Thiazide Diuretics

Overview

Overview of antihypertensive agents

Drugs in the 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 class

Drugs in this class include: 

• Hydrochlorothiazide (HCTZ; prototypical drug in this class)
• Chlorothiazide Chlorothiazide A thiazide diuretic with actions and uses similar to those of hydrochlorothiazide. Hypertension Drugs 
• Chlorthalidone (1st-line agent in 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)
• Indapamide Indapamide A benzamide-sulfonamide-indole derived diuretic that functions by inhibiting sodium chloride symporters. Hypertension Drugs
• Metolazone Metolazone A quinazoline-sulfonamide derived diuretic that functions by inhibiting sodium chloride symporters. Hypertension Drugs

Chemistry and Pharmacodynamics

Chemical structure

The chemical structure for HCTZ:

• Molecular formula: C₇H₈ClN₃O₄S₂
• A benzothiadiazine that is 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide with substitutions of:
  • A chloro group at position 6 
  • 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 at position 7

Mechanism of action (MOA)

• Primary MOA: ↓ reabsorption of NaCl through the inhibition of the Na⁺/Cl^– cotransporter in the 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 (DCT):
  • With this channel blocked → ↓ Na⁺ reabsorption
  • Water always follows Na⁺:
    • Water stays with Na⁺ in the tubules (rather than being reabsorbed).
    • Diuresis results from the osmotic effect of Na⁺.
  • Diuresis → ↓ plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products volume → ↓ BP:
    • Initially causes a transient ↑ in 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 and sympathetic tone to compensate for ↓ BP and cardiac output Cardiac output The volume of blood passing through the heart per unit of time. It is usually expressed as liters (volume) per minute so as not to be confused with stroke volume (volume per beat). Cardiac Mechanics.
    • Transient ↑ in 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 explains why there is a synergistic effect between thiazides and ACEis ACEIs A class of drugs whose main indications are the treatment of hypertension and heart failure. They exert their hemodynamic effect mainly by inhibiting the renin-angiotensin system. They also modulate sympathetic nervous system activity and increase prostaglandin synthesis. They cause mainly vasodilation and mild natriuresis without affecting heart rate and contractility. Heart Failure and Angina Medication/ ARBs ARBs Agents that antagonize angiotensin receptors. Many drugs in this class specifically target the angiotensin type 1 receptor. Heart Failure and Angina Medication.
  • There is also a modest ↑ in vasodilation Vasodilation The physiological widening of blood vessels by relaxing the underlying vascular smooth muscle. Pulmonary Hypertension Drugs via an unclear mechanism.
• 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 use results in:
  • ↑ Excretion of Na⁺, Cl^–, K⁺, and water 
  • ↑ 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⁺:
    • ↑ Na⁺ excretion → ↓ cellular Na⁺ levels → 
    • ↑ Compensatory exchange 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⁺ for Na⁺ (via the basolateral Na⁺/ 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⁺ exchanger)
• Development of 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:
  • ↓ Na⁺ reabsorption in the DCT → 
  • ↑ Na⁺ delivered to the collecting ducts (CDs) → 
  • Stimulates ↑ 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 release
  • 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 stimulates Na⁺/K⁺ exchanger to ↑ Na⁺ reabsorption and excrete K⁺ → 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
• Development of a metabolic alkalosis Alkalosis A pathological condition that removes acid or adds base to the body fluids. Respiratory Alkalosis:
  • ↑ K⁺ excretion in the CD → 
  • Aldosterone-stimulated ↑ in K⁺/H⁺ exchanger → 
  • Reabsorbs some of the extra K⁺ in the tubule in exchange for H⁺ (which is excreted) → metabolic alkalosis Alkalosis A pathological condition that removes acid or adds base to the body fluids. Respiratory Alkalosis via H⁺ loss

Pharmacokinetics

Indications

Indications

Most 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 share similar indications, including:

• 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
• As an adjunctive therapy for 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 the following conditions:
  • 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)
  • Hepatic 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 resulting in 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
  • Mild to moderate renal dysfunction ( CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease stages 1–3):
    • Includes CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease due to 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, glomerulonephritis, chronic renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome
    • Note: Thiazides are relatively contraindicated in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with 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/severe renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome ( CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease stages 4 and 5).
  • Corticosteroid use
  • Estrogen therapy Estrogen therapy The use of hormonal agents with estrogen-like activity in postmenopausal or other estrogen-deficient women to alleviate effects of hormone deficiency, such as vasomotor symptoms, dyspareunia, and progressive development of osteoporosis. This may also include the use of progestational agents in combination therapy. Menopause
• Off-label uses:
  • Hypercalciuria Hypercalciuria Excretion of abnormally high level of calcium in the urine, greater than 4 mg/kg/day. Nephrolithiasis 
  • 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 insipidus 

Clinical pearls

• All patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship should be monitored for BP, creatinine, Na⁺, and K⁺.
• Chlorthalidone and indapamide Indapamide A benzamide-sulfonamide-indole derived diuretic that functions by inhibiting sodium chloride symporters. Hypertension Drugs:
  • 1st-line agents for monotherapy when treating 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
  • 1.5–2× as potent and longer 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 than HCTZ 
  • ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Heart attack Mi is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction Trial) showed reduction in cardiovascular events (has the most evidence of all the thiazides).
  • May have ↑ side effects and risk of 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
• HCTZ:
  • Commonly used as 1st-line agent for 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, though less effective than chlorthalidone or indapamide Indapamide A benzamide-sulfonamide-indole derived diuretic that functions by inhibiting sodium chloride symporters. Hypertension Drugs
  • Comes in combination pills with ACEis ACEIs A class of drugs whose main indications are the treatment of hypertension and heart failure. They exert their hemodynamic effect mainly by inhibiting the renin-angiotensin system. They also modulate sympathetic nervous system activity and increase prostaglandin synthesis. They cause mainly vasodilation and mild natriuresis without affecting heart rate and contractility. Heart Failure and Angina Medication, ARBs ARBs Agents that antagonize angiotensin receptors. Many drugs in this class specifically target the angiotensin type 1 receptor. Heart Failure and Angina Medication, and/or calcium-channel blockers Calcium-Channel Blockers A class of drugs that act by selective inhibition of calcium influx through cellular membranes. Heart Failure and Angina Medication
  • Not as effective with creatinine clearance Creatinine clearance Kidney Function Tests < 30 ml/min
• Metolazone Metolazone A quinazoline-sulfonamide derived diuretic that functions by inhibiting sodium chloride symporters. Hypertension Drugs:
  • May be more effective than other thiazides with CrCl < 30 ml/min
  • Often combined with other diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication

Adverse Effects and Contraindications

Adverse effects

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

• 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 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:
  • Hypersensitivity reactions
  • 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 and/or renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome
  • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
  • 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
  • Allergy Allergy An abnormal adaptive immune response that may or may not involve antigen-specific IgE Type I Hypersensitivity Reaction to sulfa drugs
  • 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
• 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 precautions:
  • 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
  • Hypercalcemia Hypercalcemia Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Symptoms vary depending on calcium levels and the onset of hypercalcemia. Hypercalcemia
  • Hepatic impairment
  • Certain medications:
    • Lithium Lithium An element in the alkali metals family. It has the atomic symbol li, atomic number 3, and atomic weight [6. 938; 6. 997]. Salts of lithium are used in treating bipolar disorder. Ebstein’s Anomaly
    • Carbamazepine Carbamazepine A dibenzazepine that acts as a sodium channel blocker. It is used as an anticonvulsant for the treatment of grand mal and psychomotor or focal seizures. It may also be used in the management of bipolar disorder, and has analgesic properties. First-Generation Anticonvulsant Drugs 
    • Corticosteroids Corticosteroids Chorioretinitis 
    • NSAIDs NSAIDS Primary vs Secondary Headaches
  • 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

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 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), potassium-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), 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 (e.g., 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), 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).