Pharmacokinetics Malarkey 3 Flashcards
What is vigabatrin?
Compound used to treat epilepsy
How does vigabatrin work?
Active-site directed irreversible enzyme inhibitor
What percentage of the population suffers from epilepsy?
0.5 - 1%
What causes epilepsy?
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
How is GABA metabolised?
Glutamic acid -> GABA -> succinic semialdehyde -> succinic acid
Which enzyme metabolises GABA to succinic semialdehyde?
GABA aminotransferase
What effect does inhibition of GABA aminotransferase have?
Increase levels of GABA
What is the co-factor used by GABA aminotransferase?
Pyridoxal phosphate
Where does pyridoxal phosphate bind to GABA aminotransferase?
Binds to a special binding pocket in the enzyme active site
What does pyridoxal phosphate form?
A schiff base with an amine
What does the aromatic ring of pyridoxal phosphate act as?
Electron sink
What type of reactions are catalysed by GABA aminotransferase?
Racemisation of amino acids
Transamination
Decarboxylation
Side chain interconversion
What is the mechanism of vigabatrin?
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
What is 5-fluorouracil?
Anti-cancer agent
How does 5-fluorouracil work?
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
What is thymidine?
An essential nucleic acid
- constituent of DNA
What is thymineless death?
5-fluorouracil interferes with the only pathway that the cell has of making thymidine
How is 5-fluorouracil selective for cancer cells?
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
How is K dependent upon V if CL is fixed?
K = CL / V
How is K dependent upon CL if V is fixed?
K = CL / V
How is Css dependent on input and clearance?
Css = I0 / CL
I0 = rate of zero-order administration CL = clearance of drug form body Css = steady state drug concentration
When does steady state occur?
When the rate of drug input = rate of elimination
What type of disposition is steady-state?
First order disposition concept
How is steady state achieved with continuous input?
Rate in = rate out
How is steady state achieved with repeated intermittent dosing?
Rate in during dosing interval = rate out during dosing interval
How is steady state achieved during intermittent dosing?
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
How does rate of elimination affect Cmax and Tmax?
As K increases, Cmax and Tmax decreases
How does increased V affect elimination t1/2?
As V increases
- t1/2 increases
- lower Css max
- higher Css min
