DIURETIC DRUGS

Darmawan,dr.,M.Kes,Sp.PD
 OVERVIEW

DIURETICS:
Drugs inducing a state of increased urine flow
Ion transport inhibitors that decrease the
reabsorption of Na+ at different sites in the nephron
(water is carried passively)
The efficacy of different classes of diuretics varies
< 2% for the weak, > 20% for the potent loop diuretics
 OVERVIEW (2)

DIURETICS (CONT’)
Major Clinical Uses
Managing disorders involving abnormal fluid
retention (edema)
Treating Hypertension, causes a decreased blood
volume, leading to a reduction in blood pressure
 NORMAL REGULATION OF FLUID AND
ELECTROLYTES BY THE KIDNEYS
App 16-20% of the blood plasma is filtered from the
glomerular cappilaries into bowman’s capsules
The kidney regulates the ionic composition and volume
of urine by the reabsorption or secretion of ions
and/or water at five functional zones along the
nephron
Proximal convulated tubule
Descending loop of Henle
Ascending loop of Henle
Distal convulated tubule
Collecting tubule
 NORMAL REGULATION (2)

PROXIMAL CONVULATED TUBULE

Almost all glucose, bicarbonate, amino acids are
reabsorbed
2/3 of Na+ is also reabsorped
Most extensive reabsorption
Acid secretory system
Secretes a variety of organic acids (uric acid, some
antibiotics, diuretics)
Diuretic drugs compete for transfer with endogenous subs
(hyperuricemia )
 NORMAL REGULATION (3)

DESCENDING LOOP OF HENLE

The osmolarity increases along the descending
portion of the loop henle
Countercurrent mechanism
Three-fold increase in salt concentration
 NORMAL REGULATION (4)

ASCENDING LOOP OF HENLE

Impermeable to water
Active reabsorption of Na+, K+, Cl-
25-30% of tubular sodium chloride returns to the
interstitial fluid
Loop diuretics affecting this site
 NORMAL REGULATION (5)

DISTAL CONVULATED TUBULE

Impermeable to water
10% of the filtered sodium chloride is reabsorped
via Na+/Cl- transporter
Sensitive to thiazide diuretics
 NORMAL REGULATION (6)

COLLECTING TUBULE AND DUCT

Responsible for Na+-K+ exchange and for H+
secretion and K+ reabsorption
Stimulation of aldosterone rec in result in Na+
reabsorption and K+ secretion
ADH act in this site and mediated by cAMP
 KIDNEY FUNCTION IN DISEASE

In many diaseases the amount of Sodium

Chloride reabsorbed is abnormally high
Retention of water
Increase in blood volume
Expansion of the extravascular fluid compartment
 KIDNEY FUNCTION IN DISEASE (2)

Several commonly encountered causes of edema

Congestive heart failure
Hepatic ascites
Increased portal blood pressure
Secondary hyperaldosteronism
Nephrotic syndrome
Premenstrual edema
 CARBONIC ANHYDRASE INHIBITORS

Acetazolamide, sulfonamide without AM activity

Less efficacious than the thiazides or loop diuretics
MOA:
Inhibit carbonic anhydrase (intracellularly and on the apical
membrane of tubular epithelium); Catalyzes the reaction of
CO2 and H2O leading to H+ and HCO3-
The decreased ability to exchange Na+ and H+ results in a
mild diuresis
HCO3- is retained in the lumen with marked elevation in
urinary pH
 CARBONIC ANHYDRASE INHIBITORS (2)

Theurapeutic uses:
Treatment of glaucoma
Decreases the production of aqueous humour
Epilepsy
Conjunction, reduces the severity and magnitude
Mountain sickness
Pharmacokinetics: Once a day
Adverse effects: Metabolic acidosis, potassium
depletion, renal stone formation, drowsiness,
paresthesia
 LOOP OR HIGH-CEILING DIURETICS

Bumetanide, furosemide, torsemide, ethacrynic

acid
Major action on the acsending limp of the loop
of henle
Highest efficacy in mobilizing Na+ and Cl-
 LOOP OR HIGH-CEILING DIURETICS (2)

MOA:
Inhibit the Na+/K+/Cl- cotransport of the luminal
membrane in the ascending limb of the loop henle
Most efficacious of the diuretic drugs, account for
the reabsorption of 25-30% of filtered NaCl
Actions:
Act promptly
For poor renal function or who have not responded
to thiazides or other diuretics
Decreased renal vascular resistance, increased RBF
 LOOP OR HIGH-CEILING DIURETICS (3)

Therapeutics uses:
DOC: Acute pulmonary edema of CHF
Rapid onset, which call for a rapid, intense diuresis

Pharmacokinetics
PO and Parenteral
DOA: 1 – 4 hours
 LOOP OR HIGH-CEILING DIURETICS (4)

ADVERSE EFFECTS
Ototoxicity; particularly when used in conjunction
with the aminoglycoside, permanent damage
Hyperuricemia; Furosemide and ethacrynic acid
compete with uric acid for the renal and biliary
secretory systems
Acute hypovolemia; hypotension, shock, arrhythmias
Potassium depletion; Exchange for H+
Use of Potassium-sparing diuretics
Dietary supplementation with K+
 THIAZIDES AND RELATED AGENTS

The most widely used

Sulfonamides derivatives, related in structure to the
carbonic anhydrase inhibitors > Acetazolamide, act on
the kidney by different mechanisms
Affect the distal tubule, all have equal maximum
diuretic effect, differing only in potency
 THIAZIDES AND RELATED AGENTS (2)

CHOLOROTHIAZIDE
Prototype of thiazide diuretic
The 1st modern diuretic that was active orally and
was capable of affecting the severe edema
Minimum side effect
MOA:
Act mainly in the distal tubule to decrease the
reabsorption of Na+ by inhibition of Na+/Cl-
cotransporter
Lesser effect in the proximal tubule
 THIAZIDES AND RELATED AGENTS (3)

Chlorothiazide (cont’)
MOA:
Acid-base balance is not usually affected
These drugs must be excreted into the tubular lumen to be
effective, decreased renal function ~ efficacy
Actions:
Increased excretion of Na+ and Cl- , result in the excretion
of a very hyperosmolar urine, doesn’t change the acid-
base status of the blood
 THIAZIDES AND RELATED AGENTS (4)

Chlorothiazide (cont’)
Actions
Loss K+ (increase the Na+ in the filtrate arriving at the
distal tubule, more K+ is also exchange for Na+)
Decreased urinary calcium excretion, (promoting the
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reabsorption of Ca2+)
Reduced peripheral vascular resistance (decreased blood
volume – decreased CO – continued th – volume recovery
– continued hypotensive effects – reduced peripheral
vascular resistance – RELAX of arteriolar smooth muscle)
 THIAZIDES AND RELATED AGENTS (5)

Chlorothiazide (cont’)
Therapeutic uses:
Hypertension
Mainstay of HT medication, inexpensive, convenient,
well tolerated
After 3-7 days of th, stabilizes at a lower level and
can be maintained indefinitely by a daily dosage
CHF
If fails, loop diuretics may be useful
Renal Impairment
NS with edema
 THIAZIDES AND RELATED AGENTS (6)

Chlorothiazide (cont’)
Therapeutic uses:
Hypercalciuria
Inhibit urinary Ca2+ excretion, exp: Calcium Oxalate
stones in UT
Diabetes Insipidus

Pharmacokinetics:
PO, 1-3 weeks to produce a stable reduction
Long half life (40 hours)
 THIAZIDES AND RELATED AGENTS (6)

Chlorothiazide (cont’)
Adverse effects
Potassium depletion
The most frekuent, digitalis patient predipose to VA
Activation in RAA ~ urinary K+ losses
Can be overcome by spirolactone (interferes with
aldosterone action), triamterene (retain K+)
Hyperuricemia
Predisposed to gouty attack
Periodic blood tests
 THIAZIDES AND RELATED AGENTS (6)

Chlorothiazide (cont’)
Adverse effects
Volume depletion
Orthostatic hypotention, light-headedness
Hypercalcemia
Hyperglycemia
In patient with DM
Hypersensitivity
Bone marrow suppresion, dermatitis, necrotizing
vasculitis, interstitial nephritis; rare
 THIAZIDES AND RELATED AGENTS (6)

Hydrochlorothiazide
Thiazide derivative; less ability to inhibit carbonic
anhydrase as compared to chlorothiazide
More potent
Efikasi ~

Chlorthalidone
Thiazide derivative
Long duration, OD
 THIAZIDES AND RELATED AGENTS (7)

Thiazide Analogs
Metolazone
More potent than the thiazides, causes Na+ excretion in
advanced renal failure
Indapamide
Lipid soluble
Nonthiazide that has long DOA
Low doses, significant AH with minimal diuretic effects
Used in advanced renal failure, better than loop diuretics
Metabolized and excreted by GI tract
 POTASSIUM-SPARING DIURETICS

Act in the collecting tubule to inhibit Na+ reabsorption,

K+ secretion, H+ secretion
Used when aldosterone is present in excess
Combination with a thiazide
Patient treated with any potassium-sparing diuretic be
closely monitored for potassium levels
 POTASSIUM-SPARING DIURETICS (2)

Spironolactone
MOA:
Synthetic aldosterone antagonist that competes in
intracellular cytoplasmic receptor sites
Prevent translocation of inactive complex to produce
protein which stimulates the Na+, K+ exchange sites of the
collecting tubule
Prevent Na+ reabsorption and therefore K+ and H+
secretion
 POTASSIUM-SPARING DIURETICS (3)

Spironolactone
Actions
In most edematous states, blood level of ALD are high,
which is instrumental in retaining Na+
Antagonize the activity of the hormone, retention of K+
and excretion of Na+
Addison’s disease: no diuretic effect
 POTASSIUM-SPARING DIURETICS (4)

Spironolactone
Therapeutic uses
Diuretic
Low efficacy in mobilizing Na+
Causing retention of K+, conjunction with a thiazide or
loop diuretics
Secondary Hyperaldosteronism
Pharmacokinetics
Absorbed PO, strongly bound to proteins
Converted to canrenone, has mineralocorticoid-blocking
activity, induces cytochrome P450
 POTASSIUM-SPARING DIURETICS (5)

Spironolactone
Adverse effects
Resembles some of the steroid sex; Gynecomastia,
menstrual irregularity
Should not be given in high doses on a chronic basis
Hyperkalemia, nausea, lethargy, mental confussion
 POTASSIUM-SPARING DIURETICS (6)

Triamterene and Amiloride

Block Na+ transport channel resulting in a decrease
in Na+, K+ exchange, similar to spironolactone
Does not depend on the presence of aldosterone
Not efficacious diuretics, combination with other
diuretics
SE: Leg cramps, increased BUN as well as uric acid
and K+ retention
 OSMOTIC DIURETICS

Hydrophilic, filtered through glomerulus; MANNITOL

Have ability to carry water with them into the tubular
fluid
Only a small of Na+ may also be excreted, not useful
in treating condition in which Na+ retention occurs
To maintain urine flow in acute toxic ingestion
Mainstay for increased ICP
Parenteral only
THANKS FOR YOUR ATTENTION