Anti-Seizure Drugs (ASDs) 1 Flashcards
1
Q
What percentage of patients with epilepsy can have their seizures controlled with medication?
A
65-80%
2
Q
Pharmacotherapy of epilepsy is highly individualized and requires titration of the dose to optimize
A
ASD therapy
3
Q
Many of the new ASDs are only approved for
A
Adjunct Therapy
4
Q
ASDs can cause a rash called
A
Steven Johnsons Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN)
5
Q
Can cause Fetal Abnormalities and birth defects (“Major Congenital Malformations” or MCMs)
A
ASDs
6
Q
What are the three mechanisms of action of ASDs?
A
- ) Modification of ionic conductance
- ) Enhancement of inhibitory transmission
- ) Inhibition of excitatory transmission
7
Q
ASDs enhance inhibitory transmission (IPSPs) by increasing
A
GABAergic transmission
8
Q
ASDs inhibit excitatory transmission (EPSPs) by decreasing
A
Glutamergic transmission
9
Q
The ability of Na+ channels to recover from inactivated state is inhibited by ASDs. This prolongs the
A
Inactivation state of Na+ channels
10
Q
Neurons undergo depolarization and fire action potentials at high frequencies during
A
Seizures
11
Q
Selective inhibition of this pattern of firing should reduce
A
Seizures
12
Q
Inhibition of the high-frequency firing is thought to be mediated by reducing the ability of Na+ channels to recover from
A
Inactivation
13
Q
Prolonging the inactivation of the Na+ channels results in reducing the ability of neurons to
A
Fire at high frequencies
14
Q
Recall that inactivated channels are inactive because they are blocked by the
A
Inactivation gate
15
Q
Oldest nonsedative antiseizure drug (1938)
A
Phenytoin (Dilantin, Phenytek)
16
Q
A prodrug of phenytoin designed for parenteral use
A
Fosphenytoin
17
Q
What is the major mechanism of action of Phenytoin?
A
Na+ Channel Inhibiton
18
Q
Indications: 1) Simple Partial 2) Complex Partial 3) Secondarily Generalized and 4) Primary Generalized tonic-clonic seizures
A
Phenytoin
19
Q
What are the contraindications for Phenytoin?
A
May exacerbate myoclonic and absence seizures
20
Q
Phenytoin is especially contraindicated in
A
Lennox-Gastaut Syndrome
21
Q
The therapeutic dose for most patients is
A
10-20 ug/mL
22
Q
Only free, unbound phenytoin molecules can penetrate the bloodbrain barrier and exert
A
Pharmacological effects
23
Q
What percentage of Phenytoin is bound to plasma protein?
A
90%
24
Q
Conditions such as hypoalbuminemia and uremia can significantly impact plasma levels of
A
Phenytoin
25
Phenytoin is eliminated hepatically by conversion to
Inactive Metabolites
26
At low blood levels, phenytoin metabolism follows
First-order kinetics
27
At therapeutic range and higher, non-linear relationship of dosage and plasma concentration occurs. This is
Zero order kinetics
28
Is extensively metabolized in the liver and this process becomes saturated at about the doses needed for therapeutic effect
Saturation Kinetics
29
Thus, phenytoin at low doses exhibits first-order kinetics, but saturation or zero-order kinetics develop as we reach the
Therapeutic plasma concentration
30
Phenytoin is 90% bound to plasma proteins (albumin). Increased proportions of free (active) drug are observed in newborn, in patients with
Hypoalbuminemia and in uremic patients
31
Other protein-binding drugs, including other ASDs (e.g. valproate) can compete for protein binding sites, resulting in increases in
Free Phenytoin
32
Drugs that induce or inhibit hepatic enzymes can impact phenytoin metabolism and thus impact
Plasma concentrations
33
Phenytoin itself induces
Hepatic Enzymes
34
Nystagmus, diplopia, ataxia, drowsiness are common dose-related CNS adverse effects requiring dosage adjustment
Phenytoin
35
Seen in 20-40% of patients chronically taking phenytoin
Gingival hyperplasia
36
Phenytoin can cause vitamin D deficiency which may result in
Osteomalacia
37
A category D (bad) teratogen
Phenytoin
38
What percentage of Carbamazepine is protein-bound?
75%
39
The active metabolite of Carbamazepine is?
10,11-epoxide
40
The t½ of Carbamazepine falls significantly over the first few weeks of therapy due to the induction of
-Metabolize itself (autoinduction)
Hepatic enzymes (CYPs)
41
CYP-inducing drugs such as phenytoin may increase the metabolism of
Carbamazepine
42
What are three common symptoms of Carbamazepine?
Hyponatremia, Leukopenia, Rash
43
Can induce Stevens-Johnson Syndrome
-Incidence is highest in Asian Populations
Carbamazepine
44
The HLA allele B*1502 (10-15% incidence in ethnic Han Chinese; 2-4% in ethnic South Asian) has been identified as a marker for
Carbamazepine-induced SJS and toxic epidermal necrolysis (TEN)
45
FDA approved in 2000 for partial seizures with or without secondary generalization
-Generally fewer adverse effects than CBZ (and phenytoin)
Oxcarbazepine (Trileptal)
46
Is more likely to cause hyponatremia than carbamazepine
-Important consideration for patients taking diuretics
Oxcarbazepine
47
What are the three mechanisms of action of Valproic Acid (or Valproate)
Na+ Channel Inhibition, Inhibition of T-type Ca2+ channels, and Increased GABA produciton
48
Valproic Acid (Valproate) is contraindicated for patients with
Liver Disease
49
When the fraction of bound drug reduces as the total concentration of drug is increased
Saturable binding
50
Highly protein-bound, but the binding is saturable
Valproate
51
Valproate is eliminated through hepatic metabolism, mainly by
UGT enzymes and beta-oxidation
52
At least 10 metabolites have been identified, with one at least one (4-ene VPA) being implicated for the hepatotoxicity associated with
Valproate
53
Crosses the placenta and concentrations in cord serum blood may be 5-X higher than the mother due to higher binding in the fetal compartment
Valproate
54
Enzyme-inducing ASDs (phenytoin, carbamazepine) can decrease the concentration of
Valproate
55
Which type of antibiotics reduce valproate serum concentrations?
Carbapenems
56
As a high proportion of valproate is bound to albumin, it can displace
Phenytoin and other drugs from albumin
57
Can inhibit hepatic enzymes, so it can inhibit the metabolism of other ASDs like phenytoin, phenobarbital, lamotrigine and lorazepam when co-administered
Valproate
58
What are the three major side effects of Valproate?
Weight gain, hepatotoxicity, and teratogenic effects
59
A rare complication with valproate that is frequently fatal
Fulminant hepatitis
60
Has teratogenic effects such as neural tube defects (up to 20-fold higher risk than the general population), particularly spina bifida
Valproate
61
Can give a rash in 10% of patients and rarely progresses to serious systemic illness (SJS)
Lamotrigine
62
Lamotrigine does not induce or inhibit
CYP enzymes
63
While lamotrigine has not been shown to affect the efficacy of oral contraceptives (OCs), it has been reported that OCs can reduce effective concentrations of
Lamotrigine
64
Co-administration with valproate can double the plasma concentration of
Lamotrigine
65
Co-administration with phenytoin or carbamazapine can reduce plasma concentrations of
Lamotrigine
66
Was the most frequently used ASD for many years, but its use has declined considerably since the appearance of newer-generation ASDs with improved tolerability
Phenytoin
67
Had the best balance of efficacy and tolerability in the large cooperative VA study that also included phenytoin phenobarbital, and primidone
-Became the standard treatment for focal seizures
Carbamazepine
68
Remains the most effective ASD for idiopathic generalized epilepsy with generalized tonic-clonic seizures, and should remain a drug of first choice for men with generalized epilepsy
Valproate
69
An important first-line ASD for focal seizures and generalized tonic-clonic seizures, although it is not FDA approved for initial monotherapy (only conversion-to-monotherapy)
Lamtrigotine
70
Less sedating and has fewer cognitive adverse effects than traditional ASDs
Lamtrigotine
71
ASDs that inhibit voltage gated Ca2+ channels do so by inhibiting the
T-type Ca2+ channels
72
T-type channel inhibitors reduce the pacemaker current that underlies the
Thalamic rythm in spikes and waves seen in generalized absence seizures
73
Specifically used for absence seizures
-Inhibits T-type Ca2+ currents
Ethosuximide (Zarontin)
74
Has the adverse effects of leukopenia, thrombocytopenia, pancytopenia, and aplastic anemia
Ethosuximide (Zarontin)
75
Activation of the GABAA receptor inhibits the postsynaptic cell by increasing the inflow of
-Will hyperpolarize the neuron
Cl- ions into the cell
76
Enhance GABAA receptor–mediated inhibition of action potential by enhancing inflow of Cl–
Benzodiazepines and barbiturates
77
Used for virtually every seizure type, especially when attacks are difficult to control
-The oldest of the currently available antiseizure drugs
Phenobarbital
78
Used to treat status epilepticus
Phenobarbital
79
Binds to GABAA receptor, prolonging the opening of the
Chloride channels
80
Also reproted to inhibit glutamate release, enhance GABA transmission, and inhibit Na+ and Ca2+ conductance
Phenobarbital
81
Is metabolized to phenobarbital in the body
Primidone
82
Phenobarbital is metabolized by
Hepatic Microsomal Enzymes (CYP)
83
Drugs metabolized by hepatic enzymes (e.g. oral contraceptives ) can be more rapidly degraded when co-administered with
Phenobarbital
84
What are 4 major side effects of phenobarbital?
Sedation, Cognitive impairment, Hyperactivity in children, and CNS depression
85
The ASD of choice for generalized absence seizures
Ethosuximide
86
Are typically used as adjunctive therapy and have limited data to support monotherapy use
Benzodiazapines
87
What are the two GABA analogs?
Tiagabine and Vigabatrine
88
Functions by Inhibition of GABA transporter (GAT-1)
Tiagabine (Gabitril)
89
Reduces reuptake of GABA by neurons and glial cells
Tiagabine (Gabitril)
90
Inhibits the breakdown of GABA by targeting the enzyme GABA transaminase (GABA-T)
Vigabatrin (Sabril)
91
Only available through a restricted distribution program due to concerns about retinal toxicity and permanent visual field loss
Vigabatrin (Sabril)
92
Selective inhibitors of voltage-gated Ca2+ channels containing the α2δ1 subunit
-Originally designed to be GABA analogs
Gabapentin and Pregabalin
93
What are the two main adverse effects of Gabapentin (neurontin) and Pregabalin (Lyrica)?
Weight gain and Somnolence
94
Effective as a monotherapy, but can exacerbate myoclonic and absence seizures
Gabapentin
95
Not effective for absence, myoclonic, or primary generalized tonic-clonic seizures
-Also used to treat Fibromyalgia
Pregabalin (Lyrica)
