Antiepileptics

Question 1

Anti epileptic drugs, mechanism of action

Answer 1

1) increase GABAergic NT: act on GABA-A, inhibit GABA transaminase, inhibit GABA transporter
2) decrease glutamatergic NT: inhibit NMDA and AMPA, inhibit glutamate transformation
3) enhance glutamate decarboxylase
4) inhibit Na+ channels by binding in its inactivated state
5) inhibit T-type Ca2+ channels

Question 2

therapy of partial seizures and generalized tonic-clonic seizures

Answer 2

These compounds have high affinity for the inactive Na+ channels. these drugs show a use dependence (bind to those neurons that take inactive conformation with high frequency)
Na+ channel blockers:Phenytoin (to´in truck),Fosphenytoin, Carbamazepine (classic car), Oxcarbazepine, Lamotrigine
GABAergic drugs: Phenobarbital (barbiturate), primidone, Vigibatrine, Tiagabine, Gabapentine, pregabaline

Question 3

Phenytoin

Answer 3

Na+ channel blocker.A narrow spectrum anti epileptic. half-life:1day, but at high doses half-life increases to 5 days, due to saturation of enzymes: (from linear to non-linear elimination)
Metabolism: CYP-2C9, 2C19.
Oral or IV admin.
I: generalized T/C seizures, partial seizures, epileptic state (IV, 2nd choice), class I anti arrhythmic (therapy of arrh. caused by cardiac glycosides intoxication), trigeminal neuralgia.
SE: nystagmus, dizziness, ataxia, diplopia (diminished with time, typical for all Na+ ch. blockers). GINGIVAL HYPERPLASIA, osteomalacia, teratogenic (cleft lip), megaloblastic anemia, Steven johnson sy. , strong inducer of CYP3A4 (accelerated metabolism of anticoagulants and oral contraceptives), arrhythmia when given IV (due to has to be given w/solvent)

Question 4

Fosphenytoin

Answer 4

More hydrophilic than phenytoin - less CNS effect.
Does not need solvent for IV admin - no arrhythmia.
only parenteral admin.

Question 5

Carbamazepine

Answer 5

Na+ ch. blocker. Use dependence (act on high frequency firing neurons)
Metabolism: CYP2C9,3A4. Is an inducer of the same enzymes. half-life: 36 hours –> decrease to 20 hours with use (due to accelerate own metabolism).
I: grand mal seizures, focal seizures, trigeminal neuralgia, bipolar disorder, acute alcohol withdrawal.
SE: neurological (dizziness, nystagmus, ataxia, diplopia), aplastic anemia, leukopenia (depresses BM), enzyme induction

Question 6

Oxcarbazepine

Answer 6

carbamazepine analogue, but less enzyme inducing effect and less potency.
I: partial seizures or epilepsy

Question 7

Lamotrigine

Answer 7

(Llama)
Na+ channel blocker
I: partial seizures and grand mal seizures, absence seizures, myoclonic and atonic seizures, lennox Gaustaut, mood stabilizer.
SE: neurological (headache, dizziness, ataxia, diplopia), nause, skin rash, less teratogenic
Is a broad spectrum Antiepileptic

Question 8

Phenobarbital

Answer 8

A barbiturate. Binds GABA-A R (increase duration of opening), at high doses: open GABA-A receptor itself.
I: epileptic state, hyperbilirubinemia of newborns, partial seizures, generalized TC seizures (acute tr. of seizures only).
SE: strong enzyme inducer (CYP450), dependence, narrow th. range, can block Na+ channels.

Question 9

Primidone

Answer 9

A barbiturate - is converted to phenobarbital and biproduct. Mechanism of action unclear (Na+ ch. blockade?)
I: tremor

Question 10

Vigabatrine

Answer 10

(V-cab transmission)
IRREVERSIBLE GABA transaminase inhibitor - result in increased GABA levels. narrow sp. antiepi.
I: partial seizures, west syndrome
SE: irreversible visual field loss, sedation, weight loss/gain, psychosis

Question 11

Tiagabine

Answer 11

(tied up cab driver)
Inhibits GABA reuptake - GAT1 inhibitor.
I: adjuvant in partial seizures
SE: dizziness, ataxia, confusion, tremor

Question 12

Gabapentine and pregabaline

Answer 12

(grab a pint - gabapentine)
Are both GABA analogues, mechanism of action: Inhibit GABA uptake, stimulate GABA release, Inhibit N-type Ca2+ channels.
I: abscent seizures, grand-mal seizure, partial seizure, acute mania, migraine prophylaxis, neuropathic pain (postherpetic, diabetic)
SE: neurological (ataxia, dizziness, tremor, sedation), weight gain

Question 13

Anti epileptics used in Absent seizures

Answer 13

Absent seizures: due to activation of thalamic neurons, T-type VG Ca2+ channels open.
Ethosuxamide
BZDs - clonazepam
Valproic acid

Question 14

Broad spectrum antiepileptics

Answer 14

complicated mechanism of action. Are effective in all types of seizures.
Valproic acid
BZDs - Diazepam, Lorazepam, Clonazepam, Nitrazepam
Topiramate
Levetiracetam
Felbamate
Zonisamide
Acetazolamide

Question 15

Treatment of status epilepticus

Answer 15

1) Diazepam, lorazepam or clonazepam - IV high dose
2) Phenytoin IV (if 1) is not effective)
3) Phenobarbital IV -3rd line
4) general anesthesia - in resistant cases, last resort

Question 16

Ethosuximide

Answer 16

(Ethos)
Inhibit T-type VG Ca2+ channels selectively.
I: absent seizures, 1st line
SE: GI: nausea, vomit. Ataxia
Advantages: less SE, no sedation, no dependence, no enzyme inducing effect

Question 17

Benzodiazepines used in epilepsy

Answer 17

Clonazepam - 1st line in absent seizures in children. Epileptic state
Diazepam, Lorazepam - epileptic state, parenterally
Nitrazepam - long duration of action
SE: dependence, sedation, tolerance, cognitive dist.

Question 18

Valproic acid/valproate

Answer 18

(festiVAL)
Wide spectrum antiepileptic.
Mech. of action: block VG Na+ and T-type Ca2+ ch. inhibit GABA transaminase, activate Glutamate decarboxylase
I: All types of seizures (generalized, partial, absent seizures), bipolar disorder (therapy and prophylaxis of mania), migraine prophylaxis.
SE:neurological (tremor, ataxia, somnolence, dizziness, headache), GI; nausea, vomit, anemia, thrombocytopenia, Hepatotoxic (espec. in children under 2), teratogenic (spina bifida)
Enzyme induced and blocker (less than others). No dependence

Question 19

Topiramate

Answer 19

(Toupe). Broad spectrum antiepileptic
mech of action: inh. VG Na+ ch, potentiate GABA, inhibit AMPA R.
I: all types of seizures (generalized, partial, absent), childhood epilepsy (lenox gaustaut,west syndrome), migraine prophylaxis, tremor
SE: neurological (sedation, ataxia, nystagmus, diplopia, decreased cognitive function), inhibit carbonic anhydrase (kidney stones), teratogenic, induce CYP3A4, GI symptoms

Question 20

Levetiracetam

Answer 20

(eLevator). broad spectrum anti epileptic.
mech. of action: binds synaptic vesicle proteins (modulate GABA and glutamate release), inhibit N-type Ca2+ ch.
I: generalized TC, partial and absent and myoclonic seizures.
SE: sedation, dizziness, aggressiveness

Question 21

Felbamate

Answer 21

mech.of action: inhibit NMDA Rs, inhibit Na+ ch., potentiate GABA-A receptor function.
I: partial seizures, lennox-gastaut
SE: hepatotoxic, aplastic anemia

Question 22

Zonisamide

Answer 22

Mech of action: inhibit VG Na+ ch., Inh. T-type Ca2+ channels.
I: Absent seizures, generalized TC and partial seizures
SE: neurological sy., sedation, anorexia, kidney stone (weak carbonic anhydrase inhibitor)

Question 23

Acetazolamide

Answer 23

originally an antidiuretic - effect for 2-3 days only.
mech of action: carbonic anhydrase inhibitor: decrease HCO3- reads from kidney - mild acidosis - decrease seizure activity.
I: women with epileptic exacerbation during menstruation (only used during menses). Glaucoma
SE: kidney stone (alkaline urine)