Pharmacokinetics Malarkey 3

Question 1

What is vigabatrin?

Answer 1

Compound used to treat epilepsy

Question 2

How does vigabatrin work?

Answer 2

Active-site directed irreversible enzyme inhibitor

Question 3

What percentage of the population suffers from epilepsy?

Answer 3

0.5 - 1%

Question 4

What causes epilepsy?

Answer 4

An imbalance between 2 neurotransmitters

• L-glutamic acid
• an excitatory neurotransmitter
• gamma-aminobutyric acid (GABA)
• an inhibitory neurotransmitter

When the level of GABA falls below a threshold value convulsions occur

Question 5

How is GABA metabolised?

Answer 5

Glutamic acid -> GABA -> succinic semialdehyde -> succinic acid

Question 6

Which enzyme metabolises GABA to succinic semialdehyde?

Answer 6

GABA aminotransferase

Question 7

What effect does inhibition of GABA aminotransferase have?

Answer 7

Increase levels of GABA

Question 8

What is the co-factor used by GABA aminotransferase?

Answer 8

Pyridoxal phosphate

Question 9

Where does pyridoxal phosphate bind to GABA aminotransferase?

Answer 9

Binds to a special binding pocket in the enzyme active site

Question 10

What does pyridoxal phosphate form?

Answer 10

A schiff base with an amine

Question 11

What does the aromatic ring of pyridoxal phosphate act as?

Answer 11

Electron sink

Question 12

What type of reactions are catalysed by GABA aminotransferase?

Answer 12

Racemisation of amino acids
Transamination
Decarboxylation
Side chain interconversion

Question 13

What is the mechanism of vigabatrin?

Answer 13

Vagabatrin in inactive
It is activated by the enzyme
Once activated
- powerful Michael acceptor
- forms a covalent bond to the enzyme active site
Hydrolysed to release a Michael acceptor

Question 14

What is 5-fluorouracil?

Answer 14

Anti-cancer agent

Question 15

How does 5-fluorouracil work?

Answer 15

Interferes with the biosynthesis of thymidine

• fluorine is virtually the same size as H in 5-FU
• it is mistaken by the enzymes which normally process uracil

Question 16

What is thymidine?

Answer 16

An essential nucleic acid

- constituent of DNA

Question 17

What is thymineless death?

Answer 17

5-fluorouracil interferes with the only pathway that the cell has of making thymidine

Question 18

How is 5-fluorouracil selective for cancer cells?

Answer 18

Cancer cells replicate at a much higher rate than normal cells
- much larger requirement for thymidine
- hence the selectivity
Cancer cells cannot degrade uracil and 5-fluorouracil unlike normal cells

Question 19

How is K dependent upon V if CL is fixed?

Answer 19

K = CL / V

Question 20

How is K dependent upon CL if V is fixed?

Answer 20

K = CL / V

Question 21

How is Css dependent on input and clearance?

Answer 21

Css = I0 / CL

I0 = rate of zero-order administration
CL = clearance of drug form body
Css = steady state drug concentration

Question 22

When does steady state occur?

Answer 22

When the rate of drug input = rate of elimination

Question 23

What type of disposition is steady-state?

Answer 23

First order disposition concept

Question 24

How is steady state achieved with continuous input?

Answer 24

Rate in = rate out

Question 25

How is steady state achieved with repeated intermittent dosing?

Answer 25

Rate in during dosing interval = rate out during dosing interval

Question 26

How is steady state achieved during intermittent dosing?

Answer 26

Rate of drug input during a dosing interval = rate of drug elimination during a dosing interval

• at which point there is no net change in drug levels and a steady-state is achieved
• intermittent dosing means there will be fluctuation as a result of the intermittent dosing

Question 27

How does rate of elimination affect Cmax and Tmax?

Answer 27

As K increases, Cmax and Tmax decreases

Question 28

How does increased V affect elimination t1/2?

Answer 28

As V increases

• t1/2 increases
• lower Css max
• higher Css min