Login
Continue
Start Now
Login
Continue
Start

Achieve Mastery of Medical Concepts

Study for medical school and boards with Lecturio

USMLE Step 1    |    USMLE Step 2    |    COMLEX Level 1    |    COMLEX Level 2    |    ENARM    |    NEET    

Create your free account
Continue Learning
The Lecturio Medical Concept Library
Loop Diuretics

Loop Diuretics

Loop diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication are a group of diuretic medications primarily used to treat fluid overload in edematous conditions such as heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR) and cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis. Loop diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication also treat hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, but not as a 1st-line agent. The medication inhibits sodium reabsorption Sodium reabsorption Tubular System through the NKCC2 NKCC2 Renal Potassium Regulation cotransporter in the thick ascending limb Thick ascending limb Renal Sodium and Water Regulation of the loop of Henle Loop of Henle The U-shaped portion of the renal tubule in the kidney medulla, consisting of a descending limb and an ascending limb. It is situated between the proximal kidney tubule and the distal kidney tubule. Tubular System ( TAL TAL Renal Sodium and Water Regulation), leading to significant diuresis. Careful monitoring is important because loop diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication result in increased excretion of sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia, potassium Potassium An element in the alkali group of metals with an atomic symbol k, atomic number 19, and atomic weight 39. 10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. Hyperkalemia, chloride Chloride Inorganic compounds derived from hydrochloric acid that contain the Cl- ion. Electrolytes, calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes, magnesium Magnesium A metallic element that has the atomic symbol mg, atomic number 12, and atomic weight 24. 31. It is important for the activity of many enzymes, especially those involved in oxidative phosphorylation. Electrolytes, and water. In addition to electrolyte and fluid abnormalities, loop diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication can lead to nephrotoxicity Nephrotoxicity Glycopeptides and ototoxicity Ototoxicity Damage to the ear or its function secondary to exposure to toxic substances such as drugs used in chemotherapy; immunotherapy; or radiation. Glycopeptides.

Last updated: Jul 10, 2023

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Contents

Overview

Definition

Loop diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication are a group of medications primarily used to treat edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema (and sometimes hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension) by inhibiting sodium reabsorption Sodium reabsorption Tubular System through the NKCC2 NKCC2 Renal Potassium Regulation cotransporter (as known as the Na+-K+-Cl– cotransporter) in the thick ascending limb Thick ascending limb Renal Sodium and Water Regulation of the loop of Henle Loop of Henle The U-shaped portion of the renal tubule in the kidney medulla, consisting of a descending limb and an ascending limb. It is situated between the proximal kidney tubule and the distal kidney tubule. Tubular System ( TAL TAL Renal Sodium and Water Regulation), which lead to significant diuresis.

Overview of antihypertensive agents

Table: Drugs used to treat hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
Location of action Class Subclasses
Renal drugs Drugs affecting the RAAS RAAS A blood pressure regulating system of interacting components that include renin; angiotensinogen; angiotensin converting enzyme; angiotensin i; angiotensin ii; and angiotensinase. Renin, an enzyme produced in the kidney, acts on angiotensinogen, an alpha-2 globulin produced by the liver, forming angiotensin I. Angiotensin-converting enzyme, contained in the lung, acts on angiotensin I in the plasma converting it to angiotensin II, an extremely powerful vasoconstrictor. Angiotensin II causes contraction of the arteriolar and renal vascular smooth muscle, leading to retention of salt and water in the kidney and increased arterial blood pressure. In addition, angiotensin II stimulates the release of aldosterone from the adrenal cortex, which in turn also increases salt and water retention in the kidney. Angiotensin-converting enzyme also breaks down bradykinin, a powerful vasodilator and component of the kallikrein-kinin system. Adrenal Hormones
Diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication
Extrarenal drugs Direct vasodilators Vasodilators Drugs used to cause dilation of the blood vessels. Thromboangiitis Obliterans (Buerger’s Disease)
  • Calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes channel blockers
  • Potassium Potassium An element in the alkali group of metals with an atomic symbol k, atomic number 19, and atomic weight 39. 10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. Hyperkalemia channel openers
  • Nitrodilators
  • Endothelin antagonists
Agents acting via the sympathetic nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. Nervous System: Anatomy, Structure, and Classification
  • Drugs affecting CNS sympathetic outflow (e.g., clonidine Clonidine An imidazoline sympatholytic agent that stimulates alpha-2 adrenergic receptors and central imidazoline receptors. It is commonly used in the management of hypertension. Sympathomimetic Drugs)
  • Drugs affecting the ganglia (e.g., hexamethonium)
  • Drugs affecting the nerve terminals (e.g., guanethidine, reserpine)
  • Drugs affecting the α and β receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors

Drugs in the loop diuretic class

Drugs include: 

  • Furosemide (prototypical drug in the class)
  • Bumetanide
  • Torsemide
  • Ethacrynic acid

Related videos

8:44
Diuretics – Drugs in Hypertension

Chemistry and Pharmacodynamics

Chemical structure

Chemical structure of furosemide

Chemical structure of furosemide

Image: “Furosemide” by Fvasconcellos. License: Public Domain

Mechanism of action

  • Blocks reabsorption of Na+, K+, and Cl– through the inhibition of NKCC2 NKCC2 Renal Potassium Regulation cotransporter in the TAL TAL Renal Sodium and Water Regulation:
    • The channel is located on the apical side.
    • Reabsorbs 1 Na+, 1 K+, and 2 Cl– from the tubule lumen into the cells
  • With the channel blocked → ↓ Na+ reabsorption
  • Water always follows Na+:
    • Water stays with Na+ in the tubules and is not reabsorbed.
    • The osmotic effect of Na+ results in diuresis.
Action of loop diuretics

Action of loop diuretics in the thick ascending limb of the loop of Henle (TAL)

Image by Lecturio. License: CC BY-NC-SA 4.0

Physiologic effects

  • ↑ Excretion of Na+, K+, Cl– by blocking the NKCC2 NKCC2 Renal Potassium Regulation cotransporter
  • ↑ Diuresis:
    • ↓ Blood volume → ↓ cardiac preload Preload Cardiac Mechanics
    • Removes fluid from the body → improves edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
  • Inhibits the ability of the kidney to dilute or concentrate urine
  • ↑ Excretion of Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)2+ and Mg2+:
    • The interstitial fluid Interstitial fluid Body Fluid Compartments is relatively more negative compared to the tubular lumen.
    • The electrochemical gradient Electrochemical gradient The Cell: Cell Membrane drives passive paracellular Paracellular Renal Potassium Regulation reabsorption of Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)2+ and Mg2+.
    • Blocking the NKCC2 NKCC2 Renal Potassium Regulation transporter leads to ↓ reabsorption of Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)2+ and Mg2+ → ↑ excretion of Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)2+ and Mg2+
    • Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship have an increased risk of hypomagnesemia Hypomagnesemia A nutritional condition produced by a deficiency of magnesium in the diet, characterized by anorexia, nausea, vomiting, lethargy, and weakness. Symptoms are paresthesias, muscle cramps, irritability, decreased attention span, and mental confusion, possibly requiring months to appear. Deficiency of body magnesium can exist even when serum values are normal. In addition, magnesium deficiency may be organ-selective, since certain tissues become deficient before others. Electrolytes, hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia, and nephrolithiasis Nephrolithiasis Nephrolithiasis is the formation of a stone, or calculus, anywhere along the urinary tract caused by precipitations of solutes in the urine. The most common type of kidney stone is the calcium oxalate stone, but other types include calcium phosphate, struvite (ammonium magnesium phosphate), uric acid, and cystine stones. Nephrolithiasis.
Passive paracellular reabsorption of magnesium and calcium

Passive paracellular reabsorption of magnesium and calcium in the thick ascending limb of the loop of Henle (TAL): driven by the voltage gradient between the tubular lumen (apical side) and the interstitial fluid (basolateral side)

Image by Lecturio. License: CC BY-NC-SA 4.0

Related videos

8:29
Corticopapillary Osmotic Gradient

Pharmacokinetics

  • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption:
    • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption varies among agents
    • Can be absorbed orally (slightly slower onset of action) or intravenously (faster)
    • Bioavailability Bioavailability Pharmacokinetics and Pharmacodynamics: bumetanide and torsemide > furosemide
  • Distribution:
    • Highly protein-bound → no renal filtration
    • Renal excretion in the proximal tubule Proximal tubule The renal tubule portion that extends from the bowman capsule in the kidney cortex into the kidney medulla. The proximal tubule consists of a convoluted proximal segment in the cortex, and a distal straight segment descending into the medulla where it forms the u-shaped loop of henle. Tubular System via organic anion transport (OAT) pumps
  • Metabolism:
    • Bumetanide and torsemide: mostly inactivated in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy by cytochrome P450 Cytochrome P450 A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism. Drug-Induced Liver Injury (CYP450)
    • Furosemide: minimal hepatic metabolism
  • Excretion:
    • Mostly renal excretion as an unchanged drug
    • Half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics range: 1–4 hours
Table: Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics of loop diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication
Drug Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption Distribution Metabolism Excretion
Furosemide (Lasix®) Protein binding: 95% Minimal hepatic metabolism
  • Urine (some fecal)
  • Half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics:
    • Normal renal function: 0.5–2 hours
    • ESRD: 9 hours
Bumetanide (Bumex®)
  • Vd: 9–25 L
  • Protein binding: 95%
 Partial hepatic metabolism
  • Urine
  • Feces (2%)
  • Half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics: 60–90 minutes
Torsemide (Demadex®)
  • Vd: 12–15 L
  • Protein binding: > 99%
 Hepatic (80%) via CYP2C9 CYP2C9 A cytochrome p-450 subtype that has specificity for acidic xenobiotics. It oxidizes a broad range of important clinical drugs that fall under the categories of nonsteroidal anti-inflammatory agents; hypoglycemic agents; anticoagulants; and diuretics. Anticoagulants
Ethacrynic acid (Edecrin®) Peak effect:
  • Oral: 2 hours
  • IV: 30 minutes
 Protein binding: > 90% Hepatic (40%) via active cysteine Cysteine A thiol-containing non-essential amino acid that is oxidized to form cystine. Synthesis of Nonessential Amino Acids conjugate
  • Feces and urine
  • Half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics: 2–4 hours
ESRD: end-stage renal disease

Indications, Contraindications, and Adverse Effects

Indications

  • Edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema:
    • Includes:
      • Peripheral edema Peripheral edema Peripheral edema is the swelling of the lower extremities, namely, legs, feet, and ankles. Edema
      • Pulmonary edema Pulmonary edema Pulmonary edema is a condition caused by excess fluid within the lung parenchyma and alveoli as a consequence of a disease process. Based on etiology, pulmonary edema is classified as cardiogenic or noncardiogenic. Patients may present with progressive dyspnea, orthopnea, cough, or respiratory failure. Pulmonary Edema
      • Generalized edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
      • Ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites
    • Resulting from:
      • Heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR) (used for symptomatic management; no mortality Mortality All deaths reported in a given population. Measures of Health Status benefit)
      • Hepatic disease/ cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis
      • Renal disease, including nephrotic syndrome Nephrotic syndrome Nephrotic syndrome is characterized by severe proteinuria, hypoalbuminemia, and peripheral edema. In contrast, the nephritic syndromes present with hematuria, variable loss of renal function, and hypertension, although there is sometimes overlap of > 1 glomerular disease in the same individual. Nephrotic Syndrome
  • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension:
    • Not 1st-line agents
    • Typically used in combination with other agents
    • Most commonly used in heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR) patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension presenting with fluid overload

Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation

  • Anuria Anuria Absence of urine formation. It is usually associated with complete bilateral ureteral (ureter) obstruction, complete lower urinary tract obstruction, or unilateral ureteral obstruction when a solitary kidney is present. Acute Kidney Injury
  • Allergy Allergy An abnormal adaptive immune response that may or may not involve antigen-specific IgE Type I Hypersensitivity Reaction to sulfa drugs (except ethacrynic acid)
  • Hepatic coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma
  • Severe electrolyte depletion
  • Ethacrynic acid in infants

Significant adverse effects and toxicity Toxicity Dosage Calculation

  • Nephrotoxicity Nephrotoxicity Glycopeptides
  • Ototoxicity Ototoxicity Damage to the ear or its function secondary to exposure to toxic substances such as drugs used in chemotherapy; immunotherapy; or radiation. Glycopeptides
  • Fluid and electrolyte loss, which may predispose to:
    • Cardiac arrhythmias 
    • Orthostatic hypotension Orthostatic hypotension A significant drop in blood pressure after assuming a standing position. Orthostatic hypotension is a finding, and defined as a 20-mm hg decrease in systolic pressure or a 10-mm hg decrease in diastolic pressure 3 minutes after the person has risen from supine to standing. Symptoms generally include dizziness, blurred vision, and syncope. Hypotension
    • Dehydration Dehydration The condition that results from excessive loss of water from a living organism. Volume Depletion and Dehydration
    • Dizziness Dizziness An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. Lateral Medullary Syndrome (Wallenberg Syndrome)/ vertigo Vertigo Vertigo is defined as the perceived sensation of rotational motion while remaining still. A very common complaint in primary care and the ER, vertigo is more frequently experienced by women and its prevalence increases with age. Vertigo is classified into peripheral or central based on its etiology. Vertigo/ syncope Syncope Syncope is a short-term loss of consciousness and loss of postural stability followed by spontaneous return of consciousness to the previous neurologic baseline without the need for resuscitation. The condition is caused by transient interruption of cerebral blood flow that may be benign or related to a underlying life-threatening condition. Syncope
    • Headaches
    • GI symptoms (abdominal cramps Cramps Ion Channel Myopathy, nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea)
    • Muscle cramps Cramps Ion Channel Myopathy
  • Photosensitivity Photosensitivity Tetracyclines

Mnemonic:

To recall the adverse effects of loop diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication, remember “Ohh Daang”:

  • Ototoxicity
  • Hypokalemia
  • Hypomagnesemia
  • Dehydration
  • Allergy (sulfa)
  • Alkalosis (metabolic)
  • Nephritis (interstitial)
  • Gout

Precautions

Loop diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication should be used with caution in the following situations:

  • In electrolyte, fluid, or acid-base abnormalities, loop diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication can cause:
    • Hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia (↓ K+)
    • Hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia (↓ Na+)
    • Hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia (↓ Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)2+) (thiazides tend to cause hypercalcemia)
    • Hypomagnesemia Hypomagnesemia A nutritional condition produced by a deficiency of magnesium in the diet, characterized by anorexia, nausea, vomiting, lethargy, and weakness. Symptoms are paresthesias, muscle cramps, irritability, decreased attention span, and mental confusion, possibly requiring months to appear. Deficiency of body magnesium can exist even when serum values are normal. In addition, magnesium deficiency may be organ-selective, since certain tissues become deficient before others. Electrolytes (↓ Mg2+)
    • Metabolic alkalosis Alkalosis A pathological condition that removes acid or adds base to the body fluids. Respiratory Alkalosis
    • Prerenal azotemia Azotemia A biochemical abnormality referring to an elevation of blood urea nitrogen and creatinine. Azotemia can be produced by kidney diseases or other extrarenal disorders. When azotemia becomes associated with a constellation of clinical signs, it is termed uremia. Acute Kidney Injury
    • Hypovolemia Hypovolemia Sepsis in Children
  • Taken with another medication increasing the risk for hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia:
  • Taken with another medication increasing the risk for nephrotoxicity Nephrotoxicity Glycopeptides and/or ototoxicity Ototoxicity Damage to the ear or its function secondary to exposure to toxic substances such as drugs used in chemotherapy; immunotherapy; or radiation. Glycopeptides:
    • Aminoglycosides Aminoglycosides Aminoglycosides are a class of antibiotics including gentamicin, tobramycin, amikacin, neomycin, plazomicin, and streptomycin. The class binds the 30S ribosomal subunit to inhibit bacterial protein synthesis. Unlike other medications with a similar mechanism of action, aminoglycosides are bactericidal. Aminoglycosides 
    • Probenecid Probenecid The prototypical uricosuric agent. It inhibits the renal excretion of organic anions and reduces tubular reabsorption of urate. Probenecid has also been used to treat patients with renal impairment, and, because it reduces the renal tubular excretion of other drugs, has been used as an adjunct to antibacterial therapy. Gout Drugs
  • Certain medical conditions:
    • Hyperuricemia Hyperuricemia Excessive uric acid or urate in blood as defined by its solubility in plasma at 37 degrees c; greater than 0. 42 mmol per liter (7. 0 mg/dl) in men or 0. 36 mmol per liter (6. 0 mg/dl) in women. Gout/ gout Gout Gout is a heterogeneous metabolic disease associated with elevated serum uric acid levels (> 6.8 mg/dL) and abnormal deposits of monosodium urate in tissues. The condition is often familial and is initially characterized by painful, recurring, and usually monoarticular acute arthritis, or “gout flare,” followed later by chronic deforming arthritis. Gout (may precipitate gout Gout Gout is a heterogeneous metabolic disease associated with elevated serum uric acid levels (> 6.8 mg/dL) and abnormal deposits of monosodium urate in tissues. The condition is often familial and is initially characterized by painful, recurring, and usually monoarticular acute arthritis, or “gout flare,” followed later by chronic deforming arthritis. Gout)
    • Systemic lupus erythematosus Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus ( SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus) (may cause a flare)
    • Kidney and/or liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease
    • QT prolongation (may worsen secondary to diuretic-induced hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia)
    • Pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care and lactation Lactation The processes of milk secretion by the maternal mammary glands after parturition. The proliferation of the mammary glandular tissue, milk synthesis, and milk expulsion or let down are regulated by the interactions of several hormones including estradiol; progesterone; prolactin; and oxytocin. Breastfeeding

Comparison of Medications

Thiazide Thiazide Heterocyclic compounds with sulfur and nitrogen in the ring. This term commonly refers to the benzothiadiazines that inhibit sodium-potassium-chloride symporters and are used as diuretics. Hyponatremia diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication, potassium-sparing diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication, carbonic anhydrase Carbonic anhydrase A family of zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide. They play an important role in the transport of carbon dioxide from the tissues to the lung. Carbonic Anhydrase Inhibitors inhibitors, and osmotic diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication are also common diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication.

Table: Comparison of diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication
Medication Mechanism Physiologic effect Indication
Thiazide Thiazide Heterocyclic compounds with sulfur and nitrogen in the ring. This term commonly refers to the benzothiadiazines that inhibit sodium-potassium-chloride symporters and are used as diuretics. Hyponatremia diuretic: Hydrochlorothiazide Hydrochlorothiazide A thiazide diuretic often considered the prototypical member of this class. It reduces the reabsorption of electrolytes from the renal tubules. This results in increased excretion of water and electrolytes, including sodium, potassium, chloride, and magnesium. It is used in the treatment of several disorders including edema, hypertension, diabetes insipidus, and hypoparathyroidism. Thiazide Diuretics ↓ Reabsorption of NaCl in the DCT through the inhibition of Na+/Cl– cotransporter
  • ↓ Blood pressure
  • ↓ Edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
  • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
  • Edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
Loop diuretic: Furosemide Inhibits the luminal Na+/K+/Cl– cotransporter in the thick ascending limb Thick ascending limb Renal Sodium and Water Regulation of the loop of Henle Loop of Henle The U-shaped portion of the renal tubule in the kidney medulla, consisting of a descending limb and an ascending limb. It is situated between the proximal kidney tubule and the distal kidney tubule. Tubular System
  • ↓ Edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
  • ↓ Blood pressure
  • Edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema/ ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites
  • HF
  • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
Potassium-sparing diuretic: Spironolactone Spironolactone A potassium sparing diuretic that acts by antagonism of aldosterone in the distal renal tubules. It is used mainly in the treatment of refractory edema in patients with congestive heart failure, nephrotic syndrome, or hepatic cirrhosis. Its effects on the endocrine system are utilized in the treatments of hirsutism and acne but they can lead to adverse effects. Potassium-sparing Diuretics
  • ↓ Reabsorption of Na through the ENaC ENaC Sodium channels found on salt-reabsorbing epithelial cells that line the distal nephron; the distal colon; salivary ducts; sweat glands; and the lung. They are amiloride-sensitive and play a critical role in the control of sodium balance, blood volume, and blood pressure. Liddle Syndrome channels Channels The Cell: Cell Membrane in the CD
  • Inhibition of aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors in the CD
  • ↓ Blood pressure
  • ↓ Edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
  • Does not cause ↑ excretion of K+
  • Anti-androgenic effects
  • HF
  • Edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema/ ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites
  • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
  • Hirsutism Hirsutism A condition observed in women and children when there is excess coarse body hair of an adult male distribution pattern, such as facial and chest areas. It is the result of elevated androgens from the ovaries, the adrenal glands, or exogenous sources. The concept does not include hypertrichosis, which is an androgen-independent excessive hair growth. Polycystic Ovarian Syndrome in females
  • Primary hyperaldosteronism Primary hyperaldosteronism Autonomous (renin-independent) secretion of aldosterone. Hyperaldosteronism
Carbonic anhydrase inhibitor Carbonic Anhydrase Inhibitor Glaucoma: Acetazolamide Acetazolamide One of the carbonic anhydrase inhibitors that is sometimes effective against absence seizures. It is sometimes useful also as an adjunct in the treatment of tonic-clonic, myoclonic, and atonic seizures, particularly in women whose seizures occur or are exacerbated at specific times in the menstrual cycle. However, its usefulness is transient often because of rapid development of tolerance. Its antiepileptic effect may be due to its inhibitory effect on brain carbonic anhydrase, which leads to an increased transneuronal chloride gradient, increased chloride current, and increased inhibition. Carbonic Anhydrase Inhibitors Inhibits both the hydration of CO2 in the PCT PCT The renal tubule portion that extends from the bowman capsule in the kidney cortex into the kidney medulla. The proximal tubule consists of a convoluted proximal segment in the cortex, and a distal straight segment descending into the medulla where it forms the u-shaped loop of henle. Osmotic Diuretics epithelial cells and the dehydration Dehydration The condition that results from excessive loss of water from a living organism. Volume Depletion and Dehydration of H2CO3 in the PCT PCT The renal tubule portion that extends from the bowman capsule in the kidney cortex into the kidney medulla. The proximal tubule consists of a convoluted proximal segment in the cortex, and a distal straight segment descending into the medulla where it forms the u-shaped loop of henle. Osmotic Diuretics lumen; results in ↑ HCO3– and Na+ excretion
  • ↑ Urinary excretion of HCO3– → metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis
  • ↓ Intraocular pressure Intraocular Pressure The pressure of the fluids in the eye. Ophthalmic Exam
  • Edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with metabolic alkalosis Alkalosis A pathological condition that removes acid or adds base to the body fluids. Respiratory Alkalosis
  • Altitude sickness Altitude Sickness Altitude sickness refers to a spectrum of symptoms caused by physiological changes in the human body at altitudes above 2,500 m. Altitude sickness includes acute mountain sickness (AMS), high-altitude cerebral edema (HACE), and high-altitude pulmonary edema (HAPE). Altitude Sickness
  • ↑ Intraocular pressure Intraocular Pressure The pressure of the fluids in the eye. Ophthalmic Exam
  • Off label: normal pressure hydrocephalus Hydrocephalus Excessive accumulation of cerebrospinal fluid within the cranium which may be associated with dilation of cerebral ventricles, intracranial. Subarachnoid Hemorrhage
Osmotic diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication: Mannitol Mannitol A diuretic and renal diagnostic aid related to sorbitol. It has little significant energy value as it is largely eliminated from the body before any metabolism can take place. It can be used to treat oliguria associated with kidney failure or other manifestations of inadequate renal function and has been used for determination of glomerular filtration rate. Mannitol is also commonly used as a research tool in cell biological studies, usually to control osmolarity. Osmotic Diuretics ↑ Osmotic pressure Osmotic pressure The pressure required to prevent the passage of solvent through a semipermeable membrane that separates a pure solvent from a solution of the solvent and solute or that separates different concentrations of a solution. It is proportional to the osmolality of the solution. Intravenous Fluids in the glomerular filtrate → ↑ tubular fluid and prevents water reabsorption
  • ↓ Free water
  • ↓ Cerebral blood volume
PCT: proximal convoluted tubule
DCT: distal convoluted tubule
HF: heart failure
Diuretics

The sites of action within the nephron for the diuretic drug classes

Image by Lecturio. License: CC BY-NC-SA 4.0

References

  1. The American Society of Health-System Pharmacists. (2021). Furosemide. Retrieved February 18, 2021, from https://www.drugs.com/monograph/furosemide.html#
  2.  Fischer, J., Ganellin, C.R. (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 458.
  3. World Health Organization. (2019). World Health Organization model list of essential medicines: 21st list 2019. http://apps.who.int/iris/handle/10665/325771
  4. Kane, S.P. (2020). Furosemide. Retrieved February 18, 2021, from https://clincalc.com/DrugStats/Drugs/Furosemide
  5. King, K.C. Goldstein, S. (2021). Congestive Heart Failure And Pulmonary Edema. StatPearls, Treasure Island (FL): StatPearls Publishing. Retrieved May 8, 2021, from https://pubmed.ncbi.nlm.nih.gov/32119444/
  6. Felker, G.M., et al. (2011). Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 364(9), 797–805. https://pubmed.ncbi.nlm.nih.gov/21366472/
  7. James, P.A., et al. (2014). 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 311(5), 507–520. https://pubmed.ncbi.nlm.nih.gov/24352797/
  8. Whelton, P.K., et al. (2018). 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 71(6), e13–e115. https://pubmed.ncbi.nlm.nih.gov/29133356/
  9. Kidney Disease Outcomes Quality Initiative (K/DOQI). (2004). K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 43(5 Suppl 1), S1–290. https://pubmed.ncbi.nlm.nih.gov/15114537/
  10. Runyon, B.A. (2013). Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline management of adult patients with ascites due to cirrhosis 2012. Hepatology. 57(4), 1651–1653. https://pubmed.ncbi.nlm.nih.gov/23463403/
  11. Shankar, S.S., Brater, D.C. (2003). Loop diuretics: from the Na-K-2Cl transporter to clinical use. Am J Physiol Renal Physiol. 284(1), F11–21. https://pubmed.ncbi.nlm.nih.gov/12473535/
  12. Brater, D.C., et al. (1983). Bumetanide and furosemide. Clin Pharmacol Ther. 34(2), 207–213. https://pubmed.ncbi.nlm.nih.gov/6872415/
  13. Ponto, L.L., Schoenwald, R.D. (1990). Furosemide (frusemide). A pharmacokinetic/pharmacodynamic review (Part I). Clin Pharmacokinet. 18(5), 381–408. https://pubmed.ncbi.nlm.nih.gov/2185908/
  14. Hammarlund, M.M., et al. (1984). Pharmacokinetics of furosemide in man after intravenous and oral administration. Application of moment analysis. Eur J Clin Pharmacol. 26(2), 197–207. https://pubmed.ncbi.nlm.nih.gov/6723758/
  15. Mann, J.F. (2020). Choice of drug therapy in primary (essential) hypertension. In Forman, J.P. (Ed.), UpToDate. Retrieved June 14, 2021, from https://www.uptodate.com/contents/choice-of-drug-therapy-in-primary-essential-hypertension 
  16. Brater, D.C., Ellison, D.H. (2019). Loop diuretics: Dosing and major side effects. In Forman, J.P. (Ed.), UpToDate. Retrieved June 15, 2021, from https://www.uptodate.com/contents/loop-diuretics-dosing-and-major-side-effects 
  17. UpToDate Lexicomp Drug Topic Pages. Furosemide; Bumetanide; Torsemide; Ethacrynic acid. Retrieved June 15, 2021, from
    1. https://www.uptodate.com/contents/furosemide-drug-information
    2. https://www.uptodate.com/contents/bumetanide-drug-information
    3. https://www.uptodate.com/contents/torsemide-torasemide-drug-information 
    4. https://www.uptodate.com/contents/ethacrynic-acid-drug-information 
  18. Huxel, C. (2021). Loop Diuretics. StatPearls. Retrieved June 15, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/24416/ 
© 2024 Lecturio GmbH. All rights reserved.

USMLE™ is a joint program of the Federation of State Medical Boards (FSMB®) and National Board of Medical Examiners (NBME®). MCAT is a registered trademark of the Association of American Medical Colleges (AAMC). NCLEX®, NCLEX-RN®, and NCLEX-PN® are registered trademarks of the National Council of State Boards of Nursing, Inc (NCSBN®). None of the trademark holders are endorsed by nor affiliated with Lecturio.

Create your free account or log in to continue reading!

Sign up now and get free access to Lecturio with concept pages, medical videos, and questions for your medical education.

Log in to your account​

User Reviews

Details