ANTIEPILEPTIC DRUGS
By:Martha I. Dávila-García, Ph.D.
Department of Pharmacology, Howard University
Epilepsy
A group of chronic CNS disorders characterized by recurrent seizures.
* Seizures are sudden, transitory, and uncontrolled episodes of brain dysfunction resulting from abnormal discharge of neuronal cells with associated motor, sensory or behavioral changes.
Causes for Acute Seizures
* Trauma
* Encephalitis
* Drugs
* Birth trauma
* Withdrawal from depressants
* Tumor
* High fever
* Hypoglycemia
* Extreme acidosis
* Extreme alkalosis Hyponatremia
* Hypocalcemia
* Idiopathic
Seizures
* The causes for seizures can be multiple, from infection, to neoplasms, to head injury. In a few subgroups it is an inherited disorder.
* Febrile seizures or seizures caused by meningitis are treated by antiepileptic drugs, although they are not considered epilepsy (unless they develop into chronic seizures).
* Seizures may also be caused by acute underlying toxic or metabolic disorders, in which case the therapy should be directed towards the specific abnormality.
Neuronal Substrates of Epilepsy
The Brain
The Synapse
The Ion Channels/Receptors
ions
Cellular and Synaptic Mechanisms of Epileptic Seizures
I. Partial (focal) Seizures
II. Generalized Seizures
Classification of Epileptic Seizures
Scheme of Seizure Spread
Simple (Focal) Partial
Contralateral spread
I. Partial (Focal) Seizures
Scheme of Seizure Spread
Complex Partial Seizures
Complex Secondarily Generalized Partial Seizures
I. Partial (focal) Seizures
II. Generalized Seizures
* Generalized Tonic-Clonic Seizures
* Absence Seizures
* Tonic Seizures
* Atonic Seizures
* Clonic and Myoclonic Seizures.
* Infantile Spasms
II. Generalized Seizures
Neuronal Correlates of Paroxysmal Discharges
B. Absence Seizures (Petite Mal)
Treatment of Seizures
Goals:
* Block repetitive neuronal firing.
* Block synchronization of neuronal discharges.
* Block propagation of seizure.
Strategies:
* Modification of ion conductances.
* Increase inhibitory (GABAergic) transmission.
* Decrease excitatory (glutamatergic) activity.
Actions of Phenytoin on Na+ Channels
* Resting State
* Arrival of Action Potential causes depolarization and channel opens allowing sodium to flow in.
* Refractory State, Inactivation
Sustain channel in this conformation
GABAergic SYNAPSE
Drugs that Act at the GABAergic Synapse
* GABA agonists
* GABA antagonists
* Barbiturates
* Benzodiazepines
* GABA synthesizing enzymes
* GABA uptake inhibitors
* GABA metabolizing enzymes
GLUTAMATERGIC SYNAPSE
* Excitatory Synapse.
* Permeable to Na+, Ca2+ and K+.
* Magnesium ions block channel in resting state.
* Glycine (GLY) binding enhances the ability of GLU or NMDA to open the channel.
* Agonists: NMDA, AMPA, Kianate.
Chemical Structure of Classical Antiseizure Agents
Treatment of Seizures
* Hydantoins: phenytoin
* Barbiturates: phenobarbital
* Oxazolidinediones: trimethadione
* Succinimides: ethosuximide
* Acetylureas: phenacemide
* Other: carbamazepine, lamotrigine, vigabatrin, etc.
* Diet
* Surgery, Vagus Nerve Stimulation (VNS).
* Most classical antiepileptic drugs exhibit similar pharmacokinetic properties.
* Good absorption (although most are sparingly soluble).
* Low plasma protein binding (except for phenytoin, BDZs, valproate, and tiagabine).
* Conversion to active metabolites (carbamazepine, primidone, fosphenytoin).
* Cleared by the liver but with low extraction ratios.
* Distributed in total body water.
* Plasma clearance is slow.
* At high concentrations phenytoin exhibits zero order kinetics.
Pharmacokinetic Parameters
Effects of three antiepileptic drugs on high frequency discharge of cultured neurons
Block of sustained high frequency repetitive firing of action potentials.
PHENYTOIN (Dilantin)
* Oldest nonsedative antiepileptic drug.
* Fosphenytoin, a more soluble prodrug is used for parenteral use.
* “Fetal hydantoin syndrome”.
* Manufacturers and preparations.
* It alters Na+, Ca2+ and K+ conductances.
* Inhibits high frequency repetitive firing.
* Alters membrane potentials.
* Alters a.a. concentration.
* Alters NTs (NE, ACh, GABA)
Toxicity:
* Ataxia and nystagmus.
* Cognitive impairment.
* Hirsutism
* Gingival hyperplasia.
* Coarsening of facial features.
* Dose-dependent zero order kinetics.
* Exacerbates absence seizures.
* At high concentrations it causes a type of decerebrate rigidity.
CARBAMAZEPINE (Tegretol)
* Tricyclic, antidepressant (bipolar)
* 3-D conformation similar to phenytoin.
* Mechanism of action, similar to phenytoin. Inhibits high frequency repetitive firing.
* Decreases synaptic activity presynaptically.
* Binds to adenosine receptors (?).
* Inh. uptake and release of NE, but not GABA.
* Potentiates postsynaptic effects of GABA.
* Metabolite is active.
Toxicity:
* Autoinduction of metabolism.
* Nausea and visual disturbances.
* Granulocyte supression.
* Aplastic anemia.
* Exacerbates absence seizures.
OXCARBAZEPINE (Trileptal)
* Closely related to carbamazepine.
* With improved toxicity profile.
* Less potent than carbamazepine.
* Active metabolite.
* Use in partial and generalized seizures as adjunct therapy.
* May aggravate myoclonic and absence seizures.
* Mechanism of action, similar to carbamazepine It alters Na+ conductance and inhibits high frequency repetitive firing.
Toxicity:
* Hyponatremia
* Less hypersensitivity and induction of hepatic enzymes than with carbamazepine
PHENOBARBITAL (Luminal)
* Except for the bromides, it is the oldest antiepileptic drug.
* Although considered one of the safest drugs, it has sedative effects.
* Many consider them the drugs of choice for seizures only in infants.
* Acid-base balance important.
* Useful for partial, generalized tonic-clonic seizures, and febrile seizures
* Prolongs opening of Cl- channels.
* Blocks excitatory GLU (AMPA) responses. Blocks Ca2+ currents (L,N).
* Inhibits high frequency, repetitive firing of neurons only at high concentrations.
Toxicity:
* Sedation.
* Cognitive impairment.
* Behavioral changes.
* Induction of liver enzymes.
* May worsen absence and atonic seizures.
PRIMIDONE (Mysolin)
* Metabolized to phenobarbital and phenylethylmalonamide (PEMA), both active metabolites.
* Effective against partial and generalized tonic-clonic seizures.
* Absorbed completely, low binding to plasma proteins.
* Should be started slowly to avoid sedation and GI problems.
* Its mechanism of action may be closer to phenytoin than the barbiturates.
Toxicity:
* Same as phenobarbital
* Sedation occurs early.
* Gastrointestinal complaints.
VALPROATE (Depakene)
ETHOSUXIMIDE (Zarontin)
CLONAZEPAM (Klonopin)
VIGABATRIN
LAMOTRIGINE (Lamictal)
FELBAMATE (Felbatrol)
TOPIRAMATE (Topamax)
TIAGABINE (Gabatril)
ZONISAMIDE (Zonegran)
GABAPENTIN (Neurontin)
Status Epilepticus
Treatment of Status Epilepticus in Adults
DIAZEPAM (Valium) AND
LORAZEPAM (Ativan)
Treatment of Seizures
PRIMARY GENERALIZED TONIC-CLONIC SEIZURES (Grand Mal)
GENERALIZED ABSENCE SEIZURES
ATYPICAL ABSENCE, MYOCLONIC, ATONIC* SEIZURES
INFANTILE SPASMS
Treatment of Seizures in Pregnancy
INTERACTIONS BETWEEN ANTISEIZURE DRUGS
ANTISEIZURE DRUG INTERACTIONS
With other drugs:
ANTIEPILEPTIC DRUGS.ppt
http://www.med.howard.edu/pharmacology/handouts/ANTIEPILEPTICS_OL2003.ppt
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