7) Pharmacology - Hepatic Clearance

Front 1

describe the hepatic vascular system?

Back 1

hepatic artery (25%) + portal veing (75%) > liver > hepatic v > vena cava

Front 2

how do substances leave the liver?

Back 2

via hepatic V or via bile into small intestine as feces

Front 3

what occurs with proteins in the liver?

Back 3

protein metabolism

Front 4

what occurs during protein metabolism?

Back 4

remove ammonia by synthesis of urea and syntehsize plasma proteins & clotting factors

Front 5

what occurs with fat in the liver?

Back 5

fat metabolism

Front 6

what occurs during fat metabolism?

Back 6

synthesize lipoproteins, oxidize triglycerides for energy and synthesize cholesterol and phospholipids

Front 7

what occurs with carbodydrates in the liver?

Back 7

carbohydrate metabolism

Front 8

what occurs during carbohydrate metabolisms?

Back 8

regulate glucose

Front 9

what occurs with drugs in the liver?

Back 9

drug metabolisms

Front 10

what occurs during drug metabolism?

Back 10

eliminate lipophilic drugs by conversion to polar metabolites which are less likely to be reabsorbed in the kidney (which reabsorbs lipophilic drugs)

Front 11

what is a consequence of drug metabolism in the liver?

Back 11

first pass effect

Front 12

what is first pass effect?

Back 12

liver gets first pickings of venous blood from intestines

Front 13

what is the term for the liver getting first pickings of venous blood from intestines?

Back 13

first pass effect

Front 14

how does blood flow through the liver?

Back 14

terminal branches of portal v & hepatic a empty together and mix as they encounter sinusoids in liver > blood flows through sinusoids > empties in central v of each lobule

Front 15

what occurs in the space of disse?

Back 15

plasma is filtered between endothelium and hepatocytes (lymph)

Front 16

what are the phases of drug metabolism in the liver?

Back 16

phase I metabolism and phase II metabolism

Front 17

what does phase I metabolism do?

Back 17

makes compounds more polar

Front 18

how does phase I Metabolism process drugs?

Back 18

oxidation (alkyl, aromatic, S, N, dealkylation), Reduction (N), Hydrolysis (esters, amides)

Front 19

what is the most commen oxidation process in phase 1 metabolism?

Back 19

Mixed Function Oxidase System found in many tissues

Front 20

what does MFOS stand for?

Back 20

Mixed Function Oxidase System

Front 21

what is MFOS?

Back 21

a hepatic cytochrome P450 system that consists of an enzyme superfamily and multiple isoenzymes that metabolizes endogenous compounds

Front 22

what are the cofactors of MFOS?

Back 22

FDA, FADH2, NADPH

Front 23

what regulates synthesis if the MFOS?

Back 23

cystolic receptor

Front 24

what do foreign compounds do to MFOS?

Back 24

induce or inhibit

Front 25

what is the output of phase I drug metabolism?

Back 25

Drug-OH & H2O

Front 26

what may have an immediate affect on MFOS?

Back 26

substrate competition

Front 27

how long does enzyme induction take on MFOS?

Back 27

days to weeks

Front 28

what is an example of a drug that affects MFOS?

Back 28

corticosteroids increase gene activation of P450 isoenzymes which can increase the metabolism of other drugs

Front 29

what does phase II metabolism do?

Back 29

makes compounds more polar and larger

Front 30

how does phase II metabolism process drugs?

Back 30

conjugation (glucuronidation, acytlation)

Front 31

what is the essential role of hepatic metabolism?

Back 31

to turn lipophilic metabolites into polar metabolites

Front 32

what is the role of hepatic metabolism on drugs?

Back 32

inactivation of active compounds (drug)

Front 33

what are examples of inactivation of active compounds?

Back 33

prodrugs (when metabolites have enhanced activity) & lethal synthesis (when metabolite is toxic)

Front 34

in hepatic metabolism induction, inhibition and competition can be caused by what?

Back 34

own metabolism, other substances, multiple mechanisms, and various effects on induction or inhibition (different enzyme systems, high or low extraction)

Front 35

what else effects drug metabolism?

Back 35

diet/nutrition, age, disease (changes in blood flow, plasma protein binding, liver damage), gender (males higher rate), and genetic polymorphism (ie ethanol and debrisoquine tolerance)

Front 36

what are some species differences in drug metabolism that affect toxicity, efficacy, and residues?

Back 36

(1) CytP450 isoenzyme make up (2) differences in substrate availability for conjugation (cats deficient in glucaronic acid - aspirin toxicosis, pigs deficient in sulfate, avian deficient in glycine) (3) high ER results in scaling of blood flow rate across species, (4) low ER = scaling of liver mass across species

Front 37

what are cats deficient in that affects hepatic metabolism and what does it cause?

Back 37

glucaronic acid conjucation resulting in aspirin toxicosis

Front 38

can hepatic metabolism be saturated?

Back 38

yes, at high doses

Front 39

what occurs if hepatic metabolism is saturated at high doses?

Back 39

delayed elimination and potential for increase in drug effects and toxicity

Front 40

what does the biliary system do?

Back 40

conveys bile from hepatocytes to lumen of small intestine

Front 41

what is bile?

Back 41

a secretory and excretory product of hepatocytes

Front 42

what is the pathway of the biliary system?

Back 42

conveys bile into bile canaliculi > flow parallel to sinusiods but in opposite direction > into bile ducts (in portal triads)

Front 43

what is biliary clearance?

Back 43

the active secretion of polar drugs, drugs with MW > 300g/mol, and the glucuronide conjugates of many drugs (nonpolar and small drugs are reabsorbed)

Front 44

is the biliary clearance system saturable?

Back 44

yes and competition may occur

Front 45

illustrate biliary clearance?

Back 45

Clbile = Qbile x Cbile / Cplasma

Front 46

how is the biliary system supplied with blood?

Back 46

enterohepatic circulation

Front 47

what are the mechanisms of biliary clearance?

Back 47

(1) secretion of weak acids (2) secretion of weak bases (3)secretion of neutral compounds (4) secretion of metals

Front 48

name some weak acid drugs that undergo biliary clearance?

Back 48

penicillin, tetracycline, flunixin, glucuronides, bile acids

Front 49

name some weak base drugs that undergo biliary clearance?

Back 49

erythromycin, isoproterenol, atropine, curare

Front 50

name some neutral drugs that undergo biliary clearance?

Back 50

digoxin, digitoxin

Front 51

name some metals that undergo biliary clearance?

Back 51

lead

Front 52

what are the differences in biliary clearance across species?

Back 52

significant differences in transport processes and MW threshold

Front 53

what species are good bilieary excretors?

Back 53

dog, chicken, rat

Front 54

what species are intermediate biliary excretors?

Back 54

cat, sheep

Front 55

what species are poor biliary excretors?

Back 55

rabbit, GP, monkey, man

Front 56

what is the toxicological significance of species differences in biliary clearance?

Back 56

high intracellular concentrations of drugs and different compounds that result from metabolism

Front 57

how does milk clearance occur?

Back 57

there is a lipid barrier between plasma and milk so lipid soluble drugs can easily cross and the pH of milk tends to be more acidic causing ion trapping of basic drugs which is important in the treatment of mastitis & drug residues in milk

Front 58

what is an example of a drug that might be ion trapped in milk clearance?

Back 58

erythromycin

Front 59

what is hepatic clearance determined by?

Back 59

the hepatic blood flow x the hepatic extraction rate

Front 60

illustrate hepatic clearance?

Back 60

ClH = QH x ERH

Front 61

give an alternative illustration of hepatic clearance?

Back 61

ClH = (QH x fub x Clint) / (QH + fub x Clint)

Front 62

what factors affect hepatic clearance?

Back 62

(1) blood flow (2) plasma protein binding (3) intrinsic clearance/enzyme activity

Front 63

how do the factors affecting hepatic clearance differ from renal clearance?

Back 63

hepatic clearance is affected by enzyme activity while renal clearance is affected by filtration/secretion

Front 64

what does QH stand for?

Back 64

hepatic blood flow

Front 65

what does ERH stand for?

Back 65

hepatic extraction ratio

Front 66

in hepatic clearance, a high ER drug can be illustrated how?

Back 66

ClH = QH

Front 67

how does blood flow affect high ER drugs in hepatic clearance?

Back 67

blood flow changes ClH but has no effect on ERH

Front 68

in hepatic clearance, a low ER drug can be illustrated how?

Back 68

CLH = (fu x Clint) where Clint is intrinsic organ clearance or metabolism

Front 69

how does blood flow affect low ER drugs in hepatic clearance?

Back 69

has no effect on ClH but has inverse effect on ERH

Front 70

in hepatic clearance the Cl is affected by what factors?

Back 70

blood flow to the organ (Q), extent of plasma protein binding (fu), and intrinsic organ clearance (Clint)

Front 71

how does high ER affect plasma protein binding?

Back 71

fast drug removal independent of binding with the rate of elimination dependent on total concentration of the drug (bound and unbound)

Front 72

how does low ER affect plasma protein binding?

Back 72

clearance depends on plasma protein binding and the rate of elimination is related to unbound concentration because it is the only fraction that penetrates membranes and is available for elimination by liver

Front 73

how does High ER affect intrinsic clearance (enzyme activity)?

Back 73

enzyme activity is so high that minor changes on it don't have signifiacant effect

Front 74

how does low ER affect intrinsic clearance (enzyme activity)?

Back 74

ClH directly proportional to enzyme activity; enzyme activity is saturable and inducilbe and inhibitable