E in ADME

Question 1

what is a one compartment model?

Answer 1

single IV bolus admin. = fast drug distrib. = rapid equilibrium established = proportional clearance of drug eliminated from blood

Question 2

how do you work out the conc. of drug in a one compartment model?

Answer 2

conc = dose/Vd

Question 3

where is majority of drugs eliminated/cleared?

Answer 3

mainly in the kidney or liver

less importantly - excretion via lung/saliva/sweat

Question 4

how does pulmonary drug excretion occur?

Answer 4

excretes gaseous and volatile substances

Question 5

how can pulmonary drug excretion be tested?

Answer 5

alcohol breathalysers tests - excretion of ethanol

Question 6

how does salivary drug excretion occur?

Answer 6

bind to saliva - depending on pH partition and protein binding

saliva drug conc. could be used to indicate drug plasma conc.

Question 7

how does renal drug excretion occur?

Answer 7

main excretion

via urine thru the kidneys during regulation of fluid volume and composition within the body

Question 8

what is an issue with swallowed saliva in terms of excretion?

Answer 8

saliva bound to drug depending on pH partition and protein binding = drug reabsorption

Question 9

how do the kidneys eliminate drug substances?

Answer 9

1. metabolism (sometimes)
2. excretion in the urine

Question 10

what processes handle renal excretion?

Answer 10

1. glomerular filtration
2. tubular secretion
3. tubular reabsorption - active/passive

Question 11

what molecules are excreted in glomerular filtration?

Answer 11

free drug - unbound drug
small, water soluble drugs
depends on size - fit thru pores

Question 12

what molecules are excreted in tubular secretion?

Answer 12

secreted molecules
specialised active transport systems

Question 13

what molecules are excreted in tubular reabsorption?

Answer 13

lipophilic and unionised drug crosses
Hydrophilic and ionised drugs cannot cross
influenced by drug lipophilicity

Question 14

what is GFR?

Answer 14

Rate of blood filtering in the glomeruli = glomerular
filtration rate

Question 15

what is the GFR in a normal adult male?

Answer 15

125 mL/min in normal adult male

Question 16

what can lower GFR?

Answer 16

impaired kidney functions

Question 17

what drugs are excreted via tubular secretion?

Answer 17

weak acids
penicillins

Question 18

how can we alter renal eliminiation?

Answer 18

change urine pH

Question 19

what happens when reduce urine pH?

Answer 19

acidic urine

1. weakly acidic drugs = unionised + reabsorbed = reduced elimination
2. weakly basic drugs = ionised = increased elimination

Question 20

how can you get acidic urine?

Answer 20

protein rich diets
ascorbic acid co-administration

Question 21

what happens when increase urine pH?

Answer 21

basic urine

1. weakly basic drugs = unionised + reabsorbed = reduced elimination
2. weakly acidic drugs = ionised = increased elimination

Question 22

how can you get basic urine?

Answer 22

co-administer bicarbonates

Question 23

how do you calculate the renal excretion?

Answer 23

glomerular filtration + tubular secretion - tubular reabsorption

Question 24

how is the rate of renal elimination calculated?

Answer 24

determining the renal clearance of creatinine

Question 25

what is creatinine?

Answer 25

calculates rate of renal elimination endogenous compound eliminated by the kidney only - tests kidney function

Question 26

how are drugs excreted in the liver?

Answer 26

mainly via drug metabolism. - phase

Question 27

how are drugs excreted in the liver?

Answer 27

mainly via drug metabolism. - phase1 AND phase 2 reactions

Question 28

what drug metabolism reactions undergo in the liver?

Answer 28

phase 1 - drug oxidised/reduced/hydrolysed polar groups phase 2 - couples the drug to an endogenous molecule to form a metabolite to become pharmacologically inactive and highly water soluble

Question 29

pathology of drugs eliminated in the liver

Answer 29

must enter hepatocytes, may be metabolised, secreted into the blood or bile bile enters the small intestine ( some material may resorb into the blood) or excreted in faeces

Question 30

what is enterohepatic circulation?

Answer 30

material reabsorbed into the blood from the bile in the small intestine

Question 31

what drugs enter enterohepatic circulation?

Answer 31

NSAIDs opioids digoxin warfarin some antibiotics

Question 32

how does drugs MW impact excretion route in the liver?

Answer 32

Drugs with MW <300 are excreted almost exclusively into urine Drugs with MW 300-500 are excreted in both urine and bile Drugs with MW >500 are excreted almost exclusively into bile

Question 33

what is drug clearance influenced by?

Answer 33

dose blood flow function of liver/kidney plasma protein binding

Question 34

how do you work out the clearance of a drug?

Answer 34

(ELIMINATION RATE CONSTANT)/fraction of drug cleared per unit time x Vd

Question 35

what drugs bind to albumin?

Answer 35

acidic drugs

Question 36

what reduces albumin binding?

Answer 36

disease state e.g. cancer competition e.g. presence of a second acidic drug

Question 37

what does reduce albumin binding mean?

Answer 37

more free drug = more drug able to be excreted

Question 38

describe the total body clearance?

Answer 38

overall clearance of a drug by all eliminating organs

Question 39

describe the organ body clearance?

Answer 39

clearance of a drug by a specific organ e.g. renal clearance = volume of plasma/blood cleared of drug per unit time by the kidney

Question 40

how do you calculate total body clearance?

Answer 40

renal Cl+ hepatic Cl+ other organs Cl renal Cl (CLr) + metabolic Cl (CLm) blood flow to the organ (Q) X extraction rate of the organ (E)

Question 41

how do you work out the renal elimination rate constant?

Answer 41

renal clearance/ Vd

Question 42

how do you work out the metabolic elimination rate constant?

Answer 42

metabolic clearance/Vd

Question 43

what is Fe?

Answer 43

fraction of the (bioavailable) drug dose that is unchanged in urine

Question 44

how do you workout Fe?

Answer 44

CLr/CLt kR/ke

Question 45

what is hepatic extraction?

Answer 45

Hepatic extraction = the rate at which the liver extracts drug from the blood – by metabolism and removal into bile

Question 46

what does the hepatic extraction rate depend on?

Answer 46

hepatic blood flow (HBF) intrinsic ability of the liver to handle (e.g. metabolise) the drug

Question 47

how do you workout the maximum hepatic extraction rate?

Answer 47

drug conc x HBF (hepatic blood flow)

Question 48

what is the extraction ratio (E)?

Answer 48

Fraction of drug amount presented to the organ which is eliminated during a single pass through the organ

Question 49

what do the extraction values (E) mean?

Answer 49

0 - most of the drugs escapes elimination during a single pass through the organ 1 - most of the drug is eliminated during a single pass through the organ

Question 50

how do you workout the extraction rate (E)?

Answer 50

(conc in - conc out)/ conc in

Question 51

what is the value for hepatic blood flow?

Answer 51

1.5L/min

Question 52

what are low extraction drugs?

Answer 52

diazepam, warfarin, salicylic acid, phenytoin, and procainamide

Question 53

what are high extraction drugs?

Answer 53

lidocaine, propranolol, morphine, verapamil

Question 54

what does it mean if the hepatic extraction ratio <0.3?

Answer 54

low extraction ratio drugs

Question 55

what does it mean if the hepatic extraction ratio >0.7?

Answer 55

high extraction ratio drugs

Question 56

what does it mean if the hepatic extraction ratio 0.3-0.7?

Answer 56

intermediate extraction ratio drugs

Question 57

what are low extraction ratio drugs affected by?

Answer 57

unchanged by changes in blood flow

Question 58

what are high extraction ratio drugs affected by?

Answer 58

greatly affected by changes in blood flow hepatic blood flow increase = during meal digestion hepatic blood flow decrease = exercise/ cirrhosis/ heart failure/ old age

Question 59

when does hepatic blood flow increase?

Answer 59

during meal digestion

Question 60

when does hepatic blood flow decrease?

Answer 60

exercise/ cirrhosis/ heart failure/ old age