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What mechanism does furosemide use to inhibit sodium transport in the thick ascending limb of the loop of Henle?
Which is the most likely consequence of furosemide usage regarding uric acid levels?
What is the primary route of elimination for furosemide?
Why might furosemide bioavailability be markedly reduced in some patients?
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In which scenario is the use of high ceiling diuretics, like furosemide, typically indicated?
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What effect does furosemide have on potassium levels within the body?
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Which is NOT a common condition for which furosemide would be used?
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What is the average plasma half-life of furosemide in healthy individuals?
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What is the primary role of V2 receptors in the kidney's collecting duct?
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Which of the following actions is NOT triggered by persistent V1 receptor stimulation?
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What mechanism accounts for the rapid adjustment of water excretion by vasopressin?
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What is the effect of V2 receptor stimulation in chronic water deprivation?
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Which cellular process is inhibited by vasopressin to enhance water retention?
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Which type of intracellular signaling is primarily utilized by V2 receptors?
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What is the outcome of DAG mediated protein kinase C activation?
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Which diuretic class produces a maximal natriuretic effect greater than others?
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What is the typical onset of action time for intravenous Furosemide?
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What biochemical substances are generated as a result of V1 receptor activation and phospholipase A2 function?
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Which of the following diuretics leads to increased excretion of Ca2+ and Mg2+?
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How does Furosemide primarily affect systemic venous capacitance?
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What is one of the main actions of Furosemide regarding renal blood flow post-injection?
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Which class of diuretics is characterized by a weak carbonic anhydrase inhibitory action?
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What effect does Furosemide have on the glomerular filtration rate (GFR)?
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Which diuretic class is less effective in patients with severe renal failure?
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What is the primary indication for the use of antidiuretics?
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What regulates the rate of ADH release in the body?
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Which receptor type functions mainly through the phospholipase C–IP3/DAG pathway?
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Which of the following is NOT classified as an antidiuretic drug?
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Where is the antidiuretic hormone synthesized?
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Which structure contains osmoreceptors that help regulate ADH release?
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V1 receptors are found in which of the following tissues?
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What effect does vasopressin primarily have on the kidneys?
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What is the primary action of vasopressin (AVP) on the collecting duct principal cells?
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Which receptor is primarily involved in vasopressin-mediated vasoconstriction?
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What effect does vasopressin have on the urea transporter in the terminal part of collecting ducts?
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How does the pharmacokinetics of AVP affect its administration route?
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Which of the following actions occurs in the thick ascending limb of the loop of Henle due to vasopressin activity?
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What is the duration of action of aqueous vasopressin after administration?
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What is a significant characteristic of lypressin compared to vasopressin?
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Which physiological effect is NOT associated with exogenously administered vasopressin?
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Study Notes
Furosemide
- Greatest natriuretic effect among diuretic classes.
- Dose-dependent diuretic response, with up to 10L urine production daily.
- Effective even in patients with severe renal impairment.
- Rapid onset of action (2-5 minutes IV, 10-20 minutes IM, 20-40 minutes oral).
- Short duration of action (3-6 hours).
- Weak carbonic anhydrase inhibitory action, leading to increased HCO3- excretion.
- Transient increase in renal blood flow after IV administration, redistributing blood flow from outer to midcortical zone.
- Glomerular filtration rate typically remains unchanged due to compensatory mechanisms despite increased blood flow.
- Alters pressure equilibrium between vascular, interstitial and tubular compartments, reducing proximal tubule reabsorption.
- Intrarenal haemodynamic changes are driven by increased local prostaglandin synthesis.
- Prompt increase in systemic venous capacitance and decreased left ventricular filling pressure following IV administration.
- This vasodilation is mediated by prostaglandins, providing rapid relief in left ventricular failure and pulmonary edema.
- Increases Ca2+ and Mg2+ excretion (opposite to thiazides).
- Elevates blood uric acid levels, competing with its proximal tubular secretion and increasing reabsorption in the proximal tubule due to reduced extracellular fluid volume.
- Hyperuricaemia is less pronounced compared to thiazides.
- May cause a slight increase in blood glucose levels with regular use.
- The primary site of action is the thick ascending limb of the loop of Henle (TALH), where it inhibits the Na+-K+-2Cl¯ cotransporter.
- Attaches to the chloride binding site of the protein to inhibit its transport function.
- Secreted in the proximal tubule by organic anion transport and reaches the TALH to act from the luminal side of the membrane.
- Eliminates the corticomedullary osmotic gradient.
- Increased potassium excretion primarily due to high sodium load reaching the distal tubule.
- Rapidly absorbed orally, but bioavailability is around 60%.
- Oral bioavailability can be significantly reduced in severe congestive heart failure, necessitating parenteral administration.
- Low lipid solubility, highly bound to plasma proteins.
- Partly conjugated with glucuronic acid and mainly excreted unchanged by glomerular filtration and tubular secretion.
- Some excretion in bile and directly into the intestine occurs.
- Plasma half-life averages 1-2 hours but is prolonged in patients with pulmonary edema, renal and hepatic insufficiency.
Uses of High-Ceiling Diuretics
- Edema: Effective for all types of edema, including cardiac, hepatic, and renal.
- Acute pulmonary edema: Intravenous administration provides rapid relief.
- Cerebral edema: Osmotic diuretics are primarily used to lower intracranial pressure.
- Hypertension: Indicated in hypertension only in the presence of renal insufficiency, congestive heart failure, or in resistant cases and hypertensive emergencies.
- Blood transfusions in severe anemia: To prevent volume overload.
- Hypercalcemia of malignancy: Used in severe volume depletion. Rapid, high-dose treatment may be necessary in medical emergencies.
Antidiuretics
- Reduce urine volume, especially in diabetes insipidus (DI).
- Drugs include:
- Antidiuretic hormone (ADH, Vasopressin)
- Desmopressin
- Lypressin
- Terlipressin.
- Thiazide diuretics
- Amiloride
- Miscellaneous: Indomethacin, Chlorpropamide, Carbamazepine.
Antidiuretic Hormone (Arginine Vasopressin - AVP)
- Nonapeptide secreted by the posterior pituitary (neurohypophysis) along with oxytocin.
- Synthesized in the hypothalamic supraoptic and paraventricular nerve cell bodies as a large precursor peptide together with its binding protein 'neurophysin'.
- Transported down axons to nerve endings in the median eminence and pars nervosa.
- Release is primarily regulated by osmoreceptors and volume receptors.
- Osmoreceptors in the hypothalamus sense changes in plasma osmolarity.
- Volume receptors in the left atrium, ventricles, and pulmonary veins sense blood volume changes.
- Osmoreceptors in the hepatic portal system sense ingested salt and release AVP before plasma osmolarity is increased by the ingested salt.
- Impulses from baroreceptors and higher centers also affect AVP release.
- The two main triggers for AVP release are elevated plasma osmolarity and decreased extracellular fluid volume.
AVP Receptors
- G protein-coupled cell membrane receptors.
- Two subtypes: V1 and V2.
-
V1 receptors
- Present on all vasopressin receptor subtypes except those in renal collecting duct cells (CD), ascending limb of Henle cells (TALH), and vascular endothelium.
- Subtypes V1a and V1b.
- V1a receptors are found on vascular smooth muscle (including vasa recta), uterine and other visceral smooth muscles, interstitial cells in renal medulla, cortical CD cells, adipose tissue, brain, platelets, liver, etc.
- V1b receptors are localized to the anterior pituitary, certain brain areas, and pancreas.
- Functionality through the phospholipase C-IP3/DAG pathway, releasing Ca2+ from intracellular stores.
- Contribute to vasoconstriction, visceral smooth muscle contraction, glycogenolysis, platelet aggregation, ACTH release, etc.
- Augmented by increased Ca2+ influx through Ca2+ channels and DAG-mediated protein kinase C activation, phosphorylating relevant proteins.
- Activate phospholipase A2, releasing arachidonic acid, generating prostaglandins and eicosanoids that contribute to V1-mediated effects.
- Persistent V1 receptor stimulation activates protooncogenes, possibly through IP3/DAG pathway, leading to growth (hypertrophy) of vascular smooth muscle and responsive cells.
-
V2 receptors
- Primarily located on CD principal cells in the kidney, regulating water permeability through cAMP production.
- Some V2 receptors are also present on TALH cells, activating the Na+ cotransporter.
- Vasodilatory V2 receptors are found on the endothelium of blood vessels.
- More sensitive to AVP than V1 receptors.
Mechanisms of AVP Action
-
Kidney:
- AVP acts on CD principal cells to increase their water permeability, facilitating water diffusion from the duct lumen to the interstitium, equilibrating with the hyperosmolar renal medulla.
- To achieve maximum urine concentration, V2 receptor activation increases urea permeability in the terminal part of CDs in the inner medulla by stimulating the vasopressin-regulated urea transporter (VRUT or UT-1), further enhancing medullary hypertonicity.
-
Blood vessels:
- AVP constricts blood vessels through V1 receptors, raising blood pressure (hence the name vasopressin), but much higher concentrations are needed compared to those required for maximal antidiuresis.
- V2 receptor-mediated vasodilation can be observed when AVP is administered in the presence of a V1 antagonist.
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Other actions:
- Most visceral smooth muscles contract.
- Increased peristalsis in the gut (especially large bowel), evacuation, and expulsion of gases may occur.
- Uterus is contracted by AVP acting on oxytocin receptors.
- CNS: Exogenously administered AVP does not penetrate the blood-brain barrier.
Pharmacokinetics of AVP
- Inactive orally due to enzymatic degradation by trypsin.
- Administered parenterally or by intranasal application.
- Rapidly cleaved enzymatically in many organs, particularly in the liver and kidney, resulting in a short plasma half-life of approximately 25 minutes.
- However, the action of aqueous vasopressin lasts 3-4 hours.
Vasopressin Analogues
- Lypressin (8-lysine vasopressin)
- Less potent than AVP, but acts on both V1 and V2 receptors.
- Longer duration of action (4-6 hours).
- Terlipressin
- Synthetic prodrug of vasopressin specifically used for bleeding esophageal varices.
- May produce less severe adverse effects than lypressin.
Rapid Actions of AVP
- Translocation of water channel-containing vesicles (WCVs) and exocytotic insertion of aquaporin 2 water channels into the apical membrane of collecting duct principal cells; the primary action responsible for antidiuresis.
- Inhibition of endocytotic removal of aquaporin 2 channels from the apical membrane.
- Activation of vasopressin-regulated urea transporter (VRUT) at the apical membrane of collecting ducts in the inner medulla.
- Translocation of the Na+ K+ 2Cl¯ cotransporter to the luminal membrane of cells in the thick ascending limb of the loop of Henle (TALH).
- Activation of the Na+ K+ 2Cl¯ cotransporter in TALH cells.
- V1a receptor (V1aR) mediated vasoconstriction of vasa recta.
Long-Term Actions of AVP
- Gene-mediated increased expression of aquaporin 2 channels in collecting duct cells.
- Gene-mediated increased expression of the Na+K+2Cl¯ cotransporter in TALH cells.
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Description
This quiz explores the pharmacological properties of Furosemide, a potent diuretic with the greatest natriuretic effect. It covers its mode of action, effects on urine production, and its use in patients with renal impairment. You'll learn about its rapid onset and short duration of action, as well as its hemodynamic effects.
