2.1.2 Clinical Pharmacokinetics and Pharmacodynamics II

Question 1

Name a Phase I enzyme and what it is involved in

Answer 1

Cytochorome P450 (CyP450)

Oxidation
Reduction
Hydrolysis

Question 2

What do Phase II enzymes produce?

Answer 2

Glucuronide
Sulphate
Glutathione
N-acetyl

Question 3

Once drugs gave been broken down by the liver what happens?

Answer 3

Excreted via kidney in the urine

or

Via gall bladder in bile, into faeces

Question 4

What factors affect drug metabolism?

Answer 4

Size
Lipophilicity
Hydrophobicity
Structural complexity

Question 5

What are the majority of phase 1 catalysed reactions catalysed by?

Answer 5

CYP450s

Found abundantly in smooth ER in hepatocytes and most other tissues

Question 6

What is the most important reaction by Phase I enzymes?

Answer 6

Oxidation

Question 7

What CYPs deal with most reactions?

Answer 7

CYP families 1-4

Question 8

Label the image

Answer 8

Question 9

What do CYPs do to drugs?

Answer 9

Active form - inactive (most drugs)

Inactive - active e.g. perindopril - preindoprilat

Active - active e.g. codeine- morphine or diazepam- oxazepam

Question 10

What can affect CYPs?

Answer 10

Induced or inhibited by endo/exogenous compounds affecting Phase I metabolism

Age- Decreased
Hepatic disease- Decreased
Blood flow- Increased/ decreased
Chronic alcohol- Increased
Smoking- Increased

Question 11

How does CYP 2D6 differ between populations?

Answer 11

Absent in 7% of european caucasians

Hyperactive in 30% of N/E Africans

More complex now due to more mixing

Question 12

What are some substrates for CYP2D6?

Answer 12

Beta blockers
SSRIs
Opioids- e.g. codiene may not have any effect for some people

Question 13

What can inhibit CYP2D6?

Answer 13

Some SSRIs, antiarrhythmics or antidepressants

Question 14

What is the clinical importance of CYPs?

Answer 14

Drug prescribing and complexity of polypharmacy

Question 15

What can affect CYPs from OTC or generically?

Answer 15

St John’s Wort
Grapefruit juice
Alcohol
Valerian

Question 16

What is self induced metabolism?

Answer 16

Drug can induce a CYP and simultaneously be a substrate for the same CYP

e.g. Carbamazepine, induces CYP3A4 and is a substrate for CYP3A4

Makes dosing difficult as can suddenly induce itself

Question 17

How are drugs removed from the body?

Answer 17

Metabolism and excretion
Primarily via kidney (typically low molecular weight polar metabolites) , sweat,tears, breast milk, genital secretions etc.

Solids- faeces

Question 18

What is renal excretion affected by?

Answer 18

GFR and protein binding e.g. gentamicin

Competition for transporters such as OATs e.g. penicillin

Lipid solubility, pH, flow rate e.g. aspirin

Question 19

How is renal excretion measured?

Answer 19

GFR

Question 20

How can gout be treated?

Answer 20

Make urine alkaline, Uric acid dissociates giving up its protons to neutralise pH of urine

It is then excreted as it cannot be reabsorbed

Question 21

What type of metabolite does the liver usually excrete?

Answer 21

High molecular weights, conjugated with glucoronic acid

Question 22

How does the hepatic system excrete metabolites?

Answer 22

Bile- excreted in faeces or reabsorbed

Enterohepatic circulation- recycles drugs from liver e.g. steroid hormones

Question 23

What can affect hepatic excretion?

Answer 23

Antibiotic drug interactions e.g. warfarin, antibiotic can decrease how much drug gets to liver and ergo less will be broken down

Question 24

Why does hepatic disease need to be considered when prescribing drugs?

Answer 24

May have reduced excretion so drug will have more affects