1. DIURETICS
Dr. Auwais Ahmed Khan
Assistant Professor
Department of Pharmacology
Dow College of Pharmacy
DUHS
1
2. Topic objectives:
At the end of this topic students will be able to,
• Explain basic physiology of renal excretion of ions and
water
• Discuss diuretics
• Propose class of any diuretic drug with respect to to
mechanism of action
• Predict side effects and toxicity of class of drug on the
basis of pharmacodynamics
• State indications of different diuretic drugs
• Interpret choice of diuretic with respect to indication
and patient history
2
3. • Technically,
– Diuretic:
• An agent that increases urine volume
– Natriuretic:
• An agent that causes an increase in renal sodium excretion
• Because natriuretics almost always also increase water excretion, they are usually
called diuretics
– Aquaretic:
• Agent that increases excretion of solute-free water
• E.g. Osmotic diuretics and ADH antagonists
– Urearetic:
• These agents result in increased urine output and increased urea excretion but not
increased excretion of electrolytes
3
8. • PROXIMAL TUBULE
– Sodium bicarbonate (NaHCO3), sodium chloride (NaCl),
glucose, amino acids, and other organic solutes are
reabsorbed via specific transport systems in the early
proximal tubule
– Approximately 66% of total sodium ions (Na+, but 85% of
the filtered NaHCO3), 65% of the K+, 60% of the water, and
virtually all of the filtered glucose and amino acids are
reabsorbed in the proximal tubule
– Of the various solutes reabsorbed in the proximal tubule,
the most relevant to diuretic action are NaHCO3 and NaCl
8
9. • Sodium bicarbonate
reabsorption by the PCT is
initiated by the action of a
Na+/H+ exchanger
• Bicarbonate reabsorption
by the proximal tubule is
dependent on carbonic
anhydrase
• Free H+ causes luminal pH
to fall, activating a poorly
defined Cl–/base exchanger
• More recently, inhibitors of
the sodium-glucose
cotransporter, (SGLT2) have
been approved to treat
diabetes mellitus 9
10. • LOOP OF HENLE
– Water is extracted from
the descending limb of
this loop by osmotic forces
found in the hypertonic
medullary interstitium
– Impermeant luminal
solutes such as mannitol
oppose this water
extraction
– The thick ascending limb
(TAL) of the loop of Henle
actively reabsorbs NaCl
from the lumen (about
25% of the filtered
sodium)
10
12. • DISTAL CONVOLUTED TUBULE
– Only about 10% of the filtered NaCl is reabsorbed in
the distal convoluted tubule (DCT)
– This segment is relatively impermeable to water and
NaCl reabsorption
– The mechanism of NaCl transport in the DCT is an
electrically neutral thiazide-sensitive Na+ and Cl-
cotransporter
12
13. • Because K+ does not recycle
across the apical membrane of
the DCT as it does in the TAL,
there is no lumen-positive
potential in this segment, and
Ca2+ and Mg2+ are not driven out
of the tubular lumen by electrical
forces
• Instead, Ca2+ is actively
reabsorbed by the DCT, This
process is regulated by
parathyroid hormone
13
14. • COLLECTING TUBULE
– The collecting tubule (CCT) is responsible for only 2-5% of
NaCl reabsorption by the kidney.
– Despite this small contribution, the CCT plays an important
role in renal physiology and in diuretic action.
– As the final site of NaCl reabsorption, the collecting tubule
is responsible for tight regulation of body fluid volume and
for determining the final Na+ concentration of the urine.
– Antidiuretic hormone (ADH, also called arginine
vasopressin, AVP) controls the permeability of this
segment to water.
14
15. • Reabsorption of Na+ via the epithelial
Na channel (ENaC) and its coupled
secretion of K+ is regulated by
aldosterone
• Na+ entry into the principal cell
predominates over K+ secretion, a 10–
50 mV lumen-negative electrical
potential develops
• There is an important relationship
between Na+ delivery to the CCT and
the resulting secretion of K+ and H +.
(hypokalemic alkalysing effect of
diuretics)
15
18. CARBONIC ANHYDRASE INHIBITORS
Predominant location of this enzyme is the luminal membrane of the PCT,
where it catalyzes the dehydration of H2CO3. By blocking carbonic
anhydrase, inhibitors block NaHCO3 reabsorption and cause diuresis.
Acetazolamide
Methazolamide
Dorzolamide
Brinzolamide
18
19. Pharmacodynamics
• At its maximal safely
administered dosage, 85% of the
HCO3
- reabsorptive capacity of
the superficial PCT is inhibited
• Some HCO3
- can still be
absorbed at other nephron sites
by carbonic anhydrase-
independent mechanisms, so
the overall effect of maximal
acetazolamide dosage is only
about 45% inhibition of whole
kidney HCO3
- reabsorption
19
20. PHARMACOKINETICS
• The carbonic anhydrase inhibitors are well absorbed
after oral administration
• An increase in urine pH from the HCO3- diuresis is
apparent within 30 minutes, maximal at 2 hours, and
persists for 12 hours after a single dose
• Excretion of the drug is by secretion in the proximal
tubule S2 segment. Therefore, dosing must be
reduced in renal insufficiency
20
21. CLINICAL INDICATIONS
• GLAUCOMA
– Most common indication for use of carbonic anhydrase inhibitors
– By direct antagonist activity on the ciliary epithelial carbonic anhydrase
• TO INDUCE URINARY ALKALINIZATION
– Uric acid, cystine, and other weak acids are most easily reabsorbed from acidic urine
• METABOLIC ALKALOSIS
– Acetazolamide can be useful in correcting the alkalosis
• ACUTE MOUNTAIN SICKNESS
– CA inhibitors helps in increasing ventilation that is required for acclimatization at higher altitude
– CA inhibitors also prevent formation of CSF
• OTHER USES
– Used as adjuvants in the treatment of epilepsy
– In some forms of hypokalemic periodic paralysis
– Useful in treating patients with CSF leakage
– Used to increase urinary phosphate excretion during severe hyperphosphatemia
– Finally, acetazolamide may have a role in the treatment of Meniere’s disease, nephrogenic diabetes insipidus, idiopathic
intracranial hypertension, and Kleine-Levin syndrome (episodes of hypersomnia and cognitive and behavioral
abnormalities).
21
22. TOXICITY
HYPERCHLOREMIC METABOLIC ACIDOSIS
Acidosis predictably results from chronic reduction of body HCO3
- stores by carbonic anhydrase inhibitors
and limits the diuretic efficacy of these drugs to 2 or 3 days. Unlike the diuretic effect, acidosis persists as
long as the drug is continued.
RENAL STONES
1. Phosphaturia and hypercalciuria occur during the bicarbonaturic response to inhibitors of carbonic
anhydrase
2. Renal excretion of solubilizing factors (eg, citrate) may also decline with chronic use
3. Calcium salts are relatively insoluble at alkaline pH
RENAL POTASSIUM WASTING
Potassium wasting can occur because Na+ presented to the collecting tubule is partially reabsorbed,
increasing the lumen-negative electrical potential in that segment and enhancing K+ secretion. This effect
can be counteracted by simultaneous administration of potassium chloride.
OTHER TOXICITIES
– Drowsiness and paresthesias are common following large doses of acetazolamide
– Carbonic anhydrase inhibitors may accumulate in patients with renal failure, leading to nervous
system toxicity
– Hypersensitivity reactions (fever, rashes, bone marrow suppression, and interstitial nephritis) may
also occur.
22
25. DOSAGE
• Acetazolamide:
– Adult (>12 yrs)
– 250 -500 mg q12h PO
– Paediatric (20 kg)
– 4mg/kg q8h I/V, PO
– Neonatal (3kg)
– 4 mg/kg q8h I/V, PO
25
26. SODIUM GLUCOSE COTRANSPORTER 2 (SGLT2)
INHIBITORS
• In the normal individual, the proximal convoluted tubule reabsorbs almost
all of the glucose filtered by the glomeruli
– Ninety percent of the glucose reabsorption occurs through SGLT2
– Inhibiting this transporter using the currently available drugs will result in
glucose excretion of only 30–50% of the amount filtered
– Four SGLT2 inhibitors (dapagliflozin, canagliflozin, empagliflozin, and
ipragliflozin [available in Japan]) are currently available
– Angiotensin II has been shown to induce SGLT2 production via the AT1
receptor
– Thus, blockade of the renin-angiotensin-aldosterone axis may result in lower
SGLT2 availability
26
27. • Pharmacokinetics
– Rapidly absorbed by the gastrointestinal (GI) tract
– The elimination half-life of dapagliflozin is 10–12
hours, and up to 70% of the given dose is excreted
in the urine
– The drugs are not recommended in patients with
more severe renal failure or advanced liver
disease
27
28. • Clinical Indications and Adverse Reactions
– Currently, the only indication for the use of these drugs is as third-line
therapy for diabetes mellitus
– They do have other minor effects,
• Weight loss
• Diuretic
• Decrease in SBP
– Possible ADRs include,
• Acute kidney injury
• Genital fungal infection in women
28
29. LOOP DIURETICS (High-Ceiling Diuretics)
• PHARMACODYNAMICS
– These drugs inhibit NKCC2, the luminal
Na+/K+/2Cl- transporter in the thick
ascending limb of Henle's loop.
– By inhibiting this transporter, the loop
diuretics reduce the reabsorption of NaCl
and also diminish the lumen-positive
potential that comes from K+ recycling.
– This positive potential normally drives
divalent cation reabsorption in the loop,
and by reducing this potential, loop
diuretics cause an increase in Mg2+ and
Ca2+ excretion.
29
30. CLINICAL INDICATIONS
• The most important indications for the use of the loop diuretics include
acute pulmonary edema, other edematous conditions, and acute
hypercalcemia
• HYPERKALEMIA
• ACUTE RENAL FAILURE
Loop agents can increase the rate of urine flow and enhance K+ excretion
in acute renal failure. However, they do not shorten the duration of renal
failure
• ANION OVERDOSE
Loop diuretics are useful in treating toxic ingestions of bromide, fluoride,
and iodide, which are reabsorbed in the thick ascending limb. Saline
solution must be administered to replace urinary losses of Na+ and to
provide Cl-, so as to avoid extracellular fluid volume depletion 30
31. PHARMACOKINETICS
• The loop diuretics are rapidly absorbed
• They are eliminated by the kidney by glomerular filtration and tubular
secretion
• Absorption of oral torsemide is more rapid (1 hour) than that of
furosemide (2-3 hours) and is nearly as complete as with intravenous
administration
• The duration of effect for furosemide is usually 2-3 hours and that of
torsemide is 4-6 hours. Half-life depends on renal function. Reduction in
the secretion of loop diuretics may result from simultaneous
administration of agents such as NSAIDs or probenecid, which compete for
weak acid secretion in the proximal tubule.
31
32. TOXICITY
• HYPOKALEMIC METABOLIC ALKALOSIS
• OTOTOXICITY
Loop diuretics occasionally cause dose-related hearing loss that is usually
reversible
• HYPERURICEMIA
Loop diuretics can cause hyperuricemia and precipitate attacks of gout. This is
caused by hypovolemia-associated enhancement of uric acid reabsorption in
the proximal tubule
• HYPOMAGNESEMIA
Occurs most often in patients with dietary magnesium deficiency
• ALLERGIC & OTHER REACTIONS
Except for ethacrynic acid, the loop diuretics are sulfonamides. This toxicity
usually resolves rapidly after drug withdrawal
32
33. CONTRAINDICATIONS
• Furosemide, bumetanide, and torsemide may
exhibit allergic cross-reactivity in patients who
are sensitive to other sulfonamides but this
appears to be very rare
• Overzealous use of any diuretic is dangerous in,
– Hepatic cirrhosis,
– Borderline renal failure, or
– Heart failure
33
34. DOSING
• By mouth, oedema, initially 40 mg in the morning;
maintenance 20–40 mg daily, increased in resistant
oedema to 80 mg daily or more; child 1–3 mg/kg daily,
max. 40 mg daily
• By intramuscular injection or slow intravenous
injection, initially 20–50 mg, increased if necessary in
steps of 20 mg not less than every 2 hours; doses
greater than 50 mg by intravenous infusion only; max.
1.5 g daily; child 0.5–1.5 mg/kg daily, max. 20 mg daily
34
35. THIAZIDES
• Pharmacodynamics
– Thiazides inhibit NaCl
reabsorption from
the luminal side of
epithelial cells in the
DCT by blocking the
Na+/Cl- transporter
(NCC)
– Less intracellular Na+
enhances Na+/Ca++
exchanger
35
37. PHARMACOKINETICS
• All of the thiazides can be administered orally,
but there are differences in their metabolism
• Chlorothiazide, the parent of the group, is not
very lipid-soluble and must be given in relatively
large doses
• Chlorothiazide is the only thiazide available for
parenteral administration
• Chlorthalidone is slowly absorbed and has a
longer duration of action
37
38. TOXICTY
• HYPOKALEMIC METABOLIC ALKALOSIS AND HYPERURICEMIA
These toxicities are similar to those observed with loop diuretics
• IMPAIRED CARBOHYDRATE TOLERANCE
– Hyperglycemia may occur in patients who are overtly diabetic or who have even mildly abnormal glucose tolerance
tests
– Thiazides have a weak, dose-dependent, off-target effect to stimulate ATP-sensitive K+ channels and cause
hyperpolarization of beta cells, thereby inhibiting insulin release.
• HYPERLIPIDEMIA
Thiazides cause a 5-15% increase in total serum cholesterol and low-density lipoproteins
(LDL). These levels may return toward baseline after prolonged use
• HYPONATREMIA
Hyponatremia is an important adverse effect of thiazide diuretics
• ALLERGIC REACTIONS
The thiazides are sulfonamides and share cross-reactivity with other members of this
chemical group
• OTHER TOXICITIES
Weakness, fatigability, and paresthesias similar to those of carbonic anhydrase inhibitors may
occur. Impotence has been reported but is probably related to volume depletion 38
41. POTASSIUM-SPARING DIURETICS
• Pharmacodynamics
– These diuretics prevent K+ secretion by
antagonizing the effects of aldosterone at the
late distal and cortical collecting tubules
– Inhibition may occur by ,
• Direct pharmacologic antagonism of
mineralocorticoid receptors
(spironolactone, eplerenone)
or
• By inhibition of Na+ influx through ion
channels in the luminal membrane
(amiloride, triamterene)
41
42. PHARMACOKINETICS
Substantial inactivation of spironolactone
occurs in the liver. Overall, spironolactone has
a rather slow onset of action, requiring several
days before full therapeutic effect is achieved.
Eplerenone is a spironolactone analog with
greater selectivity for the aldosterone
receptor.
42
43. CLINICAL INDICATIONS
• Potassium-sparing diuretics are most useful in states of
mineralocorticoid excess or hyperaldosteronism
• In the setting of enhanced mineralocorticoid secretion
and excessive delivery of Na+ to distal nephron sites,
renal K+ wasting occurs. Potassium-sparing diuretics of
either type may be used in this setting to blunt the K+
secretory response
43
44. TOXICITY
• HYPERKALEMIA
Unlike other diuretics, K+-sparing diuretics can cause mild, moderate, or even life-threatening
hyperkalemia
• METABOLIC ACIDOSIS
By inhibiting H+ secretion in parallel with K+ secretion.
• GYNECOMASTIA
Synthetic steroids may cause endocrine abnormalities by actions on other steroid receptors.
Gynecomastia, impotence, and benign prostatic hyperplasia have all been reported with
spironolactone. Such effects have not been reported with eplerenone.
• ACUTE RENAL FAILURE
The combination of triamterene with indomethacin has been reported to cause acute renal
failure. This has not been reported with other K+-sparing diuretics.
• KIDNEY STONES
Triamterene is only slightly soluble and may precipitate in the urine, causing kidney stones.
44
45. CONTRAINDICATIONS
• Concomitant use of other agents that blunt the renin-
angiotensin system (β blockers or ACE inhibitors)
increases the likelihood of hyperkalemia
• Patients with liver disease may have impaired
metabolism of triamterene and spironolactone, so
dosing must be carefully adjusted
• Strong CYP3A4 inhibitors (eg, ketoconazole,
itraconazole) can markedly increase blood levels of
eplerenone
45
47. Osmotic Diuretics
• Pharmacodynamics
– The proximal tubule and descending limb of Henle's loop are
freely permeable to water. Any osmotically active agent that is
filtered by the glomerulus but not reabsorbed causes water to
be retained in these segments and promotes a water diuresis
• Pharmacokinetics
– Osmotic diuretics are poorly absorbed, which means that they
must be given parenterally. If administered orally, mannitol
causes osmotic diarrhea. Mannitol is not metabolized and is
excreted by glomerular filtration within 30-60 minutes
47
48. • Clinical Indications:
– To increase urine volume
– Reduction of intracranial and intraocular pressure
• Toxicity:
– Extracellular Volume Expansion
– Dehydration, Hyperkalemia and Hypernatremia
– Hyponatremia(in patients with diminished renal function)
48
49. Antidiuretic Hormone (ADH) Agonists
• Vasopressin and desmopressin are used in the
treatment of central diabetes insipidus.
49
50. Antidiuretic Hormone (ADH) Antagonists
• Pharmacodynamics
– Antidiuretic hormone antagonists inhibit the effects of ADH in the
collecting tubule.
• Pharmacokinetics
– Conivaptan and demeclocycline are orally active. Conivaptan and
demeclocycline have half-lives of 5-10 hours.
• Clinical Indications
– Syndrome of inappropriate adh secretion (siadh)
– Other causes of elevated antidiuretic hormone (adh)
50
51. • Toxicity
– Nephrogenic diabetes insipidus.
– Renal failure.
– Demeclocycline should be avoided in patients with
liver disease and in children younger than 12
years.
51
