Renal Pharmacology 2023

Renal Pharmacology
Mesud Mohammed (Clinical Pharmacy Specialist, Lecturer, &

Clinical Preceptor)
MWU, school of medicine, 2023
Goba, Ethiopia
Renal Pharmacology: Objectives
 At the end of this learning:
 The site of action
 The mechanism of action
 The clinical indications & uses
 The possible adverse effects
& drug interactions
2
Introduction to renal pharmacology
The kidney
Maintain the stability of the body
 Volume control
 PH control
 Electrolyte balance
 Waste removal
Major organ for the removal of drugs and their metabolites

Target of several drug toxicities
Targets for several drug actions
 Diuretics
 Many others ….
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The Nephron
Segments
 The glomerulus,
 The proximal tubule
 The loop of Henle
 The distal convoluted tubule
 Collecting tubules and the collecting ducts
Juxtaglomerular apparatus
 The DCT
 Glomerulus
 Arterioles (afferent, efferent)
 Maculla densa cells
 Granular cells
Introduction to renal pharmacology
5
Functions of the nephron
Glomerular filtration
Driven by hyrodynamic force
Solutes with small MW and water pass in to the
proximal tubule
Electrolytes, glucose, water,…..to be reabsorbed at
different stages down the nephron
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Transport systems in the nephron
Apical membrane
1. Na+/H+ exchange
2. Na+/K+/2Cl- cotransport
3. Na+/Cl- cotransport
4. Na+ channels
5. Cl-/organic base exchanger
Basolateral membrane
1. Na+/K+ ATPase
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The proximal tubule
NaHCO3, NaCl, glucose, amino acids and other organic
solutes are reabsorbed via specific transport systems
60-70% of Na+ ions reabsorbed
65% of the K+, 60% of the water, and virtually all of the
filtered glucose and amino acids are reabsorbed
>90% of HCO-3 is reabsorbed
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FIGURE–2 Mechanism of sodium bicarbonate and glucose reabsorption in the
proximal tubule cell. NHE3, Na+/H+ exchanger 3
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Secretory systems in the proximal tubule
Organic acid secretory systems

 Uric acid
 NSAIDs
 Diuretics
 Antibiotics , etc
Organic base secretory systems
 Creatinine
 Choline, etc
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The Loop of Henle
Two portions
The thin descending limb
 Highly permeable to water
 Ihibition by inulin, mannitol…etc.
The thick ascending limb

 Almost impermeable to water
 Reabsorbs NaCl (25% of Na+ filtered)
 Results in dilution of the tubular fluid (“diluting
segment”)
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The thick ascending limb
 Major mechanism of reabsorption is Na+/K+/2Cl-
cotransporter
 Electrically neutral transport, but…. Intracellular
build up of K+
 Back diffusion of K+ … lumen positive electrical

potential.. …. Driving force for Mg2+ and Ca2+
reabsorption
Inhibition of the transporter causes indirect excretion of
divalent cations
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The Na+/K+/2Cl- cotransporter
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The distal convoluted tubule
Relatively impermeable to water
Electrically neutral transport system
Na+/Cl- cotransporter
PTH dependent channel … also affected by calcitriol
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The DCT
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The collecting ducts
Impermeable to water and ions
Transportations independently controlled by hormones
 NaCl reabsorbed by the action of aldosterone

 Water reabsorbed by the action of ADH
Principal cells… reabsorb Na+, secret K+
Intercalated cells … secret acids and bases
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Aldosterone
 Stimulate Na+/H+ exchange … (rapid)
 activates sodium channels in the apical membrane

… (delayed)
 Increase the number of Na+ pumps on the

basolateral membrane
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Antidiuretic hormone (ADH)- Vasopressin
 Binds to V2 receptors
 Increase the expression of aquaporins (water channels)
 Monitors the concentration of urine
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Regulation of potassium excretion
K+ is lost
More Na+ reaches the collecting duct,
Na+ reabsorption in the collecting duct is increased

directly (e.g. in hyperaldosteronism).
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K+ is retained
 Na+ reabsorption in the collecting duct is decreased
 Amiloride and triamterene block the sodium
channel in this part of the nephron
 Spironolactone and eplerenone antagonise
aldosterone
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The CT and CD
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Diuretics- introduction
Definition: drugs that increase urine volume.
Renal diuretics: they act on the nephrons and may be classified into:
1. Loop diuretics: they are high efficacy diuretics- they inhibit Na+ transport in
the loop of Henle.
2. Thiazide diuretics: they are moderate efficacy- they inhibit Na+ transport in
proximal segment of distal convoluted tubules (DCT).
3. K+-sparing (retaining=conserving) diuretics: they are low efficacy
diuretics- they are either aldosterone antagonists as spironolactone, or non-
aldosterone antagonists as amiloride and triamterene.
4. Carbonic anhydrase inhibitor(CAIs): they inhibit Na+/H+ exchange in
proximal convoluted tubules (PCT) mainly.
5. Osmotic diuretics: as Mannitol.
N.B. Thiazide diuretics, loop diuretics, K+-sparing diuretics, and CAIs are known
as "Natriuretics“ or "Saluretics" because they increase urinary excretion of Na+
with its iso-osmotic water.
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Carbonic Anhydrase Inhibitors
A. Prototypes and Mechanism of Action
Acetazolamide is the prototypic agent
 These diuretics are sulfonamide derivatives.
 The mechanism of action is inhibition of carbonic anhydrase in the brush

border and cytoplasm (Figure).
 CA is also found in other tissues and plays an important role in the

secretion of cerebrospinal fluid and aqueous humor.
 Acetazolamide inhibits carbonic anhydrase in all tissues of the body.
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27
FIGURE–2 Mechanism of sodium bicarbonate and glucose reabsorption
in the proximal tubule cell. NHE3, Na+/H+ exchanger 3
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Carbonic Anhydrase Inhibitors…
Diuretic effects of CAIs

 The major renal effect is bicarbonate diuresis (ie, sodium
bicarbonate is excreted); body bicarbonate is depleted, and
metabolic acidosis results.
 As increased Na+ is presented to the cortical collecting tubule, some of the

excess Na+ is reabsorbed and K+ is secreted, resulting in significant
potassium wasting
 As a result of HCO3- depletion, sodium NaHCO3 excretion slows -even with

continued diuretic administration -and the diuresis is self-limiting within
2–3 days.
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Diuretic effects of CAIs …
 Secretion of bicarbonate into aqueous humor by the ciliary epithelium in
the eye and into the cerebrospinal fluid by the choroid plexus is reduced.
 In the eye, a useful reduction in intraocular pressure can be achieved.
 In the central nervous system (CNS), acidosis of the CSF results in

hyperventilation, which can protect against high-altitude sickness.
 The ocular and cerebrospinal fluid effects are not self-limiting.
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Diuretic effects of CAIs
 45% of the filtered HCO3- excreted
 Delivery of more Na+ and Cl- to the loop of Henle
 Only 5% of filtered Na+ is lost, with only slight increase in Cl-
excretion
 Up to 70% of K+ may be lost due to a CAI, due to …
 Increased distal delivery of Na+ enhances K+ excretion

 Other mechanisms including RAAS
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CAIs…
 Inhibition of CA ….. loss of HCO3- ….results in metabolic acidosis

 Metabolic acidosis decreases the amount of HCO3- filtered
… poor diuretic efficacy
 Inhibition of bicarbonate synthesis in the aqueous humor
 Reduction of IOP
 Anticonvulsant effect in the CNS….???
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Pharmacokinetic properties of CAIs
 Diuretic action starts within 30 minutes, peak at 2 hours, and persists for 12
hours after a single dose.
 Secreted into the proximal tubule
 Dosing must be reduced in renal insufficiency
CAI Oral bioavailabity T1/2 (hrs) Elimination
Acetazolamide ~100% 6-9 Renally excreted

unchanged
Methazolamide ~100% ~14
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Therapeutic uses of CAIs
Not widely employed as diuretics
 Acetazolamide inhibit the enzyme carbonic anhydrase in renal tubular

cells and lead to increased excretion of bicarbonate, sodium and
potassium ions in urine
a. Treatment of metabolic alkalosis
b. Decrease formation of aqueous humor

 Most commonly used for treatment of acute angle glaucoma
- Topically active CAIs (dorzolamide, brinzolamide) are preferred
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c. Treatment of “Altitude sickness”
 Caused by rapidly ascending over 3000 meters, poor
ventilation(breath)
 Weakness, dizziness, insomnia, headache, and nausea
 Rapidly progressing pulmonary or cerebral edema
 CAIs improve symptoms by

 Decreasing the formation of CSF
 Reduction of the PH of the CSF
 Increasing ventilation
d. Adjunct therapy for some type of infantile epilepsy
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Adverse effects
 Drowsiness and paresthesia toxicities are commonly reported after oral
therapy.
 Cross-allergenicity between these and all other sulfonamide derivatives

(other sulfonamide diuretics, hypoglycemic agents, antibacterial
sulfonamides) is uncommon but can occur.
 Alkalinization of the urine by these drugs may cause precipitation of

calcium salts and formation of renal stones.
 Renal potassium wasting may be marked.
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Adverse effects…
 Patients with hepatic impairment often excrete large amounts of ammonia
in the urine in the form of ammonium ion.
 If they are given acetazolamide, alkalinization of the urine prevents

conversion of ammonia to ammonium ion.
 As a result, they may develop hepatic encephalopathy because of increased

ammonia reabsorption and hyperammonemia.
 Carbonic anhydrase inhibitors may also cause potassium and phosphate

wasting.
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SGLT2 ANTAGONISTS
 Sodium-glucose cotransporter-2 is important in the renal reabsorption of
glucose.
 Dapagliflozin, canagliflozin, empagliflozin, and ipragliflozin are
SGLT2 inhibitors approved for the treatment of diabetes.
 They reduce the active reabsorption of filtered glucose in the proximal

tubule and increase its excretion by 30–50%.
 Although they increase the volume of urine, they are not used as diuretics
except in diabetics with heart failure (off label).
 High glucose concentration in the urine may result in urinary tract

infections.
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SGLT2 ANTAGONISTS
39
SGLT-2 inhibitors DM
 Glucose is freely filtered by the kidney glomeruli and is reabsorbed in the
proximal tubules by the action of sodium-glucose co-transporters
(SGLT).
 SGLT2 accounts for about 90% of glucose reabsorption and its inhibition
causes glycosuria in people with diabetes, lowering plasma glucose levels.
 The oral SGLT2 inhibitors canagliflozin, dapagliflozin, empagliflozin, and

ertugliflozin are approved for clinical use in the United States.
 These agents reduce the threshold for glycosuria from a plasma glucose
threshold of about 180 mg/dL to about 40 mg/dL; and lower HbA1c by
0.5–1% when used alone or in combination with other oral agents or
insulin.
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 The efficacy is higher at higher HbA1c levels when more glucose is
excreted as a result of SGLT2 inhibition.
 The loss of calories results in modest weight loss of 2–5 kg.
 Empagliflozin, added to standard of care, was shown to reduce the

composite of cardiovascular death, all-cause mortality, and death from
cardiovascular causes.
 Canagliflozin was evaluated in two trials which enrolled patients with

T2DM at high cardiovascular risk.
 Canagliflozin reduced the risk of primary outcome of death from
cardiovascular causes, nonfatal myocardial infarction, or nonfatal
stroke.
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SAFETY
 An increased risk for amputation was detected in this study, primarily
involving the toe or metatarsal.
 Possible adverse reactions with SGLT2 inhibitors include:

urinary tract infections (UTIs) and genital mycotic infections which are
increased due to increased glucose excretion that occurs as a function of the
drugs’ mechanism of action.
 Osmotic diuresis occurs as well which may result in symptomatic

hypotension.
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SAFETY…
 Renal function should be monitored at baseline to guide initial dosing

and periodically during treatment to assess suitability of continuation.
 Volume status including BP, hematocrit, serum potassium, serum

magnesium, serum phosphate, and LDL cholesterol are also
recommended monitoring parameters for this class of drug.
 Cases of euglycemic ketoacidosis have been reported with SGLT2

inhibitors
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SAFETY…
 Before initiation, patients should have their risk for ketoacidosis assessed
(some risk factors include insulin deficiency, dose decreases of insulin,
caloric restriction, surgery, and infection).
 Should ketoacidosis occur, the SGLT2 inhibitor should be held or

discontinued.
 Increased risk for bone fracture has also been associated with SLGT2
inhibitor use as well as newly diagnosed bladder cancer with
dapagliflozin.
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Osmotic Diuretics
 Mannitol, the prototypical osmotic diuretic, is given intravenously.
 Other drugs often classified with mannitol (but rarely used) include
glycerin, isosorbide (not isosorbide dinitrate), and urea.
 They increase osmotic pressure of plasma leading to withdrawal of

transcellular fluid (e.g. aqueous humor, excessive CSF, etc)
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Osmotic Diuretics
 Because they are freely filtered at the glomerulus but poorly reabsorbed
from the tubule, they remain in the lumen and “hold” water by virtue
of their osmotic effect.
 Increase osmotic pressure of the tubular fluid leading to reduced active
Na+ and H2O reabsorption by renal tubules.
 The major location for this action is the proximal convoluted tubule.
 Reabsorption of water is also reduced in the descending limb of the

loop of Henle and the collecting tubule.
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Osmotic
Diuretics…
48
Osmotic Diuretics
B. Effects
 The volume of urine is increased.
 Most filtered solutes are excreted in larger amounts unless they are
actively reabsorbed.
 Sodium excretion is usually increased because the rate of urine flow

through the tubule is greatly accelerated and sodium transporters cannot
handle the volume rapidly enough.
 Mannitol can also reduce brain volume and intracranial pressure by

osmotically extracting water from the tissue into the blood.
 A similar effect occurs in the eye.
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Osmotic Diuretics
C. Clinical Use and Toxicities
 The osmotic drugs are used to maintain high urine flow (eg, when renal
blood flow is reduced and in conditions of solute overload from severe
hemolysis, rhabdomyolysis, or tumor lysis syndrome).
 Mannitol: Reduction of increased intracranial pressure associated

with cerebral edema; reduction of increased intraocular pressure;
promoting urinary excretion of toxic substances; genitourinary
irrigant in transurethral prostatic resection or other transurethral
surgical procedures
 Note: Although FDA-labeled indications, the use of mannitol for the

prevention of acute renal failure and/or promotion of diuresis is not
routinely recommended
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Osmotic Diuretics
C. Clinical Use and Toxicities….
 Movement of water from the intracellular compartment to the

extracellular may cause hyponatremia and pulmonary edema.
 As the water is excreted, dehydration and hypernatremia may follow.
 Headache, nausea, and vomiting are common.
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Thick ascending limb of the loop of Henle
2. Thick ascending limb of the loop of Henle

 reabsorbs 25% of the filtered Na+.
 contains a Na+–K+–2Cl- cotransporter in the luminal membrane.
 is the site of action of the loop diuretics (furosemide, ethacrynic acid,

bumetanide), which inhibit the Na+–K+–2Cl− cotransporter.
 is impermeable to water.
 Thus, NaCl is reabsorbed without water.
 As a result, tubular fluid [Na+] and tubular fluid osmolarity decrease to less than
their concentrations in plasma
 This segment, therefore, is called the diluting segment.
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53
Thick ascending limb of the loop of Henle
 This cotransporter provides part of the concentration gradient for the
countercurrent concentrating mechanism in the kidney and is
responsible for the reabsorption of 20–30% of the sodium filtered at the
glomerulus.
 Because potassium is pumped into the cell from both the luminal
and basal sides, an escape route must be provided; this occurs into
the lumen via a potassium-selective channel.
 Because the potassium diffusing through these channels 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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Loop Diuretics
FIGURE : Mechanism of sodium, potassium, and

chloride reabsorption by the transporter NKCC2 in
the thick ascending limb of the loop of Henle. Note
that pumping of potassium into the cell from both
the lumen and the interstitium would result in
unphysiologically high intracellular K+
concentration. This is avoided by movement of K+
down its concentration gradient back into the
lumen, carrying with it excess positive charge. This
positive charge drives the reabsorption of calcium
and magnesium.
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Loop Diuretics
Furosemide is the prototypical loop agent
 Furosemide, bumetanide, and torsemide are sulfonamide derivatives.
 Ethacrynic acid is a phenoxyacetic acid derivative; it is not a sulfonamide

but acts by the same mechanism.
 Loop diuretics inhibit the cotransport of sodium, potassium, and chloride

(NKCC2, Figure 15–3).
 The loop diuretics are relatively short-acting (diuresis usually occurs over a
4-h period following a dose).
56
Loop Diuretics
 Increase renal PG production leading to VD and increased RBF and GFR

 NSAIDs inhibit PG synthesis and antagonise the effects of loop
diuretics.
 VD of pulmonary vascular bed also occurs due to increased PG
formation ( used in acute pulmonary edema= venodilation=
decrease venous return)
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Absorption & Bioavailability of Loop Diuretics
 Furosemide, bumetanide, and torsemide are absorbed relatively quickly
after oral administration, reaching peak concentrations within 0.5–2 hours;
 when administered intravenously, their effects are nearly instantaneous.
 The oral bioavailability of bumetanide and torsemide typically exceeds

80%, whereas that of furosemide is substantially lower, at approximately
50%.
 Although the t1/2 of furosemide is short, its duration of action is longer

when administered orally, as its gastrointestinal absorption may be slower
than its elimination t1/2.
 On the basis of oral bioavailability, when a patient is switched from

intravenous to oral loop diuretic, the dose of bumetanide or torsemide
should be maintained, whereas the dose of furosemide should be
doubled; in practice, however, a fixed intravenous/oral conversion cannot
be given
 Although limited bioavailability is a concern with furosemide, a larger
problem may be its inconsistent bioavailability.
 Furosemide absorption varies from day to day in an individual, and

between individuals. Absorption is also affected by food consumption,
unlike that of bumetanide or torsemide
 conditions that predispose to ECF volume expansion and edema alter

both the pharmacokinetics and pharmacodynamics of diuretics.
 Gastrointestinal absorption can be slowed, especially during
exacerbations of edematous disorders such as heart failure, although
again, this may be true primarily of furosemide
 The more consistent bioavailability of torsemide, compared with

furosemide, and its relatively longer t1/2, have suggested that it may be a
superior loop diuretic.
 Loop diuretics are organic anions that circulate tightly bound to albumin
(95%).
 Thus, their volumes of distribution are low, except during extreme
hypoalbuminemia.
 This has suggested that severe hypoalbuminemia might impair diuretic

effectiveness, owing to impaired delivery to the kidneys, and that albumin
administration might enhance natriuresis.
 Some guidelines continue to suggest that albumin infusion should be used as

an adjunct to diuretics when nephrotic patients appear to have vascular
volume depletion
 Approximately 50% of an administered furosemide dose is excreted

unchanged into the urine. The remainder appears to be eliminated by
glucuronidation, predominantly also in the kidney.
 Torsemide and bumetanide are eliminated both by hepatic processes and

urinary excretion, although hepatic metabolism may predominate, especially
for torsemide.
 The differences in metabolic fate mean that the t1/2 of furosemide is
prolonged in kidney failure, where both excretion by the kidney and
kidney-mediated glucuronidation are slowed.
 In contrast, the t1/2 of torsemide and bumetanide tend to be preserved in

CKD
 Deafness and tinnitus from loop diuretics appear to result

primarily from high serum concentrations, which inhibit an Na-K-
2Cl isoform (NKCC1, encoded by SLC12A2).
 The tendency of bolus infusion to lead to high peak furosemide

concentrations is one reason that many investigators recommend
continuous infusions instead
LOOP DIURETICS…
B. Effects
 A full dose of a loop diuretic produces a massive sodium chloride diuresis
if glomerular filtration is normal; blood volume may be significantly
reduced.
 If tissue perfusion is adequate, edema fluid is rapidly excreted.
 The diluting ability of the nephron is reduced because the loop of Henle
is the site of significant dilution of urine.
 Inhibition of the Na+/K+/2Cl– transporter also results in loss of the

lumen-positive potential, which reduces reabsorption of divalent cations
as well.
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LOOP DIURETICS
 As a result, calcium excretion is significantly increased.
 The presentation of large amounts of sodium to the collecting tubule may

result in significant potassium wasting and excretion of protons;
hypokalemic alkalosis may result
 Loop diuretics also reduce pulmonary vascular pressures; the mechanism

is not known.
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Clinical indications
Acute renal failure
Improve urine flow
Hyperkalemia
With simultaneous adminstration of NaCl and H2O
Edematous conditions (CHF, cirrhosis, nephrotic syndrome, etc)

 Not used to treat edema due to lymphatic obstruction
(lymphedema) or inflammatory edema (localized edema with
high protein content)
Anion overdose
Removal of toxic anions [fluoride, bromide, iodide]; which are
reabsorbed from the TAL
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Clinical indications…
 They are sometimes used in hypertension if response to thiazides is
inadequate, but the short duration of action of loop diuretics is a
disadvantage in this condition.
 A less common but important application is in the treatment of

severe hypercalcemia.
 This life-threatening condition can often be managed with large doses of
furosemide together with parenteral volume and electrolyte (sodium and
potassium chloride) replacement.
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Toxicities from loop agents
Hypokalemic metabolic alkalosis

 Increased delivery in to the collecting duct leads to increased
secretion of K+ and H+ causing hypokalemic metabolic alkalosis
 Can be reversed by K+ replacement and correction of hypovolemia
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Toxicities from loop agents…
Ototoxicity
 Impairment of ion transport in the inner ear
 Common in patients with diminished renal function and/or

interaction with other ototoxic agents
Hypomagnesemia
 Can be reversed by administration of oral magnesium
preparations.
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Toxicities from loop agents…
Allergic & other reactions

 All [except ethacrynic acid] are sulfonamides.
 Allergic rxns like skin rash, eosinophilia, and less often,
interstitial nephritis
Contraindications
 Patients who are sensitive to other sulfonamides
 Caution in pateints with sever hepatic cirrhosis, severe heart
failure
10/13/2023 69
Distal tubule
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Distal tubule and collecting duct
3. Distal tubule and collecting duct

 together reabsorb 8% of the filtered Na+.
 Calcium is also reabsorbed in this segment under the control of
parathyroid hormone (PTH).
a. Early distal tubule -special features

 reabsorbs NaCl by a Na+–Cl- cotransporter.
 is the site of action of thiazide diuretics.
 is impermeable to water, as is the thick ascending limb.
 Thus, reabsorption of NaCl occurs without water, which further dilutes
the tubular fluid.
 is called the cortical diluting segment.
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b. Late distal tubule and collecting duct -special features

 have two cell types.
1. Principal cells
 reabsorb Na+ and H2O.
 secrete K+.
 Aldosterone increases Na+ reabsorption and increases K+
secretion.
 Like other steroid hormones, the action of aldosterone takes several hours
to develop because new protein synthesis of epithelial Na+ channels
(ENaC) is required.
 About 2% of overall Na+ reabsorption is affected by aldosterone.
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 Antidiuretic hormone (ADH) increases H2O permeability by
directing the insertion of aquaporin 2 (AQP2) H2O channels in the
luminal membrane.
 In the absence of ADH, the principal cells are virtually impermeable to
water.
 K+-sparing diuretics (spironolactone, triamterene, amiloride) decrease
K+ secretion.
2. α-Intercalated cells
 secrete H+ by an H+-ATPase, which is stimulated by aldosterone.
 reabsorb K+ by an H+/K+-ATPase.
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THIAZIDE DIURETICS

 Hydrochlorothiazide & chlorothiazide, the prototypical agents, and
all the other members of this group are sulfonamide derivatives.
 A few derivatives that lack the typical thiazide ring in their structure
nevertheless have effects identical with those of thiazides and are
therefore considered thiazide-like.
 Metolazone
 Chlorthalidone
 Indapamide
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THIAZIDE DIURETICS
The major action of thiazides is to inhibit sodium chloride
transport in the early segment of the distal convoluted tubule
Thiazides are active by the oral route and have a duration of

action of 6–12 h, considerably longer than most loop diuretics.
Chlorothiazide is the only thiazide available for parenteral

use.
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THIAZIDE DIURETICS
FIGURE : Mechanism of sodium and chloride

reabsorption by the transporter NCC in the
distal convoluted tubule. A separate
reabsorptive mechanism, modulated by
parathyroid hormone (PTH), is present for
movement of calcium into the cell from the
urine. This calcium must be transported via the
sodium-calcium exchanger back into the blood.
R, PTH receptor.
76
THIAZIDE DIURETICS
B. Effects
 In full doses, thiazides produce moderate but sustained sodium and
chloride diuresis.
 Hypokalemic metabolic alkalosis may occur.
 Reduction in the transport of sodium from the lumen into the tubular cell
reduces intracellular sodium and promotes sodium-calcium exchange at
the basolateral membrane.
 As a result, reabsorption of calcium from the urine is increased, and urine

calcium content is decreased --the opposite of the effect of loop diuretics.
77
THIAZIDE DIURETICS
Because they act in a diluting segment of the nephron, thiazides may
reduce the excretion of water and cause dilutional hyponatremia.
Thiazides also reduce blood pressure, and the maximal pressure-

lowering effect occurs at doses lower than the maximal diuretic doses
Chlorthalidone is longer acting than hydrochlorothiazide and may

be particularly valuable in hypertension.

Inhibition of renal prostaglandin synthesis reduces the efficacy of the
thiazides.
When a thiazide is used with a loop diuretic, a synergistic effect
occurs with marked diuresis.
78
THIAZIDE DIURETICS
C. Clinical Use and Toxicities
The major application of thiazides is in hypertension, for which

their long duration and moderate intensity of action are
particularly useful.
Chronic therapy of edematous conditions such as mild heart

failure is another application, although loop diuretics are
usually preferred.
Chronic renal calcium stone formation can sometimes be

controlled with thiazides because they reduce urine calcium
concentration.
79
THIAZIDE DIURETICS
Thiazides are also used in the treatment of nephrogenic
diabetes insipidus.
Thiazides reduce urine volume in some cases of DI =
“paradoxical antidiuretic action” = not clearly
understood.
 Plasma volume reduction……….fall in GFR …..enhanced proximal
reabsorption of NaCl and water ………decreased delivery of fluid to
the downstream diluting segments….. POLYURIA TREATED !!!
It may be due to improvement in ADH receptor sensitivity

in the renal collecting tubules
80
THIAZIDE DIURETICS
Massive sodium diuresis with hyponatremia is an uncommon

but dangerous early toxicity of thiazides.
Chronic therapy is often associated with potassium wasting,

since an increased sodium load is presented to the collecting
tubules;
 the cortical collecting tubules compensate by reabsorbing
sodium and excreting potassium.
81
THIAZIDE DIURETICS
Diabetic patients may have significant hyperglycemia.
Serum uric acid increased (hyperuricemia = incident
gout)
 lipid levels are also increased in some pts (TGs, total
cholesterol, and LDL increased)
Combination with loop agents may result in rapid development
of severe hypovolemia and cardiovascular collapse.
Thiazides are sulfonamides and share potential sulfonamide

allergenicity.
Impotence has been reported …may be due to volume
depletion
82
83
84
Thiazide Diuretics in Hypertension
85
CORTICAL COLLECTING TUBULE (CCT)
 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.
 This segment is responsible for reabsorbing 2–5% of the total filtered

sodium under normal circumstances; more if aldosterone is increased.
 The reabsorption of sodium occurs via channels (ENaC, not a transporter)

and is accompanied by loss of potassium or hydrogen ions.
86
FIGURE: Mechanism of sodium, potassium, and

hydrogen ion movement in the collecting tubule
cells. Synthesis of Na+/K+ ATPase, and the
epithelial sodium channels (ENaC) and
potassium channels is under the control of
aldosterone, which combines with an
intracellular receptor, R, before entering the
nucleus.
87
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).
88
POTASSIUM-SPARING DIURETICS
 Spironolactone and eplerenone are steroid derivatives and act as

pharmacologic antagonists of aldosterone in the collecting tubules.
 competitive inhibitor of aldosterone at its receptor at distal part of DCT

leading to increased Na excretion (with excretion of equiosmotic amount
of water) and K+ retention
 By combining with and blocking the intracellular aldosterone receptor, these

drugs reduce the expression of genes that code for the epithelial sodium ion
channel (ENaC) and Na+/K+ ATPase.
89
 Amiloride and triamterene act by blocking the ENaC sodium channels
 Spironolactone and eplerenone have slow onsets and offsets of action (24–72
h).
 Amiloride and triamterene have durations of action of 12–24 h.
B. Effects
 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
90
C. Clinical Uses and Toxicities

 Potassium wasting caused by chronic therapy with loop or thiazide
diuretics, if not controlled by dietary potassium supplements, usually
responds to these drugs.
 They are also available in combination with a thiazide in a single pill.
 Aldosteronism (eg, the elevated serum aldosterone levels that occur in

cirrhosis) is an important indication for spironolactone.
 Aldosteronism is also a feature of heart failure, and spironolactone and

eplerenone have been shown to have significant long-term benefits in this
condition
91
 Other clinical uses of spironolactone in dermatology:

 Female acne vulgaris, female pattern hair loss, hirsutism
 mechanism: interference with hormone-controlled sebum and sweat
gland secretion and with androgen stimulated hair growth.
 50-100mg/day……..
 Not used in:
=> pregnant and lactating women
=> men (risk of feminization)
92
 The most important toxic effect of potassium-sparing diuretics is
hyperkalemia.
 These drugs should never be given with potassium supplements.
 Other aldosterone antagonists (eg, angiotensin [ACE] inhibitors and

angiotensin receptor blockers [ARBs]), if used at all, should be used with
caution in patients taking potassium-sparing diuretics.
 Spironolactone can cause endocrine alterations including gynecomastia

and antiandrogenic effects.
 Eplerenone has less affinity for gonadal steroid receptors = little
antiandrogenic effects but more hyperkalemic effects.
93
ANTIDIURETIC HORMONE AGONISTS & ANTAGONISTS
 Antidiuretic hormone (ADH) and desmopressin are prototypical ADH

agonists.
 They are peptides and must be given parenterally.
 Conivaptan and tolvaptan are ADH antagonists.
 Demeclocycline was previously used as an antagonist.
 Lithium also has ADH-antagonist effects but is never used for this
purpose.
94
FIGURE: Mechanism of water reabsorption

across the membranes of collecting duct cells.
 Aquaporins 3 and 4 (AQP3, 4) are normally
present in the basolateral membranes, but
the luminal water channel, AQP2, is inserted
only in the presence of ADH or similar
antidiuretic peptides acting on the
vasopressin V2 receptor.
95
 ADH facilitates water reabsorption from the collecting tubule by

activation of V2 receptors, which stimulate adenylyl cyclase.
 The increased cAMP causes the insertion of additional aquaporin AQP2

water channels into the luminal membrane in this part of the tubule.
 Conivaptan is an ADH inhibitor at V1a and V2 receptors.
 Tolvaptan is a more selective V2 blocker with little V1 affinity.
 Demeclocycline and lithium inhibit the action of ADH at some point

distal to the generation of cAMP and presumably interfere with the
insertion of water channels into the membrane.
96
ADH AGONISTS & ANTAGONISTS
B. Effects and Clinical Uses

1. Agonists: ADH and desmopressin reduce urine volume and increase its
concentration.
 Thus, ADH and desmopressin are useful in pituitary diabetes insipidus
(insufficient ADH).
 They are of no value in the nephrogenic form of the disease (resistance to

ADH),
 but salt restriction, water restriction, thiazides, and loop diuretics may
be used.
 These therapies reduce blood volume, a very strong stimulus to proximal

tubular reabsorption.
 The proximal tubule thus substitutes -in part -for the deficient
concentrating function of the collecting tubule in nephrogenic DI.
97
2. Antagonists: ADH antagonists oppose the actions of ADH and other
naturally occurring peptides that act on the same V2 receptor.
 Such peptides are produced by certain tumors (eg, small cell carcinoma of
the lung) and can cause significant water retention and dangerous
hyponatremia.
 This syndrome of inappropriate ADH secretion (SIADH syndrome) causes
hyponatremia and can be treated with demeclocycline and conivaptan or
tolvaptan.
 Lithium also works but has greater toxicity and is never used for this
indication.
 Conivaptan and tolvaptan are also used off label in some patients with
heart failure complicated by hyponatremia.
98
C. Toxicity
 In the presence of ADH or desmopressin, a large water load may cause
dangerous hyponatremia.
 Large doses of either peptide may cause hypertension in some persons.
 Conivaptan and tolvaptan may cause demyelination with serious

neurologic consequences if hyponatremia is corrected too rapidly.
 Conivaptan may cause infusion site reactions.
 In children younger than 8 years, demeclocycline (like other tetracyclines)

causes bone and teeth abnormalities.
 Lithium causes nephrogenic diabetes insipidus as a toxic effect;
because of its other toxicities, the drug is never used to treat
SIADH.
99
100
101
102
TABLE: Electrolyte changes produced by diuretic drugs
103
Clinical remarks on the use of diuretics in some edematous
conditions (summary)
Congestive heart failure (CHF)

These patients have weak cardiac muscles (decreased blood flow), salt
and water retention, and pulmonary congestion.
Advantages of diuretics:
 Correction of salt & water retention
 To decrease preload (venodilatation and decreased
venous return) and afterload (due to arterial vd) =
improvement of cardiac function
 To decrease pulmonary congestion = improvement of
tissue oxygenation
104
Congestive heart failure (CHF)…
 Disadvantages of diuretics:
 Excessive hypovolemia can decrease COP.
 Electrolyte imbalance may impair cardiac function
 Diuretic-induced hypokalemia may increase digitalis toxicity and
predispose to arrhythmia.
 combination of K sparing and loop diuretics is the best choice
CKD
Most of patients with chronic renal diseases (e.g. chronic RF, diabetic
nephropathy, etc.) have salt & water retention, hyperkalemia, and HTN.
 Loop diuretics are best choice
105
CKD…
 Advantages of diuretics:
 Correction of salt & water retention
 Correction of hyperkalemia
 Correction of hypertension
 Disadvantages of diuretics:
 Thiazides are ineffective when GFR is <30ml/min, and it may be
harmful.
 K-sparing diuretics are contraindicated because they produce
hyperkalemia
106
Liver cirrhosis
 Pts with chronic liver disorder have edema, ascites, hyperammonemia,
and secondary hyperaldosteronism.
 K-sparings are best choice b/c they don’t cause excessive diuresis and
they have anti-aldosterone effects.
 Advts of diuretics: correction of edema and ascites

 Disadvts: -vigorous diuresis may precipitate hepatorenal syndrome and
electrolyte & acid-base disturbances are dangerous in those pts.
107
Diuretic resistance
 Loop diuretics access to the tubular fluid and therefore to their sites of
activity, they must be secreted across the proximal tubule, as their protein
binding in plasma largely prevents glomerular filtration.
 Peritubular uptake is mediated by the organic anion transporters OAT1

and OAT3, whereas the apically located multidrug resistance-associated
protein 4 (Mrp-4) appears to mediate at least a portion of secretion into
the tubular fluid.
 Mice lacking OAT1, OAT3, or Mrp-4 are resistant to loop and thiazide
diuretics, illustrating the functional importance of these proteins
Diuretic resistance…
 Although human mutations in OAT1 have not been described, these
pathways may be inhibited by drugs and endogenous toxins, thereby
causing diuretic resistance
 Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit diuretic secretion

and alter diuretic responsiveness, and because of their frequent use, are an
important cause of heart failure exacerbations.
 Yet other classes of drugs, including antihypertensives, antibiotics, and

antivirals, may also interact with these transporters and cause resistance.
 Endogenous metabolites also compete for diuretic secretion,

 Loop diuretics are characterized by relatively short t1/2.
 Thus, the initial natriuresis typically wanes within 3–6 hours, so that a
single daily dose leaves some 16–21 hours for the kidneys to compensate
for salt and water losses.
 For individuals in steady state, the phenomenon of “postdiuretic NaCl

retention” defines the fact that urinary NaCl excretion declines below the
baseline when the diuretic effect wears off.
 One strategy to address t1/2 issues, at least for hospitalized patients, is to

infuse loop diuretics continuously (especially, recommended for AKI pts
to reduce high peak conc. Toxicities).
Somewhat different considerations apply to patients with cirrhotic ascites.
 Here, relative gastrointestinal absorption tends to be preserved.
 Coupled with the tendency for relative underfilling in this setting, it is

typically recommended to avoid intravenous diuretics, if possible.
 In this situation, a combination of furosemide with spironolactone, in a

ratio of 40 mg furosemide to 100 mg spironolactone, is recommended in
most patients, to balance efficacy and safety, although in patients with
concomitant kidney disease, this ratio may need to be adjusted, with the
goal of maintaining normokalemia
 Combination diuretic therapy (CDT), comprising of loop plus a thiazide
diuretic, is recommended for overcoming diuretic resistance in patients
with severe volume overload, refractory to adequate dosage (IV
furosemide, 160 to 320 mg per day) of intravenous loop diuretic.
 This approach produces diuretic synergy via “sequential nephron

blockade.”
 Thiazide diuretics block distal tubule sodium reabsorption and can

thereby antagonize the renal adaptation to chronic loop diuretic therapy.
 This improves diuretic resistance secondary to rebound sodium retention.

 The use of CDT has been shown to result in weight loss, symptomatic
improvement, decrease in systemic congestion, hospital discharge, and
prevention of readmission.
 However, careful inspection and frequent monitoring of electrolytes and

renal function tests is essential with initiation of CDT as this therapy can
lead to severe hypokalemia.
Common Causes of Diuretic Resistance (summary)
 Nonadherence to recommended sodium and/or fluid restriction•
 Drug not reaching the kidney–
 Nonadherence–
 Dose too low or too infrequent–
 Poor absorption
 Reduced diuretic secretion
 Tubular uptake of diuretic impaired by uremic toxins
 Decreased kidney blood flow
 Decreased functional kidney mass
 Insufficient kidney response to drug
 Low glomerular filtration rate
 Decreased effective intravascular volume despite elevated total extracellular fluid
volume–
 Activation of the renin-angiotensin system
 Nephron adaptation
 Use of nonsteroidal anti-inflammatory drugs
THANK
YOU ALL!
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Renal Pharmacology 2023

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Renal Pharmacology 2023

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Renal Pharmacology

Mesud Mohammed (Clinical Pharmacy Specialist, Lecturer, &

Major organ for the removal of drugs and their metabolites

Solutes with small MW and water pass in to the

different stages down the nephron

60-70% of Na+ ions reabsorbed

>90% of HCO-3 is reabsorbed

Organic acid secretory systems

The thick ascending limb

 Results in dilution of the tubular fluid (“diluting

 Back diffusion of K+ … lumen positive electrical

Relatively impermeable to water

Electrically neutral transport system

Transportations independently controlled by hormones

 NaCl reabsorbed by the action of aldosterone

Intercalated cells … secret acids and bases

 Stimulate Na+/H+ exchange … (rapid)

 activates sodium channels in the apical membrane

 Increase the number of Na+ pumps on the

 Increase the expression of aquaporins (water channels)

 Monitors the concentration of urine

More Na+ reaches the collecting duct,

Na+ reabsorption in the collecting duct is increased

 The mechanism of action is inhibition of carbonic anhydrase in the brush

 CA is also found in other tissues and plays an important role in the

 Acetazolamide inhibits carbonic anhydrase in all tissues of the body.

Diuretic effects of CAIs

 As increased Na+ is presented to the cortical collecting tubule, some of the

 As a result of HCO3- depletion, sodium NaHCO3 excretion slows -even with

 In the eye, a useful reduction in intraocular pressure can be achieved.

 In the central nervous system (CNS), acidosis of the CSF results in

 The ocular and cerebrospinal fluid effects are not self-limiting.

 Delivery of more Na+ and Cl- to the loop of Henle

 Only 5% of filtered Na+ is lost, with only slight increase in Cl-

 Increased distal delivery of Na+ enhances K+ excretion

 Inhibition of CA ….. loss of HCO3- ….results in metabolic acidosis

CAI Oral bioavailabity T1/2 (hrs) Elimination

Acetazolamide ~100% 6-9 Renally excreted

 Acetazolamide inhibit the enzyme carbonic anhydrase in renal tubular

a. Treatment of metabolic alkalosis

b. Decrease formation of aqueous humor

 Rapidly progressing pulmonary or cerebral edema

 CAIs improve symptoms by

 Reduction of the PH of the CSF

d. Adjunct therapy for some type of infantile epilepsy

 Cross-allergenicity between these and all other sulfonamide derivatives

 Alkalinization of the urine by these drugs may cause precipitation of

 Renal potassium wasting may be marked.

 If they are given acetazolamide, alkalinization of the urine prevents

 As a result, they may develop hepatic encephalopathy because of increased

 Carbonic anhydrase inhibitors may also cause potassium and phosphate

 They reduce the active reabsorption of filtered glucose in the proximal

 High glucose concentration in the urine may result in urinary tract

 The oral SGLT2 inhibitors canagliflozin, dapagliflozin, empagliflozin, and

 The loss of calories results in modest weight loss of 2–5 kg.

 Empagliflozin, added to standard of care, was shown to reduce the

 Canagliflozin was evaluated in two trials which enrolled patients with

 Possible adverse reactions with SGLT2 inhibitors include:

 Osmotic diuresis occurs as well which may result in symptomatic

 Renal function should be monitored at baseline to guide initial dosing

 Volume status including BP, hematocrit, serum potassium, serum

 Cases of euglycemic ketoacidosis have been reported with SGLT2

 Should ketoacidosis occur, the SGLT2 inhibitor should be held or

 Mannitol, the prototypical osmotic diuretic, is given intravenously.