Physiology of Liver and Renal Function in Drug Elimination

Pre-Class Readings: Liver and Renal Physiology Related to Drug Elimination

• Drug elimination involves metabolism (biotransformation) and excretion.
• Liver and kidneys are major drug-eliminating organs.
• Hydrophilic drugs are readily excreted by the kidneys.
• Lipophilic drugs are transformed by the liver into more water-soluble metabolites for excretion by the kidneys or bile.

Overview of Liver Structure and Function

• Liver is vital for fat digestion, carbohydrate storage, blood detoxification, and protein production.
• Dual blood supply: 25% from hepatic artery, the remainder from portal vein (oxygen-poor, rich in absorbed substances from the gut).
• Portal triads (portal veins, hepatic arteries, and bile ducts) associate with afferent blood vessels.
• Blood from hepatic artery and portal vein combine in hepatic sinusoids, then drains into central veins, which merge into the hepatic vein.
• Hepatic cells lining bile canaliculi produce bile.
• Liver has a complex lymphatic drainage system.

Summary of Normal Liver Function

• The liver functions as a digestive, endocrine, hematologic, and excretory organ.
• Digestive: Bile salt secretion for fat digestion; Processing and storage of absorbed fats, carbohydrates, proteins; Processing and storage of vitamins and minerals.
• Endocrine: Metabolism of glucocorticoids, mineralocorticoids, and sex hormones; Regulation of carbohydrate, fat, and protein metabolism.
• Hematologic: Temporary storage of blood; Removal of bilirubin; Hematopoiesis (in some diseases); Synthesis of blood clotting factors.
• Excretory: Excretion of bile pigment, cholesterol; Synthesis of urea; Detoxification of drugs and foreign substances.

Drug Elimination and Biotransformation Reactions

• Liver drug metabolism is flow and site-dependent: varies in enzyme quantity, blood flow, and diseases.
• Enzymes like mixed-function oxidases (e.g., CYP enzymes) and non-CYP enzymes are involved in drug oxidation and reduction.
• Conversion into more polar metabolites increases elimination speed.
• Lipid-soluble drugs are reabsorbed; polar metabolites are not readily reabsorbed and excreted.
• Some metabolites are pharmacologically active or toxic. Prodrugs require biotransformation.

First-Pass Effects and Biliary Clearance

• First-pass effect: Oral drugs are metabolized in the liver or intestines before reaching systemic circulation, reducing bioavailability.
• Enterohepatic circulation: Drugs excreted in bile may be reabsorbed by intestines and returned to the liver.
• Many drugs excreted in bile are metabolites (often glucuronide conjugates).
• Biliary clearance (CLbiliary) measures drug removal by biliary secretion.
• Drug excretion in bile can be clinically significant, as it affects absorption, recycling.

Kidney Physiology

• Kidneys are located just below the diaphragm.

• Each kidney has a hilum (point where blood vessels, lymphatic vessels, nerves enter/exit).

• Blood supply is significant, approximately 25% cardiac output.

• Renal blood supply - the majority goes through the cortex, a smaller amount goes through the medulla.

• Nephrons: Functional units of the kidneys, essential for glomerular filtration, reabsorption, and secretion.

• Glomerulus: Filters fluid from blood into Bowman's capsule; prevents blood cells and protein passage.

• Proximal convoluted tubule: Transports filtered water, electrolytes, bicarbonate, glucose, amino acids, and vitamins to interstitial fluid.

• Descending Loop of Henle: Transports water, concentrates the filtrate

• Ascending loop of Henle. Actively transports Na+, K+, and Cl-, creating a hypo-osmotic filtrate.

• Distal convoluted tubule: Transports Na+, Cl-, water, and urea; responsive to aldosterone, site for macula densa regulation of GFR.

• Collecting tubule: Passive transport of water under ADH influence. Secretes H+ and K+.

• Glomerular filtration rate (GFR): Rate of filtration. Normal GFR is 125 ml/minute. Factors affect filtration pressure (blood volume, pathological states).

Regulation of Blood Volume and Osmolality

• Hormones regulate these through tubular reabsorption.
• ADH (antidiuretic hormone): Increases water reabsorption.
• Aldosterone: Increases sodium and water reabsorption
• ANP (atrial natriuretic peptide) and Urodilatin: Decrease reabsorption..

Renal Function Tests & Diagnostic Tests

• Urinalysis of serum creatinine and blood urea nitrogen (BUN).
• Glomerular filtration rate (GFR) measurements, assessing renal function. Using creatinine clearance.
• Imaging, blood tests, and biopsy.