The document discusses different classes of diuretic drugs, including their mechanisms of action and examples. It covers carbonic anhydrase inhibitors like acetazolamide; thiazide diuretics like hydrochlorothiazide and their effects on sodium reabsorption in the distal convoluted tubule; and loop diuretics like furosemide which act on the thick ascending limb of the loop of Henle by inhibiting sodium-potassium-chloride reabsorption. Individual drugs within each class are described in more detail regarding their mechanisms and uses for conditions like heart failure and hypertension.
Diuretics
Pharmacology
Katzung
Abnormalities in fluid volume and electrolyte composition are common and important clinical disorders. Drugs that block specific transport functions of the renal tubules are valuable clinical tools in the treatment of these disorders. Although various agents that increase urine volume (diuretics) have been described since antiquity, it was not until 1937 that carbonic anhydrase inhibitors were first described and not until 1957 that a much more useful and powerful diuretic agent (chlorothiazide) became available. Technically, a “diuretic” is an agent that increases urine volume, whereas a “natriuretic” causes an increase in renal sodium excretion and an “aquaretic” increases excretion of solute-free water. Because natriuretics almost always also increase water excretion, they are usually called diuretics. Osmotic diuretics and antidiuretic hormone antagonists (see Agents That Alter Water Excretion) are aquaretics that are not directly natriuretic.
Any substance that promotes the production of urine
All diuretics increase the excretion of water from bodies
Alternatively, an antidiuretic such as vasopressin, or antidiuretic hormone.
Diuretics are used to treat heart failure, liver cirrhosis, hypertension, water poisoning, and certain kidney diseases
Diuretics
Pharmacology
Katzung
Abnormalities in fluid volume and electrolyte composition are common and important clinical disorders. Drugs that block specific transport functions of the renal tubules are valuable clinical tools in the treatment of these disorders. Although various agents that increase urine volume (diuretics) have been described since antiquity, it was not until 1937 that carbonic anhydrase inhibitors were first described and not until 1957 that a much more useful and powerful diuretic agent (chlorothiazide) became available. Technically, a “diuretic” is an agent that increases urine volume, whereas a “natriuretic” causes an increase in renal sodium excretion and an “aquaretic” increases excretion of solute-free water. Because natriuretics almost always also increase water excretion, they are usually called diuretics. Osmotic diuretics and antidiuretic hormone antagonists (see Agents That Alter Water Excretion) are aquaretics that are not directly natriuretic.
Any substance that promotes the production of urine
All diuretics increase the excretion of water from bodies
Alternatively, an antidiuretic such as vasopressin, or antidiuretic hormone.
Diuretics are used to treat heart failure, liver cirrhosis, hypertension, water poisoning, and certain kidney diseases
This presentation covers about the classification of diuretics, structures with mechanism of action and SAR and therapeutic uses of drugs according to PCI syllabus
A detailed information about the diuretics - classification of drugs, mechanism of action, side effects, dosage and indications.
Classification based on the efficacy of the diuretics.
1. High
2. Moderate
3. Weak
A brief introduction given about the nephron structure and its indications.
This ppt tells us about the topics diuretics and antidiuretics.
It also indicates us about their classification, mechanism of action, side effects and many more.
This presentation covers about the classification of diuretics, structures with mechanism of action and SAR and therapeutic uses of drugs according to PCI syllabus
A detailed information about the diuretics - classification of drugs, mechanism of action, side effects, dosage and indications.
Classification based on the efficacy of the diuretics.
1. High
2. Moderate
3. Weak
A brief introduction given about the nephron structure and its indications.
This ppt tells us about the topics diuretics and antidiuretics.
It also indicates us about their classification, mechanism of action, side effects and many more.
Observation of Io’s Resurfacing via Plume Deposition Using Ground-based Adapt...Sérgio Sacani
Since volcanic activity was first discovered on Io from Voyager images in 1979, changes
on Io’s surface have been monitored from both spacecraft and ground-based telescopes.
Here, we present the highest spatial resolution images of Io ever obtained from a groundbased telescope. These images, acquired by the SHARK-VIS instrument on the Large
Binocular Telescope, show evidence of a major resurfacing event on Io’s trailing hemisphere. When compared to the most recent spacecraft images, the SHARK-VIS images
show that a plume deposit from a powerful eruption at Pillan Patera has covered part
of the long-lived Pele plume deposit. Although this type of resurfacing event may be common on Io, few have been detected due to the rarity of spacecraft visits and the previously low spatial resolution available from Earth-based telescopes. The SHARK-VIS instrument ushers in a new era of high resolution imaging of Io’s surface using adaptive
optics at visible wavelengths.
Seminar of U.V. Spectroscopy by SAMIR PANDASAMIR PANDA
Spectroscopy is a branch of science dealing the study of interaction of electromagnetic radiation with matter.
Ultraviolet-visible spectroscopy refers to absorption spectroscopy or reflect spectroscopy in the UV-VIS spectral region.
Ultraviolet-visible spectroscopy is an analytical method that can measure the amount of light received by the analyte.
Nutraceutical market, scope and growth: Herbal drug technologyLokesh Patil
As consumer awareness of health and wellness rises, the nutraceutical market—which includes goods like functional meals, drinks, and dietary supplements that provide health advantages beyond basic nutrition—is growing significantly. As healthcare expenses rise, the population ages, and people want natural and preventative health solutions more and more, this industry is increasing quickly. Further driving market expansion are product formulation innovations and the use of cutting-edge technology for customized nutrition. With its worldwide reach, the nutraceutical industry is expected to keep growing and provide significant chances for research and investment in a number of categories, including vitamins, minerals, probiotics, and herbal supplements.
The increased availability of biomedical data, particularly in the public domain, offers the opportunity to better understand human health and to develop effective therapeutics for a wide range of unmet medical needs. However, data scientists remain stymied by the fact that data remain hard to find and to productively reuse because data and their metadata i) are wholly inaccessible, ii) are in non-standard or incompatible representations, iii) do not conform to community standards, and iv) have unclear or highly restricted terms and conditions that preclude legitimate reuse. These limitations require a rethink on data can be made machine and AI-ready - the key motivation behind the FAIR Guiding Principles. Concurrently, while recent efforts have explored the use of deep learning to fuse disparate data into predictive models for a wide range of biomedical applications, these models often fail even when the correct answer is already known, and fail to explain individual predictions in terms that data scientists can appreciate. These limitations suggest that new methods to produce practical artificial intelligence are still needed.
In this talk, I will discuss our work in (1) building an integrative knowledge infrastructure to prepare FAIR and "AI-ready" data and services along with (2) neurosymbolic AI methods to improve the quality of predictions and to generate plausible explanations. Attention is given to standards, platforms, and methods to wrangle knowledge into simple, but effective semantic and latent representations, and to make these available into standards-compliant and discoverable interfaces that can be used in model building, validation, and explanation. Our work, and those of others in the field, creates a baseline for building trustworthy and easy to deploy AI models in biomedicine.
Bio
Dr. Michel Dumontier is the Distinguished Professor of Data Science at Maastricht University, founder and executive director of the Institute of Data Science, and co-founder of the FAIR (Findable, Accessible, Interoperable and Reusable) data principles. His research explores socio-technological approaches for responsible discovery science, which includes collaborative multi-modal knowledge graphs, privacy-preserving distributed data mining, and AI methods for drug discovery and personalized medicine. His work is supported through the Dutch National Research Agenda, the Netherlands Organisation for Scientific Research, Horizon Europe, the European Open Science Cloud, the US National Institutes of Health, and a Marie-Curie Innovative Training Network. He is the editor-in-chief for the journal Data Science and is internationally recognized for his contributions in bioinformatics, biomedical informatics, and semantic technologies including ontologies and linked data.
(May 29th, 2024) Advancements in Intravital Microscopy- Insights for Preclini...Scintica Instrumentation
Intravital microscopy (IVM) is a powerful tool utilized to study cellular behavior over time and space in vivo. Much of our understanding of cell biology has been accomplished using various in vitro and ex vivo methods; however, these studies do not necessarily reflect the natural dynamics of biological processes. Unlike traditional cell culture or fixed tissue imaging, IVM allows for the ultra-fast high-resolution imaging of cellular processes over time and space and were studied in its natural environment. Real-time visualization of biological processes in the context of an intact organism helps maintain physiological relevance and provide insights into the progression of disease, response to treatments or developmental processes.
In this webinar we give an overview of advanced applications of the IVM system in preclinical research. IVIM technology is a provider of all-in-one intravital microscopy systems and solutions optimized for in vivo imaging of live animal models at sub-micron resolution. The system’s unique features and user-friendly software enables researchers to probe fast dynamic biological processes such as immune cell tracking, cell-cell interaction as well as vascularization and tumor metastasis with exceptional detail. This webinar will also give an overview of IVM being utilized in drug development, offering a view into the intricate interaction between drugs/nanoparticles and tissues in vivo and allows for the evaluation of therapeutic intervention in a variety of tissues and organs. This interdisciplinary collaboration continues to drive the advancements of novel therapeutic strategies.
Earliest Galaxies in the JADES Origins Field: Luminosity Function and Cosmic ...Sérgio Sacani
We characterize the earliest galaxy population in the JADES Origins Field (JOF), the deepest
imaging field observed with JWST. We make use of the ancillary Hubble optical images (5 filters
spanning 0.4−0.9µm) and novel JWST images with 14 filters spanning 0.8−5µm, including 7 mediumband filters, and reaching total exposure times of up to 46 hours per filter. We combine all our data
at > 2.3µm to construct an ultradeep image, reaching as deep as ≈ 31.4 AB mag in the stack and
30.3-31.0 AB mag (5σ, r = 0.1” circular aperture) in individual filters. We measure photometric
redshifts and use robust selection criteria to identify a sample of eight galaxy candidates at redshifts
z = 11.5 − 15. These objects show compact half-light radii of R1/2 ∼ 50 − 200pc, stellar masses of
M⋆ ∼ 107−108M⊙, and star-formation rates of SFR ∼ 0.1−1 M⊙ yr−1
. Our search finds no candidates
at 15 < z < 20, placing upper limits at these redshifts. We develop a forward modeling approach to
infer the properties of the evolving luminosity function without binning in redshift or luminosity that
marginalizes over the photometric redshift uncertainty of our candidate galaxies and incorporates the
impact of non-detections. We find a z = 12 luminosity function in good agreement with prior results,
and that the luminosity function normalization and UV luminosity density decline by a factor of ∼ 2.5
from z = 12 to z = 14. We discuss the possible implications of our results in the context of theoretical
models for evolution of the dark matter halo mass function.
1. LECTURE NO-26
UNIT – II 10 Hours
Drugs acting on Cardiovascular system
b) Diuretics:
Carbonic anhydrase inhibitors: Acetazolamide, Methazolamide, Dichlorphenamide.
Thiazides: Chlorthiazide, Hydrochlorothiazide, Hydroflumethiazide, Cyclothiazide
Loop diuretics: Furosemide, Bumetanide, Ethacrynic acid.
Potassium sparing Diuretics: Spironolactone, Triamterene, Amiloride.
Osmotic Diuretics: Mannitol
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2. Drugs acting on Cardiovascular system
b) Diuretics:
MC2.pdf
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Diuretics ("water pills") increase the
kidneys' excretion of salt (sodium) and
water, decreasing the volume of fluid in
the bloodstream and the pressure in the
arteries. Diuretics are the oldest and
most studied antihypertensive agents.
Diuretics
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Drugs promoting urine output are known as diuretic drugs, which refer only to those agents that act directly on
the kidneys. These drugs primarily increase the excretion of water and ions like sodium (Na +), chloride ( Cl- ), or
bicarbonates ( HCO3-) from the body.
Glomerular filtration , tubular reabsorption , and tubular secretion in kidneys determine the excretion of
substances.
Tubular reabsorption is a process which involves active transport of electrolytes and other solutes from tubular
urine to tubular cells, and then to extra cellular fluid. As a result, glomerular filtration is increased.
The mechanism of action of diuretic drugs also involves a decrease in tubular reabsorption. However, these drugs
have no effect on glomerular filtration rate or on the action of Anti-Diuretic Hormone (ADH) on the distal portion
of nephron.
Diuretics effectively treat cardiac oedema (accumulation of fluid in extra vascular tissues), especially the one
which is associated with congestive heart failure.
It is also employed in the treatment of various disorders like nephrotic syndrome, diabetes insipidus,
hypertension, nutritional oedema, oedema of pregnancy, and liver cirrhosis.
They also decrease the intracellular and cerebrospinal fluid pressure.
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Carbonic anhydrase inhibitors:
Acetazolamide, Methazolamide, Dichlorphenamide.
Thiazide:
Chlorthiazide, Hydrochlorothiazide,
Hydroflumethiazide, Cyclothiazide
Loop
Furosemide, Bumetanide, Ethacrynic acid
Potassium-sparing
Spironolactone, Triamterene, Amiloride.
Osmotic Diuretics: Mannitol
CLASSIFICATION
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Study of Individual Drugs
The following carbonic anhydrase inhibitors are discussed below:
1) Acetazolamide,
2) Methazolamide,
3) Dichlorphenamide.
Acetazolamide
Acetazolamide is the prototype carbonic anhydrase inhibitor. This type of diuretics inhibit
carbonic anhydrase enzyme in the membrane and cytoplasm of epithelial cell.
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Mechanism of Action
Carbonic anhydrase enzyme is inhibited by acetazolamide; thus, preventing the
formation of H+ ions. As a result, the exchange of Na + ions with H+ ions does not take place.
The Na+ and HCO3¯ ions undergo urinary excretion. Increased exchange of Na + and K+ ions
in the distal convoluted tubule resulted in the loss of K+ ions.
On the whole, the urine produced is alkaline in nature as the Na +, K+, and HCO3¯ ions are
lost.
Uses
Acetazolamide is self-limiting in nature. It produces adverse effects like acidosis and
hypokalaemia. Thus, it is not used as a diuretic anymore; instead, it is currently being employed
in the treatment of:
1) Glaucoma: As an adjuvant to other ocular hypotensives.
2) Alkalinising Urine: For urinary tract infection or to promote excretion of certain acidic
drugs.
3) Epilepsy: As an adjuvant in absence seizures when primary drugs are not fully effective.
4) Acute Mountain Sickness: Symptomatic relief as well as prophylaxis.
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Methazolamide
Methazolamide is a carbonic anhydrase inhibitor. It is used as a diuretic and for treating
glaucoma
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Mechanism of Action
Methazolamide is a potent inhibitor of carbonic anhydrase enzyme. It inhibits the enzyme in
the ciliary processes of eye , thus reduces aqueous humor secretion by delaying the formation
of bicarbonate ions and reducing sodium and fluid transport.
Uses
1) It is used for treating chronic open-angle glaucoma and acute angle –closure glaucoma.
2) It is used in cystoid macular oedema and pseudotumour cerebri.
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Dichlorphenamide
Dichlorphenamide is a carbonic anhydrase inhibitor. It is used for treating glaucoma.
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Mechanism of Action
Carbonic anhydrase inhibitors decrease intraocular pressure by partially suppressing aqueous
humor secretion. The mechanism behind this is however not known completely. It has been
proved that HCO3− ions are formed in the ciliary body by hydration of carbon dioxide
catalysed by carbonic anhydrase . The HCO3− ions formed diffuse into the hypertonic
posterior chamber containing more Na + and HCO3− ions than the plasma . Then, w ater is
attracted to the posterior chamber by osmosis, thereby causing a pressure drop.
Uses
1) It is used for adjunctive treatment of chronic simple (open -angle) glaucoma and secondary
glaucoma.
2) It is used pre-operatively in acute angle closure glaucoma in which surgery is delayed so
that the intraocular pressure decreases
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THIAZIDES
Introduction
Thiazide diuretics are referred to as moderately efficacious diuretics as a majority
(nearly 90%) of the filtered sodium is already re -absorbed before it reaches the distal tubule.
These diuretics comprise of two distinct groups:
1) Diuretics containing a benzothiadiazine ring; these agents are referred to as thiazide
diuretics and include agents like chlorothiazide, hydrochlorothiazide, polythiazide, etc.
2) Diuretics not containing benzothiadiazine ring , but containing an un - substituted
sulphonamide group ; these agents are termed as thiazide-like diuretics and include
chlorthalidone, indapamide, metolazone, etc.
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Mechanism of Action
Thiazide diuretics inhibit the reabsorption of Na+ and Cl– ions at the first portion of the distal
tubules. They block a Na + Cl– symport in the luminal membrane of the epithelial cells in the
distal convoluted tubule, thus, blocking the reabsorption of NaCl. Thiazide diuretics exert a
minor effect on NaCl reabsorption in the proximal tubule. They block the entry of Na + ions
and enhance the activity of Na+-Ca++ exchanger in the basolateral membrane of epithelial
cells. Thus, the reabsorption of Ca++ ions in the distal convoluted tubule is enhanced . Thiazide
diuretics also inhibit the carbonic anhydrase enzyme. The resulting diuretics are
supplemented by increased excretion of potassium, bicarbonates, chloride, and water
The anti-hypertensive action of thiazide diuretics is influenced by the following
two factors:
1) Reduced plasma concentration of sodium due to its depletion, and
2) Decrease in peripheral resistance
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Mechanism of Action
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Study of Individual Drugs
The following thiazide diuretics are discussed below:
1) Chlorothiazide,
2) Hydrochlorothiazide,
3) Hydroflumethiazide,
4) Cyclothiazide.
Chlorothiazide
Chlorothiazide is 4H-1,2,4-benzothiadiazine 1,1-dioxide in which the hydrogen at position is substituted by
chlorine and that at position 7 is substituted by a sulfonamide group. A diuretic, it is used for treatment of oedema
and hypertension. It has a role as a diuretic and an antihypertensive agent.
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Like other thiazides, chlorothiazide promotes water loss from the body (diuretics). It inhibits Na+/Cl-
reabsorption from the distal convoluted tubules in the kidneys. Thiazides also cause loss of potassium
and an increase in serum uric acid. Thiazides are often used to treat hypertension, but their
hypotensive effects are not necessarily due to their diuretic activity.
Mechanism of Action
Uses
1) It is used as an adjunct in oedema related to congestive heart failure, hepatic cirrhosis, and
corticosteroid and estrogen therapy.
2) It is used alone in the management of hypertension, but in combination with other antihypertensive
drugs in the more severe forms of hypertension.
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Hydrochlorothiazide
Hydrochlorothiazide is a benzothiadiazine that is 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-
dioxide substituted by a chloro group at position 6 and a sulfonamide at 7.
It is a benzothiadiazine, a sulfonamide and an organochlorine compound.
Hydrochlorothiazide reduces the reabsorption of electrolytes from renal tubules.
This causes an increase in the excretion of water and electrolytes, including sodium, potassium,
chloride, and magnesium.
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Uses
1) It reduces sodium and water retention in preeclampsia during pregnancy.
2) It is used for the management of hypertension, and as an adjunct in oedema related to congestive
heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy.
Hydrochlorothiazide inhibits the Na+-Cl– symporter in the distal convoluted tubule (responsible for
5% of total sodium reabsorption), thus blocks the reabsorption of water in nephron s.
Hydrochlorothiazide prevents the reabsorption of sodium and water from the distal convoluted
tubule, allowing for the increased elimination of water in the urine.
Mechanism of Action
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Hydroflumethiazide
Hydroflumethiazide is a benzothiadiazine consisting of a 3,4-dihydro-HH-1,2,4
benzothiadiazine bicyclic system dioxygenated on sulfur and carrying trifluoromethyl and
aminosulfonyl groups at positions 6 and 7 respectively.
A diuretic with actions and uses similar to those of hydrochlorothiazide.
It has a role as a diuretic and an antihypertensive agent. It is a benzothiadiazine and a thiazide.
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Mechanism of Action
Hydroflumethiazide inhibits the Na +-Cl– symporter in the distal convoluted tubule (responsible for
5% of total sodium reabsorption), thus blocks the reabsorption of water in nephrons.
The Na +-Cl– symporter transports Na+ and Cl–ions from the lumen into the epithelial cell lining the
distal convoluted tubule.
A sodium gradient established by Na +-K+ ATPases on the basolateral membrane provides energy
for transporting Na+ and Cl– ions.
Uses
1) It is used as an adjunct in oedema related to congestive heart failure, hepatic cirrhosis, and
corticosteroid and estrogen therapy.
2) It is used alone in the management of hypertension, but in combination with other antihypertensive
drugs in the more severe forms of hypertension.
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Cyclothiazide is 3,4-Dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide substituted at positions 3, 5 and 6
by a 2-norbornen-5-yl group, chlorine, and a sulfonamide group, respectively.
A thiazide diuretic, it has been used in the management of hypertension and oedema.
Cyclothiazide
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As a diuretic, cyclothiazide inhibits active chloride reabsorption at the early distal tubule via the Na-Cl
cotransporter, resulting in an increase in the excretion of sodium, chloride, and water.
Thiazides like cyclothiazide also inhibit sodium ion transport across the renal tubular epithelium
through binding to the thiazide sensitive sodium-chloride transporter.
This results in an increase in potassium excretion via the sodium-potassium exchange mechanism.
Mechanism of Action
Uses
1) It is used as an adjunctive therapy in oedema related to congestive heart failure, hepatic cirrhosis,
and corticosteroid and estrogen therapy.
2) It is used alone in the management of hypertension, but in combination with other antihypertensive
drugs in the more severe forms of hypertension.
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Loop diuretics
Loop or high efficacy diuretics exhibit their effects by acting on the ascending limb of the loop of
Henle.
They are the most effective of all diuretic agents since the reabsorptive capacity of the ascending limb
of the loop of Henle is very high.
The loop diuretics are also known as high ceiling diuretics, or Na+-K+-2Cl– cotransporter
inhibitors.
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Mechanism of Action
Loop diuretics inhibit the Na +-K+-2Cl– symport in the luminal membrane of the Thick Ascending
Limb (TAL) of loop of Henle, thus inhibit the reabsorption of NaCl and KCl.
The TAL is responsible for the reabsorption of 35% of filtered sodium and there no downstream
compensatory reabsorption mechanisms, thus the loop diuretics are highly efficacious and are also
termed as high ceiling diuretics.
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The Na+-K+-2Cl– symport along with the sodium pump generate a positive lumen potential
that initiates the reabsorption of Ca ++ and Mg ++ ions. Therefore, the inhibition of Na+-K+-
2Cl– symport also results in the inhibition of Ca++ and Mg++ ions reabsorption. Loop diuretics
also have direct effect on vasculature including increased renal blood flow and increased
systemic venous capacitance through unknown mechanisms (prostaglandin-mediated probably).
Study of Individual Drugs
The following loop diuretics are discussed below:
1) Furosemide,
2) Bumetanide,
3) Ethacrynic acid.
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Furosemide
Furosemide is a benzoic -sulfonamide-furan with fast onset and short duration of action. It is
used for treating oedema and chronic renal insufficiency.
Furosemide is a chlorobenzoic acid that is 4-chlorobenzoic acid substituted by a (furan-2-
ylmethyl)amino and a sulfamoyl group at position 2 and 5 respectively.
It is a diuretic used in the treatment of congestive heart failure. It has a role as a xenobiotic, an
environmental contaminant and a loop diuretic.
It is a sulfonamide, a chlorobenzoic acid and a member of furans.
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4-chloro-2-(furan-2-ylmethylamino)-5-sulfamoylbenzoic acid
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Mechanism of Action
Furosemide competitively inhibits the binding of Cl– ions at the Na+-K+-2Cl– cotransporter
in the thick ascending limb of Henle’s Loop. This in turn inhibits the reabsorption of water in nephron.
As a result, the sodium transport from the lumen of the loop of Henle into the basolateral interstitium
is prevented. Hence, the hypertonicity of lumen increases (due to more sodium) while that of the
interstitium decreases (as the sodium is lesser). This altered concentration of sodium reduces the
osmotic gradient for the reabsorption of water all over the nephron.
Uses
1) It is used for the treatment of oedema related to congestive heart failure, liver cirrhosis, and renal disease.
2) It is also used either alone or with other antihypertensive agents for the management of hypertension.
Toxicity Summary
Clinical consequences from overdose depend on the extent of electrolyte and fluid loss and include dehydration,
blood volume reduction, hypotension, electrolyte imbalance, hypokalemia, hypochloremic alkalosis,
hemoconcentration, cardiac arrhythmias
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Bumetanide
Bumetanide is a loop diuretic of sulfamyl category. It is used for treating heart failure. It is used by the people who are not
responding to high doses of furosemide or other diuretics.
Bumetanide is a member of the class of benzoic acids that is 4-phenoxybenzoic acid in which the hydrogens ortho to the
phenoxy group are substituted by butylamino and sulfamoyl groups.
Bumetanide is a diuretic, and is used for treatment of oedema associated with congestive heart failure, hepatic and renal
disease.
It is a sulfonamide, an amino acid and a member of benzoic acids.
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Mechanism of Action
Bumetanide inhibits renal cAMP and/or the Na+-K+ ATPase pump. It also inhibits the active
reabsorption of Cl– and Na+ ions i n the ascending loop of Henle, thus disturbing the
electrolyte transfer in proximal tubule. This causes excretion of Cl– and Na+ ions, and water,
and results in diuresis.
Uses
It is used for treating oedema related to congestive heart failure, hepatic and renal disease
including nephrotic syndrome.
Toxicity Summary
Overdosage can lead to acute profound water loss, volume and electrolyte depletion, dehydration, reduction of
blood volume and circulatory collapse with a possibility of vascular thrombosis and embolism. Electrolyte
depletion may be manifested by weakness, dizziness, mental confusion, anorexia, lethargy, vomiting and cramps.
Treatment consists of replacement of fluid and electrolyte losses by careful monitoring of the urine and electrolyte
output and serum electrolyte levels.
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Ethacrynic Acid
Ethacrynic acid is an unsaturated ketone derivative of aryloxyacetic acid without a sulfonamide substituent. It
belongs to the class of loop diuretics.
Ethacrynic Acid is an unsaturated ketone derivative of aryloxyacetic acid without a sulfonamide substituent
belonging to the class of loop diuretics.
Ethacrynic acid is extensively bound to plasma proteins; both ethacrynic acid in its unchanged form as well as its
metabolites are excreted in bile and urine.
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Mechanism of Action
Ethacrynic acid blocks Na+-K+-2Cl– symport in the ascending limb of Henle loop and in the proximal and distal
tubules. This causes excretion of Na+, K+, and 2Cl– ions, increases urinary output, and decrease d extracellular
fluid. Ethacrynic acid also reduces the blood pressure by lowering the plasma and extracellular fluid volume,
which in turn reduces the cardiac output . Ultimately, the cardiac output returns to normal with a reduction in
peripheral resistance.
Uses
It is used in the treatment of high blood pressure and oedema caused by diseases like congestive heart failure, liver
failure, and kidney failure.
Toxicity Summary
Overdosage may lead to excessive diuresis with electrolyte depletion.
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POTASSIUM SPARING DIURETICS
Introduction
Potassium sparing diuretics include triamterene and amiloride.
Only less than 5% of total filtered (amount of a substance filtered per unit time) Na+ load is excreted by
the use of these agents, and this is its maximal effect.
As the name suggests, these agents ( triamterene and amiloride) form sparing diuretics for K + ions
contrary to loop and thiazide diuretics, which are K+ ion depleting agents.
Mechanism of Action
The late distal tubule and the collecting duct comprise of principal cells and intercalated cells.
A Na + ion channel, present in the luminal membrane of the principal cells, forms a pathway for the entry
of Na + ions into the cells mediated by the basolateral Na+ ion pump, against the electrochemical gradient.
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The luminal membrane is highly permeable to Na + ions, thereby, creating a lumen negative trans-
epithelial potential difference. This potential difference between the lumen and epithelium forms an
important driving force enabling the secretion of K+ ions into the lumen.
The H+ ion is secreted into the tubular lumen by the intercalated cells.
This secretion is mediated by the H +-ATPase pump or proton pump and the lumen
negative trans-epithelial voltage difference acts as the driving force.
The potassium sparing diuretics (triamterene and amiloride) act by blocking the Na+ ion channels in the
luminal membrane of the principal cells (within the late distal tubule and collecting duct).
This inhibits the transport of Na + ions through the cells, thereby, reducing the luminal secretion of H +
ions from the intercalated cells and K + ions from the principal cells.
The net effect is increase in the excretion of Na+ ions through urine, and retention of K+ and H+ ions.
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Study of Individual Drugs
The following potassium sparing diuretics are discussed below:
1) Spironolactone,
2) Triamterene,
3) Amiloride.
Spironolactone
Spironolactone is a potassium sparing diuretic which acts by antagonizing aldosterone in the distal renal
tubules.
Spironolactone is a steroid lactone that is 17alpha-pregn-4-ene-21,17-carbolactone substituted by an oxo group at
position 3 and an alpha-acetylsulfanyl group at position 7. It has a role as a diuretic, an aldosterone antagonist, an
antihypertensive agent, an environmental contaminant and a xenobiotic. It is a steroid lactone, an oxaspiro
compound, a thioester and a 3-oxo-Delta(4) steroid.
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Mechanism of Action
Spironolactone is a specific pharmacologic antagonist of aldosterone. It acts by competitive binding of receptors at
the aldosterone -dependent Na+- K+ exchange site in the distal convoluted renal tubule. Spironolactone increases the
amounts of Na+ ions and water to be excreted, while retaining the K+ ions.
Through this mechanism, spironolactone acts as a diuretic as well as an antihypertensive drug.
It is administered either alone or along with other diuretics that act more proximally in the renal tubule.
Aldosterone improves the expression of Na +-K+- ATPase and the Na+ ion channel involved in Na+-K+ transport in
the distal tubule by interacting with a cytoplasmic mineralocorticoid receptor.
Spironolactone binds to t his receptor and inhibits aldosterone actions on gene expression. Aldosterone hormone
retains Na+ ions and excrete s K+ ions in the kidneys.
Uses
1) It is used for treating refractory oedema in patients having failure, nephrotic syndrome, or hepatic
cirrhosis.
2) It is also used for treating hypokalaemia, Conn’s syndrome, and low –renin hypertension
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Triamterene
Triamterene is a potassium -sparing diuretic. It is used with thiazide diuretics in the treatment of hypertension and
swelling.
Triamterene is a pteridine derivative with potassium-sparing diuretic property.
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Mechanism of Action
Triamterene blocks the sodium-potassium exchange pump (Na-K-ATPase) in the luminal membrane
of principal cells in the late distal tubule, cortical collecting tubule and collecting duct in the kidney.
This reversible inhibition of the electrogenic sodium transport decreases the lumen-negative
transepithelial potential difference and thus reduces the driving force for K+ movement into the
tubular lumen resulting in the inhibition of sodium reabsorption in exchange for K+ and H+.
Uses
1) It is used for treating oedema related to congestive heart failure, liver cirrhosis, and nephrotic syndrome.
2) It is also used for treating steroid-induced oedema, idiopathic oedema, and oedema caused by secondary
hyperaldosteronism.
Overdosage of triamterene may cause electrolyte imbalance, especially hyperkalemia. Nausea, vomiting, other
GI disturbances, and weakness may also occur.
Hypotension may also result, especially when the drug is used concomitantly with hydrochlorothiazide or other
diuretics or hypotensive agents.
Toxicity Summary
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Amiloride
Amiloride is a pyrazine compound that inhibits sodium reabsorption through sodium channels in
renal epithelial cells.
Amiloride is a member of the class of pyrazines resulting from the formal monoacylation
of guanidine with the carboxy group of 3,5-diamino-6-chloropyrazine-2-carboxylic acid.
It has a role as a sodium channel blocker and a diuretic.
It is a member of pyrazines, an organochlorine compound, an aromatic amine and a
member of guanidines. It is a conjugate base of an amiloride(1+).
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Mechanism of Action
Amiloride binds to the amiloride -sensitive sodium channels and inhibits sodium reabsorption in the
distal convoluted tubules and collecting ducts in the kidneys.
As a result, sodium and water loss from the body occurs, while retaining potassium.
Amiloride inhibits sodium reabsorption at the distal convoluted tubule, cortical collecting tubule, and
collecting duct; and this explains its potassium sparing effect.
This effect of amiloride reduces the net negative potential of the tubular lumen and decreases the
secretion and excretion of potassium and hydrogen. Amiloride is not an aldosterone antagonist, and can
acetven in the absence of aldosterone .
Uses
It is used with thiazide diuretics or other kaliuretic -diuretic agents in the treatment of congestive heart
failure or hypertension.
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OSMOTIC DIURETICS
Introduction
Osmotic diuretics are pharmacologically inert agents. They are comparatively large in size (though they
are smaller than albumin); yet, they are filtered freely through the glomerulus. They show poor
reabsorption by the renal tubules.
Mechanism of Action
Osmotic diuretics are filtered at the glomerulus. They are not reabsorbed by the renal tubule. The
primary sites of action for osmotic diuretics are the loop of Henle and the proximal tubule (membrane is
most permeable to water). They prevent water absorption due to its osmotic action in the proximal
tubules and impair sodium reabsorption by decreasing sodium concentration in the tubular fluid.
Osmotic diuretics decrease medullary hypertonicity in the loop of Henle by raising the medullary blood
flow. They decrease sodium and water reabsorption in the collecting duct due to papillary washout and
high flow rate.
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Mannitol
Mannitol is a naturally occurring alcohol found in fruits and vegetables. It is used as an osmotic
diuretic. It undergoes glomerulus filtration and poor renal tubule reabsorption, thus increases
osmolarity of the glomerular filtrate.
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Mannitol is freely filtered by the glomerulus and poorly reabsorbed from the renal tubule, thereby
causing an increase in osmolarity of the glomerular filtrate. An increase in osmolarity limits tubular
reabsorption of water and inhibits the renal tubular reabsorption of sodium, chloride, and other solutes,
thereby promoting diuresis. In addition, mannitol elevates blood plasma osmolarity, resulting in
enhanced flow of water from tissues into interstitial fluid and plasma.
Uses
1) It is used for producing diuresis before irreversible renal failure becomes established.
2) It is also used for reducing intracranial pressure, in treating cerebral oedema, and for facilitating
urinary excretion of toxic substances.
Mannitol overdose may result in bronchoconstriction and should be counteracted using a short-acting
bronchodilator and other symptomatic and supportive care, as necessary.
Mechanism of Action
Toxicity Summary
