Pre-Class Readings: Liver and Renal Physiology Related to Drug Elimination (PBS604) PDF

**Pre-Class readings: Liver and Renal Physiology related to drug elimination (PBS604)** **Liver Physiological Functions (related to drug elimination)** **[Overview of the Liver Structure ]** - The liver is vital in digestion of fats, storage of carbohydrates, detoxification of blood, and pr...

**Pre-Class readings: Liver and Renal Physiology related to drug elimination (PBS604)** **Liver Physiological Functions (related to drug elimination)** **[Overview of the Liver Structure ]** - The liver is vital in digestion of fats, storage of carbohydrates, detoxification of blood, and production of proteins. - The liver has a dual blood supply. Arterial inflow from the aorta via the celiac trunk and **hepatic artery** provides 25% of the organ's blood supply. - The remainder comes from the **portal vein**, which drains the capillary bed of the alimentary canal and pancreas. This oxygen-depleted venous blood is rich in substances absorbed and secreted by the gut. - The afferent blood vessels are in association with the bile ducts and form the **portal triads** (consisting of the **portal veins, hepatic arteries, and bile ducts**). Blood from both the hepatic artery and the portal vein drains into the hepatic **sinusoids**, which surround sheets of liver cells, or hepatic plates. The sinusoids are lined by endothelial cells and Kupffer cells (phagocytic macrophage). This blood drains into the central veins, which finally coalesce into the hepatic vein and empty into the **inferior vena cava** *([left figure below])* - The hepatic cells lining the bile canaliculi are responsible for the production of bile. Efflux transporter may pump drug into bile if located in the liver **canaliculi**. (*[right figure below]*) - The liver also has a rich and complex lymphatic drainage system. **[Summary of Normal Liver Function]**\ The liver is one of the most metabolically active organs in the body and functions simultaneously as a digestive organ, an endocrine organ, a hematologic organ, and an excretory organ - **The Liver as a Digestive Organ: Bile salt secretion for fat digestion;** Processing and storage of fats, carbohydrates, and proteins absorbed by the intestines; Processing and storage of vitamins and minerals. - **The Liver as an Endocrine Organ:** Metabolism of glucocorticoids, mineralocorticoids, and sex hormones; Regulation of carbohydrate, fat, and protein metabolism - **The Liver as a Hematologic Organ:** Temporary storage of blood; Removal of bilirubin from the bloodstream; Hematopoiesis in certain disease states; Synthesis of blood clotting factors. - **The Liver as an Excretory Organ:** Excretion of bile pigment; Excretion of cholesterol via bile; Synthesis of urea; **Detoxification of drugs and other foreign substances.**  **Renal Physiological Functions** **[Overview of Kidney Anatomy and Physiology]:** - The kidneys are located just under the diaphragm. One kidney is on each side of the vertebral column between the level of the twelfth thoracic (T12) and third lumbar vertebrae (L3). **Costovertebral angle (CVA)** is an external landmark useful for locating the kidneys. - **Hilum**: A thin, fibrous capsule covers each kidney and encloses blood vessels, lymphatic vessels, and never fibers, including pain receptors. - On cross-section, the kidney is seen to contain three principal areas: **pelvis**, **medulla** and **cortex** - The kidneys are innervated by the **sympathetic** division of autonomic nervous system. - Renal blood supply: Approximately **25%** of the cardiac output is delivered to the kidneys, the majority of which circulates through the cortex, whereas only 1% to 2% perfuse the medulla. - The peritubular capillaries wrap around the proximal and distal convoluted tubules. Some capillaries, called ***vasa recta***, dip down into the medulla to surround the loops of Henle and collecting tubules; The loop structure of the *vasa recta* enable them to pick up interstitial fluid without removing excessive solute. - The kidneys play critical roles in regulating many diverse and complex physiological processes: **Maintaining fluid and electrolyte homeostasis; Ridding the body of water-soluble wastes; Production of erythropoietin; Activation of vitamin D; Maintaining acid-base balance.** **[Functions of the Nephron segments: ]** - **Nephron is the functional unit of kidneys, responsible for:** *Glomerular ultrafiltration*; Tubular *reabsorption*, - All of glomeruli and 85% of nephron tubules are in the **cortex**. 15% of nephrons send their loops of Henle deep into the medulla (called juxtamedullary nephrons). The medulla contains renal pyramids, which consist of collecting tubules, collecting ducts, long loops of Henle, and *vasa recta*. - ***Glomerulus***: Filters fluid from blood into Bowman Capsule; prevent passage of blood cells and proteins. - ***Proximal convoluted tubule*:** Transports ***two thirds*** of filtered water and electrolytes and all of the filtered bicarbonate, glucose, amino acids, and vitamins from filtrate to interstitium; - ***Descending loop of Henle*:** **Transports water**; delivers a concentrated filtrate to ascending loop of Henle. - ***Ascending loop of Henle***: Actively transports Na^+^, K^+^, Cl^-^ to produce a **hypo-osmotic** filtrate and a high interstitial osmolality. - ***Distal convoluted tubule***: Transports Na^+^, Cl^-^, water, and urea; responsive to **aldosterone**; site of *macula densa* regulation of GFR; secrets H^+^ and K^+^. - ***Collecting tubule***: Passive transports water under influence of antidiuretic hormone (**ADH)**; secretes H^+^ and K^+^. **[Glomerular filtration rate (GFR): ]** - GFR= K~f~ \[(P~GC~+π~BC~)-(P~BC~+π~GC~)\]. **Normal GFR=125 ml/min.** P~GC~ is glomerular capillary hydrostatic pressure (mm Hg); π~BC~ is oncotic pressure in the Bowman capsule (mm Hg); P~BC~ is Bowman capsule hydrostatic pressure (mm Hg); π~GC~ is oncotic pressure in the glomerular capillary (mm Hg). - It can be regulated by 1), Factors affect filtration pressure: blood volume, pathological states. Myogenic reflexes in afferent arterioles. 2), **Tubuloglomerular feedback**: juxtaglomerular apparatus: **macula densa cells** (**sense changes in the amount of Na^+^**) and juxtaglomerular **cells** (**produce and release renin**); 3), Effect of Glucose and amino acids: high serum glucose leads to excessive GFR and hyper filtration; 4), Mesangial cells can regulate GFR by responding to chemical signals (AII, endothelin, ANP, and NO) that induce them to contract or relax to regulate GFR by altering the filtration constant K~f~. **[Transport and secretion across renal tubules]:** Transport and secretion occur by **transcellular** and **paracellualr** routs. 1). reabsorption of Glucose: by a sodium-dependent cotransporter called **SGLT2** in proximal tubular cells. Then Glucose diffuses out of the tubule cell and back into the interstitial fluid through passive carrier proteins (**GLUT2**) (**FIG 26.20)**. 2), regulation of Acid-Base Balance: HCO3^-^ is not directly reabsorbed across the renal epithelium; it is firstly converted to CO2 by the enzyme **carbonic anhydrase**. The H^+^ ions needed for this reaction are provided by Na^+^-K^+^ pump and Na^+^-H^+^ exchanger. Renal compensation process: Pa~CO2~ in blood and Alkalosis (FIG 26.21). 3), secretion of potassium: Principle cells in the [distal tubule] and [collecting duct] are the sites of potassium excretion. Na^+^-K^+^ pump moves K^+^ into tubule cell and then by the K^+^-H^+^ exchanger. Aldosterone enhances potassium excretion (FIG 26.22). **[Regulation of blood volume and osmolality]:** Hormone signals fine-tune tubular reabsorption: ADH, aldosterone, AII, **ANP (Atrial natriuretic peptide),** Urodilatin, uroguanylin, and guanylin. 1). **ADH** (Vasopressin): by translocating water pores (aquaporin 2) to apical membrane, make the tubule permeable to water and allow water [reabsorption]. *Diabetes insipidus/nephrogenic diabetes insipidus.* 2). **Aldosterone** and Angiotensin II **(AII)** increase sodium and water [reabsorption], whereas **ANP** and Urodilatin decrease their absorption. Uroguanylin and guanylin produce an effect similar to ANP and Urodilatin. 3). Diuretic Agents: Osmotic diuretics; ACE inhibitors; Loop diuretics; Thiazide-like diuretics; Aldosterone inhibitors (**Potassium sparing**) **[Endocrine Functions]:** two important endocrine hormones. **Erythropoietin**: growth factor for red blood cells; hypoxemia and decreased circulating red cell mass are known to increase its release. Active form of Vitamin D. The first occurs in the liver, resulting in the formation of 25-hydroxycholecalciferol. The kidney performs the second hydroxylation to form 1, 25-dihydroxycholecalciferol, which is the **active form of vitamin D**. **[Age-related changes in renal function]:** Infant: the GFR is less than half the adult rate; Elderly: After age 40 years old, at the rate of \~10% decrease per decade **[Test of renal structure and function]:** - Urinalysis of serum **creatinine** and blood urea nitrogen (**BNU**). The average creatinine level is about **0.7 to 1.5** mg/dl; The average BUN average is about **10 to 20** mg/dl. - *Urine casts present*: WBC casts associate with renal infection (**pyelonephritis**); RBC casts indicate; inflammation of glomerulus (**glomerulonephritis**); Epithelial cell casts indicate sloughing of tubular cells (**acute tubular necrosis**). - An estimate of GFR called the Modification of Diet in Renal Disease study equation (MDRD) can be made using only patient demographics and serum creatinine value (Scr). This estimate is based on an average body surface area for an adult of 1.73 m^2^. It does not require urine collection, making it simple compared with other measures of clearance: The **MDRD** is a calculated method of estimating GFR using serum **creatinine** values. - *Measures of Glomerular filtration rate: **GFR*** (ml/min/1.73 m^2^) = 186 x (S~cr~)^-1.154^ x (Age)^-0.203^ x (0.742 if **female**) x (1.210 if **African American**). - A diagnostic test of serum **creatinine** (or **inulin**) clearance rate is used to determine the GFR in an individual. At low GFR, creatinine clearance is unreliable and administration of **cimetidine** can improve the accuracy of creatinine clearance test. - BUN value is less specific **[Diagnostic tests]:** 1), Kidney, Ureter, and Bladder Roentgenography; 2), Intravenous Urography/pyelography; **3**), Radionuclide studies; 4), Ultrasonography; 5), Computed Tomography; 6), Magnetic Resonance Imaging, 7), Renal Biopsy.