Psychopharmacology: Antiepileptics antiseizures anticonvulsants

ANTI EPILEPTIC DRUGS ANTI SEIZURE DRUGS ANTICONVULSANTS

Classification of AEDs

Classical

·         Phenytoin

·         Phenobarbital

·         Primidone

·         Carbamazepine

·         Ethosuximide

·         Valproate (valproic acid)

Newer

·         Lamotrigine  

·         Felbamate

·         Topiramate    

·         Gabapentin

·         Tiagabine

·         Vigabatrin

·         Oxycarbazepine

·         Levetiracetam

·         Fosphenytoin

Chemical based classification of Anti-epileptic drugs (AED)

Chemical compound class	Member Drug
Barbiturate	Phenobarbitone
Deoxybarbiturate	Primidone
Hydantoin	phenytoin
Iminostilbene	Carbamazepine
Succinimide	Ethosuximide
Aliphatic carboxylic acid	Sodium valproate
Benzodiazepines	Clonazepam,Diazepam,Clobazam
Phenyltriazine	Lamotrigine
Cyclic GABA analogue	Gabapentin
Newer drugs	Vigabatrin , Topiramate,Tiagabine, Levitiracetam, Zonisamide

           

Newer (Second Generation) Antiepileptic

·         Largely target partial seizures

·         Fewer and less severe drug interactions compared to older drugs

Mechanism

Enhance neurotransmitter release, activation of NMDA subtype Of glutamate receptors, which causes ca influx & neuronal activation.

PHENYTOIN (Dilantin)

·         Oldest nonsedative antiepileptic drug.

·         Fosphenytoin, a more soluble prodrug is used for parenteral use.

·         "Fetal hydantoin syndrome"

·         It alters Na+, Ca2+ and K+ conductances. 

·         Inhibits high frequency repetitive firing.  

·         Alters membrane potentials.

Toxicity:

·         Ataxia and nystagmus.

·         Cognitive impairment.

·         Hirsutism

·         Gingival hyperplasia.

·         Coarsening of facial features.

USES

·         Partial seizure

·         Generalized (including tonic-clonic) seizures

·         Contraindicated in absence seizures

·         Nonseizure indications include  

o   Trigeminal neuralgia

o   Manic-depressive disorders

Fetal Hydantoin Syndrome

·         Pre- and postnatal growth deficiency with psychomotor retardation, microcephaly with a ridged metopic suture, hypoplasia of the nails and finger like thumb and hypoplasia of the distal phalanges.

·         Radiological skeletal abnormalities reflect the hypoplasia and fused metopic suture.

·         Cardiac defects and abnormal genitalia.

CARBAMAZEPINE (Tegretol)

·         Mechanism of action, similar to phenytoin. Inhibits high frequency repetitive firing

·         Decreases synaptic activity presynaptically.

·         Inh. uptake and release of NE, but not GABA.

·         Potentiates postsynaptic effects of GABA.   Metabolite is active.

           Toxicity:        

·         Auto induction of metabolism.         

·         Nausea and visual disturbances.  

·         Granulocyte suppression.

·         Aplastic anemia.

·         Exacerbates absence seizures.

USES

·         Partial seizure

·         Generalized (including tonic-clonic) seizures

·         Contraindicated in absence seizures

·         Nonseizure indications include  

o   trigeminal neuralgia 

o   manic-depressive disorders

OXCARBAZEPINE

·         Closely related to carbamazepine.

·         With improved toxicity profile.

·         Less potent than carbamazepine.

·         Active metabolite.

·         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 carb

PHENOBARBITAL

·         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 infant

·         Useful for partial, generalized tonic-clonic seizures, and febrile seizures

·         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

·         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 Gl problems.

·         Its mechanism of action may be closer to phenytoin than the barbiturates.

Toxicity:

·         Same as phenobarbital           

·         Sedation occurs early.

·         Gastrointestinal complaints.

VALPROATE

·         Fully ionized at body pH, thus active form is valproate ion.

·         One of a series of carboxylic acids with antiepileptic activity. Its amides and esters are also active.

·         Mechanism of action, similar to phenytoin.

·         ↑↑levels of GABA in brain.

USES

A broad-spectrum anti-seizure drug (effective against most partial and generalized seizures, including myoclonic and absence seizures)

 Non-seizure indications include:

·         Migraine (prophylaxis) 

·         Bipolar disorder

ETHOSUXIMIDE

·         Drug of choice for absence seizures. 

·         High efficacy and safety.

·         Mechanism of action involves reducing low-threshold Ca2+ channel current in thalamus.

 At high concentrations:

·         Inhibits GABA aminotransferase.

Phensuximide = less effective

Methsuximide = more toxic

          

CLONAZEPAM

 A benzodiazepine.

·         Long acting drug with efficacy for absence seizures.

·         One of the most potent antiepileptic agents known.

·         Also effective in some cases of myoclonic seizures.

·         Has been tried in infantile spasms.

·         Doses should start small.

LAMOTRIGINE    

·         Presently use as add-on therapy with valproic acid

·         Almost completely absorbed 

·         T1/2 = 24 hrs

·         Low plasma protein binding

·         Also effective in myoclonic and generalized seizures in childhood and absence attacks.

·         Suppresses sustained rapid firing of neurons and produces a voltage and use dependent inactivation of sodium channels, thus its efficacy in partial seizures.

TOPIRAMATE      

Blocks repetitive firing of cultured neurons, thus its mechanism may involve blocking of voltage-dependent sodium channels.

Toxicity:

·         Somnolence

·         Fatigue

·         Dizziness

·         Cognitive slowing

·         Paresthesia

·         Nervousness

·         Confusion

·         Urolithiasis

ZONISAMIDE

·         Sulfonamide derivative

·         T1/2= l - 3 days

·         Effective against partial and generalized tonic-clonic seizures.

·         Mechanism of action involves voltage and use-dependent inactivation of sodium channels (?).

·         May also involve Ca2+ channels.

 FELBAMATE

           Effective against partial seizures but has severe side effects.

 Because of its severe side effects, it has been relegated to a third-line drug used only for refractory cases.

GABAPENTIN (Neurontin)

·         Used as an adjunct in partial and generalized tonic-clonic seizures.

·         Does not induce liver enzymes.

·         Not bound to plasma proteins. 

·         Drug-drug interactions are negligible.   

·         Low potency.

Status Epilepticus

·         Status epilepticus exists when seizures recur within a short period, such that baseline consciousness is not regained between the seizures.

·         They last for at least 30 minutes.

·         Can lead to systemic hypoxia, academia, hyperpyrexia, cardiovascular collapse, and renal shutdown.

·         The most common, generalized tonic-clonic status epilepticus is life threatening and must be treated immediately with concomitant cardiovascular, respiratory and metabolic management.

DIAZEPAM (Valium) AND LORAZEPAM (Ativan)

·         Benzodiazepines       

·         Given I.V.

·         Lorazepam may be longer acting.

·         First line drugs for treating status epilepticus

·         Have muscle relaxant activity.

·         Potentiates GABA function, by increasing the frequency of channel opening.  

·         Treatment of Status Epilepticus in Adults

Initial

 Diazepam, i.v. 5-10 mg (1-2 mg/min)

           repeat dose (5-10 mg) every 20-30 min.

 Lorazepam, i.v. 2-6 mg (l mg/min)

           repeat dose (2-6 mg) every 20-30 min.

Follow-up

           Phenytoin, i.v. 15-20 mg/Kg (30-50 mg/min).

           repeat dose (100-150 mg) every 30 min.       

           Phenobarbital, i.v. 10-20 mg/Kg (25-30mg/min).

           repeat dose (120-240 mg) every 20 min.