensitivity reactions

Mr. R: A case of acute heart failure

Pharmacologic therapy is started, including a


positive inotrope, a coronary vasodilator, an
antihypertensive ACE inhibitor, and a loop
diuretic. After Mr. Rs condition stabilizes over
the course of 3 days, the dose of the loop
diuretic is decreased and then discontinued.

LOOP DIURETICS
Generic name

Trade name(s)

Available doses

Furosemide

Lasix, others

Oral: 20, 40, 80 mg


Parenteral: 10mg/mL

Bumetanide
(40x more potent)

Bumex

Oral: 0.5, 1, 2 mg
Parenteral: 0.5mg/2mL

Torsemide

Demadex

Oral: 5, 10, 15, 20mg


Parenteral: 10mg/mL

Ethacrynic Acid

Edecrin

Oral: 25, 50mg


Parenteral: 50mg/mL

Loop of Henle
(Thick ascending limb)

Loop Diuretics

Inhibit Na+/K+/2Cl- cotransporter mechanism in thick


ascending limb. ( fractional Na+ excretion by ~20%)
lumen-+ve potential results in Mg2+ and Ca2+ excretion:

Chronic use may cause hypomagnesemia

Prostaglandin-mediated venous and renal vasodilation.

Pharmacokinetics

Extremely rapid onset; duration of action: 1-4 hrs.


Furosemide well absorbed, high plasma protein
binding, hepatic metabolism.
Ethacrynic acid usually iv, highly plasma protein
bound, hepatic metabolism.

Indications

Acute pulmonary edema first-line


Edema associated with heart failure first-line
Hyperkalemia
Acute renal failure
Anion overdose: to increase urine flow (Br , F , I )
Hypercalcemia: with simultaneous normal saline infusion
Hypertension: in patients with renal insufficiency or heart failure
-

Toxicity

Hypokalemic metabolic alkalosis: K+ & H+


loss
Ototoxicity:
dose-related, reversible; concomitant aminoglycoside antibiotics should be avoided.

Hyperuricemia: compete for biliary and renal secretory systems.


Hypomagnesemia
Reversible allergic reactions: (sulfonamide derivatives, except
ethacrynic acid)

Dehydration

THIAZIDES
Generic name

Trade name(s)

Available doses

Chlorothiazide

Diuril, others

Oral: 250, 500; 250mg/mL oral


suspension

Hydrochlorothiazide Microzide,
HydroDIURIL, others

Oral: 25, 50, 100mg tabs; 12.5mg


capsules. 10mg/mLsoln

Chlorthalidone

Thalitone, Hygroton,
combination drugs

Oral: 250, 500 mg; 250 mg/5mL


oral suspension

Indapamide

Lozol, others

Oral: 1.25, 2.5mg

Metolazone

Mykrox, Diulo,
Zaroxolyn, others

Oral: 0.5mg

Distal convoluted tubule

Thiazides
Unsubstituted
Sulfonamide

Cl

H2N-O2S

Main effects in the Early Distal Tubule:


+
1.Inhibit Na and Cl reabsorption
2.Stimulate Ca2+ reabsorption (hypercalcemia rare)

Pharmacokinetics

Moderate absorption from GI tract. Effect within 1-2


hrs, peak effect within 2-6 hrs. In hypertension stable
BP reduction within 1-3 weeks.

Variable drug lipid solubility affect duration of action

Excreted unchanged in urine

Indications

Hypertension (first line)

Heart failure (concomitantly with loop diuretics)

Reducing hypercalciuria in patients at risk for


nephrolithiasis
Nephrogenic diabetes insipidus (impaired ADH
secretion) large volumes of hypotonic urine.

Toxicity

Hypokalemia increases risk of

exacerbate gout

cardiac arrhythmias

Hyponatremia

Metabolic alkalosis

Hyperuricemia may

Hyperglycemia may unmask


diabetes in patients with impaired glucose
tolerance

Hyperlipidemia - may revert to


baseline after chronic use

Mr. R: A case of acute heart failure

Elective coronary angiography reveals


significant stenosis of the left anterior
descending coronary artery. Mr. R undergoes
balloon angioplasty and stent placement and
remains stable. An ECG demonstrates an
ejection fraction of 35%. Mr. R is discharged on
a regimen that includes an ACE inhibitor and
spironolactone.

Clinical Evidence to
support treatment
The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure
B Pitt, F Zannad, WJ Remme, R Cody, A Castaigne, A Perez, J Palensky, J Wittes, for the Randomized Aldactone
Evaluation Study Investigators. N Engl J Med 1999; 341:709-717
In a double-blind study, 1663 patients with severe HF and LVEF <35% on ACE inhibitor, loop diuretic, and in most
cases digoxin. 822 randomly assigned to 25 mg of spironolactone daily, and 841 to receive placebo. Primary end point:
Death.
Spironolactone caused:
30% reduction in the risk of death
35% reduction frequency of hospitalization for worsening HF
Significant improvement in the symptoms of HF, assessed by New York Heart Association functional class

Conclusions:
Blockade of aldosterone receptors by spironolactone, in addition to standard therapy, substantially reduces
the risk of both morbidity and death among patients with severe heart failure.

POTASSIUM-SPARING DIURETICS
Generic name

Trade name(s)

Available doses

Spironolactone

Aldactone

Oral: 25, 50, 100mg

Eplerenone

Inspra (hypertension only)

Oral: 25, 50mg

Amiloride

Midamor, combination drugs

Oral: 5mg

Triamterene

Dyrenium

Oral: 50, 100mg

Also used as combinations with loop diuretics or thiazides

Collecting tubule principal cell

K+-sparing Diuretics

Most diuretics present more Na+ to the collecting duct;


Na+ reabsorption = exchange for K+.
Mild natriuretic effect as fractional Na+ reabsorbed ~3%
of filtered load.

Contraindicated in disease or drug-induced hyperkalemia

Sometimes co-administered with loop agents & thiazides.

Sub-Class I:Aldosterone Inhibition


Direct aldosterone-receptor antagonism: synthesis of
mediator proteins responsible for stimulation of the
Na+/K+ exchange sites in the Collecting duct.

SPIRONOLACTONE, EPLERENONE

Indications
Mineralicorticoid excess:

Primary hyperaldosteronism: Conns syndrome, ectopic ATCH


production, adrenal adenoma or bilateral adrenal hyperplasia.

Secondary hyperaldosteronism (modulation of RAA


system): HF, cirrhosis, nephrotic syndrome.
Diuretics of choice for treatment of ascites and edema associated
with impaired plasma protein biosynthesis secondary to hepatic
failure

Spironolactone: Pharmacokinetics

Good oral bioavailability; slow rate of onset; several


days for full therapeutic effect.
Rapid hepatic metabolism to highly active metabolite
with long t1/2 (10 - 35 hrs). Metabolite highly bound to
plasma proteins.
Excretion by renal & GI tract.

Spironolactone: Toxicity

Hyperkalemia

Metabolic acidosis: inhibition of H

Endocrine effects:

secretion

Men gynecomastia (~10%), libido and impotence


Women - amenorrhea, hirsutism and breast swelling
and tenderness
High doses should ONLY be used for short periods
No reports of such endocrine effects with eplerenone

Sub-Class II:
Na+ transport inhibition

Blocks channels necessary for Na+/K+


counter-transport in Collecting duct
AMILORIDE & TRIAMTERENE

Amiloride & Triamterene

Oral bioavailability - 50 and 70%, onset - 2-4 hrs.

Duration of action:

triamterene (7-9hrs)
amiloride (24hrs).

Amiloride excreted unchanged in urine.

Amiloride & Triamterene:


Toxicity

Hyperkalemia and metabolic acidosis

GI effects: nausea, vomiting and diarrhea

Triamterene - leg cramps, possibly BUN &


uric acid

Contraindications:
Hyperkalemia alert

1.
2.
3.
4.
5.

ACE inhibitors (captopril, enalapril) blunts RAA System


-blockers blunts RAA System
NSAIDs
Oral K+ supplementation
Chronic renal insufficiency

OSMOTIC DIURETICS
Mannitol

Osmotic Diuretics

Pharmacologically inert electrolytes mannitol confined to


ECF

Induce bulk H2O flow between body compartments


When excreted, carry an amount of H2O equivalent to
their osmotic drawing power.
High solute intra-tubular concentrations cause hyperosmolarity which prevents H2O reabsorption.

Osmotic Diuretics

Freely filtered (ideally should not be reabsorbed or secreted)

tonicity of tubular fluid causes water to be retained in the tubule.


blood tonicity, drawing water from intracellular spaces into
blood

Action mostly in segments of the nephron permeable to


water proximal tubule and descending limb of loop of
Henle.
Mannitol poorly absorbed, given parenterally in the hospital setting

Indications

intracranial pressure in cerebral edema associated with


tumors, neurological procedures or similar conditions.

urine volume

IOP prior ophthalmologic procedures.

Prophylaxis to prevent acute renal failure associated with severe


shock, CV and other complicated surgical procedures.
Promote renal excretion in cases of drug toxicities and
overdose, eg. bromides, barbiturates and salicylates.

Toxicity

Rapid administration can cause excessive fluid shift into


extracellular compartment & unintended hypernatremia.

Hypovolemia & Hypotension

CNS Effects: headache, blurred vision, dizziness,


disorientation

GI Effects: nausea and vomiting

Conclusions