Medicinal Chemistry II By Dr. Mehnaz Kamal Assistant Professor, Pharmaceutical Chemistry Prince Sattam Bin Abdulaziz University.

Slides:



Advertisements
Similar presentations
Chapter 51 Diuretic Agents
Advertisements

Diuretics Clinical Conditions Requiring Diuretic Therapy:
Diuretics. A. Kidney functions Kidneys have a number of essential functions:
Chapter 41 Diuretics 1.
Diuretics and Dehydrants. §1 Diuretics Abnormalities in fluid volume and electrolyte composition are common and important clinical problems. Drugs that.
DIURETICS. Functions of the kidneys Volume Acid-base balance Osmotic pressure Electrolyte concentration Excretion of metabolites and toxic substances.
Urinary System Spring 2010.
H + Homeostasis by the Kidney. H + Homeostasis Goal:  To maintain a plasma (ECF) pH of approximately 7.4 (equivalent to [H + ] = 40 nmol/L Action needed:
Diuretics. Why do we want to know about diuretics? What do kidneys do? What can go wrong? Interventions that can be used how do they work? Effects, side.
Excretion of Water and Electrolytes
BIMM118 Renal Pharmacology Diuretics: Carbonic Anhydrase Inhibitors Thiazides Loop Diuretics Potassium-sparing Diuretics.
DIURETICS Brogan Spencer and Laura Smitherman. What is a diuretic? Substance that promotes the formation (excretion) of urine.
Control of Renal Function. Learning Objectives Know the effects of aldosterone, angiotensin II and antidiuretic hormone on kidney function. Understand.
Diuretics Chris Hague, PhD
DIURETICS By: Prof. A. Alhaider.
Diuretic Agents in Hypertension and other disorders
 Paired kidneys  A ureter for each kidney  Urinary bladder  Urethra 2.
Prof. Hanan Hagar Pharmacology Department
Diuretics Remove sodium & water
DIURETIC DRUGS.
1-Overview 2-Classification 3-Indiviual drugs 1-Indications of Diuretics. 2-Adverse effects. 3-Mannitol and Carbonic Anhydrase inhibitors.
Diuretics the role of different portions of the nephron in ion exchange; the sites of action and pharmacology of diuretics; the therapeutic applications.
Diuretics Diuretics Heny Ekowati Pharmacy Departement Faculty of Medicine and Health Sciences.
CARBONIC ANHYDRASE INHIBITORS ACETAZOLAMIDE E It is a sulfonamide derivative. It is a sulfonamide derivative. noncompetitively but reversible inhibits.
DIURETICS Part 1 Prof. Hanan Hagar Pharmacology Unit.
CHAPTER © 2012 The McGraw-Hill Companies, Inc. All rights reserved. 25 Diuretics.
DIURETIC DRUGS (DR.Farooq Alam) DIURETIC DRUGS (DR.Farooq Alam)
DIURETICS Part 1 Prof. Hanan Hagar Pharmacology Department.
Prof. Hanan Hagar Pharmacology Department
Class 3:Thiazide and Thiazide-like diuretics
Tambahkanlah Ilmuku dan Berilah aku pengertian dengan baik Tiada sia-sia Meraih Ilmu dan Mengamalkannya.
DIURETICS Diuretics are drugs which increase the excretion of sodium and water from the body by an action on the kidney. Their primary effect is to decrease.
DR. MOHD NAZAM ANSARI.  Some of pathological conditions associated with retention of sodium and water in the body e.g. Congestive Heart failure, Pulmonary.
Diuretics.
Sodium Reabsorption, Diuretics, and Diet Vivek Bhalla, MD Division of Nephrology Stanford University School of Medicine September 14th, 2015.
Drugs Used for Diuresis Chapter 29 Mosby items and derived items © 2010, 2007, 2004 by Mosby, Inc., an affiliate of Elsevier Inc.
Vilasinee Hirunpanich B.Pharm(Hon), M.Sc In Pharm (Pharmacology)
Diuretic Agents.
Class 4- LOOP DIURETICS High ceiling Diuretics
DIURETICS How do they work? WHAT DO THEY DO? When do I use them? How do I use them?
Pharmacology – I [PHL 313] DiureticsDiuretics Dr. Hassan Madkhali Assistant Professor Department of Pharmacology E mail:
Mosby items and derived items © 2008, 2002 by Mosby, Inc., an affiliate of Elsevier Inc. Chapter 21 Diuretic Agents.
DIURETICS By: Prof. A. Alhaider 1433 H. Anatomy and Physiology of Renal system ► Remember the nephron is the most important part of the kidney which regulates.
Proximal Convoluted Tubule
Sodium Reabsorption, Diuretics, and Diet Vivek Bhalla, MD Division of Nephrology Stanford University School of Medicine September 14th, 2015.
DIURETICS By: Prof. A. Alhaider. Anatomy and Physiology of Renal system ► Remember the nephron is the most important part of the kidney that regulates.
DIURETICS SONG Hui OUTLINE BACKGROUND CLASSIFICATION OF DIURETICS REVIEW AND QUESTIONS.
What is high ceiling diuretic & Why?
Diuretics Clinical Conditions Requiring Diuretic Therapy: Cerebral Edema Cerebral Edema Pulmonary Edema Pulmonary Edema Hypertension Hypertension Congestive.
Pharmaceutical Chemistry II Lecture 2 & 3
Diuretic Agents. Carbonic Anhydrase Inhibitors.
Osmotic diuretics Osmotic diuretics are pharmacologically inert substances (e.g. mannitol ) that are filtered in the glomerulus but not reabsorbed by the.
POTASSIUM-SPARING DIURETICS 1.Aldosterone antagonists: Spironolactone and eplerenone: The spironolactone-receptor complex is inactive complex results in.
Tubular Reabsorption and regulation of tubular reabsorption Tortora Ebaa M Alzayadneh, PhD.
Maintaining Water-Salt/Acid-Base Balances and The Effects of Hormones
Diuretics Blake Briggs, Class of 2017.
Dr. Pran Kishore Deb & Dr. Bilal Al-jaidi
Kidney Functions and regulation
Kidney functions Kidny not only eleminate wastes …* * homeostatic organ. Water & electrolyte balance. Acid-base balance. Endocrine function(rennin for.
Sodium Channel Inhibitors
(Furosemide, Ethacrynic acid, Bumetanide and Torsemide) DIURETICS: LOOP DIURETICS (Furosemide, Ethacrynic acid, Bumetanide and Torsemide)
Carbonic anhydrase inhibitors
Potassium-sparing diuretics
Thiazides Domina Petric, MD.
Kidney Functions and regulation
Urinary System.
Diuretics By S.Bohlooli, PhD.
Kidney Functions and regulation
Diuretic Drugs.
Ass. Prof. Dr. Naza M. Ali Lec G2 19 May 2019 G1 22 May 2019
Presentation transcript:

Medicinal Chemistry II By Dr. Mehnaz Kamal Assistant Professor, Pharmaceutical Chemistry Prince Sattam Bin Abdulaziz University

Diuretics are agents that increase the rate of urine formation and salt excretion. “Diuresis” = increased water formation, but the term is also used to indicate increased salt excretion. The primary action of most diuretics is the direct inhibition of Na + at one or more of the four major anatomical sites of the nephron where Na + reabsorption takes place. A Diuretic usually possess some combination of natriuretic, chloruretic, saluretic, kaliuretic, bicarbonaturetic, or calciuretic properties depending on whether it enhances the renal excretion of Na +, Cl -, Na + /Cl -, K +, HCO3 - or Ca 2+ respectively.

Sites of Action of Diuretics in the Nephron

Indications for Diuretics uses 1. Edema a. Congestive heart failure b. Hepatic cirrhosis with ascites c. Renal disease/nephrotic syndrome 2. Maintenance of urine flow a. Circulatory shock b. Surgical procedures c. Reduce the toxic effects of poisons filtered or secreted into the renal tubules 3. Hypertension 4. Nephrolithiasis (renal stones) 5. Hypercalcemia 6. Glaucoma

CLASSIFICATION OF DIURETICS 1. OSMOTIC DIURETICS 2. CARBONIC ANHYDRASE INHBITORS 3. ION TRANSPORT INHIBITORS: a. Thiazides and thiazides like diuretics b. Loop or high-ceiling diuretics c. Potassium sparing diuretics

1. OSMOTIC DIURETICS They are low-molecular-weight compounds that are freely filtered at the glomerulus into the renal tubules and are non reabsorbable solutes. Because of their osmotic action they prevent the reabsorption of water and impair Na + reabsorption thus causing water pass from the body into the tubule and inducing the diuretic effect. They include polyols (e.g. Glycerin, Isosorbide, Mannitol) and urea.

Mannitol D-Mannitol is a hexahydroxy alcohol and the most commonly used osmotic diuretic. It does not diffuse across the GIT membrane so it is given by I.V. route. It is a suitable alternative to a loop diuretic for Acute renal failure.

Isosorbide It is a bicyclic form of sorbitol obtained by acid dehydrogenation of the later. 1,4:3,6-Dianhydrosorbitol

It is used orally to reduce the intraocular pressure in glucoma patients. In spite of the diuretic effect its opthalmological properties are its primary value Urea It is a product of proteins metabolism, and excreted in human urine in average amounts of 30g/day. It is used by I.V. route for the reduction of intraocular pressure and control of cerebral edema.

2. CARBONIC ANHYDRASE INHBITORS Carbonic anhydrase is an ubiquitous enzyme responsible for the catalytic reversible hydration of CO 2 and dehydration of H 2 CO 3, a process critical to the transport of CO 2 in the erythrocyte and its exchange in the parenchyma of the lung. The renal tubular cells also contain substantial amount of Carbonic anhydrase and the CO 2 produced metabolically in the cells of renal tubule is converted to H 2 CO 3 by the enzyme Inhibition of Carbonic anhydrase results in increase of pH due to decrease of H + available to exchange with Na + which lead to retention of NaHCO 3 in tubules thus lead to diuretic effect.

Acetazolamide N-(5-(aminosulfonyl)-1,3,4-thiadiazole-2-yl)acetamide It was the first introduced Carbonic anhydrase inhibitors. It is orally effective diuretic with a duration of action of 8-12 hrs. Its diuretic action is limited due to the systemic acidosis. It reduces the rate of aqueous humor formation and is used to reduce the intraocular pressure in glucoma.

Methazolamide N-(5-(aminosulfonyl)-3-methyl-1,3,4-thiadiazol-2(3H)-ylidene)acetamide It has better penetration into the eye compared with Acetazolamide. SAR of CA inhibitors. Simple heterocyclic sulfonamide. Sulfamoyl group is essential for CA inhibitory activity and for diuresis. The sulfamoyl nitrogen should not be substituted for activity.

Thiazides and Thiazides Like Diuretics The thiazides were the first orally effective saluretic agents. They were developed from cyclization of chloraminophenamide (CA inhibitor). Thiazide and Hydrothiazide derivative

Mode and Site of Action of Thiazide Diuretics The diuretic effect of the thiazides is related to their ability to inhibit the Na + -Cl - symporter located in Distal Convoluted Tubules. They inhibit the reabsorption of Na + and Cl - ions so they are referred to as saluretics.

Chlorothiazide 6-Chloro-7-sulfamoyl-2H-1,2,4-benzothiadiazine-1,1-dioxide. The prototype of benzothiadiazine diuretics. Benzthiazide It is about 10 times as potent as chlorothiazide.

Hydrochlorothiazide Effective diuresis comparable to that produced by 0.5 g of chlorothiazide. Hydroflumethiazide It is potent orally administered thiazide diuretic useful in the management of edema associated with Congestive heart failure, hepatic cirrhosis, corticosteroid and estrogen therapy.

SAR The 2 position can tolerate the presence of relatively small alkyl groups such as CH 3. Substituents in the 3 position play a dominant role in determining the potency and duration of action of the thiazides. Saturation of the 3-4 double bond enhances the diuretic effect 10 times. An electron-withdrawing group at position 6 is necessary for diuretic activity. Electron-donating groups at position 6 result in reduction of diuretic activity.

The hydrogen atom at position 2 is acidic enough to form a water soluble sod. Salt for I.V. administration. The sulfamoyl group in the 7 position is essential for diuretic effect. Removal or replacement of this group result in significant reduction or complete loss of the diuretic activity.

Loop Diuretics (High Ceiling Diuretics) These diuretics produce a peak diuresis much greater than that observed with the other commonly used diuretics, hence the name high ceiling diuretics. They are characterized by a quick onset (~30 min) and short duration (~ 6 hr) of action.

Mode and Site of Action of High Ceiling Diuretics The diuretic effect of the high ceiling diuretics is attributed to inhibition the luminal Na + / K + /2Cl - symporter located in Thick Ascending Limb of Loop of Henle leading to a Na + -rich diuresis.

Furosemide/Frusemide 4-Chloro-N-furfuryl-5-sulfamoylanthranilic acid It has a saluretic effect 8-10 times that of the thiazides. 5-Sulfamoyl-2-aminobenzoic acid derivatives

SAR Substituent at the 1 position must be acidic. The carboxyl group provide optimal diuretic activity but other groups such as a tetrazole may impart respectable diuretic activity. A sulfamoyl group in the 5 position is a prerequisite for optimal high- ceiling diuretic activity. The activating group (-X) in the 4 position can be Cl - or CF 3 - as was the case with thiazide and thiazide-like diuretics. The substituents that can be tolerated on the 2 amino group are very limited and can be arranged in the following order:

Phenoxyacetic Acid derivatives Ethacrynic acid 2,3-Dichloro-4-(2-methylene-1-oxobutyl)phenoxyacetic acid Optimum diuretic activity was obtained when: - an oxyacetic acid group was positioned para to α,β- unsaturated enone. - 2,3-dichloro substituents on the phenyl ring. - Hydrogen atoms on the terminal alkene carbon. Thus a molecule with a weakly acidic group for drug direction to the kidney, an alkylating moiety and lipophilic groups seemed to provide the best combination for diuretic effect of this class of compounds. SAR

Potassium Sparing Diuretics This class of diuretics are characterized by their ability to increase Na + and Cl - excretion without a concomitant increase in the urinary excretion rate of K + in collecting duct. They are also known as antikaliuretic agents. They can be classified into 2 classes with respect to mechanism of action: 1. Aldosterone antagonists 2. Na + -channel blockers

Site of Action of Potassium Sparing Diuretics

1. Aldosterone antagonists Aldosterone enhances the passage of Na + from the luminal fluid into tubular cells and the passage of intracellular K + into the luminal fluid. A substance that antagonizes the effects of aldosterone could conceivably be a good diuretic.

Spironolactone It is a competitive antagonist to the mineralocorticoids such as aldosterone on the minralocorticoid receptor. This lead to inhibition of reabsorption of Na + and Cl - as well as the associated water. Aldosterone (Hemiacetal form) Particularly useful in primary aldosteronism (adrenal adenomas or hyperplasia) and in secondary aldosteronism (CHF, hepatic cirrhosis, ascites, nephrotic syndrome) – drug of choice in hepatic cirrhosis.

Adverse Effects of K + -Sparing Diuretics Hyperkalemia (contraindicated with renal insufficiency) Gynecomastia Hormonal disturbances due to its affinity for androgen and progestrone receptors. Metabolism

Eplerenone It is a recently approved specific aldosterone antagonist with a much lower affinity for androgen and progestrone receptors than spironolactone.

The main side effects are Kidney stones and leg cramps due to hyperkalemia. 2. Na + -channel blockers Triamterene 6-phenylpteridine-2,4,7-triamine It interferes with the process of cationic exchange by blocking luminal Na + -channel in the DCT. This lead to block the reabsorption Na + and block the secretion of K + without antagonizing the aldosterone.

Amiloride It is the open chain analog of triamterene acting with the same mode of action.