Podcast
Questions and Answers
Amiloride is an open-chain analogue of ______.
Amiloride is an open-chain analogue of ______.
triamterene
Amiloride has a long duration of action, lasting between ______ hours.
Amiloride has a long duration of action, lasting between ______ hours.
10-24
Approximately ______% of amiloride is excreted unchanged in urine.
Approximately ______% of amiloride is excreted unchanged in urine.
50
The Na+ channel is opened or closed by small ______ binding to its extracellular portion.
The Na+ channel is opened or closed by small ______ binding to its extracellular portion.
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Renal impairment could increase the half-life of ______.
Renal impairment could increase the half-life of ______.
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Diuretics act directly in/on the ______ to increase urine output.
Diuretics act directly in/on the ______ to increase urine output.
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Increased urine volume is referred to as ______.
Increased urine volume is referred to as ______.
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Increased sodium ion output from the kidney is called ______.
Increased sodium ion output from the kidney is called ______.
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Diuretics can be used in various clinical situations including ______ disease.
Diuretics can be used in various clinical situations including ______ disease.
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The specific site in the nephron where a diuretic class works is determined by the ______ present at that site.
The specific site in the nephron where a diuretic class works is determined by the ______ present at that site.
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The mechanism of action of diuretics often involves modifying normal ______ flow.
The mechanism of action of diuretics often involves modifying normal ______ flow.
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Recognizing important structural features of diuretics involves understanding the ______ features.
Recognizing important structural features of diuretics involves understanding the ______ features.
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It is important to differentiate between ______ and potency in relation to diuretics.
It is important to differentiate between ______ and potency in relation to diuretics.
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The adenosine A1-receptor antagonists target a type of ______ receptor.
The adenosine A1-receptor antagonists target a type of ______ receptor.
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Eplerenone is an example of an ______ antagonist.
Eplerenone is an example of an ______ antagonist.
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The loop of Henle in the kidney is primarily associated with ______ diuretics.
The loop of Henle in the kidney is primarily associated with ______ diuretics.
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Thiazide diuretics, including thiazide-like drugs, are classified based on their ______.
Thiazide diuretics, including thiazide-like drugs, are classified based on their ______.
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Potassium-sparing diuretics work by ______ sodium while conserving potassium.
Potassium-sparing diuretics work by ______ sodium while conserving potassium.
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Vasopressin, also known as ______, is classified as an anti-diuretic hormone.
Vasopressin, also known as ______, is classified as an anti-diuretic hormone.
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Carbonic anhydrase inhibitors are historical diuretics that target a specific ______.
Carbonic anhydrase inhibitors are historical diuretics that target a specific ______.
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The functional unit of the kidney, responsible for filtering blood and producing urine, is called the ______.
The functional unit of the kidney, responsible for filtering blood and producing urine, is called the ______.
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Sodium channel inhibitors are a class of diuretics that act on the ______ Na+ channel.
Sodium channel inhibitors are a class of diuretics that act on the ______ Na+ channel.
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Very weak diuretics such as Theophylline and caffeine are now ______ in cardiovascular disease.
Very weak diuretics such as Theophylline and caffeine are now ______ in cardiovascular disease.
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What is the primary mechanism of action for amiloride?
What is the primary mechanism of action for amiloride?
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Which condition would most likely be treated with amiloride?
Which condition would most likely be treated with amiloride?
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How does renal impairment affect the pharmacokinetics of amiloride?
How does renal impairment affect the pharmacokinetics of amiloride?
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What distinguishes amiloride from triamterene in terms of chemical structure?
What distinguishes amiloride from triamterene in terms of chemical structure?
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Which of the following statements regarding the sodium channel and amiloride is true?
Which of the following statements regarding the sodium channel and amiloride is true?
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Which diuretic class primarily acts on the ascending loop of Henle?
Which diuretic class primarily acts on the ascending loop of Henle?
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What is the main site of action for thiazide diuretics in the nephron?
What is the main site of action for thiazide diuretics in the nephron?
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Which of the following is not a common clinical use for diuretics?
Which of the following is not a common clinical use for diuretics?
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Which GPCR type is primarily targeted by adenosine A1-receptor antagonists?
Which GPCR type is primarily targeted by adenosine A1-receptor antagonists?
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Which potassium-sparing diuretic acts primarily by inhibiting the epithelial sodium channel?
Which potassium-sparing diuretic acts primarily by inhibiting the epithelial sodium channel?
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What structural feature is important for the efficacy of thiazide diuretics?
What structural feature is important for the efficacy of thiazide diuretics?
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Which diuretic is most associated with natriuresis?
Which diuretic is most associated with natriuresis?
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Which diuretic class has a historical significance in treating glaucoma?
Which diuretic class has a historical significance in treating glaucoma?
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Which class of diuretics primarily targets the epithelial sodium channel?
Which class of diuretics primarily targets the epithelial sodium channel?
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Which of the following is an example of an adenosine A1-receptor antagonist?
Which of the following is an example of an adenosine A1-receptor antagonist?
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Which diuretic class acts in the loop of Henle?
Which diuretic class acts in the loop of Henle?
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Which of the following is a physiological effect of potassium-sparing diuretics?
Which of the following is a physiological effect of potassium-sparing diuretics?
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Which molecular target is associated with carbonic anhydrase inhibitors?
Which molecular target is associated with carbonic anhydrase inhibitors?
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What type of receptor do vasopressin (ADH) receptor antagonists target?
What type of receptor do vasopressin (ADH) receptor antagonists target?
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Which drug is a thiazide-like diuretic?
Which drug is a thiazide-like diuretic?
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In which part of the nephron do aldosterone antagonists primarily act?
In which part of the nephron do aldosterone antagonists primarily act?
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Which diuretic is classified as an osmotic diuretic?
Which diuretic is classified as an osmotic diuretic?
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Which drug is commonly used for its action as a vasopressin receptor antagonist?
Which drug is commonly used for its action as a vasopressin receptor antagonist?
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Study Notes
Diuretics Pharmacology and Medicinal Chemistry
- This slide pack covers the mechanism of action of all diuretic medications.
- Some diuretics are used in cardiovascular disease, others in renal disease, and some in other situations.
- The therapeutic use of these medications in the diseases covered in the course will be covered in PHP 327.
Learning Objectives
- Students will learn to distinguish between filtration, reabsorption, excretion, and secretion.
- Students will understand the medicinal chemistry and pharmacology of diuretics.
- Students will learn the mechanism of action and target for each class of diuretics (which transporters are affected).
- Students will learn the effect of diuretic drugs at each site, modifying normal flow.
- Students will learn where in the nephron a given diuretic class works, defined by the transporters present.
- Students will recognize the important structural features of each class of diuretics, including pharmacophore features and structure-function information presented in class and in course packets
- Students will learn structural bases for similarities and differences amongst different marketed diuretics within each class.
A Few Words About Diuretics
- Diuretics act directly on the kidneys to increase urine output.
- Diuresis is increased urine volume (output of pure water from the kidney).
- Pronounced as DYE-you-ree-sis.
- Natriuresis is increased sodium ion output from the kidney.
- Pronounced as NAY-tree-you-ree-sis.
- Both diuresis and natriuresis are closely related but not exactly the same (volume versus sodium output).
Diuretic Sub-Class Names
- Loop (high-ceiling) - Site of action: loop of Henle; high efficacy.
- Thiazide (includes thiazide-like) - Chemical class, based on structure.
- Potassium-sparing - Physiological effect (excrete Na+, not K+).
- Sodium channel inhibitors - Molecular target (ion channel), e.g. ENaC.
- Aldosterone antagonists - Molecular target (transcription factor).
- Osmotic - Physical-chemical characteristic (no molecular target).
- Vasopressin (ADH) receptor antagonists - Molecular target.
- Carbonic anhydrase inhibitors - Historical; not used as diuretics. Molecular target (enzyme).
- Adenosine A1-receptor antagonists - GPCR molecular target. Somewhat effective as diuretic, natriuretic, only at high doses.
- Theophylline, caffeine.
Diuretics by Drug Class
- List of diuretics categorized by drug class.
Reminder of Kidney Anatomy
- The kidney's functional unit is the nephron.
- The nephron includes the glomerulus, proximal convoluted tubule, loop of Henle, distal convoluted tubule, and collecting duct
- The slides provide a zoom into the structures within the nephron.
Nephron
- The nephron is the functional unit of the kidney, responsible for filtering waste products from the blood and producing urine.
- Different components of the nephron (glomerulus, proximal convoluted tubule, loop of Henle, distal convoluted tubule, collecting duct) contain different molecular targets for different classes of diuretic agents.
- The action of each class of diuretic is controlled by the specific target and location within the nephron.
- Structural differences within each class of diuretics cause variations in potency, onset of action, and duration of action (pharmacodynamics and pharmacokinetics).
Preview—Simple diagram of Nephron and where some diuretics work
- Urine formation involves filtration of plasma in the glomerulus, reabsorption of water and solutes from the filtrate, secretion of selected solutes into the tubular fluid, and flow of remaining fluid into the calyx, then to the bladder for excretion
Preview: All types of Diuretics and location of action
- Illustrations of different classes of diuretics and their location in the nephron.
Targets (receptors) of Diuretic drugs, Where does each fit in the classification?
- Figure showing different types of targets for diuretic drugs (enzymes, transporters, channels, GPs,etc.)
Animated movie: Diuretic action in the kidney
- Animated movie explaining diuretic action on renal flow is available.
Sites of Na+ reabsorption within the nephron
- Shows different parts of the nephron where sodium reabsorption occurs.
Watch the beginning of the movie
- Directions on how to watch the movie and use slides to explain how various parts of the nephron work and how different classes of diuretics affect each part of the nephron
Loop diuretics
- Bind to and inhibit Na+/K+/2Cl- co-transporter (NKCC2).
- This transporter is mainly located on the luminal membrane of the thick ascending limb of the loop of Henle.
- See movie for sequence of movements in the presence and absence of loop diuretics.
Transporters present in the thick ascending limb loop of Henle
- List of transporters present in the thick ascending limb loop of Henle and their role.
Result of normal action in thick ascending Limb
- Illustration of the expected outcome of normal action in the thick ascending limb.
Result in presence of loop diuretic in thick ascending limb
- Illustration of the effect of loop diuretics on the thick ascending limb.
Loop Diuretics
- Describes the effects and adverse effects of loop diuretics. Lists specific diuretic agents used today.
- Hypokalemia is a side effect due to less reabsorption of K+ in the loop and increased delivery of Na+ to the distal tubule, which then activates the RAAS.
Sulfonamide-based Loop Diuretics
- Describes structural features of diuretics for binding.
- Explains that the carboxyl group is the most important for binding to the receptor.
Sulfonamide-based Loop Diuretics
- Describes the side effects, mechanism, and differences between the various loop diuretics available.
Other types of diuretics
- List of other types of diuretics (vasopressin receptor antagonists, osmotic diuretics, carbonic anhydrase inhibitors, aldosterone antagonists, adenosine antagonists).
Osmotic diuretics
- Examples include mannitol, glycerin, isosorbide (sorbitol), urea.
- Mechanism: inhibit water reabsorption and maintain urine flow (promote diuresis & natriuresis)
- No molecular target, act by osmosis; low molecular weight, freely filtered in glomerulus, not reabsorbed due to high water solubility.
- Osmosis occurs in aquaporins, which are not effective in orally absorbed mannitol or urea. Glycerin and isosorbide are more orally absorbed.
Osmotic diuretics, example of mechanism
- Explanation on how osmosis occurs and how osmotic diuretics act.
Three Locations of osmotic diuretic action
- Diagram showing the three locations of osmotic diuretic action in the nephron.
Anti Diuretic Hormone (ADH) what does it do?
- Antidiuretic hormone (ADH), also called vasopressin, is a nine amino acid peptide.
- ADH acts as an agonist for V2-vasopressin receptors in the collecting duct of the nephron in the kidney; ADH is anti-diuretic (water-retaining)
Vasopressin receptor antagonists
- Vasopressin, also called antidiuretic hormone, ADH
- In the kidneys, V2-receptor antagonists are natriuretic and weak diuretics.
- Treatments for hyponatremia including Tolvaptan and Conivaptan
Mechanism of action
- Vasopressin (ADH) receptors are GPCRs (two kinds V2, V2).
- Antagonism at V₂ receptors in the kidney promotes excretion of free water without loss of serum electrolytes, resulting in fluid loss, increased urine output, decreased urine osmolality, and subsequent restoration of normal serum sodium levels.
- Vasopressin antagonists are used for treating hyponatremia, particularly in congestive heart failure patients.
- V1 receptors are in vascular smooth muscle and activation causes vasoconstriction.
- V1 antagonists cause vasodilation.
Vasopressin V2 receptor
- Cryo-EM structure of the AVP-vasopressin receptor 2-G₄ signaling complex
CVR Uses of Diuretics
- Diuretics are covered in PHP 327
Diuretics also used for other diseases
- Diuretic use in conditions such as altitude sickness, glaucoma, edema, raised intracranial pressure, liver disease, cirrhosis.
Review: All types of Diuretics and location of action
- Diagram showing different classes of diuretics and their location in the nephron.
Learning Objectives-did we meet them?
- Summary of learned objectives from the course material.
Thiazide diuretics
- Inhibit the Na+/Cl- co-transporter (NCC) located on the luminal membrane of the distal convoluted tubule.
- Compete for Cl⁻-binding site.
- Sequence of movements for diuretic usage.
- Intermediate efficacy.
Restart the movie
- Instructions to restart the movie to view the relevant aspects of the material
Transporters present in distal convoluted tubule
- List of transporters present in the distal convoluted tubule.
Result of normal action in distal convoluted tubule
- Illustration of normal action in the distal convoluted tubule.
Result in presence of thiazide diuretic in distal convoluted tubule
- Illustration of the effect of thiazide diuretics on the distal convoluted tubule.
Thiazide (and hydrothiazide, thiazide-like) diuretics
- Named for their chemical class—all contain a thiazide
- All 3 types included in more general term “thiazides”
- Bind at the chloride-binding site of the Na⁺/Cl⁻ co-transporter on the luminal membrane of the early distal convoluted tubule.
- Cause increased renal loss of Na⁺, Cl⁻ and water.
- Also decrease Ca²⁺, uric acid excretion, and increase bicarbonate excretion.
- Intermediate efficacy (1-2 L/24 hr) between loop and potassium-sparing diuretics
Pharmacophore Structural features affecting activity of thiazide and thiazide-like diuretics
- Details of pharmacophore features and their influence on diuretic activity.
Structure of Na, Cl transporter published 2023
- Details of the structure of the Na⁺/Cl⁻ transporter.
Na⁺ channel (ENaC) inhibitors (Potassium-sparing)
- Bind to and inhibit sodium channels on the luminal membrane of distal tubule and collecting duct.
- Physically blocks the luminal opening of the Na⁺ channel.
- Sequence of movements for the use of diuretics
Transporters present in distal tubule and collecting ducts
- List of transporters present in the distal tubule and collecting ducts.
Result of normal action in collecting tubules
- Illustration of normal action in the collecting tubules
Result in presence of sodium channel inhibitors in collecting tubules
- Illustration of the effects of sodium channel inhibitors in collecting tubules.
Epithelial Na⁺ channel (ENaC) inhibitors (Potassium-sparing)
- Block reabsorption of sodium and block secretion of potassium (resulting in retention of potassium), resulting in increased sodium excretion and almost no potassium secretion.
- A side effect is hyperkalemia, which is increased retention of potassium.
Na+ channel inhibitors (Potassium-sparing)
- Details of triamterene and amiloride—two classes of Na⁺ channel inhibitors.
2018: Structure Biology of ENaC
- Structure and function of ENaC
Review: Common features of ALL Na+ transport inhibitors
- Common features of all Na⁺ transport inhibitors
Cause of different efficacies of diuretics
- The most efficacious diuretics are those that act in the ascending limb of the loop of Henle.
- Diuretics that act at the most distal sites (Na+ channel blockers, aldosterone antagonists) are least efficacious.
- Diuretics that act at the early distal tubule (thiazide and thiazide-like) have intermediate efficacy.
- Diuretics that act primarily on the proximal tubule are weakest.
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Description
Test your knowledge on diuretics, their mechanisms of action, and their clinical uses. This quiz covers important concepts such as the duration of action, renal effects, and structural features of diuretics. Suitable for students or professionals in pharmacology or medicinal chemistry.
