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Diuretics

Definition Transports
Diuresis
Drug that ↑ Rate of Bodily Urine Excretion
Diuretics
↑ H2O Excretion from Body
Affect [Electrolytes], [Substances] in Body

Anatomy
Nephron

Glomerulus
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Renal Physiology, Diuretics

Renin-Angiotensin-Aldosterone System (RAAS)

Functions
Segment Function H2O Permeability 1° Transporter Diuretic with Major Action
Glomerulus Glomerular Filtrate Extremely ↑ None None
Proximal Convulated Tubule Reabsorb 65% (Na, K, Ca, Mg) Very ↑ Na/H Carbonic Anhydrase Inhibitors
Reabsorb 85% (NaHCO) (NHE3)
Reabsorb 100% (Glucose, a.a.) Carbonic Anhydrase
Isoosmotic – Reabs orb H2O
Proximal Tubule Secretion/ Reabsorption of Very ↑ Acid, Base Transporters None
(Straight Segment) Organic Acids/ Bases
Thin Descending Loop Henle Passive Reabsorption of H2O ↑ Aquaporins None
Thick Ascending Loop He nle Active Reabsorption 15-25% Very ↓ Na/K/2Cl Loop Diuretics
(Na,K,Cl) (NKCC2 )
Secondary Reabsorption
Distal Convulated Tubule Active Reabsorption of 4-8% Very ↓ Na/Cl Thiazides
(of Filtered Na, Cl) (NCC)
Ca Absorbed - PTH control
Cortical Collecting Tubule Na Reabsorption (2-5%) ADH Controlled Na Channels (ENaC) K Sparing Diuretics
coupled to K, H Secretion K Channel
H Transporter
Medullary Collecting Duct H2O Reabsorption ↑ Aquaporins Vasopressin Antagonist
(ADH Controlled)
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Diuretics
Mineralocorticoid
Na-K-2Cl Symport Inhibitors Na-Cl Symport Inhibitors Na Channel Inhibitors Carbonic Anhydrase Inhibitors Osmotic Diuretics ADH Antagonists
Receptor Antagonists
Loop Diuretics Thiazide Diuretics K-Sparing Diuretics K-Sparing Diuretics
High Ceiling Diuretics Thiazide-Like Diuretics Aldosterone Antagonists
Furosemide (Lasix) Hydrochlorothiazide (Hydrodiuril) Triamterene (Dy renium) Spironolactone (Aldactone) Acetazolamide Mannitol Conivaptan (V1a, V2 Antagonist)
Bumetanide (Bumex) Chlorothiazide (Diuril) Amiloride (Midamor) Eplerenone (Inspra) Dichlorphenamide Lithium
Torsemide (Demadex) Metolazone (Zaroxolyn) Dorzolamide Demeclocycline (↓ cAMP)
Ethacrynic Acid (Edecrin) Chlorthalidone (Hygroton)
MOA MOA MOA MOA

Act on Na-K-2Cl Symporter Block Na-Cl Symporter

(Thick Ascending Limb LOH) Inhibit Na, Cl Reabsorption
Inhibit Na, Cl Reabsorption (Distal Convulated Tubule) Directly blocking Na Channels (ENaC) Competitive Antagonists compete
Inhibit Mg, Ca Reabsorption
with Aldosterone for receptor sites
(dependent on Na, Cl conc.)
Rapidly Absorbed Oral Preparation Amiloride Triamterene Spironolactone Main Site of Enzyme Poorly absorbed Oral
Excreted by Kidney Chlorthalidone – Slow Absorption, Excreted Extensively Competitive Antagonist, Slow Onset Luminal Membrane IV Half-Life (Conivaptan) - 5-10h
Duration of Effect – 2-3h (Frusemide) Longer Duration of Action unchanged in Metabolised in (may take few days for full effect) Ciliary Body of Eye Not Metabolized
Effect blunted by weak acids Indapamide – Excreted 1° in Bile Urine Liver Choroid Plexus Excreted by Filtration
competing for secretion Secreted by organic acid secretory Active Metabolite
(NSAID/ Probenecid) system excreted in Urine
Competes with Uric Acid
Therapeutic Effects Therapeutic Effects Therapeutic Effects Therapeutic Effects Therapeutic Effects Therapeutic Effects
↑ Na Excretion (25% of Filtered load) ↑ Na Excretion (5% of Filtered load) Used in Combination with Used in Combination with Loop, Block NaHCO3 Reabsorption H2O Diuresis
(Treat - Sev ere Edema) (Treat – Mild Edema, Hypertension, Loop, Thiazide Diuretics Thiazide Diuretics HCO3 Diuresis (↑ Compared to Natriuresis)
↑ Urine Volume Nephrogenic Diabetes Insipidus) • Enhance Natriuresis caused by • Enhances Natriuresis caused by (Alkaline urine within ½h for 12h) (Lead to Hypernatremia)
(Treat - Oliguric ARF) ↓ Ca Excretion other diuretics other diuretics ↑ NaCl Absorption
↑ Ca Excretion (Treat – Calcium Nephrolithiasis) • Prevent Hypokalemia • Prevent Hypokalemia (due to HCO3 depletion)
(Treat - Hypercalcaemia) Block Na Channels Blocks Aldosterone (efficacy limited by ↓HCO3, Acidosis)
↑ Free H2O Reabsorption • Treat – Liddle’s Syndrome • Treat – 1° Hyperaldosteronism Indications Indications Indications
(Treat – Hyponatremia) • Treat – Lithium-induced Diabetes • Treat – Edema of Liver Cirrhosis Glaucoma (↓ Intraocular Pressure) ↑ Urine Volume Syndrome of Inappropriate ADH
↑ Venous Capacitance Insipidus • Treat – Hypertension Urinary Alkalinization ↓ Intracranial/ Intraocular Pressure secretion (SIADH)
(Treat – Pulmonary Edema) • Treat – Heart Failure Metabolic Alkalosis
Other Effects
Release PGs
↑ Renin Release
↑ & Redistribute RBF
Adverse Effects Adverse Effects Adverse Effects Adverse Effects Adverse Effects Adverse Effects Adverse Effects
Profound ECF Volume Depletion ECF Volume Depletion Amiloride Triamterene Hyperk alemia Hyperchloremic Metabolic Acidosis ECF Volume Expansion Severe Hyp ernatremia
Hypokalaemia Hypokalaemia Hyperk alaemia Hyperk alaemia Metabolic Acidosis Renal Stones (Phosphaturia, • Headache Nephrogenic Diabetes Insipidus
Metabolic Acidosis Metabolic Alkalosis Renal Stones Impotence Hypercalciuria, ↓ Citrate) • Nausea Interstitial Nephritis (Li)
Hypomagnesemia Hypomagnesemia Interstitial Nephritis CNS Side Effects Potassium Wasting • Vomiting
Hypocalcaemia Hypercalcemia Megaloblastosis Gynecomastia Drowsiness Dehydration
Ototoxicity Hyponatremia Gastritis Paraesthesia Hyperk alemia
Hyperuricemia Hyperuricemia Peptic Ulcers Hypernatremia
Hyperglyc aemia Hyperglyc aemia Deepening of Voice
↑ LDL Hirsutism
Impotence Menstrual Irregularities
Contraindications
Cirrhosis
(cause Hepatic Encephalopathy -
↓ NH4+ Excretion)
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Edema Diuretics

Definition Drug Interactions

Accumulation of Abnor mal amounts of Extravascular, Extracellular Fluid Diminished Diuretic Response
ANASARCA NSAIDs
Severe, Widely Distributed Pitting Edema Salt
Decongestants
Types Probenecid
Localized Generalized Hyperkalemia-Induced by K-Sparing Diuretics
Inflammation Cardiac ACE Inhibitors
Lymphatic Obstruction Hepatic β-Blockers
Venous Obstruction Renal K Supplements
Thrombophlebitis K-Sparing Diuretics
• Nephrotic Syndrome
Heparin
• Acute GN
Enhanced Ototoxicity of Loop Diuretics
• CRF
Ototoxic Drugs
Idiopathic
Other
Management
• Cyclic
• Myxedema
• Vasodilator-Induced
• Pregnancy-Induce d
• Capillary Leak Syndrome

Mechanism of Edema Formation

Balance of Starling Forces
No Edema Edema
Filtration ≤ Lymphatic Drainage Filtration > Lymphatic Drainage

Cardiac Edema (Pathophysiology)

Heart Disease
↙ ↘
Left Ventricular Dysfunction Right Ventricular Dysfunction
↓ ↓
↑ Pulmonary Venous Pressure Hypotension
↓ ↓
Pulmonary Edema Renal Na Retention
↓
Systemic Edema