MR.BESTHA. CHAKRAPANI M.PHARM ASSOCIATE PROFESSOR DEPARTMENT OF PHARMACOLOGY BALAJI COLLEGE OF PHARMACY ANANTAPURAMU

1. Anti-epileptics
MR.BESTHA. CHAKRAPANI M.PHARM
ASSOCIATE PROFESSOR
DEPARTMENT OF PHARMACOLOGY
BALAJI COLLEGE OF PHARMACY
ANANTAPURAMU
ANANTHAPURAMU
9618279507
Email:chakrispecial@gmail.com

24. classification
1. Hydantoins: Phenytoin, Mephenytoin
2. Barbiturates : phenobarbitone, Mephobarbitone
3. Deoxybarbiturate :primidone
4. Iminostilbene: carabamazepine
5. Succinimide: Ethosuximide
6. GABA transaminase inhibitors: Valporic acid,
Vigabatrain.
7. Benzodiazepines:
Diazepam,clonazepam,iorazepam,clorazepate.

25. 8.NEWER AGENTS
GABA analogs : Gabapentin, Vigabatrain , Tiagabine.
9.OTHERS:Lamotrigine,Levetiracetam,Felbamate,Top
iramate,Zonisamide.

26. PHENYTOIN
Synthesized in 1908.
But its anticonvulsant property was discovered
only in 1938.

27. Pharmacological actions
CNS Phenytoin has good anti-seizure activity.
 One of the most effective drugs against
generalized tonic-Clonic seizures and partial
seizures .
It brings about its effects without causing general
depression of the CNS.

28. Mechanism of action
Phenytoin causes blockade of the voltage
dependent sodium channels and stabilizes the
neuronal membrane.
Voltage dependent Na+ channels enter an in
active stage after each action potential .
Phenytoin blocks the Na+ channels which are in
an inactivated state and delay the recovery of
these channels from in activation.
It inhibits the generation of repetitive action
potentials.

29. pharmacokinetics
Phenytoin is poorly water soluble.
Hence absorption is slow.
Phenytoin is 90%bound to plasma proteins.
Valproic acid competes with phenytoin for plasma
protein binding sites and may result in phenytoin
toxicity.
It is metabolized in the liver initially by first order
and later by zero order kinetics as the dose
increases.
There fore ,monitoring of plasma concentraton is
useful.

30. Adverse effects
Adverse effects depend on the dose , duration,
and route of administration .
Nausea, vomiting, epigastric pain, anorexia.
Hyper glycemia- as Phenytoin inhibits insulin
release.
Teratogenicity : when taken by the pregnant
lady , phenytoin produces fetal hydantoin
syndrome.

31. TOXIC DOSES
Cerebellar and vestibular effects are prominent
; drowsiness, delirium, confusion,
hallucinations, altered behavior and coma
follow.

32. Uses
Generalized tonic –clonic seizures and partial
seizures (not useful in absence seizures).
Status epilepticus –phenytoin is used by slow
IV injection.
Cardiac arrythmias –phenytoin is useful in
digitalis induced arrhythmias.

33. Drug interactions
Phenytoin is an enzyme inducer.
Given with phenobarbitone ,both increase each other
metabolism .
Also phenobarbitone competitively inhibits phenytoin
metabolism.
Carbamazepine and phenytoin enhance each other
metabolism.
Valporate displaces protein bound phenytoin and may result
in phenytoin toxicity.
Cimetidine and chloroamphenicol inhibit the metabolism of
phenytoin resulting in toxicity.
Antacids decreases absorption of phenytoin.

34. FOSPHENYTOIN
Fosphenytoin is a prodrug of phenytoin that has
certain advantage over phenytoin for parenteral
use:
Its is quick converted to phenytoin in the body.
More potent.
Less cardiotoxic.
Safer on the intestine.
It can be injected into a glucose drip unlike
phenytoin.
It can be given intramuscular.

35. Because of the above advantages ,
fosphenytoin is prefered over phenytoin in
status epilepticus.

36. 36
What is epilepsy
Epilepsy can be defined as:
 A neurological condition causing the
tendency for repeated seizures of primary
cerebral origin.

37. Causes of acute epilepsy
Cortical damage
Trauma
Stroke
Neoplasm

38. Cortical damage Stroke

41. Stroke

42. Nature of Epilepsy
Seizures may be partial or generalized depending
on the location and spread of the abnormal
neuronal discharge.
 The attack may involve mainly:
 Motor, sensory or behavioral phenomena.
 Unconsciousness occurs when the reticular
formation is involved.

43. 43
Physical Causes
Head injury from accidents, brain trauma, stroke, brain
parasites, infections or diseases (such as cerebral malaria),
scars on the brain and brain tumours.
In young children: head trauma and/or lack of oxygen
during birth. Prolonged febrile convulsions. Brain
malformations and/or ‘birthmarks’ on the brain cause
seizures to start early in life or later on.

50. Two types of seizures
Partial
General

51. Partial seizures
In motor cortex - results in localized contractions of
contra lateral muscles that may spread to other
muscles following the somatotopic organization of the
motor cortex
Complex partial seizures may occur in psychomotor
epilepsy. These originate in the limbic lobe and result
in illusions and semi-purposeful motor activity.

52. Generalized seizures
Involve wide areas of the brain and loss of
consciousness
Petit mal
Grand mal

53. 53
Generalised seizures

54. Two types of general seizures
Petit mal seizures: consciousness is transiently lost and
the EEG displays spike and wave activity.
Grand mal seizures: consciousness lost for a longer
period and the individual will fall if standing when
seizure starts.
.Tonic phase: generalized increased muscle tone.
.Clonic phase: series of jerky movements. Bowel and
bladder may evacuate.

55. STATUS EPILEPTICUS
Is a neurological emergency characterized
by a series of convulsions , rapidly
repeated without intervals of
consciousness.
 if untreated may lead to coma and death.

56. 56
Drug history
Phenobarbitone 1912
Phenytoin 1938
Primidone 1952
Ethosuximide 1955
Carbamazepine 1965
Sod. Valproate 1973
Valproic acid 1993
Clonazepam 1974
Clobazam 1979
Vigabatrin 1989
Lamotrigine 1991
Gabapentin 1993
Tiagabine
Topiramate 1995
Levetiracetam 2000
Fosphenytoin 2001
Zonisamide 2005

57. 57
Drugs to be used with care
 Aminophylline
 Amphetamines
 Analgesics
 Antibiotics
 Antidepressants
 Antimuscarinics
 Antipsychotics
 Baclofen
 Bupropion
 Donepezil etc
 Cyclosporin
 Cocaine
 Isoniazid
 Lignocaine
 Mefloquine
 NSAIDs
 Opioids
 Oral contraceptives
 Vincristine

58. 58
Choice of antiepileptic 1
Seizure type Drug of choice Alternatives
Partial simple &
Partial complex
Carbamazepine
Phenytoin
Valproate
Lamotrigine
Gabapentin
Levetiracetam
Topiramate
Tiagabine
Oxcarbazepine
Phenobarbital

59. 59
Choice of antiepileptic 2
Seizure type Drug of choice Alternatives
Generalised tonic
clonic
Carbamazepine
Phenytoin
Valproate
Lamotrigine
Topiramate
Phenobarbital
Absence Ethosuximide
Valproate
Lamotrigine
Clonazepam
Atypical absence
Atonic, myoclonic
Valproate Clonazepam

60. Classifying Epilepsy and Seizures
 Classifying epilepsy involves more than just
seizure type
 Seizure types:
Partial Generalized
Simple Complex Absence Convulsive
Consciousness
is maintained
Consciousness
is lost or impaired
Altered awareness Characterized by
muscle contractions
with or without loss
of consciousness

61. 61
Seizure management
General guidelines
 Note the time
 Make the person safe
 Put something soft under their head
 TC: once seizure has stopped put the person on their side and clear the airway if
necessary
 CP: speak reassuringly, calmly and quietly. Do not physically engage the person
unless you need to for their safety
 Prevent others from crowding around and minimise embarrassment
 Stay with them until they are themselves again
 Call for medical help if:
 They have injured themselves or are having difficulty breathing
 If they have one seizure after another or the seizure lasts 2 mins longer than
normal
 The tonic clonic seizure goes on for more than 5 mins
 It is the persons first seizure

64. Mechanism of Action
Current antiepileptic drugs are thought to act
mainly by two main mechanisms:

65. Mechanism of Action
Reducing electrical excitability of cell
membranes, possibly through inhibition of
sodium channel.
Enhancing GABA-mediated synaptic inhibition.
This may be achieved by an enhanced pre- or
post- synaptic action of GABA, by inhibiting
GABA-transaminase, or by drugs with direct
GABA-agonist properties.

66. Mechanism of Action
A few drugs appear to act by a third mechanism,
namely inhibition of T-type calcium channels.
Newer drugs act by other mechanism, yet to be
elucidated.
Drugs that block excitatory amino acid receptors
are effective in animal models, but not yet
developed for clinical use.

67. The Major Antiepileptic Drugs
The main drugs in current use are: phenytoin,
carbamazepine, valproate and ethosuximide.
Secondary drugs include:
Phenobarbitone: highly sedative
Various benzodiazepines (e.g. clonazepam);
Diazepam used in treating status epilepticus.

68. Phenytoin
Mechanism of Action: acts by stabilizing membranes
(1)Blocking voltage-dependence Na+ channel
(2) Blocking voltage-dependence Ca2+ channel
(3) Inhibiting calcium-induced secretory processes,
including release of hormones and neurotransmitters.
(4) Inhibiting post tetanic potentiation (PTP).

69. PHARMACOKINETICS
Because phentoin is a weak acid, its intestinal
absorption is variable and plasma
concentration can vary widely. Monitoring is
therefore needed
It is metabolized by the microsomal system
and is excreted first in the bile and then in the
urine.

70. Therapeutic uses
Antiseizure: used in the treatment of grand mal
epilepsy and tonic-clonic seizure disorders, not
in absence seizures.
Treatment on peripheral neuralgia .
Antiarrhythmias

71. Adverse effects
Gastrointestinal irritation
Ataxia and diplopia.
Blood dyscrasias.
Gingival hyperplasia, hirsutism, increased
collagen proliferation.

72. Adverse effects
Hepatitis.
Fetal malformations: fetal hydantion
syndrome
Drug interactions: increased plasma
concentrations of phenytoin can occur by
concurrent administration of
chloramphenicol, isoniazid, cimetidine,
dicumarol, et al.

73. Carbamazepine
Derivative of tricyclic antidepressants
Similar profile to that of phenytoin, but with
fewer unwanted effects
Effective in most forms of epilepsy (except
absence seizures); particularly effective in
psychomotor epilepsy; also useful in trigeminal
neuralgia and mania.

74. Carbamazepine
Strong inducing agent; therefore many drug
interactions
Low incidence of unwanted effects; principally
sedation, ataxia, mental disturbances, water
retention

75. Valproate
Valproate is very effective against absence
seizure.
Mechanism: facilitate glutamic acid
decarboxylase; inhibit GABA-transaminase;
enhance synaptic responses. some effect on
sodium channels
Relatively few unwanted effects: anorexia,
nausea, teratogenicity, liver damage (rare,
but serious)

76. Ethosuximide
The main drug used to treat absence seizures,
may exacerbate other forms
Acts by blocking T-type Ca2+-channels
Relatively few unwanted effects, mainly
nausea and anorexia. (mental disturbances)

77. Benzodiazepine
Diazepam: preferred drugs for Status
epilepticus.
Nitrazepam: petit mal ,especially myoclonic
seizures and infantile spasms.
Clonazepam: is one of the most effective in
some cases of myoclonic seizures. Used in
petit mal and status epilepticus

78. Barbiturates
Phenobarbital, Luminal: is useful in the treatment of
generalized tonic-clonic seizures and statue
epilepticus.
Mechanism:(1) block Ca2+ currents presynaptic
membrane and decrease neurotransmitter release.(2)
prolong the openings of the Cl- channel in
postsynaptic membrane and decrease it’s response.
Adverse effects: sedation, depression, drug
interaction.

79. Clinical Uses of Antiepileptic Drugs
Tonic-clonic (grand mal) seizures: carbamazepine
preferred because of low incidence of side-effects,
phenytoin, valproate. Use of single drug is preferred
when possible, because of risk of pharmacokinetic
interactions.
Partial (focal) seizures: carbamazepine, valproate;
clonazepam or phenytoin are alternatives.

80. Clinical Uses of Antiepileptic Drugs
Absence seizures (petit mal): ethosuximide or
valproate. Valproate is used when absence seizures
coexist with tonic-clonic seizures, since most drugs
used for tonic-clonic seizures may worsen absence
seizures.
Myoclonic seizures: valproate or clonazepam.
Status epilepticus: must be treated as an emergency,
with diazepam intravenously.

81. Attentions
Selection of an appropriate antiseizure agent
Use of single drug
Withdrawal
Toxicity
Fetal malformations