Metabolism of AED drugs Flashcards
1
Q
Valproic acid/ divalproex sodium inhibits what?
A
Inhibits: 2C9, UGTs, and epoxide hydrolase
2
Q
How is valproic acid/ divalproex sodium metabolized?
A
Direct glucuronidation - inactive
B-oxidation forming a 2-ene metabolite
3
Q
How is the half-life valproic acid affected by other AEDs?
A
It is reduced from 9-16 hours with other AEDs
4
Q
How does valproic acid act on the CNS?
A
It blocks fast Na+ channel inactivation
It modifies aa metabolism in GABA process
It blocks T-type Ca2+ channels
5
Q
What does a minor pathway of valproic acid lead to?
A
Hepatotoxictiy. Liver functioning required. Can cause fetal malformations. Rare pancreatitis.
6
Q
AED 1st gen
A
potassium bromide phenobarbital phenytoin primidone ethosuximide
7
Q
Half life of phenobarbital
A
2-6 days
8
Q
Where does phenobarbital act?
A
Acts at GABA-a receptors
9
Q
How is phenobarbital metabolized?
A
p-hydroxylation (2C9/2C19)
10
Q
What does phenobarbital induce?
A
Potent inducer of some P450’s and some UGTs
11
Q
What are the 3 active drugs in primidone?
A
Primidone, PEMA, and phenobarbital (oxidized to)
12
Q
What does primidone do to the CNS?
A
It blocks Na+ channels, and the metabolite PEMA is a GABA potentiater
13
Q
What are the 2nd gen AEDs?
A
diazepam carbamazepine valproate clonazepam clobazam (benzos have broad anti-seizure activity but are not approved for chronic treatment of epilepsy because they desensitize)
14
Q
PEMA
A
anticonvulsant formed from metabolizing primidone. GABA potentiator.
15
Q
Hyndantoin
A
Condensed barbiturate
16
Q
Phenytoin action on CNS?
A
Blocks fast inactivation of Na+ channels
17
Q
Which is more sedating, phenobarbital or phenytoin?
A
phenobarbital
18
Q
What does phenytoin induce?
A
P450’s and UGTs
19
Q
Is the p-hydroxy metabolite of phenytoin active or inactive?
A
Inactive metabolite formed through 2C9/2C19. There is an arena oxide intermediate that is linked to SJS/TEN by its interaction with cellular proteins.
20
Q
What suggests the role of the arena oxide in potential toxicities associated with phenytoin?
A
The glutathione and mercaptic acid metabolites.
21
Q
What is fosphenytoin used for?
A
It is a water-soluble pro-drug of phenytoin used for IV/IM injections. Phosphates chop it up into phenytoin, PO3 3- and formaldehyde quickly (~15min)
22
Q
Ethosuximide requires what kind of tests?
A
Blood and liver
23
Q
How does ethosuximide effect the CNS?
A
It blocks T-type Ca2+ channels
24
Q
How is ethosuximide metabolized?
A
It is hydroxylated on the ethyl (3A4/2E1)
25
What type of seizures does ethosuximide treat, and why?
1st line for absence seizures uncomplicated by other seizure types.
It has small alkyl groups as opposed to aromatic, which would be used for general seizures.
26
What types of toxicities limit the use of ethosuximide?
anemia, hepatotoxicity, reduced kidney function
27
How does carbamazepine work?
Blocks fast inactivation of Na+ channels
28
What side effects accompany CBZ?
1) aplastic anemia
2) SJS w/ Asian population
clinical monitoring required, also rare liver toxicity
29
What kind of products does CBZ form?
3A4 can form a reactive AED epoxide, which can either hydrolyze to an inactive alcohol (which can be excreted as it is or conjugated first) or form toxic alkylated proteins. CBZ can also form an iminoquinone which can attract nucleophiles that can also lead to alkylated proteins and toxicities.
30
What does CBZ induce?
Strong P450 (3A4 included)
Autoinducer
UGT inducer
31
How is oxcarbazepine different than CBZ?
It cannot form toxic compounds
| Reduced to monohydroxy alcohol in 2 hours, whose t1/2 is 9-11 hours
32
How does oxcarbazepine and its metabolite effect the CNS?
Blocks fast inactivation of Na+ channels
33
What AEDS are prodrugs?
Eslicarbazepine acetate
Primidone
Fosphenytoin
34
What is formed through hydrolysis of eslicarbazepine acetate? This is the s-enatiomer of what?
Eslicarbazepine, which is the s-enantiomer of monohydroxy metabolite of oxcarbazepine.
35
How do licarbazepine and eslicarbazepine differ in their induction properties than CBZ?
They still induce 3A4, but less than CBZ. No UGTs , but induce 2C19.
36
Are licarbazepine and eslicarbazepine as toxic as CBZ?
They lack the major blood toxicity and minor liver toxicity, but can cause skin reactions still (although less than CBZ)
37
What is the precursor of GABA?
aa L-glutamate
38
What enzyme changes L-glutamate to GABA?
GAD (decarboxylate)
39
What are inhibitor of GABA aminotranferase? (GABA-AT)
Valproate and vigabatrin
40
What does GABA-AT form from GABA?
Succinate semialdehyde
41
What inhibits SSA dehydrogenase?
valproate
42
What is produced by the SSA dehydrogenase?
Succinate, which enters the TCA cycle
43
What inactivates GAD?
valproate
44
What do you get with a pentyl modification to GABA?
gabapentin
45
Where does gabapentin work?
Not at GABA receptors. It acts at alpha-2-delta Ca2+ channels as a blocker.
46
What is the t1/2 of gabapentin compared to pregabalin?
5-7 hours compared to 6 hours... about the same
47
Why is gabapentin great for adjunctive therapy?
1. Not appreciably metabolized
2. Doesn't induce/inhibit hepatic enzymes
3. Doesn't alter pharmacokinetics of other AEDs
4. It's pharmacokinetics are not altered by other AEDs
5. Lacks blood/liver toxicities
48
What drug with AED structure is used to treat pain associated with shingles?
Gabapentin encarbil
49
What GABA analog has an isobutyl group?
Pregabalin
50
Where does pregabalin act?
At same alpha-2-delta Ca2+ channels as gabapentin
51
Can you use pregabalin adjunctively?
Yes, it has similar advantages to gabapentin.
52
How much of pregabalin is metabolized?
~2%
53
How does the effectiveness of pregabalin compare to that of gabapentin?
It is similar, but pregabalin is better for pain. There is some euphoria reported, giving it a schedule V status.
54
How does vigabatrin work?
It inhibits the breakdown of GABA (GABA-AT inhibitor) irreversibly, which increases the lifetime of GABA.
55
What major side effect is associated with vigabatrin?
Black box warning for vision loss.
56
what does vigabatrin induce?
CYP 2C9
57
What GABA analog uses only the s-enantiomer for its activity?
Vigabatrin
58
What is the t1/2 of vigabatrin?
7& 1/2 hours
59
Which drug blocks NMDA receptors and potentiates GABA responses as its mode of action?
Felbamate
60
What are the effects of felbamate?
It is a 3rd line drug because of its toxicities (aplastic anemia and hepatic failure).
Used only in patients resistant to other treatments
Dosed up to 3600mg/day
Minor metabolism pathways become more important
61
What does felbamate require?
Clinical monitoring due to aplastic anemia and hepatic failure... because of minor metabolism pathways
62
What drug can be metabolized to form a good Michael-acceptor? Is it good?
Felbamate. It can alkylate biomolecules to form toxic compounds. GSH can detoxify, but if exhausted can lead to liver toxicity.
63
What is the main route of metabolism for lamotrigine? Minor?
Glucuronidation major. Minor is P450, which forms a reactive arena oxide metabolite that can lead to skin rashes.
64
Lamotrigine: what is the half-life in and out of the presence of 1st gen AEDs?
24-35 hours without, and ~15 hours with. The 1st gen AEDs act as co-inducers.
65
How does lamotrigine act on the CNS?
Inhibits fast inactivation of Na+ channels
66
What two drugs have either a sulfamate or sulfonamide group, and have side effects of kidney stones? What % develop them? What is the theory for the development?
Topiramate (1.5%) and zonisamide (4%). Possibly carbonic anhydrase inhibition causes the kidney stones.
67
What part of topiramate is metabolized?
Only 30% through minor pathway... 70% excreted unchanged.
68
What does topiramate induce and inhibit?
Induces 3A4 and inhibits 2C19, both weakly.
69
What is the half-lives of topiramate and zonisamide?
Topiramate is 20-30 hours, but can be decreased by CBZ and phenytoin.
Zonisamide is ~63 hours
70
Which drug has the potential for sulfa allergies?
The sulfonamide: zonisamide.
71
What effects do topiramate and zonisamide have on the CNS?
They both block fast inactivation of Na+ channels.
72
What is the metabolism of zonisamide?
1) 3A4-mediated reduction and
| 2) n-acetylation of the sulfonamide (adding acetyl group)
73
What drug binds GAT-1?
Tigabine. It preferentially binds GAT-1, which is part of the GABA transporter. The transporter takes the GABA-like portion inside, and the left bulky side gets stuck and blocks the rest.
74
What metabolite is given by a 3A4 metabolism of tigabine?
A 5-oxo metabolite at position 5.
75
What is the t1/2 of tigabine?
8 hours
76
What drugs modulate GABAa?
Benzodiazepines and barbiturates are allosteric modulators, and topiramate is a distinct modulator.
77
What drug is a modified D-serine?
Lacosamide
78
What is the half-life of lacosamide?
12-13 hours
79
What is the main route of metabolism of lacosamide, and is it much affected by other AEDs?
40% is excreted unchanged, and the main route is D-methylation by 2C19. This has relatively minor effects from P450 inducers.
80
What is the effect of lacosamide on the CNS?
It blocks slow inactivation of the Na+ channels.
81
How does levetiracetam act on the CNS?
As an SV2A protein modulator
82
Is levetiracetam a good choice for adjunctive therapy? Why?
1) Not P450 metabolized
2) 66% excreted unchanged
3) Most remain 1/4 of drug metabolized to inactive acid
4) No blood/liver/skin toxicities
5) No P450 ir UGT induction/inhibition
83
What is the half-life of levetiracetam? What enantiomer is used?
6-8 hours, S enantiomer
84
What is the metabolism of brivaracetam?
1) 2C19 hydroxylation propyl side chain
| 2) Also amide hydrolysis
85
Compare levetiracetam and brivaracetam.
Brivaracetam also is an SV2A ligand, but is more potent. A smaller portion is excreted unchanged: 40% rather than 66%. It is a more lipophilic analog of levetiracetam.
86
How does rufinamide work on the CNS?
It blocks slow inactivation of Na channels
87
How is rufinamide metabolized?
Through hydrolysis, a major metabolite is produced, which is inactive. This can go through glucuronidation.
88
What does rufinamide inhibit and induce?
Inhibits 2E1 and induces 3A4, both weakly
89
What is the half-life of rufinamide, and are there drug interactions?
T1/2 = 8-12 hours, and there are still some interaction despite no P450 routes.
90
What drug works on the CNS through glutamate AMPA antagonism?
Perampanel.
91
How is perampanel metabolized?
3A4 hydroxylation, and then further glucuronidation
92
What is the half-life of perampanel?
105 hours
93
Which drug is a K+ channel opener and used for partial seizures?
Ezogabine (also called retigabine)
94
What is the half-life of ezogabine?
6-10 hours
95
How is ezogabine metabolized?
glucuronidation and N-acetylation. No major P450 metabolism.
