L36 - Drug Elimination - Metabolism

Question 1

What is elimination?

Answer 1

Irreversible loss of drug by excretion and/or metabolism

Question 2

What is excretion?

Answer 2

Irreversible loss of chemically unchanged drug
- mainly by kidneys (bile, sweat, saliva, air, milk

Question 3

What is metabolism?

Answer 3

Conversion of the drug into a different chemical species, aldo called biotransformation
- mainly by liver (lungs, GI wall, blood, skin, kidney)

Question 4

What does understanding elimination of a drug help to predict? (4)

Answer 4

• drug conc after uptake of med
• how liver and renal disease may affect drug conc
• interactions modifying the elimination of drugs
• variability in drug therapy

Question 5

What interaction modifying the elimination of drugs do we want to predict? (3)

Answer 5

• drug-drug interactions
• food-drug interactions
• natural/herbal products - drug interactions

Question 6

What are the variabilities in drug therapy? (2)

Answer 6

• age
• genetic differences in metabolisin enzymes

Question 7

What is clearance (CI)?

Answer 7

The way the elimination process for each drug is described and quantified by

Question 8

What are the most important pharmacokinetics parameters for a drug? (2)

Answer 8

• clearance (CI)
• volume of distribution (V)

Question 9

What does CI and V for a drug determine? (3)

Answer 9

• the conc that will be achieved after dose
• how the conc of a drug will evolve with time
• the body exposure to the drug

= effects and toxicity

Question 10

What is clearance defined as (proportionality)?

Answer 10

The proportionality factor that relates the elimination rate of a drug with the drug concentration in blood (plasma)

Question 11

What is clearance (volume)?

Answer 11

Volume of fluid (blood, plasma) that is completely cleared of drug per unit time

Question 12

What is the eqn for rate of elimination?

Answer 12

Rate = clearance x Cdrug
Mass/time = volume/time x mass/volume

Question 13

The steeper the slope…

Answer 13

The greater the CI (vol/time)

Question 14

In clearance and plasma profiles, the more curved…

Answer 14

The higher the CI of the drug, the faster the plasma levels decay

Question 15

What is the steady state?

Answer 15

Rate in = rate out
Dose/time = CI x Css

Question 16

What is additivity of clearance?

Answer 16

• clearance by one organ/tissue adds to the – - clearance by other organs/tissues

Question 17

What is the total elimination rate?

Answer 17

The sum of the elimination rate by each organ

Question 18

What is the eqn for rate of elimination (Sum)?

Answer 18

Rate of elimination - rate of renal excretion + rate of hepatic metabolism

Question 19

What is the total CI?

Answer 19

Total CI = renal clearance + hepatic clearance
Sum of clearance(organ)

Question 20

What is metabolism (biotransformation)?

Answer 20

A defence mechanism against undesriable foreign compounds, including drugs

Question 21

What are the most common routes of metabolism? (2)

Answer 21

• ox, red, hydrolysis - phase I
• conjugation - phase II

Question 22

What can metabolites be? (4)

Answer 22

• inactive
• toxic
• active, as the drug administered
• exploited therapeutically

Question 23

What does administration of prodrugs relies on?

Answer 23

Metabolism to form the active compound (the metabolite) from the inactive prodrug

Question 24

Where does the liver receive blood from? (3)

Answer 24

• hepatic artery 25%
• hepatic portal vein from various GI segments 75%
• liver receives ~ 1.5L/min

Question 25

What is the pathway of blood in the liver? (2)

Answer 25

- blood arrives from both systems fuse and enter the liver capilaries called sinusoids - blood leaves the liver via the hepatic vein -> vena cava

Question 26

What does the liver do? (2)

Answer 26

- secrete bile acids, empty common bile duct -> gall bladder - excretes and metabolises drugs

Question 27

What does hepatic elimination processes include?

Answer 27

Metabolism and biliary excretion

Question 28

What does liver elimination work on?

Answer 28

Endo and exogenous substances

Question 29

What are lipophilic chemical usually metabolised into?

Answer 29

More hydrophilic entities - excreted into urine or bile

Question 30

What may drugs in blood be? (3)

Answer 30

- bound to plasma protein - bound to blood cells - free (unbound)

Question 31

What high biliary clearance like? (3)

Answer 31

- polar - MW >350 - actively secreted // drugs - pravastatine, metabolies - glucuronide conjugates of drugs

Question 32

what must a drug be like to be metabolised by one specific enzyme? (2)

Answer 32

- right 3D structure to interact with enzyme site responsible for the reaction - have a certain affinity for this site

Question 33

What are enzyme drug reactions typically described by?

Answer 33

The michaelis menten equation

Question 34

What do the P450 enzymes do?

Answer 34

ox and red of many drugs

Question 35

What are some characteristics of drug metabolism? (5)

Answer 35

- substrate specificity - enzymatic reactions follow mm kinetics - drug metabolism is saturable - drug interactins - variability

Question 36

What is the elimination rate eqn following michaeli menten kinetics?

Answer 36

Elimination rate = Vmax + C/ Km + C Vmax - max elim rate Km - michaelis constant (conc of drug at which the rate of process equals 1/2 Vmax

Question 37

When is drug metabolism saturable?

Answer 37

At high concs, the rate of elim becomes constant and equals Vmax

Question 38

How is the MM kinetics model used for describing enzymatic reactions? (3)

Answer 38

- D forms complex ED with E - ED metabolised = M - M leaves enzymatic site and E can accept D

Question 39

What are the 2 drug interactions looked into?

Answer 39

- enzyme inhibition - direct or competitive - enzyme induction - other chem increases activity of enzyme

Question 40

What are enzyme inducers? (4)

Answer 40

- smoking - insecticides - rifampin - phenobarbita;

Question 41

What are enzyme inhibitors? (2)

Answer 41

- SSRIs inhibit CYP2D6 system - grapefruit inhibits CYP3A4

Question 42

What is variability?

Answer 42

Levels and activity of enzymes may differ in individuals = different values of clearance for a same drug

Question 43

What are variability examples? (2)

Answer 43

- genetic variations - fast/slow/ultra fast metaboliser - age, physiopathology (hepatic disease)