Dr .Rahul
Associate Professor
Dept. of Pharmacology
A group of chronic CNS disorders characterized by
recurrent, periodic and unpredictable seizures.
 Seizures are sudden, t...
 More than 40 forms of epilepsy have been
identified.
 Therapy is symptomatic in that the majority
of drugs prevent seiz...
 Trauma
 Encephalitis
 Drugs
 Birth trauma
 Withdrawal from
depressants
 Tumor
 High fever
 Hypoglycemia
 Extreme...
(From Brody et al., 1997)
I. Partial (focal) Seizures
A. Simple Partial Seizures
B. Complex Partial Seizures
II. Generalized Seizures
A. Generalized...
A. Simple Partial Seizures
B. Complex Partial Seizures.
A. Simple Partial Seizures (Jacksonian)
 Involves one side of the brain at onset.
 Focal with motor, sensory or speech
d...
B. Complex Partial Seizures (Temporal Lobe
epilepsy or Psychomotor Seizures)
 Produces confusion and inappropriate or daz...
 In Generalized
seizures, both
hemispheres are widely
involved from the
outset.
 Manifestations of the
seizure are deter...
Recruitment of neurons throughout the cerebrum
Major convulsions, usually with two phases:
1) Tonic phase
2) Clonic phase
...
Tonic phase:
Sustained powerful muscle contraction(involving
all body musculature) which arrests ventilation.
Clonic phase...
 This is the most common and most severe form of
epilepsy.
 It is characterized by an initial rigid extension of trunk
a...
 Brief and abrupt loss of consciousness, vacant
stare.
 Sometimes with no motor manifestations.
 Minor muscular twitchi...
Often begin during childhood (daydreaming
attitude, no participation, lack of
concentration).
 Attacks may occur up to a ...
Neuronal Correlates of Paroxysmal Discharges
C. Tonic Seizures
 Opisthotonus, loss of
consciousness.
 Marked autonomic
manifestations
D. Atonic Seizures (atypical)
...
E. Clonic Seizures
 Clonic Seizures: Rhythmic clonic contractions of
all muscles, loss of consciousness, and marked
auton...
F. Infantile Spasms
 An epileptic syndrome.
 Attacks, although fragmentary, are often
bilateral.
 Characterized by brie...
 Excitation (too much)
• Ionic-inward Na+, Ca++ currents
• Neurotransmitter: glutamate,
aspartate
 Inhibition (too littl...
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 (glu...
Classification of AEDs
• Phenytoin
• Phenobarbital
• Primidone
• Carbamazepine
• Ethosuximide
• Valproate
(valproic acid)
...
6/15/2014 Anti-epileptics 34
Chemical basedclassification of Anti-epilepticdrugs
(AED)
Chemical compound class Member Drug...
Largely target partial seizures
Fewer and less severe drug
interactions compared to older
drugs
A. Resting State
B. Arrival of Action
Potential causes
depolarization and
channel opens allowing
sodium to flow in.
C. Ref...
Na+
Na+
Open
Inactivation
gate
Activation
gate
Na+
Carbamazepine
Phenytoin
Felbamate
Lamotrigine
Na+
Inactivated
channel
Block channels
firing at high
frequencies
Barbit...
Ca++
Ca++
Voltage regulated Ca++
current,low threshold “T”
current in thalamus
Gitanjali-14:
Involved in 3 per
second spik...
Ca++
Reduction in the flow of Ca++ through
T - type Ca++ channels in thalamus
Gitanjali-15:
GABA
metabolites
Succinic
Semialdehyde
Gabapentin
GT: GABA transaminase SSD: Succinic semialdehyde dehydrogenase
GT
SSD
Vi...
.
(From Katzung B.G., 2001)
Block of sustained high frequency repetitive firing of
action potentials.
PHENYTOIN (Dilantin)
 Oldest nonsedative antiepileptic
drug.
 Fosphenytoin, a more soluble
prodrug is used for parentera...
USES
 Partial seizure
 Generalized (including tonic-clonic) seizures
 Contraindicated in absence seizures
 Nonseizure ...
Fetal Hydantoin Syndrome
 Pre- and postnatal growth deficiency with psychomotor
retardation, microcephaly with a ridged m...
CARBAMAZEPINE (Tegretol)
 Tricyclic, antidepressant (bipolar)
 3-D conformation similar to
phenytoin.
 Mechanism of act...
OXCARBAZEPINE
 Closely related to
carbamazepine.
 With improved toxicity profile.
 Less potent than
carbamazepine.
 Ac...
PHENOBARBITAL
Toxicity:
 Sedation.
 Cognitive impairment.
 Behavioral changes.
 Induction of liver
enzymes.
 May wors...
PRIMIDONE
 Metabolized to phenobarbital and
phenylethylmalonamide (PEMA),
both active metabolites.
 Effective against pa...
VALPROATE
 Fully ionized at body pH, thus active
form is valproate ion.
 One of a series of carboxylic acids
with antiep...
USES
 A broad spectrum anti-seizure drug
(effective against most partial and generalized
seizures, including myoclonic an...
ETHOSUXIMIDE
 Drug of choice for absence
seizures.
 High efficacy and safety.
 Mechanism of action involves
reducing lo...
CLONAZEPAM
 A benzodiazepine.
 Long acting drug with efficacy
for absence seizures.
 One of the most potent
antiepilept...
LAMOTRIGINE
 Presently use as add-on therapy with
valproic acid (v.a. conc. are be reduced).
 Almost completely absorbed...
TOPIRAMATE
Toxicity:
 Somnolence
 Fatigue
 Dizziness
 Cognitive slowing
 Paresthesias
 Nervousness
 Confusion
 Uro...
ZONISAMIDE
 Sulfonamide derivative
 Good bioavailability, low pb.
 T1/2 = 1 - 3 days
 Effective against partial and
ge...
FELBAMATE
 Effective against partial seizures
but has severe side effects.
 Because of its severe side effects, it
has b...
VIGABATRIN (-vinyl-GABA)
 Absorption is rapid, bioavailability
is ~ 60%, T 1/2 6-8 hrs, eliminated
by the kidneys.
 Use...
TIAGABINE
 100% bioavailable, highly protein
bound.
 T1/2 = 5 -8 hrs
 Effective against partial and
generalized tonic-c...
GABAPENTIN (Neurontin)
 Used as an adjunct in partial and
generalized tonic-clonic seizures.
 Does not induce liver enzy...
Status Epilepticus
Status epilepticus exists when seizures recur within a short
period of time , such that baseline consci...
DIAZEPAM (Valium) AND
LORAZEPAM (Ativan)
 Benzodiazepines
 Given I.V.
 Lorazepam may be longer acting.
 1° for treatin...
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 ...
Treatment of Seizures
PARTIAL SEIZURES ( Simple and Complex,
including secondarily generalized)
Drugs of choice: Carbamaze...
Treatment of Seizures
PRIMARY GENERALIZED TONIC-
CLONIC SEIZURES (Grand Mal)
Drugs of choice: Carbamazepine
Phenytoin
Valp...
Treatment of Seizures
GENERALIZED ABSENCE SEIZURES
Drugs of choice: Ethosuximide
Valproate*
Alternatives: Lamotrigine, Clo...
Treatment of Seizures
ATYPICAL ABSENCE, MYOCLONIC,
ATONIC* SEIZURES
Drugs of choice: Valproate**
Lamotrigine***
Alternativ...
Na+ Channel Blockers Phenytoin
Carbamazepine
Oxcarbamazepine
Primione
Valproic acid
Lamotrigine
Topitramate
Zonisamide
Phe...
Experimental evaluation
 Partial seizures in human correlates with MES
test (maximal electroshock test) in animals.
 Ant...
Antiepileptic drugs : Dr Rahul Kunkulol's Power point preparations
Antiepileptic drugs : Dr Rahul Kunkulol's Power point preparations
Antiepileptic drugs : Dr Rahul Kunkulol's Power point preparations
Antiepileptic drugs : Dr Rahul Kunkulol's Power point preparations
Antiepileptic drugs : Dr Rahul Kunkulol's Power point preparations
Antiepileptic drugs : Dr Rahul Kunkulol's Power point preparations
Antiepileptic drugs : Dr Rahul Kunkulol's Power point preparations
Antiepileptic drugs : Dr Rahul Kunkulol's Power point preparations
Antiepileptic drugs : Dr Rahul Kunkulol's Power point preparations
Antiepileptic drugs : Dr Rahul Kunkulol's Power point preparations
Antiepileptic drugs : Dr Rahul Kunkulol's Power point preparations
Antiepileptic drugs : Dr Rahul Kunkulol's Power point preparations
Antiepileptic drugs : Dr Rahul Kunkulol's Power point preparations
Antiepileptic drugs : Dr Rahul Kunkulol's Power point preparations
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Antiepileptic drugs : Dr Rahul Kunkulol's Power point preparations

  1. 1. Dr .Rahul Associate Professor Dept. of Pharmacology
  2. 2. A group of chronic CNS disorders characterized by recurrent, periodic and unpredictable 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.
  3. 3.  More than 40 forms of epilepsy have been identified.  Therapy is symptomatic in that the majority of drugs prevent seizures, but neither effective prophylaxis or cure is available.
  4. 4.  Trauma  Encephalitis  Drugs  Birth trauma  Withdrawal from depressants  Tumor  High fever  Hypoglycemia  Extreme acidosis  Extreme alkalosis  Hyponatremia  Hypocalcemia  Idiopathic
  5. 5. (From Brody et al., 1997)
  6. 6. I. Partial (focal) Seizures A. Simple Partial Seizures B. Complex Partial Seizures II. Generalized Seizures A. Generalized Tonic-Clonic Seizures B. Absence Seizures C. Tonic Seizures D. Atonic Seizures E. Clonic Seizures F. Myoclonic Seizures G. Infantile Spasms
  7. 7. A. Simple Partial Seizures B. Complex Partial Seizures.
  8. 8. A. Simple Partial Seizures (Jacksonian)  Involves one side of the brain at onset.  Focal with motor, sensory or speech disturbances.  Confined to a single limb or muscle group.  Seizure-symptoms don’t change during seizure.  No alteration of consciousness.
  9. 9. B. 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). Purposeless movements like lips smacking or hand wringing  Wide variety of clinical manifestations and are accompanied by sensory, motor, psychic symptoms.  Consciousness is impaired or lost.
  10. 10.  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.
  11. 11. Recruitment of neurons throughout the cerebrum Major convulsions, usually with two phases: 1) Tonic phase 2) Clonic phase Convulsions:  Motor manifestations  May or may not be present during seizures  Excessive neuronal discharge  Convulsions appear in Simple Partial and Complex Partial Seizures if the focal neuronal discharge includes motor centers  They occur in all Generalized Tonic-Clonic Seizures regardless of the site of origin.  Atonic, Akinetic, and Absence Seizures are non-convulsive
  12. 12. Tonic phase: Sustained powerful muscle contraction(involving all body musculature) which arrests ventilation. Clonic phase: Alternating contraction and relaxation, causing a reciprocating movement which could be bilaterally symmetrical or “running” movements.
  13. 13.  This is the most common and most severe form of epilepsy.  It is characterized by an initial rigid extension of trunk and limbs (tonic phase) lasting 10-20 sec, followed by a rhythmic contraction of arms and legs (clonic phase).  There is loss of consciousness and autonomic signs  A period of confusion and exhaustion lasting several minutes follows the seizure episode. ; not usually improved by anticonvulsant therapy
  14. 14.  Brief and abrupt loss of consciousness, vacant stare.  Sometimes with no motor manifestations.  Minor muscular twitching restricted to eyelids (eyelid flutter) and face.  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.  No loss of postural control.
  15. 15. Often begin during childhood (daydreaming attitude, no participation, lack of concentration).  Attacks may occur up to a hundred times a day. Age of onset is 3-5 years; may last till puberty.  A low threshold Ca2+ current has been found to govern oscillatory responses in thalamic neurons (pacemaker)
  16. 16. Neuronal Correlates of Paroxysmal Discharges
  17. 17. C. Tonic Seizures  Opisthotonus, loss of consciousness.  Marked autonomic manifestations D. Atonic Seizures (atypical)  Loss of postural tone, with sagging of the head or falling.  May loose consciousness. Most common in children
  18. 18. E. Clonic Seizures  Clonic Seizures: Rhythmic clonic contractions of all muscles, loss of consciousness, and marked autonomic manifestations. F. Myoclonic Seizures  Myoclonic Seizures: Isolated clonic jerks, brief shock like contraction of muscles restricted to one part/ extremity associated with brief bursts of multiple spikes in the EEG.
  19. 19. F. 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.
  20. 20.  Excitation (too much) • Ionic-inward Na+, Ca++ currents • Neurotransmitter: glutamate, aspartate  Inhibition (too little) • Ionic-inward Cl; outward K+ currents • Neurotransmitter: GABA
  21. 21. 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
  22. 22. Strategies:  Modification of ion conductances.  Increase inhibitory (GABAergic) transmission.  Decrease excitatory (glutamatergic) activity.
  23. 23. Classification of AEDs • Phenytoin • Phenobarbital • Primidone • Carbamazepine • Ethosuximide • Valproate (valproic acid) Classical Newer Lamotrigine Felbamate Topiramate Gabapentin Tiagabine Vigabatrin Oxycarbazepine Levetiracetam Fosphenytoin
  24. 24. 6/15/2014 Anti-epileptics 34 Chemical basedclassification of Anti-epilepticdrugs (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
  25. 25. Largely target partial seizures Fewer and less severe drug interactions compared to older drugs
  26. 26. A. Resting State B. Arrival of Action Potential causes depolarization and channel opens allowing sodium to flow in. C. Refractory State, Inactivation
  27. 27. Na+ Na+ Open Inactivation gate Activation gate
  28. 28. Na+ Carbamazepine Phenytoin Felbamate Lamotrigine Na+ Inactivated channel Block channels firing at high frequencies Barbiturates Valproate Topiramate
  29. 29. Ca++ Ca++ Voltage regulated Ca++ current,low threshold “T” current in thalamus Gitanjali-14: Involved in 3 per second spike and wave rhythm
  30. 30. Ca++ Reduction in the flow of Ca++ through T - type Ca++ channels in thalamus Gitanjali-15:
  31. 31. GABA metabolites Succinic Semialdehyde Gabapentin GT: GABA transaminase SSD: Succinic semialdehyde dehydrogenase GT SSD Vigabatrin Valproate Benzodiazepines Barbiturates Cl- Gabapentin Tiagabine Topiramate
  32. 32. . (From Katzung B.G., 2001) Block of sustained high frequency repetitive firing of action potentials.
  33. 33. 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.  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.
  34. 34. USES  Partial seizure  Generalized (including tonic-clonic) seizures  Contraindicated in absence seizures  Nonseizure indications include - Trigeminal neuralgia - Manic-depressive disorders
  35. 35. 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. Teratogenicity of several anticonvulsant medications is associated with an elevated level of oxidative metabolites that are normally eliminated by the enzyme epoxide hydrolase.
  36. 36. CARBAMAZEPINE (Tegretol)  Tricyclic, antidepressant (bipolar)  3-D conformation similar to phenytoin.  Mechanism of action, similar to phenytoin. Inhibits high frequency repetitive firing (Na++)  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.
  37. 37. 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.
  38. 38. PHENOBARBITAL Toxicity:  Sedation.  Cognitive impairment.  Behavioral changes.  Induction of liver enzymes.  May worsen absence and atonic seizures.  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  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.
  39. 39. 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 GI problems.  Its mechanism of action may be closer to phenytoin than the barbiturates. Toxicity: •Same as phenobarbital •Sedation occurs early. •Gastrointestinal complaints.
  40. 40. 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.  May facilitate Glutamic acid decarboxylase (GAD).  Inhibits GAT-1.  Toxicity: •Elevated liver enzymes •Nausea and vomiting. •Abdominal pain, •heartburn. •Tremor, hair loss, •Weight gain. •Idiosyncratic,hepatotox •Teratogen: spina bifida
  41. 41. 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
  42. 42. ETHOSUXIMIDE  Drug of choice for absence seizures.  High efficacy and safety.  Mechanism of action involves reducing low-threshold Ca2+ channel current (T-type channel) in thalamus. At high concentrations:  Inhibits GABA aminotransferase.  Phensuximide = less effective  Methsuximide = more toxic Toxicity: •Gastric distress, including, pain, nausea and vomiting •Lethargy and fatigue •Headache •Hiccups •Euphoria •Skin rashes
  43. 43. 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.  Increases the frequency of Cl- channel opening. Toxicity: • Sedation is prominent. • Ataxia. • Behavior disorders.
  44. 44. LAMOTRIGINE  Presently use as add-on therapy with valproic acid (v.a. conc. are be reduced).  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. Toxicity: •Dizziness •Headache •Diplopia •Nausea •Somnolence •Rash
  45. 45. TOPIRAMATE Toxicity:  Somnolence  Fatigue  Dizziness  Cognitive slowing  Paresthesias  Nervousness  Confusion  Urolithiasis  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.
  46. 46. ZONISAMIDE  Sulfonamide derivative  Good bioavailability, low pb.  T1/2 = 1 - 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. Toxicity: •Drowsiness •Cognitive impairment •High incidence of renal stones (?).
  47. 47. 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. Toxicity: •Aplastic anemia •Severe hepatitis
  48. 48. VIGABATRIN (-vinyl-GABA)  Absorption is rapid, bioavailability is ~ 60%, T 1/2 6-8 hrs, eliminated by the kidneys.  Use for partial seizures and Contraindicated if preexisting mental illness is present.  Irreversible inhibitor of GABA- aminotransferase (enzyme responsible for metabolism of GABA) => Increases inhibitory effects of GABA. Toxicity: •Drowsiness •Dizziness •Weight gain •Agitation •Confusion •Psychosis
  49. 49. TIAGABINE  100% bioavailable, highly protein bound.  T1/2 = 5 -8 hrs  Effective against partial and generalized tonic-clonic seizures.  GABA uptake inhibitor GAT-1. Toxicity: •Dizziness •Nervousness •Tremor •Difficulty concentrating •Depression •Asthenia •Emotional lability •Psychosis •Skin rash
  50. 50. 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. Toxicity: •Somnolence. •Dizziness. •Ataxia. •Headache. •Tremor.
  51. 51. Status Epilepticus Status epilepticus exists 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, 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.
  52. 52. DIAZEPAM (Valium) AND LORAZEPAM (Ativan)  Benzodiazepines  Given I.V.  Lorazepam may be longer acting.  1° for treating status epilepticus  Have muscle relaxant activity.  Allosteric modulators of GABA receptors.  Potentiates GABA function, by increasing the frequency of channel opening. Toxicity •Sedation •Children may manifest a paradoxical hyperactivity. •Tolerance
  53. 53. 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.
  54. 54. Treatment of Seizures PARTIAL SEIZURES ( Simple and Complex, including secondarily generalized) Drugs of choice: Carbamazepine Phenytoin Valproate Alternatives: Lamotrigine, Phenobarbital, Oxcarbamazepine. Add-on therapy: Gabapentin, Topiramate, Tiagabine, Levetiracetam, Zonisamide.
  55. 55. Treatment of Seizures PRIMARY GENERALIZED TONIC- CLONIC SEIZURES (Grand Mal) Drugs of choice: Carbamazepine Phenytoin Valproate* Alternatives: Lamotrigine, Phenobarbital, Topiramate, Oxcarbamazepine, Primidone, Levetiracetam, Phenobarbital. *Not approved except if absence seizure is involved
  56. 56. 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 present.
  57. 57. Treatment of Seizures ATYPICAL ABSENCE, MYOCLONIC, ATONIC* SEIZURES Drugs of choice: Valproate** Lamotrigine*** Alternatives: Topiramate, clonazepam, zonisamide, felbamate. * Often refractory to medications. **Not approved except if absence seizure is involved. *** Not FDA approved for this indication.
  58. 58. Na+ Channel Blockers Phenytoin Carbamazepine Oxcarbamazepine Primione Valproic acid Lamotrigine Topitramate Zonisamide Phenobarbital Gabapentin Felbamate Ca2+ Channel Blockers Ethosuxamide Phenobarbital Zonisamide Drugs that Potentiate GABA Increase opening time of channel Phenobarbital Increase frequency of openings of channel Diazepam Lorazepam Clonazepam Increase GABA in synapse Valproic Acid Increase GABA metabolism Gabapentin Increase GABA release Gabapentin Block GABA transaminase Vigabatrin Block GABA transporter (GAT-1) Valproic Acid Tiagabine
  59. 59. Experimental evaluation  Partial seizures in human correlates with MES test (maximal electroshock test) in animals.  Anti-epileptics effective against MES alters ionic conductance across cell membrane.  Absence seizures : PTZ test (subcutaneous administration of Pentyleneterazol.
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