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Diuretics
Diuretics
Diuretics
• Organic acid secretory systems are located in the middle third of the straight part of the proximal tubule (S2
segment). These systems secrete a variety of organic acids (uric acid, nonsteroidal anti-inflammatory drugs
[NSAIDs], diuretics, antibiotics, etc) into the luminal fluid from the blood.
• These systems thus help deliver diuretics to the luminal side of the tubule, where most of them act.
• Organic base secretory systems (creatinine, choline, etc) also are present, in the early (S1) and middle (S2)
segments of the proximal tubule.
Carbonic anhydrase inhibitors
• Carbonic anhydrase is present in many nephron sites, but the predominant location of this
enzyme is the epithelial cells of the PCT
• The prototypical carbonic anhydrase inhibitor is acetazolamide.
• Well absorbed
• Increase urine ph after 30 minutes
• Effects last for about 12 hours
• Acetazolamide, dorzolamide, brinzolamide
• Pharmacodynamics
• Inhibition of carbonic anhydrase activity profoundly depresses HCO3− reabsorption in the PCT
• 85% of the HCO3− resorptive capacity of the superficial PCT is inhibited
• Because of reduced HCO3− in the glomerular filtrate and the fact that HCO3− depletion leads to
enhanced NaCl reabsorption by the remainder of the nephron, the diuretic efficacy of
acetazolamide decreases significantly with use over several days. (hyperchloremic metabolic
acidosis)
• The ciliary body of the eye secretes HCO3− from the blood into the aqueous humour, and
similarly, formation of cerebrospinal fluid (CSF) by the choroid plexus involves HCO3− secretion.
Clinical indication
• Glaucoma
The reduction of aqueous humour formation by carbonic anhydrase inhibitors
decreases the intraocular pressure. This effect is valuable in the management of
glaucoma in some patients, making it the most common indication for use of
carbonic anhydrase inhibitors Topically active agents, (dorzolamide,
brinzolamide).
• Urinary Alkalinization
Uric acid and cystine are relatively insoluble and may form stones in acidic urine.
Therefore, in cystinuria, a disorder of cystine reabsorption, solubility of cystine
can be enhanced by increasing urinary pH to 7–7.5 with carbonic anhydrase
inhibitors. In the case of uric acid, pH needs to be raised only to 6–6.5.
• Metabolic Alkalosis
when the alkalosis is due to excessive use of diuretics in patients with severe heart failure,
replacement of intravascular volume may be contraindicated. In these cases, acetazolamide can be
useful in correcting the alkalosis as well as producing a small additional diuresis for correction of
volume overload.
• Acute Mountain Sickness
Weakness, dizziness, insomnia, headache, and nausea can occur in mountain travelers who rapidly
ascend above 3000 m. The symptoms are usually mild and last for a few days. In more serious
cases, rapidly progressing pulmonary or cerebral edema can be life-threatening. Acetazolamide
counteracts the respiratory alkalosis that occurs with climbing to high altitudes by increasing
bicarbonate excretion in the urine and thereby diminishing symptoms of mountain sickness
• Carbonic anhydrase inhibitors have been used as adjuvants in the treatment of
epilepsy and in some forms of hypokalemic periodic paralysis.
• useful in treating patients with CSF leakage (usually caused by tumor or head
trauma, but often idiopathic). By reducing the rate of CSF formation and
intracranial pressure, carbonic anhydrase inhibitors can significantly slow the
rate of CSF leakage.
• acetazolamide may have a role in the treatment of Meniere disease, nephrogenic
diabetes insipidus, idiopathic intracranial hypertension,
Toxicity
• . Hyperchloremic Metabolic Acidosis
• Renal Stones
• Phosphaturia and hypercalciuria occur during the bicarbonaturic response to inhibitors of carbonic
anhydrase.
• Renal Potassium Wasting
• Potassium wasting can occur because the increased Na+ presented to the collecting tubule
(with HCO3−) is partially reabsorbed, increasing the lumen- negative electrical potential in
that segment and enhancing K+ secretion.
• Drowsiness and paresthesias
• Hypersensitivity reactions
Contraindication
• Carbonic anhydrase inhibitor-induced alkalinization of the urine
decreases urinary excretion of NH4+ (by converting it to rapidly
reabsorbed NH3) and may contribute to the development of
hyperammonemia and hepatic encephalopathy in patients with
cirrhosis.
SODIUM GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITORS
• The proximal convoluted tubule reabsorbs almost all of the glucose filtered by the
glomeruli. Ninety percent of the glucose reabsorption occurs through SGLT2
• Dapagliflozin, canagliflozin, empagliflozin, ertugliflozin,
• Well absorbed from GIT
Clinical uses
• Diabetes mellitus
• Weight loss
• Reduce blood pressure
Toxicity
• Acute kidney injury
• Genital fungal infection
• UTI
LOOP OF HENLE
• Water is extracted from the descending limb of this loop by osmotic
forces found in the hypertonic medullary interstitium
• The thin ascending limb is relatively water-impermeable but is
permeable to some solutes.
• The thick ascending limb (TAL), which follows the thin limb of Henle’s
loop, actively reabsorbs NaCl from the lumen (about 25% of the
filtered sodium), but unlike the proximal tubule and the thin
descending limb of Henle’s loop, it is nearly impermeable to water.
• The NaCl transport system in the luminal membrane of the
TAL is a Na+/K+/2Cl−cotransporter (called NKCC2 or NK2CL)
• Back diffusion of this K+ into the tubular lumen (via the
ROMK channel) causes a lumen-positive electrical potential
that provides the driving force for reabsorption of cations—
including magnesium and calcium—via the paracellular
pathway.
Loop Diuretics
• The most efficacious diuretic agents currently available.
• Furosemide, torsemide
Sulphonamide based diuretic
• Ethacrynic acid
Not a sulphonamide
Rapidly absorbed
Eliminated by the kidney by glomerular filtration and tubular secretion
The duration of effect for furosemide is usually 2–3 hours
pharmacodynamics
• Loop diuretics inhibit NKCC2, the luminal na+/K+/2cl− transporter in the TAL of
henle’s loop.
• Reduce the reabsorption of NaCl and also diminish the lumen-positive potential
that comes from k+ recycling
• Positive potential normally drives divalent cation reabsorption in the TAL and by
reducing this potential, loop diuretics cause an increase in Mg2+ and Ca2+
excretion
• Induce expression of the cyclooxygenase cox-2, which participates in the
synthesis of prostaglandins from arachidonic acid.
• Prostaglandins, PGE2, inhibits salt transport in the TAL and thus participates in
the renal actions of loop diuretics.
Clinical uses
• Rationally of using loop diuretics in pulmonary edema:
• Furosemide increases renal blood flow via prostaglandin actions (vasodilation)
on kidney vasculature.
• Both furosemide and ethacrynic acid have also been shown to reduce
pulmonary congestion and left ventricular filling pressures in heart failure
before a measurable increase in urinary output occurs. These effects on
peripheral vascular tone are also due to release of renal prostaglandins that are
induced by the diuretics.
• Decreases the pressure caused by excess fluid on heart and lungs by increasing
water excretion
Clinical uses
• Acute hypercalcemia:
• Hyperkalemia
• Hypertension
• CHF
• Acute renal failure
• Anion overdose
• toxic ingestions of bromide, fluoride, and iodide, which are reabsorbed in the TAL. Saline solution must
be administered to replace urinary losses of Na+ and to provide Cl−, so as to avoid extracellular fluid
volume depletion.
Toxicity
• Hypokalaemic metabolic alkalosis
By inhibiting salt reabsorption in the TAL, loop diuretics increase na+ delivery to
the collecting duct. Increased Na+ delivery leads to increased secretion of K+
and H+ by the duct, causing hypokalemic metabolic alkalosis
• Ototoxicity
Dose-related hearing loss that is usually reversible.
It common in patients with diminished renal function or receiving other ototoxic
agents such as aminoglycoside antibiotics.
• Hyperuricemia
Caused by hypovolemia-associated enhancement of uric acid reabsorption in
the proximal tubule.
• Hypomagnesemia
• Allergic reactions
Sulphonamides.
Skin rash, eosinophilia, and less often, interstitial nephritis
• Hypercalciuria,
Loop agents can cause hypercalciuria, which can lead to mild hypocalcemia and secondary
hyperparathyroidism.
Contraindication
Sulphonamide allergy
Distal convulated tubule
• About 10% of the filtered NaCl is reabsorbed in the distal convoluted
tubule
• Impermeable to water, and Nacl reabsorption further dilutes the
tubular fluid
• Ca2+ is actively reabsorbed by the DCT epithelial cell via an apical
Ca2+ channel and basolateral Na+/Ca2+ exchanger. This process is
regulated by parathyroid hormone.
•
THIAZIDE DIURETICS
• Hydrochlorothiazide
• Idapamide, chlorthalidone
• Sulphonamides
• Act on proximal part of distal convulated tubule
• Inhibit NaCl co-transport, by binding to the Cl portion
• Decrease Na absorbion in distal convulated tubule, and increase
delivery of Na to collecting duct,resulting increase secretion of H
and K (hypokalemia, increase in pH)
• Increase the reabsorption of calciume by
• Increasing the calcium sodium exchanger in basolateral membrane
• Increasing calcium and sodium absorbtion from proximal convulated tubule due to
volume depletion
• can unmask hypercalcemia due to other causes (eg, hyperparathyroidism, carcinoma,
sarcoidosis)
• Interfere with uric acid secrtion
• Thiazides are secreted from proximal tubules and compete with uric acid for secretion,
so can cause hyperurecemia
Extracellular
volume
Adverse effects:
• Hyponatremia (increase ADH, increase thirst)
• Hypovolemia (volume depletion)
• Hypokalemic Metabolic alkalosis.
• Hyperuricemia (gout)
• Hypercalcemia
• Hyperglycemia
• Thiazides have a weak, dose-dependent, off-target effect to stimulate
ATP- sensitive K channels and cause hyperpolarization of beta cells,
+
• The final segment of the nephron is the last tubular site of sodium reabsorption; this is controlled by
aldosterone, a steroid hormone secreted by the adrenal cortex.
• Reabsorption of Na+ via the epithelial Na channel (ENaC) and its coupled secretion of K+ are regulated by
aldosterone
• The reabsorption of sodium occurs via channels (ENaC, not a transporter) and is accompanied by loss of
potassium or hydrogen ions.
• The collecting tubule is thus the primary site of acidification of the urine and the last site of potassium
excretion. The aldosterone receptor and the sodium channels are sites of action of the potassium-sparing
diuretics.
• Reabsorption of water occurs in the medullary collecting tubule under the control of antidiuretic hormone
(ADH).
Two types of cell:
principal cells
the major sites of Na+, K+, and water transport.
•Na+ entry into the principal cell predominates over K+ secretion into the lumen, and absorbed by Na-K
ATPase
•10–50 mV lumen-negative electrical potential drives the transport of Cl− back to the blood via the paracellular
pathway and draws K+ out of cells through the apical membrane K+ channel
intercalated cells (α, β)
primary sites of H+ (a cells, H+-ATPase ) or bicarbonate (β cells, Cl−/HCO − exchanger) secretion
• principal cells also contain a regulated system of water channels
• Antidiuretic hormone (ADH, also called arginine vasopressin, AVP) controls the permeability of these cells
to water by regulating the insertion of pre-formed water channels (aquaporin-2, AQP2) into the apical
membrane.
• Vasopressin receptors in the vasculature and central nervous system (CNS) are V1 receptors, and those in the
kidney are V2 receptors.
• ADH also stimulates the insertion of urea transporter UT1 (UT-A, UTA-1) molecules into the apical
membranes of collecting duct cells in the medulla
POTASSIUM-SPARING DIURETICS
• Spironolactone and eplerenone are steroid derivatives and act as pharmacologic
antagonists of aldosterone in the collecting tubules.
• Amiloride and triamterene act by blocking the ENaC sodium channels
• All drugs in this class cause an increase in sodium clearance and a decrease in
potassium and hydrogen ion excretion and therefore qualify as potassium-sparing
diuretics. They may cause hyperkalemic metabolic acidosis
Potassium-sparing diuretics
Steroids Nonsteroids
• 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
• Mannitol is poorly absorbed by the GI tract, and when administered
orally, it causes osmotic diarrhea rather than diuresis
• Mannitol must be given intravenously
• Mannitol is not metabolized and is excreted by glomerular filtration within
30–60 minutes, without any important tubular reabsorption or secretion
• Major effect in the proximal tubule and the descending limb of
henle’s loop
• Mannitol prevents the normal absorption of water by interposing a
countervailing osmotic force.
• Urine volume increases.
• The increase in urine flow decreases the contact time between fluid
and the tubular epithelium, thus reducing na+ as well as water
reabsorption
Clinical uses
• Reduction of intracranial and intraocular pressure
• Osmotic diuretics alter starling forces so that water leaves cells and reduces intracellular
volume
• Reduce intracranial pressure in neurologic conditions
• Reduce intraocular pressure before ophthalmologic procedures
• Glucoma
Toxicity
• Extracellular Volume Expansion
Prior to the diuresis, this leads to expansion of the extracellular volume and hyponatremia. This
effect can complicate heart failure and may produce florid pulmonary edema. Headache,
nausea, and vomiting are commonly observed in patients treated with osmotic diuretics.
• Dehydration, Hyperkalemia, and Hypernatremia
Excessive use of mannitol without adequate water replacement can ultimately lead to severe
dehydration, free water losses, and hypernatremia.
water is extracted from cells, intracellular K+ concentration rises, leading to cellular losses and
hyperkalemia.
• Hyponatremia
When used in patients with severe renal impairment, parenterally administered mannitol
cannot be excreted and is retained in the blood. This causes osmotic extraction of water from
cells, leading to hyponatremia.
Contraindication
• contraindicated in acute renal failure because ECF volume
increases but it cannot be filtered.
• It is also contraindicated in cerebral haemorrhage (active
bleeding) because in this situation, mannitol can leak from
ruptured cerebral blood vessels resulting in the increased ICT
(more fluid retention due to its osmotic effect in the cells).
RENAL AUTACOIDS
• Adenosine
• Prostaglandin
• urodilatin
ADENOSINE
• Unphophorylated ribonuleotide
• In all body, hypoxia leads to increase adenosine that increases blood
flow
• In kidney, adenosine decreses GFR (A1 present on afferent arterioles)
• In proximal tubule, biphasic effect on NHE3 activity: enhancement at
low concentrations and inhibition at very high concentrations
• Adenosine receptor antagonists have generally been found to block
the enhancement of NHE3 activity and thus exhibit diuretic activity,
also decrease potassium loss
ADENOSINE A1-RECEPTOR ANTAGONISTS
• Hypercalcemia
• Loop diuretic
• Diabetes inspidus
• ADH analogue in central diabetes ispidus
• Thiazide in nephrogenic diabetes inspidus (cause by lithium)
• Amiloride for lithium induced polyuria (block lithium in collecting ducts)