Kidney Pharmacology 1 PDF

Main functions of the kidney 1. Eliminating waste products. 2. Regulating the volume, volume electrolyte content & pH of the extracellular fluid. Under usual conditions: The kidneys receive 1300 ml blood/min (~ ¼ of the cardiac output). About 125 ml of fluid are filtered of...

Main functions of the kidney 1. Eliminating waste products. 2. Regulating the volume, volume electrolyte content & pH of the extracellular fluid. Under usual conditions: The kidneys receive 1300 ml blood/min (~ ¼ of the cardiac output). About 125 ml of fluid are filtered off per minute. Approximately 1.5 L/day is voided as urine. The kidneys perform: 1. Glomerular filtration. 2. Tubular reabsorption (transport of materials from tubular lumen into blood). 3. Tubular secretion (transport of materials from blood into tubular lumen). Afferent arteriole Efferent arteriole Bowman’s capsule  The glomerular filtrate is identical in composition with plasma, but without its proteins Factors affecting GFR Intra-glomerular hydrostatic pressure Which is increased with: VD of afferent arteriole Æ ↑ RBF Increased arterial blood pressure Æ↑ RBF GFR VC of efferent arteriole. Intra-glomerular osmotic pressure Which is increased with increased plasma proteins concentration. GFR Intra-capsular hydrostatic pressure Which is increased with : Tubular obstruction. GFR Renal edema. Efferent arteriole subdivided to form a peritubular capillaries at which secretion and reabsorption takes place then join to venous system. ¾ The lumenal surface of the tubular cell is called brush border (apical) membrane ¾ The other sides of the tubular cell is called basolateral membrane. ¾ The apex of each tubular cell is surrounded by a tight junction (specialized region of membrane) that separates the intercellular space from the lumen. The movement pathways of ions and water: 1. Transcellular pathway: Across the tubular cells. 2. Paracellular pathway: Across the tight junctions (in- between cells).  Lumen Blood H2O + CO2 H2O + CO2 CO2 CA CA H2CO3 H2CO3 H+ H+ + HCO3- HCO3- HCO3- Na+ Na+ Na+ K+ K+ Na+ reabsorption: ¾ Approximately 67% of Na+ are reabsorbed in Pct. ¾ Na+ are reabsorbed in exchange for H+ via Na+/H+ antiporter. ¾ Intracellular carbonic anhydrase is essential for production of H+ for secretion into the lumen. ¾ Na+ are transported into blood via Na+/K+ ATPase in the basolateral membrane. ¾ Transport of Na+ via Na+/H+ antiport is driven by Na+/K+ ATPase (because it transports 3 Na+ out in exchange with 2 K+ in Ælowers cytoplasmic Na+ concentration and consequently Na+ enters the cell from the lumen down its concentration gradient). HCO3- reabsorption: ¾ HCO3- are normally completely reabsorbed in Pct. ¾ HCO3- combine with H+ Æ H2CO3 (a reaction catalyzed by brush border carbonic anhydrase). ¾ H2CO3 dissociates to form CO2 and water ¾ The formed CO2 in the lumen is passively reabsorbed. Water reabsorption: ¾ Water is passively reabsorbed through the paracellular pathway. ¾ This reabsorption is secondary to Na+ reabsorption ¾ Also, Na+ secreted by Na+/K+ ATPase into the lateral intercellular space, slightly raising its osmolality Æ Osmotic movement of water through the paracellular pathway, which, in turn, causing Na+ reabsorption by convection (solvent drag). CL- reabsorption: ¾ CL- are transported into blood partly by passive reabsorbed through the paracellular pathway down its concentration gradient and partly in exchange for anions, such as formate and oxalate. ¾ Since both water and ions are absorbed in Pct the fluid leaving the Pct remains approximately isosmotic to the filtrate entering Bowman's capsule. Descending Limb: ¾ Water is passively reabsorbed because the interstitial fluid of the medulla is hypertonic. Thus, as the filtrate passes down the descending limb, it becomes more concentrated (hyperosmotic).  Ascending Limb Lumen Blood Na+ Na+ Na+ 2CL- 2CL- K+ K+ K+ K+ CL- CL- CL- CL- Ascending Limb: ¾ Here, approximately 20% of filtered Na+ is reabsorbed. ¾ Ions (Na, K, CL) move into the cell across the apical membrane by a Na+/K+/2Cl- symporter. The energy for this is derived from the Na+/K+ ATPase (as in Pct). ¾ Na+ are transported into blood via Na+/K+ ATPase. ¾ CL- are transported into blood partly by diffusion through CL- channels and partly via K+/Cl- symporter. ¾ Most of the K+ taken by the Na+/K+/2Cl- symporter returns to the lumen through apical K+ channels. Ascending Limb: ¾ Since the thick ascending limb is relatively impermeable to water, reabsorption of salt from this part is not accompanied by reabsorption of water Æ Thus, as the filtrate passes upward in the ascending limb, it becomes more diluted (hyposmotic). ¾ Therefore, the thick ascending limb is called the 'diluting segment'. ¾ The process of concentration and then dilution of filtrate in the loop of Henle is known as the “counter-current multiplier theory”. Lumen Blood Na+ Na+ Na+ CL- CL- K+ K+ CL- CL- K+ K+ CL- CL- ¾ Here, approximately 7% of filtered Na+ is reabsorbed. ¾ In the early Dct, NaCl is reabsorbed without water (Dct is relatively impermeable to water) Æ Further dilution of the filtrate. ¾ NaCl is reabsorbed via Na+/Cl- symporter. This transport is driven by Na+/K+ ATPase (as in Pct). Ca2+ reabsorption: ¾ Ca2+ are transported through channels in the apical membrane then transported into blood via Na+/Ca2+ antiporter. ¾ PTH and calcitriol increase Ca reabsorption. ¾ Note: Ca is also reabsorbed via paracellular pathway in the ascending limb of loop of Henle. H+ secretion: ¾ When all filtered HCO3- has been reabsorbed in Pct, Na+/H+ exchange (in the apical membrane) still continue in Dct, in this condition: H+ is added to Na2HPO4 to give NaH2PO4 H+ is added to NH3 to give NH4- ¾ Intracellular carbonic anhydrase is essential for production of H+ for secretion into the lumen.  Lumen Blood CO2 + H2O CA H+ H+ + HCO3- HCO3- Na+ Na+ Na+ Na2HPO4 K+ K+ K+ NaHPO4- NaH2PO4 ¾ Here, approximately 5 % of filtered Na+ is reabsorbed ¾ Most of K+ & H+ are secreted ¾ Collecting tubules include two types of cells: ƒ Principal cells: In which Na+ reabsorption and K+ secretion take place. ƒ Intercalated cells: In which H+ secretion takes place. ¾ The movement of ions and water in this potion is under hormonal control: ƒ Aldosterone: controls Na+ absorption & K+ secretion. ƒ Antidiuretic hormone (ADH; vasopressin): controls absorption of water in accordance with the needs of the body of water.  Lumen Blood + PK cAMP AC V2 ADH H2O H2O H2O H+ H+ + A Na+ Na+ Aldo R A + DNA Na+ Na+ + Na+ K+ K+ K+ K+ Accordingly, K+ secretion is coupled to Na+ reabsorption in this segment Consequently, K+ secretion is increased when: More Na+ reach the collecting duct (as a result of inhibition of Na+ reabsorption in previous segments by diuretics) diuretics Æ More Na+ reabsorption in the collecting duct Æ More K+ secretion Æ K+ loss and hypokalemia. hypokalemia Enhances Na+ reabsorption and K+ excretion by: 1. Stimulating Na+/H+ exchange (by an action on membrane aldosterone receptors Æ a rapid effect) 2. Activating Na channels in the apical membrane through directing the synthesis of a specific protein mediator (by an action on nuclear receptors Æ a delayed effect). 3. Increasing the number of basolateral Na+/K+ ATPase. ¾ ADH is secreted by the posterior pituitary: ƒ Increased blood osmolality Æ stimulates osmo-receptors on hypothalamus Æ Stimulates ADH secretion from post. Pituitary. ƒ Increased blood volume or blood pressure Æ Stimulates baroreceptors Æ Inhibits ADH secretion. ¾ ADH binds V2 receptors in the basolateral membranes Æ increasing expression of water channels in the apical membranes. ¾ This renders this part of the nephron permeable to water, allowing passive reabsorption of water as the collecting duct traverses the hyperosmotic region of the medulla Æ the filtrate is concentrated and hence the excretion of concentrated urine. ADH Deficiency: (Diabetes Insipidus) This may due to: 1. Deficiency of ADH secretion (Neurogenic DI) or 2. Insensitivity of kidney to ADH action (Nephrogenic DI): 1. Congenital: de to mutation of V2 receptors or of water channels 2. Acquired: due to certain drugs In these cases, collecting duct cells become impermeable to water, leading to excretion of dilute urine, polyuria, nocturia and compensatory polydipsia. Daily urine output may reach as much as 10-15 L, leading to dehydration that may be very severe. At concentrations above those required for antidiuresis, ADH stimulates V1 receptor subtype in smooth musculature, including that of blood vessels Æ VC so called (vasopressin) Æ Blood pressure increases. Derivatives of ADH: ¾ Lypressin acts like ADH. Other derivatives may display only one of the two actions: ƒ Desmopressin is used for the therapy of diabetes insipidus, nocturnal enuresis and chronic hypotension. ƒ Felypressin and ornipressin serve as adjunctive vasoconstrictors in infiltration local anesthesia. Organic Acids (anions) & Bases (cations) Secretion: ¾ Organic molecules may enter the renal tubules by GF of molecules not bound to pp or may be actively secreted directly into the tubules (Pct). ¾ Organic anions (A-) are exchanged with α-ketoglutarate by an antiport in the basolateral membrane called organic anion transporters (OATs). Then, diffuse passively into the tubular lumen ¾ Organic cations (C+) diffuse into the cell from blood and are then actively transported into the tubular lumen in exchange for H+. ¾ Both systems are powered by the energy derived from Na+/K+ ATPase in the basolateral membrane.  Pct Lumen Blood K+ K+ Na+ Na+ α-KG α-KG A- A- A-  Pct Lumen Blood K+ K+ Na+ Na+ Na+ H+ H+ C+ C+ C+ Ammonia Secretion: ¾ Ammonia is formed in Dct by deamination of glutamine by glutaminase. ¾ The formed ammonia diffuses into the lumen. Then combines with H+ forming (NH4+). ¾ This prevents undue accumulation of H+ in the filtrate and permits continued exchange of H+ for Na+.  Dct Lumen Blood CO2 + H2O CA H+ H+ + HCO3- HCO3- Na+ Na+ Na+ K+ K+ K+ Glutaminase NH3 NH3 Glutamine NH4+