Renal 2 Pharmacology PDF

# Renal System And Body Fluids ## Stephen Mensah Arhin (PhD) * Department of Pharmacology * UCCSMS # The Renal System * The main function of the kidney is to maintain the constancy of the interior environment by: * Eliminating waste products * Regulating the volume * Electrolyte conten...

# Renal System And Body Fluids ## Stephen Mensah Arhin (PhD) * Department of Pharmacology * UCCSMS # The Renal System * The main function of the kidney is to maintain the constancy of the interior environment by: * Eliminating waste products * Regulating the volume * Electrolyte content * Maintaining pH of the extracellular fluid # Structure of the Kidney * Each kidney consists of an outer cortex, an inner medulla, and a hollow pelvis. * Nephron is the functional unit, approximately 1.4 x 10⁶ in each kidney. * Each nephron consists of a: * Glomerulus * Proximal tubule * Loop of Henle * Distal convoluted tubule * Collecting duct * **Glomerulus:** Comprises a tuft of capillaries projecting into a dilated end of the renal tubule. # Regulation of Fluid and Electrolytes * Approximately 16%-20% of blood plasma entering the kidneys is filtered from the glomerular capillaries into Bowman’s capsule. * Filtrate free of proteins and blood cells, in [C] similar to that in plasma. * Contains glucose, sodium bicarbonate, amino acids, organic solutes, electrolytes (Na+, K+, and Cl-). * Kidney regulates ionic composition and urine volume by active reabsorption or secretion of ions and/or passive reabsorption of water at five functional zones along the nephron. # Proximal Convoluted Tubule * Almost all glucose, bicarbonate, amino acids are reabsorbed. * Approx. 60-65% of the filtered Na+ and water reabsorbed. * Chloride enters the lumen of the tubule in exchange for oxalate (anion). * Reabsorbed Na+ is pumped into the interstitium by Na+/K+ ATPase pump. * Carbonic anhydrase in the luminal membrane and cytoplasm of the PCT is the site of the organic acid and base secretory systems. * **The organic base secretory system:** Is responsible for the secretion of creatinine and choline. * **Organic acids:** (e.g., uric acid, some antibiotics, diuretics) are secreted from the bloodstream into PCT lumen. * Drug interactions occur, probenecid interferes with penicillin secretion. # Descending Loop Of Henle * **Osmolarity:** Increases along the descending portion of the loop of Henle. * **Due to countercurrent mechanism:** That is responsible for water reabsorption. * This results in a tubular fluid with a three-fold increase in Na+ and Cl- concentration. * **Osmotic diuretics:** Exert part of their action in this region. * Regulate the osmotic balance of the body as a whole. * H20 moves out of the tubular fluid. # Ascending Loop Of Henle * Low permeability to water due to the tight junctions. * **Builds up a substantial concentration gradient:** Across the wall of the tubule. * About 25-30% of filtered Na+ is reabsorbed. * **Active reabsorption of Na+, K+, and Cl- :** Is mediated by a Na+/K+/2CI- co-transporter. * Both Mg2+ and Ca2+ are reabsorbed via the paracellular pathway. # Distal Convoluted Tubule * **The Target of Thiazide Diuretics** * The cells of the distal convoluted tubule are impermeable to water. * About 5% to 10% of the filtered sodium chloride is reabsorbed via a Na+/Cl- transporter. * **Calcium reabsorption:** Under the regulation of parathyroid hormone, and calcitriol is mediated by an apical channel and then transported by a Na+/Ca2+-exchanger into the interstitial fluid. # Collecting Tubule and Duct * **Principal cells of CT and duct:** Are responsible for Na+, K+, and water transport. * 1%-2% of the filtered Na+ enters the principal cells through *epithelial sodium channels* that are inhibited by amiloride and triamterene. * **Inside the cell, Na+ reabsorption:** Relies on a **Na+/K+-ATPase pump** to be transported into the blood. * **Aldosterone receptors:** In principal cells influence Na+ reabsorption and K+ secretion. * **Aldosterone increases the synthesis:** Of *epithelial sodium channels* and of the *Na+/K+-ATPase pump* to increase Na+ reabsorption and K+ excretion. * **Antidiuretic hormone (ADH: vasopressin):** Binds to *V2 receptors* to promote the reabsorption of water through *aquaporin channels*. # Acid-Base Balance * The kidneys and the lungs regulate the H+ concentration of body fluids. * Acid or alkaline urine can be excreted according to need. * The usual requirement being to form acid urine to eliminate *phosphoric and sulfuric acids* generated during the metabolism of nucleic acids. * **And sulfur-containing amino acids:** Consumed in the diet. * Consequently, metabolic acidosis is common following renal failure. # Diuretic Agents * **Figure 2:** Major locations of ion and water exchange in the nephron, showing sites of action of the diuretic drugs. ## Thiazides * Widely used diuretics because of their antihypertensive effects. * Efficacy of thiazides for hypertension is not entirely dependent on their diuretic actions. * They reduce *PVR* with long-term therapy. * Are sulfonamide derivative but do not cause hypersensitivity reactions in patients with allergies to sulfonamide. * All thiazides affect the *distal convoluted tubule* and all have equal maximum diuretic effects, differing only in potency. * **Are "low ceiling diuretics." ** * Increasing the dose above normal therapeutic doses does not promote further diuretic response. ## Mechanism Of Action * The thiazide and thiazide-like diuretics act mainly in the DCT tubule to decrease the reabsorption of Na+ by inhibition of a Na+/CI-co-transporter. * **They increase the concentration:** Of Na+ and Cl- in the tubular fluid. * **Result in the excretion:** Of very *hyperosmolar* (concentrated) urine. * The antihypertensive effects of thiazides may persist even when the glomerular filtration rate is below 30mL/min/1.73 m2. * The efficacy of thiazides may be diminished with concomitant use of NSAIDs such as indomethacin, which inhibit production of renal prostaglandins, thereby reducing renal blood flow. * Promotes reabsorption of Ca2+ in DCT where parathyroid hormone regulates reabsorption (hypercalcemia). * **Increases:** The reabsorption of urea in PCT, hence precipitates gout. ## Loop Diuretics * Inhibit the **Na+/K+/2CI- co-transport** of luminal membrane in the ascending limb of the loop of Henle. * *Ascending limb* accounts for reabsorption of 25% to 30% of filtered NaCl. * Reabsorption of these ions into the renal medulla is decreased. * **Have the greatest diuretic effect.** * Decreases volume of plasma and subsequently stimulate a compensatory effect to increase BP. * Cause diuresis in patients with poor renal function or lack of response to other diuretics. * Loop diuretics display a *sigmoidal (“S”-shaped) dose-response curve:* * **A threshold effect.** * **A rapid increase in diuresis:** With small changes in drug concentration. * **A ceiling effect** * **NSAIDs inhibit renal prostaglandin synthesis:** And can reduce the diuretic action of loop diuretics. * **Unlike thiazides, loop diuretics increase the Ca2+ content of urine.** * **In patients with normal serum Ca2+ concentrations, hypocalcemia does not result, because Ca2+ is reabsorbed in the distal convoluted tubule.** * Prior to their diuretic actions, loop diuretics cause acute *venodilation* and reduce left ventricular filling pressures via enhanced prostaglandin synthesis. * Loop diuretics are administered orally or parenterally. * **Furosemide:** Has unpredictable bioavailability of 10% to 90% after oral administration. * **Bumetanide and torsemide:** Have reliable bioavailability of 80% to 100%, which makes these agents preferred for oral therapy. * **The duration of action:** Is approximately 6 hours for furosemide and bumetanide, and moderately longer for torsemide, allowing patients to predict the window of diuresis. * **Adverse effects:** * **Hyperuricemia:** Loop diuretics compete with uric acid for the renal secretory systems, thus blocking its secretion and, in turn, may cause or exacerbate gouty attacks. * **Ototoxicity:** Hearing loss may occur with loop diuretics, particularly when infused intravenously at fast rates, at high doses. (Ethacrynic acid is the most likely to cause ototoxicity). * **Hypokalemia:** The loss of K+ from cells in exchange for H+ leads to hypokalemic alkalosis. * **Acute hypovolemia:** Cause a severe and rapid reduction in blood volume, and cardiac arrhythmias. * **Hypomagnesemia** ## Potassium-Sparing Diuretics * Potassium-sparing diuretics act in the collecting tubule to inhibit Na+ reabsorption and K+ excretion. * Used cautiously in moderate renal dysfunction and avoided in patients with severe renal dysfunction because of the increased risk of hyperkalemia. * Within this class, there are drugs with two distinct mechanisms of action with different indications for use: * **Aldosterone antagonists** * **Epithelial sodium channel blockers** * **Spironolactone** is a steroid compound, which is a competitive aldosterone antagonist. * It increases Na' excretion and decreases K' and urea excretion. * Its diuretic action is weak and is achieved slowly. * Spironolactone is effective in edema caused by increased production of aldosterone ascites in liver cirrhosis and edema in congestive heart failure. * Spironolactone in low doses (25 mg/24h) potentiates the effect of ACE inhibitors. * **Synthetic steroids that antagonize aldosterone receptors:** Preventions translocation of the receptor complex into the nucleus of the target cell resulting in a lack of intracellular proteins that stimulate the Na+/K+-exchange sites of the collecting tubule. * **Aldosterone antagonists prevent Na+: **Reabsorption and therefore, K+ and H+ secretion. * **Eplerenone:** Is more selective for aldosterone receptors and causes less endocrine effects (gynecomastia) than spironolactone, which also binds to progesterone and androgen receptors. * **Triamterene and amiloride:** * Block epithelial sodium channels, leads to decrease in Na+/K+ exchange. * Have a K+-sparing diuretic action similar to that of the aldosterone antagonists. * But blockage of the Na+/K+-exchange site in the collecting tubule does not depend on the presence of aldosterone. * Not very efficacious diuretics. * Both triamterene and amiloride are commonly used for their potassium-sparing properties. # Carbonic Anhydrase Inhibitor * **A common example:** Acetazolamide. * **Acetazolamide inhibits carbonic anhydrase:** (CA) mainly in proximal tubules. * Acetazolamide inhibits carbonic anhydrase located intracellularly (cytoplasm) and on the apical membrane of the proximal tubular epithelium. * **The decrease in formation of HCO3:** Results in a mild diuresis (due to retention of water (not Na)). * **HCO3:** Is retained in the lumen, with marked elevation in urinary PH. * The loss of HCO3: Causes a *hyperchloremic metabolic acidosis*. * Acetazolamide blocks not only renal CA, but also CA in the ciliary body in the eye (reducing production of eye liquid) and in the brain. * **Facilitates GABA synthesis.** * **Therapeutic uses:** * **Glaucoma: **Decreases the production of aqueous humor reduces IOP in patients with chronic open-angle glaucoma. * **Topical carbonic anhydrase inhibitors:** Such as dorzolamide and brinzolamide have the advantage of not causing systemic effects. * **Altitude sickness:** Acetazolamide can be used in the prophylaxis of symptoms of altitude sickness. Acetazolamide prevents weakness, breathlessness, dizziness, nausea and cerebral as well as pulmonary edema characteristic of the syndrome. * **Adverse effects:** * **Metabolic acidosis (mild)** * **Potassium depletion** * **Renal stone formation** * **Drowsiness** * **Paresthesia:** May occur. * The drug should be avoided in patients with hepatic cirrhosis because it could lead to a decreased excretion of NH4. # Osmotic Diuretics * **Hydrophilic chemical substances:** That are filtered through the glomerulus, such as mannitol result in diuresis due to higher osmolarity of the tubular fluid. * **Results in osmotic diuresis:** With little additional Na+ excretion (aquaresis). * They are used to maintain urine flow following acute toxic ingestion of substances capable of producing acute renal failure, such as cisplatin elimination. * **Decrease blood volume and pressure.** * **Other examples:** Urea, glycerine, Isosorbide. * **Mannitol and urea:** Given IV. * **Isosorbide and glycerine:** PO. * Osmotic diuretics are a mainstay of treatment for patients with increased *ICP*. * **Adverse effects:** Include dehydration and extracellular water expansion. * The expansion of extracellular water occurs because the presence of mannitol in the extracellular fluid extracts water from the cells and causes *hyponatremia* until diuresis occurs. * Mannitol does not influence *renin synthesis*. * It does not cross tissue barriers ( BBB neither), does not penetrate to the eye and brain and in osmotic way reduces intraocular and intracranial pressure. * It is included in the treatment of brain edema, initial stages of acute renal failure, chronic renal failure, glaucoma intoxications with drugs excreted in the urine. # Sample Questions 1. Elevated urinary HCO3 excretion leads to the formation of: * A. Acidic urine and metabolic acidosis * B. Alkaline urine and respiratory alkalosis * C. Alkaline urine and metabolic acidosis * D. Acidic urine and respiratory acidosis 2. Loop diuretics are effective with inhibiting sodium reabsorption within the nephron because it inhibits? * A. The sodium chloride transporter * B. The effects of aldosterone on the distal convoluted tubule * C. The sodium-potassium-chloride cotransporter * D. The transport of bicarbonate by the proximal convoluted tubule 3. Your patient is ordered a loop diuretic. Which finding below would require you to hold the dose? * A. Calcium level 9 mg/L * B. Potassium level 15 mEq/L * C. Blood pressure 102/78 * D. Sodium level 144 4. You're developing a plan of care for a patient with heart failure that will be prescribed a thiazide diuretic. What interventions will you include in this patient's plan of care? Select all that apply. * A. Encourage the patient to limit the consumption of bananas, avocadoes, spinach, strawberries, and potatoes. * B. Measure the patient's intake and output daily. * C. Weigh the patient daily using a bedside scale. * D. Assess lab results for electrolyte imbalances like hypercalcemia and hyperkalemia. 5. Main Therapeutic use of CA is for the treatment: * A. Congestive heart failure * B. Increased intracranial pressure * C. Edema due to liver cirrhosis * D. Intraocular pressure