Metabolism and Excretion

Question 1

Enterohepatic recirculation

Answer 1

Drugs that are eliminated in bile can be reabsorbed in GI tract

Question 2

2 processes forming elimination?

Answer 2

Metabolism + excretion

Question 3

Where does elimination mainly occur?

Answer 3

Kidney, liver, hepato-bilary system

Question 4

Main purpose of metabolism?

Answer 4

make lipid soluble drugs more water soluble

Question 5

Metabolism?

Answer 5

Enzymatic modification of a drug

Question 6

Where does meatbolism occur?

Answer 6

Liver

Question 7

Purpose of phase 1 metabolism?

Answer 7

Activate pro-drugs (introduce functional group)

Question 8

What enzyme regulates phase 1 metabolism?

Answer 8

Cytochrome P450

Question 9

Most common phase 1 metabolism?

Answer 9

Oxidation reaction

Question 10

Result of phase 1 metabolism?

Answer 10

Decreased lipid solubility

Increase pharmacological activity (activate pro-drugs)

Question 11

Where in liver/intestine is cytochrome P450 formed?

Answer 11

In ER or hepatocytes/enterocytes

Question 12

What type of reaction is phase II metabolism?

Answer 12

Conjugation reaction

Question 13

What part of the molecule does phase II metabolism target?

Answer 13

Functional group

Question 14

End product of conjugation?

Answer 14

Further decreased lipid solubility and pharmacologically inactive molecule

Question 15

Conjugation reaction?

Answer 15

Addition of group (acetyl, glucoronide) to decrease lipid solubility

Question 16

Most common conjugate reaction phase II reaction?

Answer 16

Glucuronidation

Question 17

Why are glucuronides inactive ad rapidly secreted?

Answer 17

Highly polar

Question 18

What enzyme is used in glucoronidation?

Answer 18

UDP-glucoronyl transferase

Question 19

How is paracetamol metabolised at therapeutic doses?

Answer 19

Mostly by phase II reaction by glucuronic acid
In liver
Minor proportion by cytochrome P450 = but this forms a toxic metabolite which is detoxified by phase II

Question 20

How is paracetamol metabolised at overdose?

Answer 20

Phase II reaction substrates are saturated so more is metabolised by cytochrome P450 = more toxic metabolite
These react with liver proteins = tissue damage and hepatic necrosis

Question 21

3 phases of renal excretion?

Answer 21

Glomerular filtration
Tubular secretion
Tubular reabsorption

Question 22

How much fo drug is filtered at glomerulus?

Answer 22

20%

Question 23

Rate of glomerular function dependent on?

Answer 23

Concentration of free drug in plasma and molecular weight

Question 24

Why is albumin not filtered at glomerulus?

Answer 24

Molecular weight too high

Question 25

Is glomerular filtration affected by lipid solubility or pH?

Answer 25

No

Question 26

Where does active tubular secretion occur?

Answer 26

Proximal tubule

Question 27

How is drug transferred into the lumen of proximal tubule?

Answer 27

``` Acids = acidic carrier against electrochemical gradient Bases = Organic carrier ```

Question 28

Is PPB a barrier to carrier mediated transport?

Answer 28

No

Question 29

How can competition occur in tubular secretion?

Answer 29

If drugs use same transporter

Question 30

Where does tubular reabsorption occur?

Answer 30

Loop of Henle

Question 31

As more water is reabsorbed how does drug concentration change?

Answer 31

Decreases

Question 32

What is tubular reabsorption dependent on?

Answer 32

pKa lipid solubility | pH of tubular fluid

Question 33

If tubule fluid is alkaline how will this affect reabsorption of acid and basic drugs?

Answer 33

``` Acids = ionised = won't pass through membrane = high urine concentration Bases = union ionised = pass through = less concentrated in urine ```

Question 34

Impact of urinary acidification of excretion?

Answer 34

Acidic drugs = unionised so reabsorbed | Basic drugs = ionised = high concentration = more excretion

Question 35

How do mechanisms of elimination depend on physicochemical properties? a) lipid soluble b) water soluble c) volatile gases

Answer 35

a) metabolised to water soluble and excreted into urine b) unchanged in urine c) exhalation

Question 36

Saturable elimination?

Answer 36

Above therapeutic dose the elimination mechanisms are saturated so not eliminated well

Question 37

Clearance?

Answer 37

Volume of plasma cleared of compound per unit of time

Question 38

How is clearance of IV calculated?

Answer 38

IV dose/AUC

Question 39

How is clearance of oral dose calculated?

Answer 39

Oral dose X F/oral AUC

Question 40

How can clearance be calculated without graph?

Answer 40

Ke x Vd

Question 41

Ke

Answer 41

Elimination rate constant = slope of log concentration time

Question 42

How is half life calculated?

Answer 42

0.693/Ke

Question 43

Purpose of inducers?

Answer 43

Increase synthesis of phase I and II enzymes to increase metabolism

Question 44

Implications of inducers?

Answer 44

Decrease drug effectiveness on chronic exposure Need higher dose Problem when withdrawn

Question 45

How can alcohol consumption effect paracetamol metabolism?

Answer 45

Ethanol = induces cytochrome P450 = more metabolised by CYP450 = more toxic metabolite