DIURETIC o Carbonic anhydrase, the enzyme required to reabsorb

HCO3 is the target of carbonic anhydrase inhibitor

AGENTS diuretic drugs
ELECTROLYTE CHANGES PRODUCED BY DIURETIC DRUGS o Active secretion and reabsorption of weak acids and
URINE BODY bases
Drug group Cl-  Weak acid transport occur in the straight S2
NaCl NaHCO3 K+ 2 pH segment
Carbonic anhydrase  Weak bases are transported in the S1 and S2
    acidosis segments
inhibitors
Loop diuretics     alkalosis o Uric acid transport
2. Thick Ascending Limb of the Loop of Henle (TAL)
Thiazides  ,   alkalosis
o Reabsorption of sodium (20-30%), potassium and chloride
Potassium-sparing
   , acidosis carried out by a single carrier (cotransporter) [target
diuretics
of loop diuretics]
 Arrows under URINE indicate change in amount of salt or ion o Major site of calcium and magnesium reabsorption
excreted o Potassium is pumped into the cell from both luminal and
 Arrows under BODY indicate change in concentration of basal sides, an escape route must be provided, this
chloride ion in blood 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

o
3. Distal convoluted tubule (DCT)
o Actively pumps sodium and chloride out of the lumen of
the nephron
o Responsible for the reabsorption of 5-8% of sodium via
a contransporter (target of thiazide diuretics)
o Calcium is reabsorbed under the control of parathyroid
hormone (PTH)
o Removal of the reabsorbed calcium back into the blood
requires the sodium-calcium exchange process

4. Cortical Collecting Tubules (CCT)

o The principal cells are the major sites of sodium,
potassium and water transport
o The intercalated cells are the primary sites of H+
secretion
o Last tubular site for sodium reabsorption (2-5%) via
Figure 15-2. Tubule transport systems and sites of action of channels (not a transporter) [controlled by
diuretics. Circles with arrows denote known ion cotransporters aldosterone]
that are targets of the diuretics indicated by the numerals. o Reabsorption is accompanied by equivalent loss of K+ or
Question marks denote preliminary or incompletely documented H+ ion
suggestions for the location of certain drug effects o The aldosterone receptor and sodium channels are the
RENAL TRANSPORT MECHANISM sites of K-sparing diuretic action
1. Proximal convoluted tubule o Primary site of acidification of urine
(PCT) o Reabsorption of water in the collecting tubule is under
o Isosmotic reabsorption the control of ADH
of amino acids, glucose,
and numerous cation
o Major site for sodium
chloride (60-70%)
reabsorption in exchange
for H+ ion
o Major site for
bicarbonate reabsorption
o Bicarbonate is not
absorbed through luminal
membrane, it is
converted to CO2 via
carbonic acid to permit
reabsorption and
regenerated within the
tubular cell
 o Furosemide (prototype), Bumetanide, and Torsemide
 Sulfonamide derivatives
o Ethacrynic acid
 Phenoxy acid derivative
 Acts by the same mechanism
 Uricosuric drug
o Inhibit the cotransport of sodium, potassium and
chloride
o Short-acting (diuresis over a 4-hour period)
o Rapidly absorbed
o Excreted by glomerular filtration and tubular secretion
o Loop diuretic reduce the reabsorption of both Na and Cl
by inhibiting the Na/K/Cl transporter
o 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)
o Increase of calcium excretion can be useful in acute
management of hypercalcemia
o Loop agents appear to have direct effects on blood flow
through several vascular beds
o Reduction in secretion if simultaneously administered
with NSAIDs or Probenacid
B. EFFECTS
o Full dose produces massive sodium chloride diuresis
o Diluting ability of the nephron is reduced (site of
significant dilution of urine)
o Calcium excretion is increased due to the inhibition of
the Na+/K+/2Cl-transporter
o Potassium wasting and proton excretion  hypokalemic
CARBONIC ANHYDRASE INHIBITORS alkalosis
A. PROTOTYPES AND MECHANISM OF ACTION o Non-steroidal anti-inflammatory drugs (NSAIDS)
o Acetozolamide is the prototype decreases the efficacy
o Sulfonamide derivatives o Pulmonary vasodilating effect
o Forerunners of modern diuretics C. CLINICAL USES
o Inhibition of carbonic anhydrase in the brush border o Treatment of edematous states (heart failure, acute
and intracellular carbonic anhydrase in the PCT causing pulmonary edema, ascites)
NaHCO3 diuresis and a reduction in total body HCO3 o Used in HPN if response to thiazides is inadequate
stores o Treatment of hypercalcemia (induced by malignancy)
o Inhibition of carbonic anhydrase also occurs in other  managed by parenteral volume and electrolyte
tissues of the body as well as in the kidneys supplementation
o Well absorbed orally o Hyperkalemia
o Latency = 30 min o Acute renal failure  can increase urine flow and
 peak effect in 2 hrs. and persists for 12 hrs. enhance K excretion, can help flush large pigment load
after a single dose and intratubular casts, ameliorate intratubular
o Excreted through the S2 segment of the proximal tubule obstruction
by tubular secretion o Anion overdose  toxic ingestion of bromide, fluoride,
o At maximal safely administered dosage, 85% inhibition iodide
of proximal bicarbonate reabsorption or 45% inhibition D. TOXICITY
of whole kidney HCO3 reabsorption (Acute HCO3 wasting o Can induce hypokalemic metabolic alkalosis
condition) o Potassium wasting maybe severe
o CA inhibition causes significant HCO3 losses and o Can cause hypovolemia and cardiovascular complications
hyperchloremic metabolic acidosis o Ototoxicity and sulfonamide allergy
B. EFFECTS o Hypomagnesemia
o Major renal effect is bicarbonate diuresis (eg. sodium o Hyperruricemia
bicarbonate is excreted) o Allergic and other reactions
 body bicarbonate is depleted and results to  skin rashes
metabolic acidosis  eosinophilia
o Bicarbonate depletion results to slowing of its  severe dehydration
excretion  hyponatremia
o Self-limiting diuresis in 2-3 days
o Contraindication
o As increased sodium is presented to the CCT some of the
 Cirrhosis
excess sodium is reabsorbed and potassium is secreted,
 Borderline renal failure
resulting in a significant potassium “wasting”
 Heart failure
o Inhibitory effect occurs throughout the body
o Useful reduction in IOP in the eye which is not self-
limiting Used for the treatment of glaucoma THIAZIDE DIURETICS
o In the CNS, acidosis can result to hyperventilation A. PROTOTYPE
which can protect against high altitude sickness (acute o Hydrochlorothiazide
mountain sickness) Used as diuretic if the edema is o Sulfonamide derivative
accompanied by metabolic alkalosis o Active by the oral route
o Urinary alkalinization (excretion of uric acid, o 6-12 hours duration of action
cystine, other weak acids can be enhance by increasing o Inhibit sodium chloride transport in the early segment
urine pH) of the DCT
o Metabolic alkalosis o Produces moderate sodium and chloride diuresis
o Adjuvants for the treatment of epilepsy, hypokalemic o Secreted by the organic acid secretory system in the
periodic paralysis, to increase urinary phosphate proximal tubule
excretion during hyperphosphatemia o Competes with the secretion of uric acid [can elevate
C. TOXICITIES levels of uric acid]
o Drowsiness and paresthesias occur after oral intake o Hypokalemic metabolic alkalosis may occur
o Alkalinization of the urine may cause precipitation of o Few sulfonamide derivatives lack the typical thiazide
calcium salts and formation of renal stones ring in their structure but have effects similar to
o Renal potassium wasting thiazides therefore are considered thiazide-like
o Patients with renal impairment may develop - Prototype drug
Hydrochlorothiazide
encephalopathy due to ammonia reabsorption - Sulfonamide derivative
o Hypersensivity reactions - Not very lipid soluble and
 Fever rashes must given in large doses
 BM suppression - Slowly absorbed and longer
Chlorothiazide
 Interstitial nephritis duration of action
o Contraindications - Only thiazide available as
 Decrease urinary excretion of NH4 and may parenteral administration
contribute to hyperammonemia and hepatic B. EFFECTS
encephalopathy in patients with cirrhosis o Reduction in the transport of sodium into the tubular
cell reduces intracellular sodium and promotes sodium-
LOOP DIURETICS calcium exchange  reabsorption of calcium  urine
A. PROTOTYPES AND MECHANISM OF ACTION calcium content is decreased
o Opposite of loop diuretics
 o Rarely cause hypercalcemia but may unmask hypercalcemia  1° Conn’s syndrome
due to other causes (hyperparathyroidism, carcinoma,  ectopic production
sarcoidosis)  2° heart failure
o Reduce BP (initially, reflects reduction in blood  Cirrhosis
volume)  nephrotic syndrome
o Reduce vascular resistance (continued use) [effect is D. TOXICITY
modest but significant and maximal at doses lower than 1. Hyperkalemia
the maximal diuretic dosage] 2. Hyperchloremic metabolic acidosis (inhibition of H
o Synergistic effect with loop diuretic producing marked secretion)
diuresis 3. Gynecosmastia, impotence, BPH (Spironolactone)
o Actions of thiazides can be inhibited by NSAIDs [endocrine abnormalities]
C. CLINICAL USES 4. Acute renal failure (Triamterene combined with
1. Hypertension and CHF [used for chronic therapy of mild Indomethacin)
edematous conditions (mild heart failure)] 5. Kidney stones (Triamterene)
2. Nephrolithiasis due to Idiopathic hypercalciuria [stone  slightly soluble, may precipitate in the urine
formation can be reduced because of reduction in urine o Contraindications
calcium concentration] i. Chronic renal insufficiency
3. Nephrogenic Diabetes Insipidus ii. Liver disease
D. TOXICITY iii. Fatal hyperkalemia with concomitant use of beta
1. Massive sodium diuresis with hyponatremia can be an blockers and ACE inhibitors
early dangerous effect
2. Potassium wasting and metabolic alkalosis OSMOTIC DIURETICS
3. Diabetic patients may have significant hyperglycemia A. PROTOTYPE AND MECHANISM OF ACTION
4. Serum uric acid (hyperuricemia) and lipid levels may o Mannitol is the prototype
increase (hyperlipidemia) o Glycerin, Isosorbide, Urea (these are rarely used)
5. Sulfonamide allergy o Freely filtered at the glomerulus but poorly reabsorbed
6. Impaired carbohydrates tolerance in the tubules  remains in the lumen and “holds” water
7. Allergic and other reactions by virtue of osmotic effect
 skin rashes, photosensitivity, hemolytic anemia, o Given intravenously
thrombocytopenia, acute pancreatitis, acute o Sodium excretion is increased because the rate of urine
pulmonary edema, weakness, fatigability, flow is accelerated
paresthesias, impotence o Major location of action is at the PCT, where the bulk
o Contraindications: of isoosmotic reabsorption normally takes place
i. Cirrhosis to avoid K depletion and hepatic o Reabsorbtion of water is also reduced in the ascending
encephalopathy limb of the loop of Henle and collecting tubule
ii. Renal failure (renal insufficiency may be B. EFFECTS
intensified) o Increased urine volume
iii. Digitalis toxicity may manifest as a result of o Increased excretion of most filtered solutes unless
diuretic-induced K depletion they are actively reabsorbed
o Increased sodium excretion
 because of accelerated urine flow in the tubules
and sodium transporters cannot handle the volume
POTASSIUM-SPARING DIURETICS rapidly enough
A. PROTOTYPES AND MECHANISM OF ACTION o Reduce brain volume and intracranial pressure
o Prevent K secretion by antagonizing the effects of (neurologic conditions) by osmotically extracting water
aldosterone at the cortical collecting tubule from the tissue
o Inhibition may occur by o With similar effect in the eye (acute glaucoma)
i. Direct antagonism at the level of cytoplasmic
mineralocorticoid receptors (Spirolactones)
ii. Suppression of renin or angiotensin II generation C. CLINICAL USES
(ACE inhibitors) o Used to maintain high urine flow
iii. Direct inhibition of Na transport through ion i. When renal blood flow is reduced
channels in the luminal membrane (Triamterene, ii. Solute overload (eg. severe hemolysis,
Amiloride) rhabdomyolysis)
o Combine and block intracellular aldosterone receptor iii. Reduce IOP in acute glaucoma
 reduce expression of genes controlling synthesis iv. Reduce intracranial pressure in neurologic
of sodium ion channels and Na+/K+ ATPase conditions
o Actions can be inhibited by NSAIDs [dependent on renal D. TOXICITIES
o Extracellular volume expansion causing hyponatremia and
prostaglandin production]
pulmonary edema in patients with heart failure
- Synthetic steroids that acts as a
 prior to diuresis because mannitol is rapidly
competitive antagonist to
distributed in extracellular compartment and
aldosterone [bind to aldosterone
extracts water from cells
receptors and reduce intracellular
o Headache, nausea and vomiting
formation of active metabolites of
SPIRONOLACTONE o Dehydration  leading to hypernatremia
aldosterone]
o hyperkalemia  as water is extracted from cells
- Inactivation occurs in the liver
- Slow onset of action with full
therapeutic effect achieved after ANTIDIURETIC HORMONE AGONISTS
several days A. PROTOTYPES AND MECHANISM OF ACTION
A spironolactone analog with greater o Antidiuretic hormone (ADH) [Vasopressin] and
EPLERENONE Desmopressin
selectivity for aldosterone receptor
- Extensively metabolized in the  Prototypes
liver  ADH agonists
- Major route of elimination is via  Peptides
the kidneys  Given IV
TRIAMTERENE
- Short half-life, given more  Used in the treatment of central diabetes
frequently insipidus
- Direct inhibitor of Na influx in  Renal action is mediated by V2 receptors and V1a
the cortical collecting tubule receptors
- Excreted unchanged in the urine - Nonpeptide ADH receptor antagonist
- A pyrazine carbonyl-guanidine (vaptan) approved for use
derivative - Orally active
AMILORIDE
- 50% oral absorption CONIVAPTAN - Inhibit effects of ADH in the
- Direct inhibitor of Na influx in collecting tubule
the cortical collecting tubule - Pharmacologic antagonist at V1a and V2
B. EFFECTS receptors
o Increase sodium clearance and decrease potassium and - A tetracycline antimicrobial drug
hydrogen excretion - Orally active
o May cause hyperkalemic metabolic acidosis - Inhibit effects of ADH in the
C. CLINICAL USE collecting tubule
o Treatment of potassium wasting caused by chronic DEMECLOCYCLINE - Reduce the formation of cAMP in
therapy with loop and thiazide diuretics (combination response to ADH
in a single pill) - Interfere with the actions of cAMP in
o Treatment of hyperaldosteronism (mineralocorticoid the collecting tubule cells
excess) - Mechanism is unknown
 - Orally active
- Has anti-ADH effects but is never used
as an ADH antagonist
- Inhibit effects of ADH in the
collecting tubule
LITHIUM
- Reduce the formation of cAMP in
response to ADH
- Interfere with the actions of cAMP in
the collecting tubule cells
- Mechanism is unknown
B. EFFECTS AND CLINICAL USES
o 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
o Pituitary diabetes insipidus
 ADH and Desmopressin are useful
 Not useful for nephrogenic diabetes insipidus
C. TOXICITIES
o 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)
o Renal failure
 Caused by Lithium and Demeclocycline
 Lithium can cause chronic interstitial nephritis
o Demeclocycline causes bone and teeth abnormalities in
children younger than 12 years old and those with liver
disease

CLINICAL PHARMACOLOGY OF DIURETIC AGENTS

1. Heart failure
EDEMATOUS 2. Hepatic
STATES cirrhosis
3. Kidney diseases
4. Idiopathic edema
1. Hypertension
NONEDEMATOUS 2. Nephrolithiasis
STATES 3. Hypercalcemia
4. Diabetes
insipidus