FFG2414 Pharmacology II Chapter 1 Diuretics PDF

FFG2414 Pharmacology II Chapter 1 Diuretics Learning Outcome After completing this lesson, students should be able to:  List out the component of urinary system  Describe the process of urine formation  Explain the classification of the diuretic agents Structure of the lesson...

FFG2414 Pharmacology II Chapter 1 Diuretics Learning Outcome After completing this lesson, students should be able to:  List out the component of urinary system  Describe the process of urine formation  Explain the classification of the diuretic agents Structure of the lesson 1. The urinary (renal) system a. The urinary system b. Structure of nephron c. Functions of urinary system d. Process of urine formation 2. Diuretics a. Classification of diuretics b. Therapeutic uses c. Adverse effects d. Diuretic resistance 1 8 May 2024  FFG2414 Pharmacology II The (Renal) Urinary System  The renal system, also known as the urinary system, filters blood and creates urine as a waste by-product.  It consists of the kidneys, renal pelvis, ureters, bladder, and urethra.  The process of urine formation involves the following steps: - Blood flows into your kidneys through a large blood vessel called the renal artery. - Tiny blood vessels in your kidney filter the blood. - The filtered blood returns to your bloodstream through a large blood vessel called the renal vein. - Urine travels through tubes of muscle called ureters to your bladder. - Your bladder stores urine until you release it through urination. 2 8 May 2024  FFG2414 Pharmacology II Structure of nephron  The structural units of the kidneys that actually produce urine are the nephrons, of which there are approximately 1,000,000 in each kidney.  Each nephron is composed of several segments: the glomerulus, the proximal convoluted tubule, the loop of Henle, the distal convoluted tubule and the collecting duct.  Each nephron is a long tubule (or extremely fine tube) that is closed, expanded, and folded into a double-walled cuplike structure at one end.  This structure, called the renal corpuscular capsule, or Bowman’s capsule, encloses a cluster of capillaries called the glomerulus.  The capsule and glomerulus together constitute a renal corpuscle, also called a Malpighian body.  Blood flows into and away from the glomerulus through arterioles that enter and exit the glomerulus through the open end of the capsule (the vascular pole).  The tubules of the nephrons are 30–55 millimetres (1.2–2.2 inches) long.  The corpuscle and the initial portion of each tubule, called the proximal convoluted tubule, lie in the renal cortex.  The tubule descends into a renal pyramid, makes a U-shaped turn, and returns to the cortex at a point near its point of entry into the medulla. 3 8 May 2024  FFG2414 Pharmacology II  This section of the tubule, consisting of the two parallel lengths and the bend between them, is called the loop of Henle.  The final portion of the tubule, the distal convoluted tubule, leads from the vascular pole of the corpuscle to a collecting tubule.  Several of the collecting tubules join together to form a wider tubule, the collecting duct, which carries the urine to a renal papilla and the renal pelvis. Functions of kidneys 1. Homeostasis function The kidneys regulate water balance, electrolyte levels, pH of the blood, and arterial blood pressure. 2. Decontamination function Each day, the kidneys filter ~180 L of plasma (20% of the cardiac output) to produce~1.5 L of urine, which involves the removal of excess water and nonessential substances (metabolic waste, drugs, toxins). 4 8 May 2024  FFG2414 Pharmacology II Urine formation  Urine is produced in the nephrons through the processes of filtration, reabsorption and secretion. 1. Filtration  Filtration of substances from the blood into the nephrons occurs in the glomerulus.  The blood pressure entering the glomerulus is high compared to the pressure within the glomerulus, which facilitates movement of small molecules and fluid into the glomerular filtrate.  These include vitamins, amino acids, and electrolytes pass into the glomerular filtrate (which ultimately becomes urine), but large molecules like red blood cells, and plasma protein do not.  The remaining segments (renal tubules) are involved with reabsorption and secretion. 2. Reabsorption  At proximal convoluted tubule, water, nutrients, plasma proteins and ions are reabsorbed from filtrate into peritubular capillaries (efferent arteriole side).  Then the filtrate reaches descending loop of Henle.  At descending loop of Henle further reabsorption of water from the filtrate into the peritubular capillaries (efferent arteriole side) takes place.  At ascending loop of Henle further reabsorption of sodium and chloride ions takes place.  Further reabsorption of water, sodium ions and calcium ions (under hormonal control) takes place at the distal convoluted tubule. 5 8 May 2024  FFG2414 Pharmacology II  At the collecting duct reabsorption of water, and reabsorption or secretion of sodium, potassium, hydrogen and bicarbonate ions take place. 3. Secretion  At the primary and the distal convoluted tubule, the secretion of ions, acids, drugs and toxins into the filtrate takes place.  Then the filtrate (urine) reaches the end of collecting duct i.e. papillary duct and then to the minor calyx and travels through the ureter to the urinary bladder. Diuretics  Diuretics are drugs that act at various sites in the nephron to cause diuresis (an increase in urine production).  Most diuretics inhibit the reabsorption of sodium ions from the nephron into the circulation (prevent Na+ re-entry into the blood vessel).  When sodium is reabsorbed in the kidneys, water follows it due to osmotic pressure.  Osmosis is the movement of water from an area of lower solute concentration (in this case, the filtrate in the kidney tubules) to an area of higher solute concentration (the blood).  By reabsorbing sodium, the kidneys create a higher solute concentration in the blood, which draws water back into the bloodstream.  When diuretics inhibit sodium reabsorption, they prevent this process. As a result, sodium remains in the filtrate within the kidney tubules. Because water follows sodium, it also stays in the filtrate and is excreted as urine. This leads to increased urine output and reduced fluid volume in the body.  It is necessary for diuretics to get into the tubule fluid in order to be effective.  Once a diuretic enters the tubule fluid, the nephron site at which it acts determines its effect.  In addition, the site of action also determines which electrolytes, other than sodium ions Na+, will be affected.  Diuretics also affect the excretion of potassium, magnesium, calcium, chloride and bicarbonate ions.  All diuretics, except spironolactone, exert their effects from the luminal side of the nephron. Classification of diuretics I. Proximal convoluted tubule diuretics II. Loop Diuretics III. Distal convoluted tubule diuretics IV. Collecting duct diuretics 6 8 May 2024  FFG2414 Pharmacology II I. Proximal convoluted tubule diuretics The proximal tubule (PT) determines the rate of Na+ and H2O delivery to the more distal portions of the nephron. The diuretics acting in this region are called PCT diuretics. (i) Osmotic diuretics: e.g. Mannitol, glycerol (ii) Carbonic anhydrase (CA) inhibitors: e.g. acetazolamide, dorzolamide II. Loop Diuretics Examples of loop diuretics include: frusemide (furosemide), bumetanide and ethacrynic acid. III. Distal convoluted tubule diuretics Examples: thiazides, hydrochlorothiazide IV. Collecting duct diuretics (potassium sparing diuretics) These agents are often given to avoid the hypokalemia that accompanies the agents previously described. They should never be given in the setting of hyperkalemia or with disease states likely to cause hyperkalemia. Eg. spironolactone, amiloride & triamterene Therapeutic uses of diuretics The diuretics are mainly used as the treatment for hypertension and oedema (accumulation of abnormal amounts of extra vascular and extra cellular fluid). They can also be used in:  Spironolactone: treatment of heart failure  Thiazides: prevention of renal stones (calcium oxalate), nephrogenic diabetes insipidus body’s ability to regulate fluid balance, characterized by excessive thirst and the production of large amounts of dilute urine).  Loop diuretics: treatment of edema, renal failure, hypercalcemia  Carbonic anhydrase inhibitors: lowering intra-ocular pressure in glaucoma, eye surgery; epilepsy; formerly used as antihypertensive Adverse effects of diuretics  Dehydration, thirst, dry mouth  Side effects related to electrolyte disturbances include: - Hyponatremia (all) 7 8 May 2024  FFG2414 Pharmacology II - Hypokalemia (most) - Hyperkalemia (K+-sparing diuretics) - Hypomagnesemia, hypocalcemia (loop diuretics) - Hypercalcemia (thiazides)  Thiazide and loop diuretics can cause hyperuricemia and lead to gout (inflammatory response to formation of urate crystals in the body)  High thiazide doses can cause hyperlipidemia Diuretics resistance Diuretic resistance is defined as a failure to achieve the therapeutically desired response despite a full dose of diuretic. Most common causes of resistance  Incomplete treatment of the primary disorder  Continuation of high Na+ intake  Interference by other drugs (E.g. NSAIDS)  Failure to reach tubular site of action - decreased gastrointestinal absorption - decreased availability in tubular lumen (nephrotic syndrome)  Tubular adaptation (chronic loop diuretic use).  Patient non-compliance References  Rang H.P., Dale MM, Ritter JM, Moore PK, (2003). Pharmacology (5th ed.). Churchill Livingstone  Tripathi KD, Essentials of Medical Pharmacology, 2004 (5th ed. ) Jaypee.  Kaye M., Favaro, A. (2005). Introduction to Pharmacology (10th ed.).  WB Saunders. Holland LN, Adams MP. Core concepts in Pharmacology.2003, Prentice Hall. 8 8 May 2024