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Anti-Seizure Drugs > Anti-Seizure Drugs > Flashcards

Anti-Seizure Drugs Flashcards

1
Q

Drugs for Partial Seizures

A
  • Phenytoin
  • Carbamazepine
  • Valproate
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2
Q

Drugs for Generalized Tonic-Clonic (grand mal) Seizures

A
  • Phenytoin
  • Carbamazepine
  • Valproate
  • Phenobarbital
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3
Q

Drugs for Absence (petit mal) Seizures

A
  • Ethosuximide**

- Valproate

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4
Q

Drugs for Myoclonic Seizures

A
  • Phenobarbital

- Valproate (especially for Juvenile Myoclonic)

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5
Q

Status Epilepticus

A
  • Phenobarbital
  • home use and prn use of diazepam
  • ambulance use of lorazepam
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6
Q

Major mechanisms of anti-seizure drugs

A
  1. Diminution of glutamatergic excitatory transmission
  2. Enhancement of GABA-mediated synaptic inhibition, either by a presynaptic or postsynaptic action
  3. Modification of ionic conductances
    - inhibition of sustained and repetitive firing of neurons by promoting the inactivated state of voltage-activated sodium channels
    - inhibition of voltage-activated calcium channels
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7
Q

Molecular Targets for Anti-seizure Drugs at the Excitatory (glutamatergic) Synapse

A
  1. Voltage-gated Sodium Channels (Phenytoin, Carbamazepine)
  2. Voltage-gated Calcium Channels (Ethosuximide)
  3. Potassium Channels (Retigabine)
  4. SV2A synaptic vesicle proteins (Levetiracetam)
  5. CRMP-2, collapsin-response mediator protein-2 (Lacosamide)
  6. AMPA Receptors (blocked by Phenobarbital)
  7. NMDA Receptors (blocked by Felbamate)
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8
Q

Anti-Seizure Drugs Targeting GABA-mediated Synaptic Inhibition

A
  1. GABA transporters inhibits reuptake of GABA (especially Tiagabine)
  2. GABA-transaminase inhibitor (Vigabatrin)
  3. GABAa receptors (Benzodiazepines)
    - inhibits the postsynaptic cell by increasing the inflow of Cl- ions into the cell
    - hyperpolarization
    - clinically relevant concentrations of both benzodiazepines and barbituates enhance GABAa receptor-mediated inhibition through distinct actions on GABAa receptor
  4. GABAb receptors
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9
Q

Anti-seizure drug-enhanced Na+ channel inactivaton

A
  1. Selective inhibition of depolarizaiton and fire action potentials at high frequencies would be expected to reduce seizures
  2. Thought to be mediated by reducing the ability of Na+ channels to recover from inactivation
  3. Prolong the inactivation of the Na+ channels
  4. Inactivated channel is blocked by the inactivation gate
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10
Q

Inhibiton of voltage-gated Ca++ channels

A
  1. Inhibition of the T-type calcium channels
  2. These type of anti-seizure drugs reduce the flow of Ca++ channels thus reducing the pacemaker current that underlies the thalamic rhythm in spikes and waves seen in generalized absence seizures
  3. Generalized absence seizures (thalamus and neocortex pacemaker action)
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11
Q

Phenytoin

A
  • Oldest non-sedative anti-seizure drug
  • Since non-sedative it is more uncomfortable, but is still given today
  • Fosphenytoin is a prodrug of “this drug” designed for parenteral use
  • Alters Na+, K+, and Ca++ conductance, membrane potentials
  • Decreases synaptic release of glutamate and enhances the release of GABA
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12
Q

Pharmacokinetics of Phenytoin

A
  • rapid release and extended-release forms (once-daily dosing)
  • time to peak = 3-12 hours
  • Fosphenytoin well absorbed after IV and IM admin.
  • highly-bound to plasma proteins
  • metabolized to inactive metabolites in liver and excreted in urine
  • at low blood levels, metabolism follows 1st order kinetics
  • at therapeutic range and higher, non-linear relationship of dosage and plasma concentration occurs
  • half-life = 12-36 hrs
  • at low blood levels, 5-7 days to reach steady-state blood levels after every dosage change
  • at high blood levels, it takes 4-6 weeks to reach steady-state blood levels after dosage change
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13
Q

Therapeutic Levels & Dosage of Phenytoin

A
  • loading dose can be given either orally or IV (Fosphenytoin)
  • IV injection of Fosphenytoin preferred method for status epilepticus!!!
  • because of dose-dependent kinetics, some toxicity may occur with only small increments in dosage
  • ample time should be allowed for the new steady state to be achieved before further increasing the dosage
  • only slow-release extended-action formulation can be given in a single daily dosage
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14
Q

Drug Interactions & Interference of Phenytoin

A
  • 90% bound to plasma proteins
  • increased proportions of free (active) drug are observed in newborn, in patients with hypoalbuminemia, and in uremic patients
  • other drugs (e.g. valproate) can compete for protein binding sites and inhibits phenytoin metabolism, resulting in marked and sustained increases in free phenytoin
  • phenytoin has been shown to induce microsomal enzymes responsible for the metabolism of a number of drugs (e.g. oral contraceptives)
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15
Q

Toxicity of Phenytoin

A
  • general toxicity includes diplopia, ataxia, gingival hyperplasia, hirsutism, neuropathy
  • nystagmus occurs early, as does loss of smooth extraocular pursuit movements
  • diplopia and ataxia are the most common dose-related adverse effects requiring dosage adjustment
  • sedation usually occurs only at considerably higher levels
  • gingival hyperplasia and hirsutism occurs to some degree in most patients
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16
Q

Toxicity of Phenytoin in long-term use

A
  • in some patients with coarsening of facial features and with mild peripheral neuropathy, usually manifested by diminished deep tendon reflexes in the LEs
  • serum folic acid, thyroxine and vit. K concentrations may decrease with long-term therapy
  • abnormalities of vit. D metabolism may result in osteomalacia
  • low folate levels and megaloblastic anemia have been reported, but the clinical importance of these observations is unknown
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17
Q

Carbamazepine

A
  • now considered to be a primary drug for the treatment of partial and tonic-clonic seizures
  • used for benign occipital
  • related chemically to the TCAs
  • limits the repetitive firing of action potentials evoked by a sustained depolarization
  • mediated by a slowing of the rate of recovery of voltage-gated Na+ channels from inactivation
18
Q

Pharmacokinetics of Carbamazepine

A
  • complex
  • influenced by its limited aqueous solubility and the ability of many anti-seizure drugs, including carbamazepine itself, to increase their conversion to active metabolites by hepatic oxidative enzymes
  • absorbed slowly and erratically after PO admin.
  • metabolite, 10,11-epoxide, is as active as the parent compound
  • induces CYP2C, CYP3A, and UGT, thus enhancing the metabolism of drugs (e.g. oral contraceptives) degraded by these enzymes
19
Q

Drug Interactions of Carbamazepine

A
  • phenobarbital, phenytoin, and valproate may increase the metabolism of carbamazepine by inducing CYP3A4
  • carbamazepine may enhance the biotransformation of phenytoin
  • concurrent administration of carbamazepine may lower concentrations of other anti-seizure drugs such as valproate
20
Q

Adverse Effects of Carbamazepine

A
  • Drowsiness, blurred vision, diplopia, headache, -dizziness, ataxia, nausea, and vomiting
  • cognitive effects can interfere with learning
  • mild leukopenia and hyponatremia are fairly common
  • with high doses of the drug, thrombocytopenia can occur
  • rash, particularly with high starting doses or rapid dose escalation
  • FDA recently recommended that Asian patients, who have a ten-fold higher incidence of carbamazepine-induced Stevens-Johnson syndrome (SJS), be tested for susceptibility to SJS before starting the drug
21
Q

Valproic Acid

A
  • main drug used for myoclonic seizures (along with Levetiracetam)
  • 1st line for tonic-clonic seizures
  • inhibits tonic hind limb extension in maximal electroshock seizures and kindled seizures at non-toxic doses
  • effective in absence as well as partial and generalized tonic-clonic seizures in humans
  • inhibits sustained repetitive firing induced by depolarization by a prolonged recovery of voltage-activated Na+ channels from inactivation
  • in neurons isolated from the nodose ganglion, this drug produces small reductions of T-type Ca++ currents
  • drug increases the amount of GABA that can be recovered from the brain after the drug is administered to animal studies
  • can stimulate the activity of the GABA synthetic enzyme, glutamic acid decarboxylase, and inhibit GABA degradative enzymes, GABA transaminase and succinic semialdehyde dehydrogenase
22
Q

Pharmacokinetics of Valproic acid

A
  • absorbed rapidly and completely after PO admin.
  • peak concentration = 1-4 hrs
  • 90% plasma protein binding, but fraction is reduced as the total concentration of valproate is increased through the therapeutic range
  • although concentrations of valproate in CSF suggest equilibrium with free drug in the blood, there is evidence for carrier-mediated transport of valproate both into and out of the CSF
  • vast majority of valproate (95%) undergoes hepatic metabolism
  • hepatic metabolism occurs mainly by UGT enzymes and beta-oxidation
  • half-life = ~15 hrs, but is reduced in patients taking other anti-epileptic drugs
23
Q

Drug Interactions of Valproic Acid

A
  • transient GI symptoms, including anorexia, nausea, and vomiting
  • effects on CNS include sedation, ataxia, and tremor
  • rash, alopecia, and stimulation of appetite have been observed occasionally and WEIGHT GAIN has been seen with chronic valproic acid treatment in some pts
  • dose-related tremor, transient hair thinning and loss, decreased platelet fxn, and thrombocytopenia
  • several effects on hepatic fxn (elevation of hepatic transaminases in plasma)
  • rare complication is fulminant hepatitis that is frequently fatal
  • acute pancreatitis and hyperammonemia
  • children below 2 y.o. with other medical conditions who were given anti-seizure agents were especially likely to suffer fatal hepatic injury
  • valproic acid can also produce teratogenic effects such as neural tube defects!!!
24
Q

Ethosuximide

A
  • main drug specifically used for absence seizures
  • has an important effect on Ca++ currents, reducing the low-threshold (T-type) current
  • the T-type calcium currents are thought to provide a pacemaker current in thalamic neurons responsible for generating the rhythmic cortical discharge of an absence attack
25
Q

Drug Interactions of Ethosuximide

A

-valproic acid can decrease ethosuximide clearance and higher steady-state concentrations owing to inhibition of metabolism

26
Q

Toxicity of Ethosuximide

A
  • most common is gastric distress, including pain, N/V
  • transient lethargy or fatigue
  • much less commonly headache, dizziness, hiccup, euphoria
  • urticaria and other skin reactions, including SJS, as well as systemic lupus erythematosus, eosinophilia, leukopenia, thrombocytopenia, pancytopenia, and aplastic anemia also have been attributed to the drug
27
Q

Phenobarbital

A
  • oldest of the currently available anti-seizure drugs, for virtually every seizure type, especially when attacks are difficult to control
  • many consider the barbituates the drugs of choice for seizures only in infants
  • relatively low toxicity, and low cost
  • exact mechanism unknown, but enhancement of inhibitory process and diminution of excitatory transmission probably contribute significantly
  • at high concentration, drug can suppress high-frequency repetitive firing in neurons through an action on Na+ conductance
  • also blocks some Ca++ currents
  • binds to an allosteric regulatory site on GABAa receptor, and it enhances the GABA receptor-mediated current by prolonging the openings of the Cl- channels
  • can also decrease excitatory responses such as glutamate release
28
Q

Pharmacokinetics of Phenobarbital

A
  • oral absorption is complete but somewhat slow
  • peak concentrations in plasma = several hours after single dose
  • 40-60% bound to plasma proteins and bound to a similar extent in tissues, including the brain
  • up to 25% dose is eliminated by pH-dependent renal excretion of the unchanged drug
  • inactivated by hepatic microsomal enzymes, principally CYP2C9, with minor metabolism by CYP2C19 and CYP2E1
  • induces UGT enzymes as well as the CYP2C and CYP3A subfamilies
  • drugs metabolized by these enzymes (e.g. oral contraceptives) can be more rapidly degraded when co-administered with phenobarbital
29
Q

Toxicity of Phenobarbital

A
  • sedation, but tolerance develops with chronic use
  • nystagmus and ataxia occur at excessive dosage
  • can produce irritability and hyperactivity in children, and agitation and confusion in the elderly
  • scarlatiniform or morbilliform rash, possibly with other manifestations of drug allergy, occurs in 1-2% of pts
  • hypoprothrombinemia with hemorrhage has been observed in the newborns of mothers who have received phenobarbital during pregnancy
  • megaloblastic anemia that responds to folate and osteomalacia that responds to high doses of vitamin D occur during chronic phenobarbital therapy
30
Q

Toxicity of Gabapentin (new antiseizure drug)

A
  • very high dosages are needed to achieve improvement in seizure control
  • somnolence, dizziness, ataxia, headache, and tremor
31
Q

Toxicity of Felbamate (new antiseizure drug)

A

-causes aplastic anemia and severe hepatitis (and acute hepatic failure) at unexpectedly high rates and has been relegated to the status of a third-line drug for refractory cases

32
Q

Toxicity of Lamotrigine (new antiseizure drug)

A
  • dizziness, headache, diplopia, nausea, somnolence, and skin rash
  • can cause toxic epidermal necrolysis and SJS
  • pediatric pts are at high risk of rash, some studies suggest that a potentially life-threatening dermatitis will develop in 1-2% of pediatric pts
33
Q

Toxicity of Topiramate (new antiseizure drug)

A
  • somnolence, fatigue, dizziness, cognitive slowing, paresthesias, nervousness, and confusion
  • acute myopia and glaucoma may require prompt drug withdrawal
  • urolithiasis has also been reported
  • hypospadias have been reported in male infants exposed in utero (however, no causal relationship could be established)
34
Q

Considerations of Chronic Therapy With Anti-Seizure Drugs

A
  • drug resistance
  • poor absorption or rapid metabolism, resulting in low blood levels
  • inhibit drug metabolism
  • long-term use of phenytoin is associated in some pts with coarsening of facial features and with mild peripheral neuropathy, usually manifested by diminished deep tendon reflexes in the LEs
  • long-term use of phenytoin may also result in abnormalities of fitamin D metaboism, leading to osteomalacia
  • long-term treatment of phenytoin may cause teratogenicity
35
Q

Adverse Effects of Long-Term Therapy with Carbamazepine

A
  • diplopia, cognitive dysfunction, drowsiness, ataxia
  • rare occurance of severe blood dyscrasias and SJS
  • teratogenic potential
36
Q

Adverse Effects of Long-Term Therapy with Felbamate

A
  • aplastic anemia

- hepatic failure

37
Q

Adverse Effects of Long-Term Therapy with Gabapentin

A

dizziness, sedation, ataxia, nystagmus

38
Q

Adverse Effects of Long-Term Therapy with Lamotrigine

A

dizziness, ataxia, nausea, rash, rare SJS

39
Q

Adverse Effects of Long-Term Therapy with Phenytoin

A

-nystagmus, diplopia, sedation, gingival hyperplasia, hirsutism, anemias, peripheral neuropathy, osteoporosis, induction of hepatic drug metabolism

40
Q

Adverse Effects of Long-Term Therapy with Valproic Acid

A

drowsiness, nausea, tremor, hair loss, weight gain, hepatotoxicity (infants), inhibition of hepatic drug metabolism

41
Q

BZs Lorazepam and Diazepam

A

Used for status epilepticus

Anti-Seizure Drugs (1 decks)

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