Hepatic Physiology Listen to Audio Hepatic Blood Flow Metabolic Functions Drug Metabolism HEPATIC BLOOD FLOW -hepatic blood flow ~ 1500 ml/min provided by both the hepatic artery and portal vein Hepatic artery -hepatic artery supplies 25 – 30% of total hepatic blood supply: ~ 375 - 450 ml/min -hepatic artery supplies 45 –50% of hepatic oxygen demand / metabolic requirements -hepatic artery pressure correlates with arterial pressure -hepatic artery oxygen saturation generally 100% Sa02 -hepatic artery flow generally dependent on metabolic oxygen demand / autoregulation Receptors within hepatic artery include: α1 adrenergic receptors: stimulation results in vasoconstriction β2 adrenergic receptors: stimulation results in vasodilation D1 dopaminergic receptors: stimulation results in vasodilation Cholinergic receptors: stimulation results in vasodilation Sympathetic stimulation upon hepatic artery results in: -vasoconstriction of hepatic artery -resultant decreased hepatic blood flow Portal vein -portal vein supplies 70 – 75% of total hepatic blood supply : ~ 1050 - 1125 ml/min -portal vein supplies 50 – 55% of hepatic oxygen demand / metabolic requirements -portal vein pressure correlates with venous pressure, generally x < 10mmHg -portal vein oxygen saturation generally approximately 85% Sa02 -portal vein flow generally dependent on blood flow to both GI tract and spleen Receptors within the portal vein include: α1 adrenergic receptors: stimulation results in vasoconstriction D1 dopaminergic receptors: stimulation results in vasodilation Sympathetic stimulation upon mesenteric artery results in: -vasoconstriction of mesenteric artery -resultant decrease in hepatic blood flow METABOLISM CARBOHYDRATE METABOLISM -carbohydrates are metabolized primarily into glucose, galactose and fructose -glycolysis: process of utilizing glucose to produce ATP: 1 glucose produces 2 ATP -TCA cycle: process of utilizing pyruvate (from glucose) to produce ATP: 1 glucose produces 38 ATP -when plasma glucose is abundant (ex. postprandial): may be stored as glycogen within liver and muscle -when glycogen storage exceeds its capacity extra glusose then becomes stored as fat within adipose tissue -hepatic glycogen storage capacity ≈ 70 grams -average daily glucose consumption ≈ 150 grams -gluconeogenesis helps maintain normal blood glucose levels via de novo synthesis of glucose Glycogen synthesis enhanced with: -insulin Glycogen synthesis inhibited with: -epinephrine -glucagon Gluconeogenesis enhanced with: -glucocorticoids -catecholamines -glucagon -thyroxine Gluconeogenesis inhibited with: -insulin FAT METABOLISM -fatty acids are metabolized into acetyl-CoA -acetyl-CoA is oxidized using the TCA cycle to produce ATP PROTEIN METABOLISM -deamination of amino acids -formation of urea -bidirectional conversion of amino acids ←→ protein -production of plasma proteins -production of all clotting factors (except factor VIII) -production of vitamin K dependent factors (X,IX,VII,II) -production of plasmacholinesterase -production of pseudocholinesterase -protease inhibitors (ex. antithrombin III, α2 antiplasmin, α1 antitrypsin) -transport proteins (ex. transferin, haptoglobin, ceruloplasmin) -complement proteins -glycoproteins (α1 acidic glycoprotein) -C-reactive protein -serum amyloid proteins DRUG METABOLISM Phase I reactions: attempt to inactivate the molecule ex. cytochrome P450 enzyme complex involved with: -oxidation -reduction -deamination -sulfoxidation -dealkylation -methylation Factors which may stimulate cytochrome p450 enzymes includes: -increases tolerance of drugs dependent on p450 due to increased metabolism and removal -ethanol -barbiturates -ketamine -benzodiazipine (ex. diazepam) Factors which may inhibit cytochrome p450 enzymes includes: -increases sensitivity of the drugs dependent on p450 therefore caution must be given to prevent overdose -cimetidine -chloramphenicol Phase II reactions: attempt to make the compound more water soluable via conjugation -therefore more readily excreted via urine Conjugation may occur with the following compounds: -glucuronide -sulfate -taurine -glycline Drugs dependent on Hepatic Blood Flow may be due to: -increased rate of hepatic extraction ex. lidocaine -morphine -verapamil -labetolol -propranolol