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Carbonic Anhydrase Inhibitors

Carbonic anhydrase inhibitors (CAIs) block the carbonic anhydrase enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes in the proximal convoluted tubule Proximal convoluted 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. Osmotic Diuretics, inhibiting the reabsorption 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 bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes (NaHCO3), which results in diuresis and metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis. Carbonic anhydrase inhibitors also block the carbonic anhydrase present in the eyes and glial cells Glial Cells The non-neuronal cells of the nervous system. They not only provide physical support, but also respond to injury, regulate the ionic and chemical composition of the extracellular milieu, participate in the blood-brain barrier and blood-retinal barrier, form the myelin insulation of nervous pathways, guide neuronal migration during development, and exchange metabolites with neurons. Neuroglia have high-affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitters, but their role in signaling (as in many other functions) is unclear. Nervous System: Histology, resulting in decreased aqueous humor Humor Defense Mechanisms and CSF production, respectively. Acetazolamide is the prototypical CAI. Carbonic anhydrase inhibitors are mainly used for the treatment of 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, 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 Metabolic alkalosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic alkalosis also occurs when there is an increased loss of acid, either renally or through the upper GI tract (e.g., vomiting), increased intake of HCO3-, or a reduced ability to secrete HCO3- when needed. Metabolic Alkalosis, glaucoma Glaucoma Glaucoma is an optic neuropathy characterized by typical visual field defects and optic nerve atrophy seen as optic disc cupping on examination. The acute form of glaucoma is a medical emergency. Glaucoma is often, but not always, caused by increased intraocular pressure (IOP). Glaucoma, and, sometimes, as an adjuvant Adjuvant Substances that augment, stimulate, activate, potentiate, or modulate the immune response at either the cellular or humoral level. The classical agents (freund's adjuvant, bcg, corynebacterium parvum, et al.) contain bacterial antigens. Some are endogenous (e.g., histamine, interferon, transfer factor, tuftsin, interleukin-1). Their mode of action is either non-specific, resulting in increased immune responsiveness to a wide variety of antigens, or antigen-specific, i.e., affecting a restricted type of immune response to a narrow group of antigens. The therapeutic efficacy of many biological response modifiers is related to their antigen-specific immunoadjuvanticity. Vaccination treatment for certain types of epilepsies and increased intracranial pressure Intracranial Pressure Idiopathic Intracranial Hypertension. Carbonic anhydrase inhibitors are not used for the treatment of 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.

Last updated: 20 Jul, 2021

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Chemistry and Pharmacodynamics

Definition

Carbonic anhydrase inhibitors (CAIs) are diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication that block the carbonic anhydrase enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes.

  • Drugs in this class include:
    • Acetazolamide (the prototypical CAI)
    • Methazolamide
  • Carbonic anhydrase enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes are found in the:
    • Proximal convoluted tubules (PCTs) of the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys: Anatomy: involved in HCO3 reabsorption
    • Eyes: involved in aqueous humor Humor Defense Mechanisms production
    • Glial cells Glial Cells The non-neuronal cells of the nervous system. They not only provide physical support, but also respond to injury, regulate the ionic and chemical composition of the extracellular milieu, participate in the blood-brain barrier and blood-retinal barrier, form the myelin insulation of nervous pathways, guide neuronal migration during development, and exchange metabolites with neurons. Neuroglia have high-affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitters, but their role in signaling (as in many other functions) is unclear. Nervous System: Histology in the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification: involved in CSF production

Chemical structure

Acetazolamide is a sulfonamide Sulfonamide The sulfonamides are a class of antimicrobial drugs inhibiting folic acid synthesize in pathogens. The prototypical drug in the class is sulfamethoxazole. Although not technically sulfonamides, trimethoprim, dapsone, and pyrimethamine are also important antimicrobial agents inhibiting folic acid synthesis. The agents are often combined with sulfonamides, resulting in a synergistic effect. Sulfonamides and Trimethoprim.

Chemical structure of acetazolamide

Chemical structure of acetazolamide

Image: “Acetazolamide” by Ayacop. License: Public Domain

Background: HCO3 reabsorption 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

Bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes cannot be directly reabsorbed by the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys: Anatomy; it must be converted into CO2 in the lumen and then reconverted to HCO3 once inside the cell. This reaction occurs via the following processes:

  • Na+-H+ ion exchanger 3 (NHE3) reabsorbs Na+ and secretes H+.
  • The secreted H+ combines with the filtered HCO3 to form H2CO3 in the tubular lumen.
  • H2CO3 is converted into H2O and CO2 by apical carbonic anhydrase-IV.
  • CO2 diffuses freely across the apical membrane back into the cell.
  • Intracellular carbonic anhydrase-II converts CO2 and H2O back into H2CO3.
  • H2CO3 then dissociates into H+ and HCO3:
    • H+ is recycled through the process via secretion Secretion Coagulation Studies through NHE3.
    • HCO3 is absorbed through the basolateral membrane via:
      • Na+-HCO3 cotransporter 
      • HCO3 chloride Chloride Inorganic compounds derived from hydrochloric acid that contain the Cl- ion. Electrolytes exchanger
  • Net effects of the entire process:
    • Excretion of H+
    • 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 of HCO3– 
  • Efficiency: 80% of the filtered HCO3 is reabsorbed 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 under normal circumstances.
Bicarbonate reabsorption in the proximal tubule

Bicarbonate reabsorption Bicarbonate reabsorption Acid-Base Balance 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
NHE3: Na+-H+ ion exchanger 3
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)-IV: carbonic anhydrase IV
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)-II: carbonic anhydrase II


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

Mechanism of action of CAIs

  • Non-competitively inhibit the carbonic anhydrases ( 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)-IV and 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)-II) that catalyze the carbonic reaction: H2CO3 ⇄ HCO3 + H+ ⇄ CO2 + H2O
  • Carbonic anhydrase catalyzes both:
    • 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 apical lumen
    • 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
  • Inhibition of carbonic anhydrase:
    • Keeps HCO3 in the renal tubules (at maximal safe doses, CAIs inhibit about 45% of total HCO3 reabsorption)
    • Prevents secretion Secretion Coagulation Studies of HCO3 into the aqueous humor Humor Defense Mechanisms in the eyes
    • Prevents secretion Secretion Coagulation Studies of HCO3 into the CSF in the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification

Physiologic effects

Use of CAI’s results in:

Pharmacokinetics

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 carbonic anhydrase inhibitors
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
Acetazolamide
  • Protein binding: 95%
  • Vd: 0.3 L/kg
Not metabolized
Methazolamide
  • Slower 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 compared to acetazolamide
  • Peak activity: 6‒8 hours
  • Protein binding: 55%
  • Vd: 17‒23 L
Slowly within the GI tract
Vd: volume of distribution

Indications

  • Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with 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 who have metabolic alkalosis Metabolic alkalosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic alkalosis also occurs when there is an increased loss of acid, either renally or through the upper GI tract (e.g., vomiting), increased intake of HCO3-, or a reduced ability to secrete HCO3- when needed. Metabolic 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:
    • Hypobaric hypoxia Hypobaric Hypoxia Altitude Sickness leads to respiratory alkalosis Respiratory alkalosis The respiratory system is responsible for eliminating the volatile acid carbon dioxide (CO2), which is produced via aerobic metabolism. When hypoventilation occurs, excess carbon dioxide is blown off and respiratory alkalosis develops. The kidneys respond by decreasing serum bicarbonate (HCO3-) through increased HCO3- excretion or decreased excretion of H+. Respiratory Alkalosis, which requires kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys: Anatomy to compensate with ↑ HCO3 excretion and/or ↓ H+ excretion
    • Acetazolamide leads to ↑ HCO3 excretion, improving acid-base status
    • The increased acid load allows the body to take faster, deeper breaths to bring in enough O2 without elevating serum pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance.
  • Glaucoma Glaucoma Glaucoma is an optic neuropathy characterized by typical visual field defects and optic nerve atrophy seen as optic disc cupping on examination. The acute form of glaucoma is a medical emergency. Glaucoma is often, but not always, caused by increased intraocular pressure (IOP). Glaucoma
  • Centrencephalic epilepsy Epilepsy Epilepsy is a chronic brain disorder marked by recurrent and unprovoked seizures. These seizures can be classified as focal or generalized and idiopathic or secondary to another condition. Clinical presentation correlates to the classification of the epileptic disorder. Epilepsy ( adjuvant Adjuvant Substances that augment, stimulate, activate, potentiate, or modulate the immune response at either the cellular or humoral level. The classical agents (freund’s adjuvant, bcg, corynebacterium parvum, et al.) contain bacterial antigens. Some are endogenous (e.g., histamine, interferon, transfer factor, tuftsin, interleukin-1). Their mode of action is either non-specific, resulting in increased immune responsiveness to a wide variety of antigens, or antigen-specific, i.e., affecting a restricted type of immune response to a narrow group of antigens. The therapeutic efficacy of many biological response modifiers is related to their antigen-specific immunoadjuvanticity. Vaccination therapy, works via an unknown mechanism)
  • Additional off-label uses:
    • Idiopathic intracranial hypertension Idiopathic Intracranial Hypertension Idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri, is a clinical disorder that presents with symptoms due to increased intracranial pressure (ICP; ≥ 20 mm Hg) or CSF pressure (> 250 mm H2O), with no structural changes or other attributable causes. Idiopathic Intracranial Hypertension and normal pressure hydrocephalus Hydrocephalus Excessive accumulation of cerebrospinal fluid within the cranium which may be associated with dilation of cerebral ventricles, intracranial. Subarachnoid Hemorrhage
    • Stable, hypercapnic chronic obstructive pulmonary disease Pulmonary disease Diseases involving the respiratory system. Blastomyces/Blastomycosis (used as a respiratory stimulant)
    • Metabolic alkalosis Metabolic alkalosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic alkalosis also occurs when there is an increased loss of acid, either renally or through the upper GI tract (e.g., vomiting), increased intake of HCO3-, or a reduced ability to secrete HCO3- when needed. Metabolic Alkalosis
    • Prevention of cystine Cystine A covalently linked dimeric nonessential amino acid formed by the oxidation of cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. Nephrolithiasis renal calculi Renal calculi Stones in the kidney, usually formed in the urine-collecting area of the kidney (kidney pelvis). Their sizes vary and most contains calcium oxalate. Imaging of the Urinary System

Adverse Effects and Contraindications

Adverse effects

  • Electrolyte and glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance disturbances:
    • Metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis
    • 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
    • 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
    • Hyperglycemia Hyperglycemia Abnormally high blood glucose level. Diabetes Mellitus or hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
  • Myopia Myopia Refractive Errors/blurry vision Vision Ophthalmic Exam
  • CNS symptoms:
    • 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)
    • Headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess
    • Drowsiness/ fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia
    • Paresthesias Paresthesias Subjective cutaneous sensations (e.g., cold, warmth, tingling, pressure, etc.) that are experienced spontaneously in the absence of stimulation. Posterior Cord Syndrome

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

  • Sulfa allergies Allergies A medical specialty concerned with the hypersensitivity of the individual to foreign substances and protection from the resultant infection or disorder. Selective IgA Deficiency
  • Severe 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 and/or kidney disease 
  • Adrenocortical insufficiency
  • 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
  • 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

Precautions

Carbonic anhydrase inhibitors should be used with caution in the following populations:

  • Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with respiratory acidosis Respiratory acidosis The respiratory system is responsible for eliminating the volatile acid carbon dioxide (CO2), which is produced via aerobic metabolism. In the setting of hypoventilation, this acid load is not adequately blown off, and respiratory acidosis occurs. Renal compensation occurs after 3-5 days, as the kidneys attempt to increase the serum bicarbonate levels. Respiratory Acidosis
  • Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship in whom an impairment in mental alertness is not acceptable (e.g., machine operators)
  • Diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus (may alter glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance control)
  • Mild-to-moderate 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 or kidney disease
  • Elderly patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship (may be more sensitive to side effects)
  • 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 (data is limited)

Comparison of Medications

Some of the other most common diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication include 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 (e.g., 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), loop diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication (e.g., furosemide Furosemide A benzoic-sulfonamide-furan. It is a diuretic with fast onset and short duration that is used for edema and chronic renal insufficiency. Loop Diuretics), K+-sparing diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication (e.g., 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), and osmotic diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication (e.g., 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).

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 Furosemide A benzoic-sulfonamide-furan. It is a diuretic with fast onset and short duration that is used for edema and chronic renal insufficiency. Loop Diuretics 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
  • CHF CHF Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure
  • 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 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-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 CD Cesarean delivery (CD) is the operative delivery of ≥ 1 infants through a surgical incision in the maternal abdomen and uterus. Cesarean deliveries may be indicated for a number of either maternal or fetal reasons, most commonly including fetal intolerance to labor, arrest of labor, a history of prior uterine surgery, fetal malpresentation, and placental abnormalities. Cesarean Delivery
  • 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 CD Cesarean delivery (CD) is the operative delivery of ≥ 1 infants through a surgical incision in the maternal abdomen and uterus. Cesarean deliveries may be indicated for a number of either maternal or fetal reasons, most commonly including fetal intolerance to labor, arrest of labor, a history of prior uterine surgery, fetal malpresentation, and placental abnormalities. Cesarean Delivery
  • ↓ 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
  • CHF CHF Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure
  • 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 Hyperaldosteronism Hyperaldosteronism is defined as the increased secretion of aldosterone from the zona glomerulosa of the adrenal cortex. Hyperaldosteronism may be primary (resulting from autonomous secretion), or secondary (resulting from physiological secretion due to stimulation of the RAAS). Classically, hyperaldosteronism presents with hypertension, hypokalemia, and metabolic alkalosis. Hyperaldosteronism
Carbonic anhydrase inhibitor Carbonic Anhydrase Inhibitor Glaucoma: Acetazolamide 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 Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic 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 Metabolic alkalosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic alkalosis also occurs when there is an increased loss of acid, either renally or through the upper GI tract (e.g., vomiting), increased intake of HCO3-, or a reduced ability to secrete HCO3- when needed. Metabolic 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
  • Increased intracranial pressure Intracranial Pressure Idiopathic Intracranial Hypertension
  • Increased intraocular pressure Increased intraocular pressure An ocular disease, occurring in many forms, having as its primary characteristics an unstable or a sustained increase in the intraocular pressure which the eye cannot withstand without damage to its structure or impairment of its function. The consequences of the increased pressure may be manifested in a variety of symptoms, depending upon type and severity, such as excavation of the optic disk, hardness of the eyeball, corneal anesthesia, reduced visual acuity, seeing of colored halos around lights, disturbed dark adaptation, visual field defects, and headaches. Osmotic Diuretics
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: proximal convoluted tubule Proximal convoluted 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. Osmotic Diuretics
DCT: distal convoluted tubule Distal convoluted tubule The portion of renal tubule that begins from the enlarged segment of the ascending limb of the loop of henle. It reenters the kidney cortex and forms the convoluted segments of the distal tubule. Gitelman Syndrome
CHF CHF Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure: congestive 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)
Diuretics

The sites of action within the nephron Nephron The functional units of the kidney, consisting of the glomerulus and the attached tubule. Kidneys: Anatomy for the diuretic drug classes

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References

  1. UpToDate Lexicomp Drug Topic Pages: Acetazolamide; methazolamide. Retrieved June 17, 2021, from
    1. https://www.uptodate.com/contents/acetazolamide-drug-information 
    2. https://www.uptodate.com/contents/methazolamide-drug-information 
  2. Ives, H.E. (2012). Diuretic agents. In Katzung, B.G., Masters, S.B., Trevor, A.J. (Eds.) Basic and Clinical Pharmacology, 12th Ed. pp. 256‒258.
  3. Kassamali, R., Sica, D.A. (2011). Acetazolamide: A forgotten diuretic agent. Cardiol Rev. 19(6), 276‒278. https://pubmed.ncbi.nlm.nih.gov/21983315/
  4. Van Berkel, M.A., Elefritz, J.L. (2018). Evaluating off-label uses of acetazolamide. Am J Health Syst Pharm. 75(8), 524‒531. https://pubmed.ncbi.nlm.nih.gov/29626002/
  5. Smith, S.V., Friedman, D.I. (2017). The idiopathic intracranial hypertension treatment trial: A review of the outcomes. Headache. 57(8). 1303–1310. https://pubmed.ncbi.nlm.nih.gov/28758206/
  6. Stuart, M.C., Kouimtzi, M., Hill, S.R. (Eds.). (2009). WHO Model Formulary 2008. World Health Organization. p. 439.
  7. World Health Organization. (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization.
  8. Low, E.V., et al. (2012). Identifying the lowest effective dose of acetazolamide for the prophylaxis of acute mountain sickness: Systematic review and meta-analysis. BMJ. 345, e6779. https://pubmed.ncbi.nlm.nih.gov/23081689/
  9. Saito, H., et al. (2011). Adverse effects of intravenous acetazolamide administration for evaluation of cerebrovascular reactivity using brain perfusion single-photon emission computed tomography in patients with major cerebral artery steno-occlusive diseases. Neurol Med Chir (Tokyo). 51(7), 479‒483. https://pubmed.ncbi.nlm.nih.gov/21785240/
  10. Coote, J.H. (1991). Pharmacological control of altitude sickness. Trends Pharmacol Sci. 12(12), 450‒455. https://pubmed.ncbi.nlm.nih.gov/1792688/
  11. Katayama, F., Miura, H., Takanashi, S. (2002). Long-term effectiveness and side effects of acetazolamide as an adjunct to other anticonvulsants in the treatment of refractory epilepsies. Brain Dev. 24(3), 150‒154. https://pubmed.ncbi.nlm.nih.gov/11934510/
  12. Zaidi, F.H., Kinnear, P.E. (2004). Acetazolamide, alternate carbonic anhydrase inhibitors, and hypoglycemic agents: Comparing enzymatic with diuresis induced metabolic acidosis following intraocular surgery in diabetes. Br J Ophthalmol. 88(5), 714‒715. https://pubmed.ncbi.nlm.nih.gov/15090429/
  13. Moviat, M., et al. (2006). Acetazolamide-mediated decrease in strong ion difference accounts for the correction of metabolic alkalosis in critically ill patients. Crit Care. 10(1), R14. https://pubmed.ncbi.nlm.nih.gov/16420662/
  14. Platt, D., Griggs, R.C. (2012). Use of acetazolamide in sulfonamide-allergic patients with neurologic channelopathies. Arch Neurol. 69(4), 527‒529. https://pubmed.ncbi.nlm.nih.gov/22158718/

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