DIURETIC AGENTS

A. Q. Sangalang, M.D.
University of Santo Tomas
Faculty of Pharmacy
DIURETIC AGENTS
DIURETIC AGENTS
DIURETIC AGENTS
RENAL TRANSPORT MECHANISM
1. Proximal convoluted tubule (PCT)
Isosmotic reabsorption of amino acids, glucose, and numerous
cation
Major site for sodium chloride (60-70%) reabsorption in
exchange for H+ ion
Major site for bicarbonate reabsorption
Bicarbonate is not absorbed through luminal membrane, it is
converted to CO2 via carbonic acid to permit reabsorption and
regenerated within the tubular cell
Carbonic anhydrase, the enzyme required to reabsorb HCO3 is
the target of carbonic anhydrase inhibitor diuretic drugs
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RENAL TRANSPORT MECHANISM
1. Proximal convoluted tubule (PCT)
Active secretion and reabsorption of weak acids and bases
Weak acid transport occur in the straight S2 segment
Weak bases are transported in the S1 and S2 segments
Uric acid transport
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RENAL TRANSPORT MECHANISM
2. Thick Ascending Limb of the Loop of Henle (TAL)
Reabsorption of sodium (20-30%), potassium and chloride
carried out by a single carrier (cotransporter) [target of loop
diuretics]
Major site of calcium and magnesium reabsorption
Potassium is pumped into the cell from both luminal and basal
sides, an escape route must be provided, this occurs into the
lumen via a potassium channel; since the potassium diffusing
back is not accompanied by an anion, a net positive charge is
set up in the lumen, this positive potential drives the
reabsorption of calcium and magnesium
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RENAL TRANSPORT MECHANISM
3. Distal convoluted tubule (DCT)
Actively pumps sodium and chloride out of the lumen of the
nephron
Responsible for the reabsorption of 5-8% of sodium via a
contransporter (target of thiazide diuretics)
Calcium is reabsorbed under the control of parathyroid hormone
(PTH)
Removal of the reabsorbed calcium back into the blood requires
the sodium-calcium exchange process
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RENAL TRANSPORT MECHANISM
4. Cortical Collecting Tubules (CCT)
The principal cells are the major sites of sodium, potassium
and water transport
The intercalated cells are the primary sites of H+ secretion
Last tubular site for sodium reabsorption (2-5%) via channels
(not a transporter) [controlled by aldosterone]
Reabsorption is accompanied by equivalent loss of K+ or H+ ion
The aldosterone receptor and sodium channels are the sites of
K-sparing diuretic action
Primary site of acidification of urine
Reabsorption of water in the collecting tubule is under the
control of ADH
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CARBONIC ANHYDRASE INHIBITORS
A. Prototypes and Mechanism of Action
Acetozolamide is the prototype
Sulfonamide derivatives
Forerunners of modern diuretics
Inhibition of carbonic anhydrase in the brush border and
intracellular carbonic anhydrase in the PCT causing NaHCO3
diuresis and a reduction in total body HCO3 stores
Inhibition of carbonic anhydrase also occurs in other tissues of
the body as well as in the kidneys
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CARBONIC ANHYDRASE INHIBITORS
A. Prototypes and Mechanism of Action
Well absorbed orally
Latency = 30 min; peak effect in 2 hrs. and persists for 12 hrs.
after a single dose
Excreted through the S2 segment of the proximal tubule by
tubular secretion
At maximal safely administered dosage, 85% inhibition of
proximal bicarbonate reabsorption or 45% inhibition of whole
kidney HCO3 reabsorption (Acute HCO3 wasting condition)
CA inhibition causes significant HCO3 losses and
hyperchloremic metabolic acidosis
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CARBONIC ANHYDRASE INHIBITORS
B. Effects
Major renal effect is bicarbonate diuresis (eg. sodium
bicarbonate is excreted) body bicarbonate is depleted and
results to metabolic acidosis
Bicarbonate depletion results to slowing of its excretion
Self-limiting diuresis in 2-3 days
As increased sodium is presented to the CCT some of the
excess sodium is reabsorbed and potassium is secreted,
resulting in a significant potassium wasting
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CARBONIC ANHYDRASE INHIBITORS
B. Effects
Inhibitory effect occurs throughout the body
Useful reduction in IOP in the eye which is not self-limiting
Used for the treatment of glaucoma
In the CNS, acidosis can result to hyperventilation which can
protect against high altitude sickness (acute mountain sickness)
Used as diuretic if the edema is accompanied by metabolic
alkalosis
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CARBONIC ANHYDRASE INHIBITORS
B. Effects
Urinary alkalinization (excretion of uric acid, cystine, other weak
acids can be enhance by increasing urine pH)
Metabolic alkalosis
Adjuvants for the treatment of epilepsy, hypokalemic periodic
paralysis, to increase urinary phosphate excretion during
hyperphosphatemia
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CARBONIC ANHYDRASE INHIBITORS
C. Toxicities
Drowsiness and paresthesias occur after oral intake
Alkalinization of the urine may cause precipitation of calcium
salts and formation of renal stones
Renal potassium wasting
Patients with renal impairment may develop encephalopathy
due to ammonia reabsorption
Hypersensivity reactions fever rashes, BM suppression,
interstitial nephritis
Contraindications
Decrease urinary excretion of NH4 and may contribute to
hyperammonemia and hepatic encephalopathy in patients with
cirrhosis
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LOOP DIURETICS
A. Prototypes and Mechanism of Action
Furosemide (prototype), Bumetanide, and Torsemide
Sulfonamide derivatives
Ethacrynic acid
Phenoxy acid derivative
Acts by the same mechanism
Uricosuric drug
Inhibit the cotransport of sodium, potassium and chloride
Short-acting (diuresis over a 4-hour period)
Rapidly absorbed
Excreted by glomerular filtration and tubular secretion
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LOOP DIURETICS
A. Prototypes and Mechanism of Action
Loop diuretic reduce the reabsorption of both Na and Cl by
inhibiting the Na/K/Cl transporter
Diminish the normal lumen-positive potential across the tubule
and cause an increase in Mg and Ca excretion (chronic use has
been associated with Mg wasting and severe hypomagnesemia)
Increase of calcium excretion can be useful in acute
management of hypercalcemia
Loop agents appear to have direct effects on blood flow through
several vascular beds
Reduction in secretion if simultaneously administered with
NSAIDs or Probenacid
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LOOP DIURETICS
B. Effects
Full dose produces massive sodium chloride diuresis
Diluting ability of the nephron is reduced (site of significant
dilution of urine)
Calcium excretion is increased due to the inhibition of the
Na+/K+/2Cl- transporter
Potassium wasting and proton excretion hypokalemic
alkalosis
Non-steroidal anti-inflammatory drugs (NSAIDS) decreases the
efficacy
Pulmonary vasodilating effect
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LOOP DIURETICS
C. Clinical uses
Treatment of edematous states (heart failure, acute pulmonary
edema, ascites)
Used in HPN if response to thiazides is inadequate
Treatment of hypercalcemia (induced by malignancy); managed
by parenteral volume and electrolyte supplementation
Hyperkalemia
Acute renal failure can increase urine flow and enhance K
excretion, can help flush large pigment load and intratubular
casts, ameliorate intratubular obstruction
Anion overdose toxic ingestion of bromide, fluoride, iodide
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LOOP DIURETICS
D. Toxicity
Can induce hypokalemic metabolic alkalosis
Potassium wasting maybe severe
Can cause hypovolemia and cardiovascular complications
Ototoxicity and sulfonamide allergy
Hypomagnesemia
Hyperruricemia
Allergic and other reactions skin rashes, eosinophilia, severe
dehydration, hyponatremia
Contraindication
1. Cirrhosis
2. Borderline renal failure
3. Heart failure
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THIAZIDE DIURETICS
A. Prototype
Hydrochlorothiazide
Sulfonamide derivative
Active by the oral route
6-12 hours duration of action
Inhibit sodium chloride transport in the early segment of the
DCT
Produces moderate sodium and chloride diuresis
Secreted by the organic acid secretory system in the proximal
tubule
Competes with the secretion of uric acid [can elevate levels of
uric acid]
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THIAZIDE DIURETICS
A. Prototype
Hypokalemic metabolic alkalosis may occur
Few sulfonamide derivatives lack the typical thiazide ring in
their structure but have effects similar to thiazides therefore are
considered thiazide-like
1. Hydrochlorothiazide
Prototype drug
Sulfonamide derivative
2. Chlorothiazide
Not very lipid soluble and must given in large doses
Slowly absorbed and longer duration of action
Only thiazide available as parenteral administration
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THIAZIDE DIURETICS
B. Effects
Reduction in the transport of sodium into the tubular cell
reduces intracellular sodium and promotes sodium-calcium
exchange reabsorption of calcium urine calcium content
is decreased
Opposite of loop diuretics
Rarely cause hypercalcemia but may unmask hypercalcemia
due to other causes (hyperparathyroidism, carcinoma,
sarcoidosis)
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THIAZIDE DIURETICS
B. Effects
Reduce BP (initially, reflects reduction in blood volume)
Reduce vascular resistance (continued use) [effect is modest
but significant and maximal at doses lower than the maximal
diuretic dosage]
Synergistic effect with loop diuretic producing marked diuresis
Actions of thiazides can be inhibited by NSAIDs
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THIAZIDE DIURETICS
C. Clinical uses
1. Hypertension and CHF [used for chronic therapy of mild
edematous conditions (mild heart failure)]
2. Nephrolithiasis due to Idiopathic hypercalciuria [stone formation
can be reduced because of reduction in urine calcium
concentration]
3. Nephrogenic Diabetes Insipidus
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THIAZIDE DIURETICS
D. Toxicity
1. Massive sodium diuresis with hyponatremia can be an early
dangerous effect
2. Potassium wasting and metabolic alkalosis
3. Diabetic patients may have significant hyperglycemia
4. Serum uric acid (hyperuricemia) and lipid levels may increase
(hyperlipidemia)
5. Sulfonamide allergy
6. Impaired carbohydrates tolerance
7. Allergic and other reactions skin rashes, photosensitivity,
hemolytic anemia, thrombocytopenia, acute pancreatitis, acute
pulmonary edema, weakness, fatigability, paresthesias,
impotence
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THIAZIDE DIURETICS
Contraindications :
1. Cirrhosis to avoid K depletion and hepatic encephalopathy
2. Renal failure (renal insufficiency may be intensified)
3. Digitalis toxicity may manifest as a result of diuretic-induced K
depletion
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POTASSIUM-SPARING DIURETICS
A. Prototypes and Mechanism of Action
Prevent K secretion by antagonizing the effects of aldosterone
at the cortical collecting tubule
Inhibition may occur by
1. Direct antagonism at the level of cytoplasmic mineralocorticoid
receptors (Spirolactones)
2. Suppression of renin or angiotensin II generation (ACE
inhibitors)
3. Direct inhibition of Na transport through ion channels in the
luminal membrane (Triamterene, Amiloride)
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POTASSIUM-SPARING DIURETICS
A. Prototypes and Mechanism of Action
Combine and block intracellular aldosterone receptor
reduce expression of genes controlling synthesis of sodium ion
channels and Na+/K+ ATPase
Actions can be inhibited by NSAIDs [dependent on renal
prostaglandin production]
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POTASSIUM-SPARING DIURETICS
A. Prototypes and Mechanism of Action
SPIRONOLACTONE
Synthetic steroids that acts as a competitive antagonist to
aldosterone [bind to aldosterone receptors and reduce
intracellular formation of active metabolites of aldosterone]
Inactivation occurs in the liver
Slow onset of action with full therapeutic effect achieved after
several days
EPLERENONE
A spironolactone analog with greater selectivity for aldosterone
receptor
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POTASSIUM-SPARING DIURETICS
A. Prototypes and Mechanism of Action
TRIAMTERENE
Extensively metabolized in the liver
Major route of elimination is via the kidneys
Short half-life, given more frequently
Direct inhibitor of Na influx in the cortical collecting tubule
AMILORIDE
Excreted unchanged in the urine
A pyrazine carbonyl-guanidine derivative
50% oral absorption
Direct inhibitor of Na influx in the cortical collecting tubule
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POTASSIUM-SPARING DIURETICS
B. Effects
Increase sodium clearance and decrease potassium and
hydrogen excretion
May cause hyperkalemic metabolic acidosis
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POTASSIUM-SPARING DIURETICS
C. Clinical use
Treatment of potassium wasting caused by chronic therapy with
loop and thiazide diuretics (combination in a single pill)
Treatment of hyperaldosteronism (mineralocorticoid excess)
[1 Conns syndrome, ectopic production, 2 heart failure,
cirrhosis, nephrotic syndrome]
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POTASSIUM-SPARING DIURETICS
D. Toxicity
1. Hyperkalemia
2. Hyperchloremic metabolic acidosis (inhibition of H secretion)
3. Gynecosmastia, impotence, BPH (Spironolactone)[endocrine
abnormalities]
4. Acute renal failure (Triamterene combined with Indomethacin)
5. Kidney stones (Triamterene)[slightly soluble, may precipitate in
the urine]
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POTASSIUM-SPARING DIURETICS
D. Toxicity
Contraindications
1. Chronic renal insufficiency
2. Liver disease
3. Fatal hyperkalemia with concomitant use of beta blockers and
ACE inhibitors
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OSMOTIC DIURETICS
A. Prototype and Mechanism of Action
Mannitol is the prototype
Glycerin, Isosorbide, Urea [these are rarely used]
Freely filtered at the glomerulus but poorly reabsorbed in the
tubules remains in the lumen and holds water by virtue of
osmotic effect
Given intravenously
Sodium excretion is increased because the rate of urine flow is
accelerated
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OSMOTIC DIURETICS
A. Prototype and Mechanism of Action
Major location of action is at the PCT, where the bulk of
isoosmotic reabsorption normally takes place
Reabsorbtion of water is also reduced in the ascending limb of
the loop of Henle and collecting tubule
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OSMOTIC DIURETICS
B. Effects
Increased urine volume
Increased excretion of most filtered solutes unless they are
actively reabsorbed
Increased sodium excretion [because of accelerated urine flow
in the tubules and sodium transporters cannot handle the
volume rapidly enough]
Reduce brain volume and intracranial pressure (neurologic
conditions) by osmotically extracting water from the tissue
With similar effect in the eye (acute glaucoma)
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OSMOTIC DIURETICS
C. Clinical uses
Used to maintain high urine flow
1. When renal blood flow is reduced
2. Solute overload (eg. severe hemolysis, rhabdomyolysis)
3. Reduce IOP in acute glaucoma
4. Reduce intracranial pressure in neurologic conditions
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OSMOTIC DIURETICS
D. Toxicities
Extracellular volume expansion [prior to diuresis because
mannitol is rapidly distributed in extracellular compartment and
extracts water from cells] causing hyponatremia and pulmonary
edema in patients with heart failure
Headache, nausea and vomiting
Dehydration [leading to hypernatremia], hyperkalemia [as water
is extracted from cells]
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ANTIDIURETIC HORMONE AGONISTS
A. Prototypes and Mechanism of Action
Antidiuretic hormone (ADH) [Vasopressin] and Desmopressin
Prototypes
ADH agonists
Peptides
Given IV
Used in the treatment of central diabetes insipidus
Renal action is mediated by V2 receptors and V1a receptors
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ANTIDIURETIC HORMONE ANTAGONISTS
A. Prototypes and Mechanism of Action
Conivaptan
Nonpeptide ADH receptor antagonist (vaptan) approved for use
Orally active
Inhibit effects of ADH in the collecting tubule
Pharmacologic antagonist at V1a and V2 receptors
Demeclocycline
A tetracycline antimicrobial drug
Orally active
Inhibit effects of ADH in the collecting tubule
Reduce the formation of cAMP in response to ADH
Interfere with the actions of cAMP in the collecting tubule cells
Mechanism is unknown
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ANTIDIURETIC HORMONE ANTAGONISTS
A. Prototypes and Mechanism of Action
Lithium
Orally active
Has anti-ADH effects but is never used as an ADH antagonist
Inhibit effects of ADH in the collecting tubule
Reduce the formation of cAMP in response to ADH
Interfere with the actions of cAMP in the collecting tubule cells
Mechanism is unknown
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ANTIDIURETIC HORMONE ANTAGONISTS
B. Effects and Clinical uses
Treatment of Syndrome of Inappropriate ADH secretion
(SIADH)
Condition where peptides are produced by certain tumors
Can cause water retention and dangerous hyponatremia
Lithium carbonate gives unpredictable response
Demeclocycline yields more predictable resulst and less toxic
Conivaptan given via IV, not suitable for chronic use in
outpatients
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ANTIDIURETIC HORMONE ANTAGONISTS
B. Effects and Clinical uses
Pituitary diabetes insipidus
ADH and Desmopressin are useful
Not useful for nephrogenic diabetes insipidus
C. Toxicities
Nephrogenic diabetes insipidus
If serum sodium is not monitored ADH antagonists may cause
severe hypernatremia and Nephrogenic DI
Patients with psychiatric disorder and treated with Lithium can
develop Nephrogenic DI [can be treated with thiazide diuretic or
amiloride]
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ANTIDIURETIC HORMONE ANTAGONISTS
C. Toxicities
Renal failure
Caused by Lithium and Demeclocycline
Lithium can cause chronic interstitial nephritis
Demeclocycline causes bone and teeth abnormalities in
children younger than 12 years old and those with liver disease
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Clinical Pharmacology of Diuretic Agents
A. Edematous States
1. Heart failure
2. Hepatic cirrhosis
3. Kidney diseases
4. Idiopathic edema

B. Nonedematous States
1. Hypertension
2. Nephrolithiasis
3. Hypercalcemia
4. Diabetes insipidus