Pharmacological changes of dysfunctional hepatic system

Question 1

Where do drug-drug interactions occur?

Answer 1

the liver

Question 2

how are drugs metabolised?

Answer 2

1. enzyme mediated modification of chemical structure of a molecule
2. primary purpose is to make fat soluble chemicals water soluble
3. then drug is removed from systemic circulation

Question 3

Consequences of drug metabolism?

Answer 3

1. metabolite can be more active than parent product
2. metabolite can be toxic
3. metabolite can be carcinogen

Question 4

Where does metabolism occur?

Answer 4

liver is the main organ but nearly all tissue have the capacity to metabolise.

Question 5

When does SI metabolism come in handy?

Answer 5

For metabolising orally ingested chemicals

Question 6

How many reactions/steps are involved when dealing with a drug with many metabolites?

Answer 6

• phase I
• phase II
• phase III

Question 7

What happens during phase I reactions?

Answer 7

• parent compound is converted into a chemically active more polar metabolite through adding or masking functional groups. This is to enable it to be excreted.
• Reactions are oxidative and CYP-mediated.

Question 8

What happens during phase II reactions?

Answer 8

• conjugation of parent compound with endogenous substrate (e.g. glucoronide, sulphate, amino acid etc) to increase aqueous solubility. –The metabolites produced are usually inactive.
• Three key enzymes for this phase: Glucuronyl transferases, Sulfotransferases, Glutathione-S-Transferases

Question 9

What happens during phase III reactions?

Answer 9

-Efflux of metabolites and sometimes unchanged parent molecule into bile and urine.

Question 10

Which part of the body is responsible for most Phase I biotransformations(reactions)?

Answer 10

The haem-containing proteins in the smooth ER

Question 11

Factors that affect drug metabolism?

Answer 11

1. physico-chemical factors (drug structures)
2. Biological factors (age, gender, genetics, state of health)
3. Environmental factors (diet, drug-drug interactions, stress, season)

Question 12

During drug-drug interactions drug A can competitively inhibit Phase I metabolic enzyme (CYP450). What does this mean for drug B?

Answer 12

It means it won’t be able to interact with CYP450 so drug A is reducing the clearance of drug B which will increase drug B toxicity

Question 13

If Drug A induces the expression or activity of phase I metabolic enzymes, what does this mean for drug B?

Answer 13

it increases the elimination of drug B. But also increase the production of toxic drug B metabolites

Question 14

If drug A alters the metabolic route of drug B, what will happen?

Answer 14

-different metabolites will be formed and their clearance will be altered resulting in toxicity

Question 15

How can drug interactions affect the pharmacokinetics of a drug?

Answer 15

one drug can alter the rate/extent of ADME of another drug.

Question 16

How can drug interactions affect the pharmacodynamics of a drug?

Answer 16

one drug can change a patients response to another drug without altering the drugs pharmacokinetics

Question 17

Ways that drugs interefere with each other’s pharmacodynamics?

Answer 17

1. potentiation/antagonism at target receptor or off-target receptor.
2. alteration of fluid/electrolyte environment
3. interference with transport mechanism

Question 18

How can drug interactions affect the pharmaceutics of a drug?

Answer 18

interactions occurring before systemic administrations e.g. mixing drugs in IV fluid.

Question 19

How can drug interactions affect the absorption of a drug?

Answer 19

One drug alters the absorption of another drug via:

• changing GI pH
• binding in GI tract
• changing GI motility
• Malabsorption caused by drug

Question 20

How can drug interactions affect the excretion of a drug?

Answer 20

Drug A can increase or decrease the excretion of drug B.

Question 21

How are metabolic enzymes induced?

Answer 21

CYP substrates induce CYP transcription. More CYP produced as a result, therefore drug metabolism increases.
Induction is specific for one or only a few CYPs. (slide 21 for which CYPs are induced by which substrate)

Question 22

Drugs that commonly inhibit CYPs?

Answer 22

1. macrolide antibiotics
2. antifungal agents
3. HIV protease inhibitors
4. St John’s Wort

Question 23

Explain the drug-drug interaction between St John’s Wort and warfarin?

Answer 23

• St John’s Wort binds to CYP3A4 inhibiting warfarin from binding
• results in increased blood warfarin levels
• this increases prothrombin time
• results in spontaneous bleeding

Question 24

Where else in the body can CYP3A4 be found besides the liver?

Answer 24

in the mucosa small intestines

Question 25

What type of juice can inhibit CYP3A4?

Answer 25

Grapefruit juice

Question 26

describe the 1st pass metabolism of felodipine and its interaction with grapefruit juice?

Answer 26

extensive metabolism of felodipine in intestinal enterocyte by CYP3A4 and further metabolism in liver. overall reduction in the bioavaiability of the drug.
-Grapefruit juice inhibits CYP3A4 in intestines so bioavailability of drug will increase as less is metabolised.

Question 27

how is alcohol metabolised in the body?

Answer 27

• alcohol dehydrogenase initiate detoxification of alcohol to acetaldehyde
• acetaldehyde dehydrogenase converts acetaldehyde to acetic acid (harmless)

Question 28

What drug inhibits acetaldehyde dehydrogenase and what is the consequence of this inhibition?

Answer 28

• Disulfiram
• consequence of this is a build up of acetaldehyde in the system and acetaldehyde is responsible for hang-over symptoms.

Question 29

4 ways drugs can induce liver injuries?

Answer 29

1. direct hepatocyte damage
2. mitochondrial toxicity
3. metabolite activity
4. cholestasis

Question 30

What is the periportal region of the hepatocyte(zone 1)?

Answer 30

• point of highest oxygenation with most O2 coming from hepatic artery and rest from deoxygenated blood of portal vein.
• least sensitive to ischaemia
• specialised for oxidative function
• most susceptible to viral hepatitis.

Question 31

What is the centrilobular region of the hepatocyte(zone 3)?

Answer 31

• point of lowest oxygenation
• affected during ischaemia
• major role in glycolysis, lipogenesis, CYP450 drug detoxification.

Question 32

Factors that can cause Drug Induced Liver Injuries (DILI)?

Answer 32

1. drug toxicity
2. higher dose
3. chemically active drug metabolites
4. genetic polymorphism

Question 33

what is targeted in order to cause mitochondrial toxicity?

Answer 33

ATP synthesis is inhibited which results in failure to generate ATP to sustain cells and tissues.
-also results in changes to glucose and lipid homeostasis.

Question 34

Where does Mitochondrial impairment typically affect?

Answer 34

1. most aerobically active tissues

2. tissues exposed to high drug concentrations

Question 35

How do tissues respond to mitochondrial failure?

Answer 35

• increases glycolysis resulting in increased lactate production.
• this results in abdominal pain, nausea, vomitting, dyspnea (breathing difficulties), tachypnea (rapid breathing)