ANTIEPILEPTICS Flashcards
What is epilepsy?
• Epilepsy is a chronic disorder characterized by
recurrent seizures.
• Seizures are finite episodes of brain dysfunction
resulting from abnormal discharge of cerebral
neurons.
• The pathophysiologic mechanisms underlying
seizure disorders are unknown.
• Seizures are still classified according to their
clinical manifestations rather than their biological
basis.
How are seizures classified?
1. PARTIAL SEIZURES • SIMPLE PARTIAL SEIZURES • COMPLEX PARTIAL SEIZURES • PARTIAL WITH SECONDARILY GENERALIZED TONIC-CLONIC SEIZURES
- GENERALIZED SEIZURES
• TONIC-CLONIC SEIZURES
• ABSENCE SEIZURES
Define a simple partial seizure?
• There is no loss of consciousness. • Often there is abnormal activity of a single limb or muscle group.
Define complex partial seizure?
• There is loss of consciousness.
• Motor dysfunction may involve chewing
movements, diarrhea, urination.
Define Partial With Secondarily Generalized
Tonic-Clonic Seizure?
• The partial seizure
evolves into a tonic-clonic seizure with loss of
consciousness.
Define generalized seizures?
• No evidence of localized onset. • They may be convulsive or nonconvulsive. • There is immediate loss of consciousness.
Define Absence Seizure (petit mal)
• Brief, abrupt and self-limiting loss of consciousness. • The patient stares and exhibits rapid eye-blinking. • 3 Hz spike-and-wave pattern emerges abruptly and ceases after few seconds.
Name 6 other generalized seizures?
- ATONIC SEIZURES
- TONIC SEIZURES
- CLONIC SEIZURES
- MYOCLONIC SEIZURES
- FEBRILE SEIZURES
- STATUS EPILEPTICUS
Nature and Mechanisms of Seizures, which two neurotransmitters involved?
• A decrease in inhibitory synaptic activity or an increase in excitatory activity might trigger a seizure.
• GABA and glutamate are the main inhibitory and
excitatory neurotransmitters, respectively.
Pharmacological evidence for seizures?
• Experimental data shows that:
• Antagonists of the GABAA
receptor trigger
seizures.
• Agonists of glutamate receptors trigger
seizures.
• Drugs that enhance GABAergic transmission
inhibit seizures.
• Glutamate receptor antagonists inhibit seizures.
• Therefore, pharmacological regulation of synaptic function can regulate the propensity
for seizures.
Antiepileptic Drugs: MOA
• The principal mechanisms of action of antiseizure
drugs involve:
• Blockade of Voltage-Gated Ion Channels
• Modulation of Synaptic Transmission
Drugs that Block Voltage-Gated Ion Channels in which two ways?
- Drugs that block Voltage-Gated Na+ channels
2. Drugs that block T-type Ca2+ channels
Drugs that Block Voltage-Gated Na+ Channels?
- Principal mechanism of action of
- Phenytoin
- Carbamazepine
- Lamotrigine
- Zonisamide
- It may contribute to the effects of
- Phenobarbital
- Valproate
- Topiramate
Drugs that Block T-type Ca2+ Channels through which mechanism
• Absence seizures involve oscillatory neuronal
activity between thalamus and cortex.
• The T-type Ca2+ current governs oscillatory
responses in thalamic neurons.
• Ethosuximide and valproate inhibit this
current and are effective in absence seizures.
Drugs that Affect Synaptic Transmission in regards to antiepileptics?
1. Drugs that enhance GABAergic neurotransmission (• Postsynaptically • Presynaptically) 2. Drugs that reduce glutamatergic neurotransmission (• Postsynaptically • Presynaptically)
Drugs that Enhance GABAergic Neurotransmission Postsynaptically?
- Direct action on the GABA receptor
- Benzodiazepines
- Barbiturates
- Topiramate
Drugs that Enhance GABAergic Neurotransmission Presynaptically?
• Inhibition of the reuptake of GABA: Tiagabine. • Inhibition of degradation of GABA: Vigabatrin inhibits GABA aminotransferase.
Drugs that Reduce Glutamatergic Neurotransmission Postsynaptically?
• Phenobarbital & topiramate block glutamate receptors.
Drugs that Reduce Glutamatergic
Neurotransmission Presynaptically
• Gabapentin and pregabalin decrease
glutamate release by blocking presynaptic
voltage-gated Ca2+ channels.
• Levetiracetam binds to synaptic vesicle glycoprotein 2A (SV2A). This may affect release of glutamate and GABA.
Main drugs used for Partial and Secondarily Generalized Tonic-Clonic Seizures
- The main drugs used are:
- Carbamazepine
- Oxcarbazepine
- Levetiracetam
- Zonisamide
- Phenytoin
- Valproate
- Lamotrigine
- Topiramate
- Phenobarbital
Main drugs used for tonic-clonic seizures?
- Main drugs used include:
- Carbamazepine
- Oxcarbazepine
- Valproate
- Lamotrigine
- Phenytoin
- Topiramate
Drugs used for Absence Seizures?
• Drugs of choice: ethosuximide and valproate.
• If tonic-clonic seizures are present valproate is
the drug of choice.
• Valproate is also preferred for atypical absence seizures.
• Lamotrigine is probably effective.
Drugs used for Myoclonic Seizures?
• Valproate is the drug of choice.
• Topiramate is also used.
• Levetiracetam is approved for adjunctive
therapy.
Drugs used for atonic seizures?
- Atonic seizures are often refractory to all drugs.
* Valproate and lamotrigine may be beneficial.
Guidelines for seizures as Febrile Convulsions?
• If seizures last < 15 minutes treatment is supportive.
• Seizures lasting > 15 minutes require
pharmacological treatment to prevent brain damage.
• Treatment: diazepam given IV or as a rectal solution.
Define status epilepticus?
• Status epilepticus is a single seizure lasting more than 5 minutes or two or more seizures without recovery of consciousness between
seizures.
• It may be convulsive or nonconvulsive.
• The most common type, generalized tonic-clonic status epilepticus, is a life-threatening emergency.
Status Epilepticus: Management
Initial therapy
phase:
IM Midazolam Or IV Lorazepam Or IV Diazepam
Second therapy
phase:
IV Fosphenytoin Or IV Valproic acid Or IV Levetiracetam
Third therapy phase: Repeat second therapy or IV thiopental, midazolam, pentobarbital, or propofol
How are drug induced seizures controlled in non-epileptic patients?
• Drug-induced seizures in nonepileptic patients
may be controlled with diazepam, lorazepam or
phenobarbital.
Which antiepileptics induce cytochrome p450?
Induce cytochrome P450: • Carbamazepine • Phenobarbital • Phenytoin • Oxcarbazepine is a weak P450 inducer
Valproate AE?
Valproate • Hepatotoxicity. • Inhibits cytochrome P450. • Inhibits metabolism of several drugs. • Inhibits its own metabolism.
Phenytoin AE?
Phenytoin • Diplopia, ataxia. • Gingival hyperplasia. • Coarsening of facial features in children. • Hirsutism. • Rash. Stevens-Johnson Syndrome. • Zero order kinetics of elimination.
Carbamazepine AE?
- Aplastic anemia, agranulocytosis.
* Rash. Stevens-Johnson syndrome
Which antiepileptics induce Rash & Stevens-Johnson Syndrome
High risk:
Which has a black box warning?
High risk: • Phenytoin • Lamotrigine • Carbamazepine • Phenobarbital
Lamotrigine has a black box warning:
“Lamotrigine should ordinarily be discontinued
at the first sign of rash.”
AE of phenobarbital and primidone?
Phenobarbital • Sedation, drowsiness. • Rash. Stevens-Johnson syndrome. • Tolerance, dependence. • Cognitive impairment, hyperactivity. • P450 inducer. Primidone • The adverse effects of primidone are similar to those of its metabolite, phenobarbital.
AE of Vigabatrin?
Vigabatrin
• Visual field loss.
AE of Felbamate?
Felbamate
• Aplastic anemia
• Hepatotoxicity
• For refractory epilepsy
Guidelines for Discontinuing Antiepileptic Therapy
• If a patient is seizure-free for 3-5 years
discontinuation is warranted.
• Discontinuation should be slow.
• Benzodiazepines and barbiturates should be
discontinued very gradually to avoid withdrawal
seizures.
• If the patient is on combination therapy, drugs
should be withdrawn one at a time.
Consequence of overdose on antiepileptics?
• Antiepileptic drugs are commonly taken in
intentional drug overdoses.
• Antiseizure drugs are rarely lethal.
• The most dangerous effect after large overdoses
is respiratory depression.
• Treatment is supportive.
• Stimulants should not be used.
Are antiepileptics teratogenic, which one specifically?
• There is an increased risk of congenital
malformations in infants born of women taking
antiseizure drugs.
• Valproate causes a significantly higher rate of
fetal malformations compared to other
antiepileptic drugs.
• Prophylactic folic acid decreases incidence of
neural tube defects.
What is Newborn Hemorrhagic Disease in regards to antiepileptics?
• Enzyme-inducing antiepileptic drugs may
increase degradation of vitamin K in the fetus.
• This can cause bleeding in the newborn infant.
• Vitamin K supplementation is recommended for
the mother in the final month of pregnancy and
for the newborn.
Other Uses of Antiseizure Drugs?
• Carbamazepine: Neuropathic pain; bipolar disorder. • Gabapentin: Neuropathic pain. • Lamotrigine: Bipolar Disorder. • Pregabalin: Neuropathic pain. • Topiramate: Migraine. • Valproate: Bipolar disorder; migraine. • Primidone: First line for essential tremor (propranolol is also first line).
Nonpharmacologic Approaches part 1 to antiepileptics?
• About 1/3 of patients with epilepsy continue to
have seizures on medication.
Surgery
• For most patients whose seizures originate from
a local area of abnormal brain, function improves markedly when the epileptic focus is resected.
Non-pharmacological approaches to antiepileptic management?
The Ketogenic Diet
• Four parts fat to one part protein and carbohydrate.
• The high fat content and extremely low carbohydrate content produce ketosis, which appears to have a direct anti seizure effect.
• How the ketogenic diet suppresses seizures
remains unclear.
Vagus Nerve Stimulation
• Intermittent electrical stimulation of the left vagus nerve with an implanted pacemaker-like device.
• The patient can activate the device when they sense a seizure is imminent.
