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ANTIEPILEPTIC DRUGS
EPILEPSY
• Epilepsy is a heterogeneous symptom complex – a
chronic disorder characterized by recurrent
seizures.
• Seizures are finite episodes of brain dysfunction
resulting from abnormal discharge of cerebral
neurons
CAUSES FOR ACUTE SEIZURES
• Trauma
• Encephalitis
• Drugs
• Birth trauma
• Withdrawal from depressants
• Tumor
• High fever
• Hypoglycemia
• Extreme acidosis
• Extreme alkalosis
Hyponatremia
• Hypocalcemia
• Idiopathic
CLASSIFICATION OF EPILEPTIC SEIZURES
• Partial (focal) Seizures
• Simple Partial Seizures
• Complex Partial Seizures
• Partial seizures secondarily generalised
• Generalized Seizures
• Generalized Tonic-Clonic Seizures
• Absence Seizures
• Tonic Seizures
• Atonic Seizures
• Clonic and Myoclonic Seizures
PARTIAL (FOCAL) SEIZURES
Simple Partial Seizures (Jacksonian)
• Involves one side of the brain at onset.
• Focal motor, sensory or speech disturbances.
• Confined to a single limb or muscle group.
• Seizure-symptoms don’t change during
seizure.
• No alteration of consciousness.
EEG: Excessive synchronized discharge by a small
group of neurons
I. PARTIAL (FOCAL) SEIZURES
Complex Partial Seizures (Temporal Lobe epilepsy or
Psychomotor Seizures)
• Produces confusion and inappropriate or dazed
behavior.
• Motor activity appears as non-reflex actions.
Automatisms (repetitive coordinated
movements).
• Wide variety of clinical manifestations.
• Consciousness is impaired or lost.
EEG: Bizarre generalized EEG activity with evidence
of anterior temporal lobe focal abnormalities.
Bilateral.
GENERALIZED SEIZURES
• In Generalized seizures, both hemispheres are
widely involved from the outset.
• Manifestations of the seizure are determined
by the cortical site at which the seizure arises.
• Present in 40% of all epileptic Syndromes.
II. GENERALIZED SEIZURES (CON’T)
Generalized Tonic-Clonic Seizures
• Recruitment of neurons throughout the
cerebrum
• Major convulsions, usually with two phases:
• Tonic phase
• Clonic phase
GENERALIZED SEIZURES (CON’T)
Generalized Tonic-Clonic Seizures
• Tonic phase
• Sustained powerful muscle contraction (involving all body musculature) which arrests
ventilation.
• EEG: Rythmic high frequency, high voltage
discharges with cortical neurons undergoing
sustained depolarization, with protracted trains of
action potentials.
GENERALIZED SEIZURES (CON’T)
Generalized Tonic-Clonic Seizures
• Clonic phase:
• Alternating contraction and relaxation, causing a reciprocating movement which
could be bilaterally symmetrical or “running” movements.
• EEG: Characterized by groups of spikes on the
EEG and periodic neuronal depolarizations with
clusters of action potentials.
GENERALIZED SEIZURES
Absence Seizures (Petite Mal)
• Brief and abrupt loss of consciousness.
• Sometimes with no motor manifestations.
• Usually symmetrical clonic motor activity varying from occasional
eyelid flutter to jerking of the entire body.
• Typical 2.5 – 3.5 Hz spike-and-wave discharge.
• Usually of short duration (5-10 sec), but may occur dozens of
times a day.
GENERALIZED SEIZURES
Absence Seizures (Petite Mal) (con’t)
• Often begin during childhood (daydreaming
attitude, no participation, lack of concentration).
• A low threshold Ca2+ current has been found to
govern oscillatory responses in thalamic neurons
(pacemaker)
• This low threshold probably involve in the
generation of these types of seizures.
GENERALIZED SEIZURES (CON’T)
Tonic Seizures
• Opisthotonus, loss of consciousness.
• Marked autonomic manifestations
Atonic Seizures (atypical)
• Loss of postural tone, with sagging of the head or falling.
• May loose consciousness.
GENERALIZED SEIZURES (CON’T)
Clonic and Myoclonic Seizures
• Clonic Seizures:
• Involves rhythmic clonic contractions of all muscles,
• loss of consciousness and
• marked autonomic manifestations.
• Myoclonic Seizures:
• Isolated clonic jerks associated with brief bursts of
multiple spikes in the EEG.
GENERALIZED SEIZURES (CON’T)
Infantile Spasms
• An epileptic syndrome.
• Attacks, although fragmentary, are often
bilateral.
• Characterized by brief recurrent myoclonic jerks
of the body with sudden flexion or extension of
the body and limbs.
TREATMENT OF SEIZURES
Goals:
• Block repetitive neuronal firing.
• Block synchronization of neuronal discharges.
• Block propagation of seizure.
• Minimize side effects with the simplest drug regimen.
MONOTHERAPY IS RECOMMENDED IN MOST CASES
TREATMENT OF SEIZURES
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
Na+
Na+
Na+
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
GAD
GAT
GABA-T
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
Mg++
Na+
AGONISTS
GLU
Ca2+
K+
GLY
TREATMENT OF SEIZURES
1) Hydantoins: phenytoin
2) Barbiturates: phenobarbital
3) Oxazolidinediones: trimethadione
4) Succinimides: ethosuximide
5) Acetylureas: phenacemide
6) Other: carbamazepine, lamotrigine, vigabatrin, etc.
7) Diet
8) Surgery, Vagus Nerve Stimulation (VNS)
TREATMENT OF SEIZURES
• 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.
TREATMENT OF SEIZURES
• 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).
HYDANTOINS – PHENYTOIN (DILANTIN)
• Oldest nonsedative antiepileptic drug.
• Fosphenytoin, a more soluble prodrug is used for
parenteral
MOA
• It alters Na+, Ca2+ and K+ conductances.
• Inhibits high frequency repetitive firing.
• Alters membrane potentials.
• Alters amino acid concentration.
• Alters NTs (NE, ACh, GABA)
Pharmacokinetics
• GIT absorption is nearly complete
• IM absorption is unpredictable, precipitation may occur – not
recommended
• Fosphenytoin – a more soluble, given IM
• Phenytoin is highly bound to plasma proteins.
• Metabolized in the liver an excreted in urine
Clinical Use
• Phenytoin is effective against partial seizures and
generalized tonic-clonic seizures.
• In tonic-clonic seizures it appears to be effective
against attacks that are either primary or secondary
another seizure type
Toxicity
• Nystagmus
• Diplopia and ataxia are the most common dose-
related
• Gingival hyperplasia and hirsutism
• Peripheral neuropathy
• MEPHENYTOIN, ETHOTOIN, & PHENACEMIDE
CARBAMAZEPINE (TEGRETOL)
• Closely related to imipramine and other
antidepressants,
• carbamazepine is a tricyclic compound
• 3-D conformation is similar to phenytoin.
CARBAMAZEPINE (TEGRETOL)
MoA
• 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.
• Pharmacokinetics
• Absorption is almost complete absorption but rates of absorption
varies
• 70% of the drug is bound to plasma proteins
• Carbamazepine is an enzyme inducer
• Carbamazepine is completely metabolized in the liver.
• Some of the metabolites exhibit activity
• Clinical Use
• drug of choice for both partial seizures and generalized tonic-clonic
seizures
• Carbamazepine is not sedative in its usual therapeutic range.
• Effective in management of trigeminal neuralgia
• Carbamazepine is also useful in some patients with mania (bipolar
disorder).
• Others: oxcarbazepine
• Toxicity
• Diplopia and ataxia – dose related
• Mild gastrointestinal upsets,
• Unsteadiness
• Drowsiness – at higher doses
• Aplastic anemia and agranulocytosis
BARBITURATES – 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.
PHENOBARBITAL (LUMINAL)
MoA
• Prolongs opening of Cl- channels.
• Blocks excitatory Glutamate responses.
• Blocks Ca2+ and Na+ currents
• Inhibits high frequency, repetitive firing of neurons
only at high concentrations.
PHENOBARBITAL (LUMINAL)
Clinical uses
• Useful for partial, generalized tonic-clonic seizures,
and febrile seizures
PRIMIDONE (MYSOLIN)
• Metabolized to phenobarbital and
phenylethylmalonamide (PEMA)
• The three compounds, metabolite and the parent
drug are active
MoA
• Although primidone is converted to phenobarb, its
MoA is more like that of phenytoin
PRIMIDONE (MYSOLIN)
• Pharmacokinetics
• Primidone is completely absorbed
• Low binding to plasma proteins
• Metabolised in the liver to active metabolites
• Should be started slowly to avoid sedation and GI
problems.
PRIMIDONE (MYSOLIN)
Clinical Use
• Effective against partial seizures and generalized
tonic-clonic seizures
• May be more effective than phenobarbital.
• Carbamazepine and phenytoin are superior to
primidone in management of complex partial
seizures
PRIMIDONE (MYSOLIN)
• Toxicity
• Similar to phenobarbital,
• But drowsiness occurs early in treatment and may
be prominent if the initial dose is too large.
• Gradual increments are indicated when starting the
drug in either children or adults.
VIGABATRIN (-VINYL-GABA)
• Absorption is rapid, bioavailability is ~ 60%, T 1/2 6-8 hrs,
eliminated by the kidneys.
• Use for partial seizures
• Contraindicated if preexisting mental illness is present.
• Irreversible inhibitor of GABA-aminotransferase (enzyme
responsible for metabolism of GABA)
• Increases inhibitory effects of GABA.
• S(+) enantiomer is active.
VALPROATE (DEPAKENE)
• 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.
VALPROATE (DEPAKENE)
• Mechanism of action
• similar to phenytoin.
•  levels of GABA in brain.
• Facilitates Glutamic acid decarboxylase (GAD).
• Inhibits the GABA-transporter in neurons and glia (GAT).
•  [aspartate]Brain?
• May increase membrane potassium conductance.
ETHOSUXIMIDE (ZARONTIN)
At high concentrations:
• Inhibits Na+/K+ ATPase.
• Depresses cerebral metabolic rate.
• Inhibits GABA aminotransferase.
• Phensuximide = less effective
• Methsuximide = more toxic
ETHOSUXIMIDE (ZARONTIN)
• Drug of choice for absence seizures.
• High efficacy and safety.
• VD = TBW.
• Not plasma protein or fat binding
• Mechanism of action involves reducing low-
threshold Ca2+ channel current (T-type channel) in
thalamus.
BENZODIAZEPINE CLONAZEPAM (KLONOPIN)
• 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.
• Increases the frequency of Cl- channel opening.
LAMOTRIGINE (LAMICTAL)
• Add-on therapy with valproic acid (w/v.a. conc.
have be reduced => reduced clearance).
• Almost completely absorbed
• T1/2 = 24 hrs
• Low plasma protein binding
LAMOTRIGINE (LAMICTAL)
• Effective in myoclonic and generalized seizures in
childhood and absence attacks.
• Involves blockade of repetitive firing involving Na
channels, like phenytoin.
• Also effective in myoclonic and generalized
seizures in childhood and absence attacks.
FELBAMATE (FELBATROL)
• 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.
• Causes aplastic anemia
• Severe hepatits
TOPIRAMATE (TOPAMAX)
• Rapidly absorbed, bioav. is > 80%, has no active
metabolites, excreted in urine.T1/2 = 20-30 hrs
• Blocks repetitive firing of cultured neurons, thus
its mechanism may involve blocking of voltage-
dependent sodium channels
• Potentiates inhibitory effects of GABA (acting at a
site different from BDZs and BARBs).
• Depresses excitatory action of kainate on AMPA
receptors.
• Teratogenic in animal models.
TOPIRAMATE (TOPAMAX)
Toxicity:
• Somnolence
• Fatigue
• Dizziness
• Cognitive slowing
• Parenthesis
• Nervousness
• Confusion
• Weak carbonic anhydrase inhibitor
• Urolithiasis
TIAGABINE (GABATRIL)
• Derivative of nipecotic acid.
• 100% bioavailable, highly protein bound.
• T1/2 = 5 -8 hrs
• Effective against partial seizures in pts at least 12
years old.
• Approved as adjunctive therapy.
• GABA uptake inhibitor  aminibutyric acid
transporter (GAT) by neurons and glial cells.
TIAGABINE (GABATRIL)
Toxicity:
•Abdominal pain and nausea (must be taken w/food)
•Dizziness
•Nervousness
•Tremor
•Difficulty concentrating
•Depression
•Asthenia
•Emotional liability
•Psychosis
•Skin rash
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.
• An a.a.. Analog of GABA that does not act on
GABA receptors, it may however alter its
metabolism, non-synaptic release and transport.
GABAPENTIN (NEURONTIN)
Toxicity:
•Somnolence.
•Dizziness.
•Ataxia.
•Headache.
•Tremor.
STATUS EPILEPTICUS
• Occurs when seizures recur within a short period
of time, such that baseline consciousness is not
regained between the seizures.
• They last for at least 30 minutes.
• Can lead to
• systemic hypoxia,
• acidemia,
• hyperpyrexia,
• cardiovascular collapse
• renal shutdown.
STATUS EPILEPTICUS
• The most common, generalized tonic-clonic status epilepticus is life-
threatening
• Must be treated immediately with concomitant cardiovascular,
respiratory and metabolic management.
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 (1 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.
TREATMENT OF SEIZURES
Partial seizures
• Simple and Complex, including secondarily
generalized
• Drugs of choice
• Carbamazepine
• Phenytoin
• Valproate
TREATMENT OF SEIZURES
Partial seizures
• Alternatives:
• Lamotrigine,
• phenobarbital,
• primidone,
• oxcarbamazepine.
• Add-on therapy
• Gabapentin,
• topiramate,
• tiagabine,
• levetiracetam,
• zonisamide.
TREATMENT OF SEIZURES
Primary generalized tonic-clonic seizures (grand mal)
• drugs of choice:
• Carbamazepine
• Phenytoin
• Valproate*
*not approved except if absence seizure is involved
TREATMENT OF SEIZURES
Primary generalized tonic-clonic seizures (grand mal)
• alternatives:
• lamotrigine,
• phenobarbital,
• topiramate,
• Oxcarbazepine,
• primidone,
• levetiracetam.
TREATMENT OF SEIZURES
Generalized absence seizures
• drugs of choice
• ethosuximide
• valproate*
• alternatives:
• lamotrigine,
• clonazepam,
• zonisamide,
• topiramate (?).
* first choice if primary generalized tonic-clonic seizure is also
TREATMENT OF SEIZURES
Atypical absence, myoclonic, atonic* seizures
• Drugs of choice
• Valproate
• Clonazepam
• Lamotrigine
• Alternatives:
• Topiramate,
• clonazepam,
• zonisamide,
• felbamate.
TREATMENT OF SEIZURES
Infantile spasms
• drugs of choice
• corticotropin (im) or
• corticosteroids (prednisone)
• zonisamide
• Alternatives
• clonazepam,
• nitrazepam,
• vigabatrin,
• phenobarbital.

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Antiepileptic Drugs for Seizure Control

  • 2. EPILEPSY • Epilepsy is a heterogeneous symptom complex – a chronic disorder characterized by recurrent seizures. • Seizures are finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons
  • 3. CAUSES FOR ACUTE SEIZURES • Trauma • Encephalitis • Drugs • Birth trauma • Withdrawal from depressants • Tumor • High fever • Hypoglycemia • Extreme acidosis • Extreme alkalosis Hyponatremia • Hypocalcemia • Idiopathic
  • 4. CLASSIFICATION OF EPILEPTIC SEIZURES • Partial (focal) Seizures • Simple Partial Seizures • Complex Partial Seizures • Partial seizures secondarily generalised • Generalized Seizures • Generalized Tonic-Clonic Seizures • Absence Seizures • Tonic Seizures • Atonic Seizures • Clonic and Myoclonic Seizures
  • 5. PARTIAL (FOCAL) SEIZURES Simple Partial Seizures (Jacksonian) • Involves one side of the brain at onset. • Focal motor, sensory or speech disturbances. • Confined to a single limb or muscle group. • Seizure-symptoms don’t change during seizure. • No alteration of consciousness. EEG: Excessive synchronized discharge by a small group of neurons
  • 6. I. PARTIAL (FOCAL) SEIZURES Complex Partial Seizures (Temporal Lobe epilepsy or Psychomotor Seizures) • Produces confusion and inappropriate or dazed behavior. • Motor activity appears as non-reflex actions. Automatisms (repetitive coordinated movements). • Wide variety of clinical manifestations. • Consciousness is impaired or lost. EEG: Bizarre generalized EEG activity with evidence of anterior temporal lobe focal abnormalities. Bilateral.
  • 7. GENERALIZED SEIZURES • In Generalized seizures, both hemispheres are widely involved from the outset. • Manifestations of the seizure are determined by the cortical site at which the seizure arises. • Present in 40% of all epileptic Syndromes.
  • 8. II. GENERALIZED SEIZURES (CON’T) Generalized Tonic-Clonic Seizures • Recruitment of neurons throughout the cerebrum • Major convulsions, usually with two phases: • Tonic phase • Clonic phase
  • 9. GENERALIZED SEIZURES (CON’T) Generalized Tonic-Clonic Seizures • Tonic phase • Sustained powerful muscle contraction (involving all body musculature) which arrests ventilation. • EEG: Rythmic high frequency, high voltage discharges with cortical neurons undergoing sustained depolarization, with protracted trains of action potentials.
  • 10. GENERALIZED SEIZURES (CON’T) Generalized Tonic-Clonic Seizures • Clonic phase: • Alternating contraction and relaxation, causing a reciprocating movement which could be bilaterally symmetrical or “running” movements. • EEG: Characterized by groups of spikes on the EEG and periodic neuronal depolarizations with clusters of action potentials.
  • 11. GENERALIZED SEIZURES Absence Seizures (Petite Mal) • Brief and abrupt loss of consciousness. • Sometimes with no motor manifestations. • Usually symmetrical clonic motor activity varying from occasional eyelid flutter to jerking of the entire body. • Typical 2.5 – 3.5 Hz spike-and-wave discharge. • Usually of short duration (5-10 sec), but may occur dozens of times a day.
  • 12. GENERALIZED SEIZURES Absence Seizures (Petite Mal) (con’t) • Often begin during childhood (daydreaming attitude, no participation, lack of concentration). • A low threshold Ca2+ current has been found to govern oscillatory responses in thalamic neurons (pacemaker) • This low threshold probably involve in the generation of these types of seizures.
  • 13. GENERALIZED SEIZURES (CON’T) Tonic Seizures • Opisthotonus, loss of consciousness. • Marked autonomic manifestations Atonic Seizures (atypical) • Loss of postural tone, with sagging of the head or falling. • May loose consciousness.
  • 14. GENERALIZED SEIZURES (CON’T) Clonic and Myoclonic Seizures • Clonic Seizures: • Involves rhythmic clonic contractions of all muscles, • loss of consciousness and • marked autonomic manifestations. • Myoclonic Seizures: • Isolated clonic jerks associated with brief bursts of multiple spikes in the EEG.
  • 15. GENERALIZED SEIZURES (CON’T) Infantile Spasms • An epileptic syndrome. • Attacks, although fragmentary, are often bilateral. • Characterized by brief recurrent myoclonic jerks of the body with sudden flexion or extension of the body and limbs.
  • 16. TREATMENT OF SEIZURES Goals: • Block repetitive neuronal firing. • Block synchronization of neuronal discharges. • Block propagation of seizure. • Minimize side effects with the simplest drug regimen. MONOTHERAPY IS RECOMMENDED IN MOST CASES
  • 17. TREATMENT OF SEIZURES Strategies: • Modification of ion conductances. • Increase inhibitory (GABAergic) transmission. • Decrease excitatory (glutamatergic) activity.
  • 18. 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 Na+ Na+ Na+ Sustain channel in this conformation
  • 19. GABAERGIC SYNAPSE Drugs that Act at the GABAergic Synapse • GABA agonists • GABA antagonists • Barbiturates • Benzodiazepines • GABA synthesizing enzymes • GABA uptake inhibitors • GABA metabolizing enzymes GAD GAT GABA-T
  • 20. 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 Mg++ Na+ AGONISTS GLU Ca2+ K+ GLY
  • 21. TREATMENT OF SEIZURES 1) Hydantoins: phenytoin 2) Barbiturates: phenobarbital 3) Oxazolidinediones: trimethadione 4) Succinimides: ethosuximide 5) Acetylureas: phenacemide 6) Other: carbamazepine, lamotrigine, vigabatrin, etc. 7) Diet 8) Surgery, Vagus Nerve Stimulation (VNS)
  • 22. TREATMENT OF SEIZURES • 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.
  • 23. TREATMENT OF SEIZURES • 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).
  • 24. HYDANTOINS – PHENYTOIN (DILANTIN) • Oldest nonsedative antiepileptic drug. • Fosphenytoin, a more soluble prodrug is used for parenteral MOA • It alters Na+, Ca2+ and K+ conductances. • Inhibits high frequency repetitive firing. • Alters membrane potentials. • Alters amino acid concentration. • Alters NTs (NE, ACh, GABA)
  • 25. Pharmacokinetics • GIT absorption is nearly complete • IM absorption is unpredictable, precipitation may occur – not recommended • Fosphenytoin – a more soluble, given IM • Phenytoin is highly bound to plasma proteins. • Metabolized in the liver an excreted in urine
  • 26. Clinical Use • Phenytoin is effective against partial seizures and generalized tonic-clonic seizures. • In tonic-clonic seizures it appears to be effective against attacks that are either primary or secondary another seizure type
  • 27. Toxicity • Nystagmus • Diplopia and ataxia are the most common dose- related • Gingival hyperplasia and hirsutism • Peripheral neuropathy • MEPHENYTOIN, ETHOTOIN, & PHENACEMIDE
  • 28. CARBAMAZEPINE (TEGRETOL) • Closely related to imipramine and other antidepressants, • carbamazepine is a tricyclic compound • 3-D conformation is similar to phenytoin.
  • 29. CARBAMAZEPINE (TEGRETOL) MoA • 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.
  • 30. • Pharmacokinetics • Absorption is almost complete absorption but rates of absorption varies • 70% of the drug is bound to plasma proteins • Carbamazepine is an enzyme inducer • Carbamazepine is completely metabolized in the liver. • Some of the metabolites exhibit activity
  • 31. • Clinical Use • drug of choice for both partial seizures and generalized tonic-clonic seizures • Carbamazepine is not sedative in its usual therapeutic range. • Effective in management of trigeminal neuralgia • Carbamazepine is also useful in some patients with mania (bipolar disorder). • Others: oxcarbazepine
  • 32. • Toxicity • Diplopia and ataxia – dose related • Mild gastrointestinal upsets, • Unsteadiness • Drowsiness – at higher doses • Aplastic anemia and agranulocytosis
  • 33. BARBITURATES – 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.
  • 34. PHENOBARBITAL (LUMINAL) MoA • Prolongs opening of Cl- channels. • Blocks excitatory Glutamate responses. • Blocks Ca2+ and Na+ currents • Inhibits high frequency, repetitive firing of neurons only at high concentrations.
  • 35. PHENOBARBITAL (LUMINAL) Clinical uses • Useful for partial, generalized tonic-clonic seizures, and febrile seizures
  • 36. PRIMIDONE (MYSOLIN) • Metabolized to phenobarbital and phenylethylmalonamide (PEMA) • The three compounds, metabolite and the parent drug are active MoA • Although primidone is converted to phenobarb, its MoA is more like that of phenytoin
  • 37. PRIMIDONE (MYSOLIN) • Pharmacokinetics • Primidone is completely absorbed • Low binding to plasma proteins • Metabolised in the liver to active metabolites • Should be started slowly to avoid sedation and GI problems.
  • 38. PRIMIDONE (MYSOLIN) Clinical Use • Effective against partial seizures and generalized tonic-clonic seizures • May be more effective than phenobarbital. • Carbamazepine and phenytoin are superior to primidone in management of complex partial seizures
  • 39. PRIMIDONE (MYSOLIN) • Toxicity • Similar to phenobarbital, • But drowsiness occurs early in treatment and may be prominent if the initial dose is too large. • Gradual increments are indicated when starting the drug in either children or adults.
  • 40. VIGABATRIN (-VINYL-GABA) • Absorption is rapid, bioavailability is ~ 60%, T 1/2 6-8 hrs, eliminated by the kidneys. • Use for partial seizures • Contraindicated if preexisting mental illness is present. • Irreversible inhibitor of GABA-aminotransferase (enzyme responsible for metabolism of GABA) • Increases inhibitory effects of GABA. • S(+) enantiomer is active.
  • 41. VALPROATE (DEPAKENE) • 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.
  • 42. VALPROATE (DEPAKENE) • Mechanism of action • similar to phenytoin. •  levels of GABA in brain. • Facilitates Glutamic acid decarboxylase (GAD). • Inhibits the GABA-transporter in neurons and glia (GAT). •  [aspartate]Brain? • May increase membrane potassium conductance.
  • 43. ETHOSUXIMIDE (ZARONTIN) At high concentrations: • Inhibits Na+/K+ ATPase. • Depresses cerebral metabolic rate. • Inhibits GABA aminotransferase. • Phensuximide = less effective • Methsuximide = more toxic
  • 44. ETHOSUXIMIDE (ZARONTIN) • Drug of choice for absence seizures. • High efficacy and safety. • VD = TBW. • Not plasma protein or fat binding • Mechanism of action involves reducing low- threshold Ca2+ channel current (T-type channel) in thalamus.
  • 45. BENZODIAZEPINE CLONAZEPAM (KLONOPIN) • 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. • Increases the frequency of Cl- channel opening.
  • 46. LAMOTRIGINE (LAMICTAL) • Add-on therapy with valproic acid (w/v.a. conc. have be reduced => reduced clearance). • Almost completely absorbed • T1/2 = 24 hrs • Low plasma protein binding
  • 47. LAMOTRIGINE (LAMICTAL) • Effective in myoclonic and generalized seizures in childhood and absence attacks. • Involves blockade of repetitive firing involving Na channels, like phenytoin. • Also effective in myoclonic and generalized seizures in childhood and absence attacks.
  • 48. FELBAMATE (FELBATROL) • 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. • Causes aplastic anemia • Severe hepatits
  • 49. TOPIRAMATE (TOPAMAX) • Rapidly absorbed, bioav. is > 80%, has no active metabolites, excreted in urine.T1/2 = 20-30 hrs • Blocks repetitive firing of cultured neurons, thus its mechanism may involve blocking of voltage- dependent sodium channels • Potentiates inhibitory effects of GABA (acting at a site different from BDZs and BARBs). • Depresses excitatory action of kainate on AMPA receptors. • Teratogenic in animal models.
  • 50. TOPIRAMATE (TOPAMAX) Toxicity: • Somnolence • Fatigue • Dizziness • Cognitive slowing • Parenthesis • Nervousness • Confusion • Weak carbonic anhydrase inhibitor • Urolithiasis
  • 51. TIAGABINE (GABATRIL) • Derivative of nipecotic acid. • 100% bioavailable, highly protein bound. • T1/2 = 5 -8 hrs • Effective against partial seizures in pts at least 12 years old. • Approved as adjunctive therapy. • GABA uptake inhibitor  aminibutyric acid transporter (GAT) by neurons and glial cells.
  • 52. TIAGABINE (GABATRIL) Toxicity: •Abdominal pain and nausea (must be taken w/food) •Dizziness •Nervousness •Tremor •Difficulty concentrating •Depression •Asthenia •Emotional liability •Psychosis •Skin rash
  • 53. 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. • An a.a.. Analog of GABA that does not act on GABA receptors, it may however alter its metabolism, non-synaptic release and transport.
  • 55. STATUS EPILEPTICUS • Occurs when seizures recur within a short period of time, such that baseline consciousness is not regained between the seizures. • They last for at least 30 minutes. • Can lead to • systemic hypoxia, • acidemia, • hyperpyrexia, • cardiovascular collapse • renal shutdown.
  • 56. STATUS EPILEPTICUS • The most common, generalized tonic-clonic status epilepticus is life- threatening • Must be treated immediately with concomitant cardiovascular, respiratory and metabolic management.
  • 57. 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 (1 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.
  • 58. TREATMENT OF SEIZURES Partial seizures • Simple and Complex, including secondarily generalized • Drugs of choice • Carbamazepine • Phenytoin • Valproate
  • 59. TREATMENT OF SEIZURES Partial seizures • Alternatives: • Lamotrigine, • phenobarbital, • primidone, • oxcarbamazepine. • Add-on therapy • Gabapentin, • topiramate, • tiagabine, • levetiracetam, • zonisamide.
  • 60. TREATMENT OF SEIZURES Primary generalized tonic-clonic seizures (grand mal) • drugs of choice: • Carbamazepine • Phenytoin • Valproate* *not approved except if absence seizure is involved
  • 61. TREATMENT OF SEIZURES Primary generalized tonic-clonic seizures (grand mal) • alternatives: • lamotrigine, • phenobarbital, • topiramate, • Oxcarbazepine, • primidone, • levetiracetam.
  • 62. TREATMENT OF SEIZURES Generalized absence seizures • drugs of choice • ethosuximide • valproate* • alternatives: • lamotrigine, • clonazepam, • zonisamide, • topiramate (?). * first choice if primary generalized tonic-clonic seizure is also
  • 63. TREATMENT OF SEIZURES Atypical absence, myoclonic, atonic* seizures • Drugs of choice • Valproate • Clonazepam • Lamotrigine • Alternatives: • Topiramate, • clonazepam, • zonisamide, • felbamate.
  • 64. TREATMENT OF SEIZURES Infantile spasms • drugs of choice • corticotropin (im) or • corticosteroids (prednisone) • zonisamide • Alternatives • clonazepam, • nitrazepam, • vigabatrin, • phenobarbital.

Editor's Notes

  1. N-methyl-d-aspartate isoxazolepropionic acid