Diuretics Lecture PDF - Dr. Ahmed Hassan, FU Berlin

Diuretics Dr. Ahmed A. Hasan Outline 1. Introduction of the speaker 2. A few hints and introduction on blood pressure 3. The functional zones along the nephron and the regulation of fluids and electrolytes 4. Diuretics and their general uses 5. Different types of diuretics  Introduction of...

Diuretics Dr. Ahmed A. Hasan Outline 1. Introduction of the speaker 2. A few hints and introduction on blood pressure 3. The functional zones along the nephron and the regulation of fluids and electrolytes 4. Diuretics and their general uses 5. Different types of diuretics  Introduction of the speaker PhD (Scholarship) of Bachelor of medicinal nutritional Pharmaceutical Science science PostDoc at the Institute of Pharmacy 2008 - 2012 2019 - 2020 Since 2022 2002 - 2007 2013 - 2018 2020 - current Master of Biochemistry, PostDoc at the Institute of Licensed pharmacist Zagazig Uni, Egypt Nutritional Science in Germany Strategy - Scientific terms and key words - Story telling - Priorities and fine details - Risk benefit ratio (absolute or relative contraindication) - Compensatory mechanisms - Lippincott's Illustrated Reviews: Pharmacology 6th Edition 2015  Risk benefit ratio Compensatory Treatment Diseases mechanisms Lifestyle changes Injuries Medication acute Short term Long term Chronic life-threatening Health status The circulation Cardiac output (CO) Heart frequency (HF) Stroke volume (SV) Total peripheral resistance (TPR) HF x SV = CO Blood pressure = CO x TPR Compensatory mechanisms for the regulation of blood pressure First line treatment A A B C D  Diuretics: the kidney and the nephron Vas efferens Bowman capsule Distal tubule Juxtaglomerular Vas afferens cells Extraglomerular mesangial cells Glomerulus Collecting duct Proximal tubule Loop of Henle Outline - Filtration, secretion, reabsorption - Five functional zones: A) Proximal convoluted tubule (carbonic anhydrase, bicarbonate, the organic acid and base secretory system and interactions) B) Descending loop of Henle C) Ascending loop of Henle (impermeable to water, major site for salt reabsorption, potent loop diuretics) D) Distal convoluted tubule (Calcium excretion regulated by parathormone E) Collecting tubule and duct Diuretics - Diuretics increase urine excretion - The most are inhibitors of ion transporters → ↓ reabsorption of sodium ions → water follows sodium ions - The diuretic effect varies considerably: 2% for the weak potassium-sparing diuretics and 20% for the potent loop diuretics - Other types of diuretics: osmotic diuretics, aldosterone antagonists, and carbonic anhydrase inhibitors - Indications: edema, hypertension and heart failure Diuretics Thiazide and thiazide-like diuretics - The most widely used - Site of action: Distal convoluted tubule - Low ceiling diuretics: increasing the dose above normal therapeutic doses does not promote further diuretic response - Thiazides: chlorothiazide and hydrochlorothiazide - Thiazide-like (sulfonamide derivatives, same mode of action): chlorthalidone, Indapamide und Metolazone - Site of action: on the luminal membrane, must be excreted into the tubular lumen to be effective, ↓ renal function → ↓ thiazide efficacy Thiazide and thiazide-like diuretics - Interaction: NSAIDs e.g. Indomethacin → ↓ renal prostaglandins → ↓ renal blood flow - Actions: ↑ excretion of Na+, Cl-, K+ und Mg2+ but ↓ Calcium excretion (in contrast to loop diuretics) - Therapeutic applications: A) Hypertension B) Heart failure: Loop diuretics are the diuretics of choice C) Hypercalciuria D) Diabetes insipidus (paradox) Thiazide and thiazide-like diuretics - Adverse effects: A) Potassium depletion: Hypokalemia, with digoxin → ventricular arrhythmias, K+ supplementation and/or dietary supplementation e.g. citrus fruits and bananas, combination with potassium sparing diuretics B) Hyponatremia C) Hyperuricemia: ↑ serum uric acid (the organic acid secretory system), gout D) Volume depletion: orthostatic hypotension E) Hypercalcemia - Hydrochlorothiazide was associated with risk of non-melanocytic skin cancer Loop or high ceiling diuretics - Furosemide is the most commonly used - Bumetanide and torsemide are more potent - Ethacrynic acid is used infrequently due to its adverse effect profile - ↑ Ca2+ excretion - Interaction: NSAIDs e.g. Indomethacin → ↓ renal prostaglandins → ↓ renal blood flow - Class of choice for lung edema and heart failure - Oral or parenteral, the effect within 2-4 hours Loop or high ceiling diuretics - Adverse effects: A) Ototoxicity: contraindicated with aminoglycoside antibiotics B) Hyperuricemia: compete with uric acid for the renal secretory systems → blocking its secretion → causing or exacerbating gouty attacks C) Acute hypovolemia D) Potassium depletion E) Hypomagnesemia Potassium-sparing diuretics - act in the collecting tubule to inhibit Na+ reabsorption and K+ excretion - 2 classes with 2 different mode of action A) Aldosterone antagonists: spironolactone, eplerenone and finerenone - synthetic steroid, endocrine related side effects (gynecomastia and menstrual irregularities) - Polycystic ovary syndrome (off-label use, blocks androgen receptors at high doses) - Eplerenone is more specific to mineralocorticoid receptors, thus lower side effects Potassium-sparing diuretics A) Aldosterone antagonists: spironolactone and eplerenone - Finerenone: mineralocorticoid receptor antagonist, non-steroidal structure, in heart failure associated with kidney disease - 1st choice in secondary hyperaldosteronism but not effective in Addison disease (primary adrenal insufficiency) B) Triamterene and amiloride - Sodium channel blockers - Side effects: increased uric acid, renal stones, and K+ retention Carbonic anhydrase inhibitors - ↓ diuretic effect - ↑ HCO3- in the lumen → ↑ pH of the urine - Hyperchloremic metabolic acidosis - Therapeutic uses: A) Glaucoma: - decreases the production of aqueous humor and reduces intraocular pressure Carbonic anhydrase inhibitors - Therapeutic uses: A) Glaucoma: - Topical carbonic anhydrase inhibitors e.g. dorzolamide and brinzolamide → no systemic effects B) Mountain sickness - Adverse effects A) Metabolic acidosis (mild) B) potassium depletion Osmotic diuretics - hydrophilic chemical substances, filtered through the glomerulus, such as mannitol and urea (no reabsorption) - used to maintain urine flow following acute toxic ingestion of substances capable of producing acute renal failure - Mannitol is not absorbed when given orally and should be given intravenously - Adverse effects: extracellular water expansion and dehydration, as well as hypo- or hypernatremia Match A) Light yellow B) Dark yellow C) Orange D) Brown ? 1) Potassium sparing diuretics 2) Acetazolamide 3) Thiazide diuretics 4) Loop diuretics Case study - Mr. Müller comes to your pharmacy with a prescription for Amiloride/HCT AL N1 30 tablets. - After you have explained the medication to Mr. Müller, he tells you that he now wants to do more sport and has heard that there is something new from Magnesium Verla. - You remember the representative who was there last week and presented the new Magnesium Verla Plus with potassium. - What advice would you give Mr. Müller? Case study - Mrs. Schneider comes with a prescription for Alendronic Acid Basics 70mg tablets once a week. - When asked if she is taking any other medication, she replies that she is only taking these diuretic tablets, Torasemide. - You decide to call the doctor. - What is the problem in this case?