DIURETICS

Functions of the kidneys Volume Acid-base balance Osmotic pressure Electrolyte concentration Excretion of metabolites and toxic substances Maintain internal environment by regulating composition of extracellular compartment

Anatomy of the Nephron

Renal process involved in the production of urine: 1) Glomerular filtration 2) Renal tubular secretion 3) Renal tubular reabsorption

Glomerular filtration

Tubular secretion

PCT organic acid secretory transport system

PCT organic base secretory transport system

Renal tubular sodium reabsorption

Renal handling of water and substances Average Values for Several Substances Handled by Filtration and Reabsorption Amount Filtered Amount % Substanceper DayExcreted Reabsorbed Water, L Sodium, g Glucose, g Urea, g

Renal handling of water and substances Average Values for Several Substances Handled by Filtration and Reabsorption Amount Filtered Amount % Substanceper DayExcreted Reabsorbed Water, L Sodium, g Glucose, g Urea, g

Total Body Sodium Balance: Input = Output

Renal excretion of sodium

The goal of diuretic therapy is to increase the net excretion of water by the kidneys by : interfering with the renal tubular reabsorption of sodium and subsequently water antagonizing the hydroosmotic effect of vasopressin (antidiuretic hormone)

Transport pathways across tubular cells

PROXIMAL TUBULES

Proximal Tubular Diuretics Osmotic Diuretics Mannitol Urea Glycerin Isosorbide

“Mannitol”

Sodium, glucose and bicarbonate reabsorption in the proximal convoluted tubule

Therapeutic Uses: 1. Acute renal failure (i.e., maintain urine flow) 2. Reduce cerebrospinal fluid volume and pressure 3. Glaucoma 4. Facilitate urinary excretion of toxic substances Adverse Effects: 1.Extracellular expansion and subsequent adverse effects in patients with congestive heart failure and pulmonary edema Mannitol

Proximal Tubular Diuretics Carbonic Anhydrase Inhibitors Acetazolamide

K+K+ ATP Na + Basolateral Apical CA HCO 3 - CO 2 + H 2 O H+H+ Proximal Convoluted Tubule CA H+H+ HCO 3 - H 2 CO 3 CO 2 + H 2 O

K+K+ ATP Na + Basolateral Apical CA HCO 3 - CO 2 + H 2 O H+H+ Action of Acetazolamide Acetazolamide Urine [H +, NH4 +, Cl - ] Plasma [HCO 3 - ] CA H+H+ HCO 3 - H 2 CO 3 CO 2 + H 2 O Urine [ HCO 3 -] Urine [ Na+, K+], pH, H 2 O

Therapeutic Uses: 1.Open angle glaucoma (chronic simple) – decreases formation of aqueous humor 2.Create an alkaline urine to facilitate urinary excretion of acidic drugs 3. Metabolic alkalosis 4.High altitude sickness Adverse Effects: 1.Metabolic acidosis Acetazolamide

Loop of Henle

Loop Diuretics Furosemide Bumetanide Torsemide Ethacrynic acid

Electrolyte transport pathways in the TALH

[Na +, K +, Cl -, Ca +, Mg +, H +, NH4 + ], H2O pH Urine: [HCO3 - ]No Δ

Therapeutic Uses: 1.Removal of edema (e.g., pulmonary edema) and ascites 2.Hypertension 3.Symptomatic hypercalcemia 4.Dilutional hyponatremia during SIADH (i.e., state of high ADH) Adverse Effects: 1.Volume depletion and circulatory contraction 2.Diuretic-induced hyponatremia 3.Diuretic-induced metabolic alkalosis (aka, contraction alkalosis) 4.Hypokalemia 5.Ototoxicity 6.Activation of RAS 7.Drug interactions: a) Anticoagulants (Warfarin) b) Aminoglycosides c) Cardiac glycosides d) Drugs that utilize the proximal tubule organic acid secretory pathway (e.g. probenecid, penicillin, salicylates, etc.) Loop Diuretics

Early Distal Convoluted Tubule

Thiazide and Thiazide-like Diuretics Hydrochlorothiazide Chlorothiazide Chlorothalidone Metolazone

Sodium and chloride reabsorption in the early distal convoluted tubule

Urine: [Na +, K +, Cl -, ~HCO3 - ], pH, H2O pH [Ca +, H +, NH4 + ]

Therapeutic Uses: 1. Hypertension 2. Hypocalcemia 3.Removal of edema and ascites 4.Nephrogenic diabetes insipidus Adverse Effects: 1.Volume depletion and circulatory contraction 2.Hypokalemia 3.Activation of RAS 4.Aggravate hyperglycemia 5.Increase plasma cholesterol and triglycerides 6.Increase plasma uric acid 7.Drug interactions: a) Cardiac glycosides b) Drugs that utilize the organic acid secretory pathway (eg. penicillin) Thiazide and Thiazide-like Diuretics

Late Distal Convoluted Tubule and Collecting Duct

Late Distal Tubule Diuretics (aka, potassium-sparing diuretics) Amiloride Triamterene Epithelial Na Channel (ENaC) Antagonists Spironolactone Aldosterone Receptor Antagonists

Sodium - Potassium exchange in the late distal convoluted tubule

Urine: [Na +, Cl -, HCO3 - ], pH, H2O [K +, H +, NH4 + ]

Spironolactone

Therapeutic Uses: 1. Hypertension 2. Hypokalemia 3. Refractory edema and ascites 4. Primary aldosteronism Adverse Effects: 1. Hyperkalemia Potassium-Sparing Diuretics

Antidiuretic Hormone (vasopressin) and water transport in the collecting ducts

AVP-dependent water permeability in the distal nephron

Vasopressin – mediated water reabsorption

Vasopressin antagonists (Aquaretics) Conivaptan ~ Demeclocycline and Lithium Collecting Duct Diuretics Therapeutic Uses: 1. Hyponatremia (e.g., as in SIADH)

Synthetic Vasopressin agonists Desmopressin (DDAVP) Collecting Duct Antidiuretics Therapeutic Uses: 1. Central diabetes insipidus

Nephrogenic diabetes insipidus -Thiazide diuretic Therapeutic treatment: -NSAIDs

1. Methylxanthines (eg. theophylline and caffeine) 2. Dopamine, dobutamine, cardiac glycosides 3. Alcohol (ethanol) 4. Water Other Drugs with Diuretic Activity