Undergraduate MBBS level Theory Class in Power Point presentation from drdhriti, NEIGRIHMS, Shillong, Meghalaya, India
- 1. Antiepileptic Drugs Department of Pharmacology NEIGRIHMS,
Shillong
2. SOME FAMOUS PEOPLE WHO WERE AFFLICTED
3. What are Epilepsies?
- Group of disorders of the CNS characterized by paroxysmal
cerebral dysrhythmia, manifesting as brief episodes (seizure) of
loss of consciousness, with or without characteristic body
movements (convulsions), sensory or psychiatric phenomena.
4. What are seizures?
- A seizureis a transient alteration of behaviour due to the
disordered, synchronous, and rythmic firing of populations of brain
neurones. Seizure can be nonepileptic and can be evoked in normal
brain
- A seizureis a paroxysmal behavioral spell generally caused by
an excessive disorderly discharge of cortical nerve cells.
5. What are Epilepsies Clinically?
- Epilepsy is a syndrome of two or more unprovoked or recurrent
seizureson more than one occasion.
- Epilepticseizuresrange from clinically undetectable
(electrographicseizure) to convulsions.
6. How many types?
- Generalized tonic-Clonic Seizures
7. Types of seizures contd.
- 2.Partial (focal) Seizures
8. 1. Generalized seizures
- A. Generalized tonic-clonic
- GTCS/major epilepsy/grand mal
- Aura-cry-unconsciousness-tonic phase-clonic phase
- Usually occurs in both the hemispheres
- Manifestations are determined by cortical site of seizure
occurence
9.
- - 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 contd. 10.
- - Alternating contraction and relaxation, causing a
reciprocating movement which could be bilaterally symmetrical.
- EEG: Characterized by groups of spikes on the EEG and periodic
neuronal depolarizations with clusters of action potentials.
Generalized Seizures contd. 11. Generalized Seizures contd. 12.
Generalized Seizures contd. 13. Generalized Seizures contd.
- Also called minor epilepsy/petit mal
- Usually in Children and lasts for 1-2 minutes
- Typical generalized spike-and-wave type discharges at 3 per
second (3 Hz)
- Momentary loss of consciousness, patient stares at one
direction
- No motor (muscular component)
- Minor muscular twitching restricted to eyelids (eyelid flutter)
and face.
- No loss of postural control.
14. Generalized Seizures contd.
- Unconsciousness with relaxation of all muscles
- Loss of postural tone, with sagging of the head or falling
- Isolated clonic jerks associated with brief bursts of multiple
spikes in the EEG
- Momentary contractions of muscles of limbs or whole body
- No loss of postural control
15. Generalized Seizures contd.
- Characterized by brief recurrent myoclonic jerks muscle spasm)
of the body with sudden flexion or extension of the body and
limbs.
- Progressive mental deterioration
16. 2. Partial (focal) Seizures
- A. Simple partial seizure
- Confined to a group of muscles or localized sensory
disturbances depending on area of cortex involved
- For example if motor cortex of the left thumb then jerking
movement of left thumb, and if it is sensory cortex then
paresthesia of left thumb.
- No alteration of consciousness
17. Partial (focal) Seizures contd.
- B. Complex partial seizure (temporal lobe/psychomotor
epilepsy)
- Focus is located in temporal lobe
- Confused behaviour and purposeless movements and emotional
changes lasting for 30 seconds to 2minutes
- Motor activity appears as non-reflex actions.
- Automatisms (repetitive coordinated movements).
- Wide variety of clinical manifestations
- Consciousness is impaired
18. Complex partial seizure contd. Deja vu 19. Partial (focal)
Seizures contd.
- C. Secondarily generalized:
- Partial seizures initially
- Followed by generalized tonic-clonic seizure
20. Secondarilygeneralized seizure 21. Partial (focal) Seizures
contd. 22. Types of Seizure: Summery: 23. Status epilepticus
- Continuous seizure activity for more than 30 minutes, or 2 or
more seizures without recovery of consciousness.
- Emergency:Recurrent tonic-clonic convulsions without recovery
in between.
24. Causes of Epilepsy
25. Causes of Epilepsy contd.
26. Causes of Epilepsy contd.
-
-
- Hippocampus DYSGENESIS (FAILURE OF CORTEX TO GROW
PROPERLY)
-
-
- AT LEAST EIGHT SINGLE LOCUS GENETIC DEFECTS ARE ASSOCIATED WITH
EPILEPSY motor cortex, somatosensory cortex, visual cortex,
auditory cortex, temporal lobe cortex and olfactory.
27. Experimental Models
- Maximal electroshock seizures: tonic phase abolished by drugs
effective in GTCS
- PTZ clonic seizures (Pentylenetetrazole): Can be prevented by
drugs effective in absence seizure
- Chronic focal seizure: alumina cream in monkey
- Kindled seizures: bursts of weak electrical impulses
tonic-clonic seizure
28. Classification antiepileptic drugs
- Hydantoins:phenytoin , phosphenytoin
- Barbiturates:phenobarbitone
- Iminostilbenes:carbamazepine , oxcarbazepine
- Succinimides:ethosuximide
- Aliphatic carboxylic acid:Valproic acid , divalproex
- Benzodiazepines : clonazepam, diazepam, lorazepam
- New compounds:gabapentin, lamotrigine , tiagabine,
topiramate,vigabatrin , zonisamide,felbamate
29.
- Modification of ion conductance
-
- Prolongation of Na +channel inactivation
-
- Inhibition of `T` type Ca ++current
- Increase inhibitory (GABAergic) transmission.
- Glutamate receptor antagonism (NMDA, AMPA, or kainic acid)
Mechanisms of seizure & antiseizure drugs: 30.
- Arrival of Action Potential causes depolarization and channel
opens allowing sodium to flow in.
- Refractory State, Inactivation reduce the rate of
recovery.
Na + Na + Na + Sustain channel in this conformation
Anticonvulsant mechanism contd. 31. The Sodium Channel contd.
- Drugs acting via this channel:
- Phenytoin, Sodium Valproate, Carbamezepine, Lamotrigine,
Topiramide and Zonisamide
32. Anticonvulsant mechanism contd.
- T type Ca ++current inhibition:
- T type current is responsible for 3 Hz spike-and-wave
- Throughout the thalamus `T` current has large amplitudes
- Bursts of action potential is by action of T current
- Drugs ethosuximide, valproate and trimethadione
33. Anticonvulsant mechanism contd.
- The GABA mediated CL- channel opening
- Drugs: barbiturates, benzodiazepines, vigabatrin, gabapentin
and valproate
34. Individual Drugs 35. Phenobarbitone
- First effective organic antiseizure agent
-
- Mechanism of CNS depression like other barbiturates, but less
effect on Ca++ channel and glutamate release less hypnotic
effect
-
- GABA Areceptor mediated like other Barbiturates
-
- Continued use sedation effect lost but not anticonvulsant
action
-
- Raises seizure threshold and limits spread
-
- Suppresses kindled seizures
-
- Slowly absorbed and long t 1/2(80 120 hrs)
-
- Metabolized in liver and excreted unchanged in kidney
-
- Single dose after3 wks. steady state
36. Phenobarbitone contd. (Gardenal/Luminal)
-
- Behavioural abnormalities
-
- Hyperactivity in children
-
- Rashes, megaloblastic anaemia and osteomalacia
-
- Primidone:deoxybarbiturate
-
- Phenobarbitone andPEMAShort half life 6-14 hrs
-
- Many consider them the drugs of choice for seizures only in
infants
-
- Available as tabs 30/60mg, syr. and inj.
37. Phenytoin (Dilantin/Epsolin/Eptoin)
-
- But muscular rigidity and excitement at toxic doses
-
- Abolish tonic phase of GTC seizure
-
- No effect on clonic phase
-
- Prevents spread of seizure activity
-
- Tonic-clonic phase is suppressed but no change in EEG
andaura
-
- In CVS depresses ventricular automaticity, accelerates AV
conduction
38. Phenytoin sodium contd.
-
- Prevents repetitive detonation of normal brain cells during `
depolarization shift`
-
- Prolonging the inactivation of voltage sensitive Na+
channel
-
- No high frequency discharges
-
- No interference with kindling only on high frequency
firing
39. Phenytoin sodium contd.
-
- 80-90% bound to plasma protein
-
- Metabolized in liver by hydroxylation and glucoronide
conjugation
-
- Elimination varies with dose first order to zero order
-
- T1/2 life is 12 to 24 hrs
-
- Cannot metabolize by liver if plasma conc. Is above 10
mcg/ml
-
- Monitoring of plasma concentration
40. Phenytoin sodium contd.
- Hirsutism, coarsening of facial features and acne
- Gum hypertrophy and Gingival hyperplasia.
- Hypersensitivity rashes, lymphadenopathy
- Exacerbates absence seizures
41. Phenytoin sodium contd.
- Uses:It is the first lineantiepileptic for
-
- GTCS, no effect in absence seizure
-
- Trigeminal neuralgia 2 ndto Carbamazepine
- Availableas caps/tabs/inj
- 25 to 100 mg caps and tabs.
42. Phenytoin sodium contd.
-
- Phenytoin and carbamazepine increases each others
metabolism
-
- Induces microsomal enzyme steroids, digitoxin etc
-
- Phenytoin metabolism inhibition by warfarin, isoniazide
etc.
-
- Sucralfate decreases phenytoin ebsorption
43. Phenytoin sodium contd. 44. Phenytoin sodium contd.
Phenytoin Toxicities Fetal Hydantoin Syndrome 45. Images of
Phenytoin preparations 46. Carbamazepine (Tegretol/Tegrital)
- Chemically related to imipramine
- Resembles phenytoin in pharmacological actions
- Unlike phenytoin inhibits kindling, modifies electroshock
seizures and raises threshold to PTZ and electroshock
47. Carbamazepine contd.
-
- Poorly water soluble and oral absorption is low
-
- 75% bound to plasma protein
-
- Metabolized in liver: active 10-11 epoxy carbamazepine
-
- Substrate and inducer of CYP3A4
-
- Half life 20 to 40hrs. Decreases afterwards due to
induction
48. Carbamazepine contd.
-
- Autoinduction of metabolism
-
- Nausea, vomiting, diarrhoea and visual disturbances
-
- Hypersensitivity rash, photosensitivity, hepatitis, granulocyte
supression and aplastic anemia
-
- ADH action enhancement hyponatremia and water retention
-
- Exacerbates absence seizures
49. Carbamazepine contd.
-
- Trigeminal and related neuralgias
-
- Manic depressive illness and acute mania
- Availableas tabs (100mg 200, 400 etc.) and syr.
50. Carbamazepine contd.
-
- Enzyme inducer reduce efficacy of OCPs and others
-
- Metabolism is induced by phenobarbitone, phenytoin,
valproate
-
- Inhibits its metabolism isoniazide and erythromycin
51. Ethosuximide
- Drug of choice for absence seizures
- Does not modify maximal electroshock seizure or inhibit
kindling
- Not plasma protein or fat binding
- Mechanism of action involves reducing lowthreshold Ca2+ channel
current (T-type channel) in thalamus
- Depresses cerebral metabolic rate
-
-
- Phensuximide = less effective
-
-
- Methsuximide = more toxic
52. Ethosuximide contd.
-
- Gastric distress, including, pain, nausea and vomiting
53. Valproic acid (Encorate/Valparin)
- Broad spectrum anticonvulsant
- Effects on chronic experimental seizure and kindling
- Potent blocker of PTZ seizure
- Effective in partial, GTCS and absence seizures
-
- Ca++ mediated `T` current attenuation
-
- Inhibition of GABA transaminase
- Pharmacokinrtics: well absorbed orally, 90% bound to plasma
protein and completely metabolized in liver and excreted in urine t
1/2is 10-15 hrs.
54. Valproic acid contd.
-
- Elevated liver enzymes including own rise in serum
transaminase
-
- Abdominal pain and heartburn
-
- Tremor, hair loss, weight gain
-
- Idiosyncratic hepatotoxicity
-
- In Girls polycystic ovarian disease and menstrual
irregularities
-
- Negative interactions with other antiepileptics
-
- Teratogenicity:spina bifida
- Availableas tabs. (200/300/500, syr. and inj.)
55. Valproic acid contd.
-
- Valproate and carbamazepine induce each others metabolism
-
- Inhibits phenobarbitone metabolism and increases its plasma
level
-
- Displaces phenytoin from protein binding sites and thereby
decreases its metabolism phenytoin toxicity
56. Benzodiazepines
- Mainly used agents Clonazepam, Diazepam, Lorazepam and
Clobazam
-
- Prevents PTZ induced seizures prominently and modifies
electroshock seizure pattern
-
- Clonazepam has potent effect on PTZ induced seizures but almost
nil action on ME seiures
-
- Suppress the spread of kindled seizures and generalized
convulsions
-
- Do not abolish abnormal discharges at site of stimulation
57. Benzodiazepines contd.
- Pharmacokinetic properties:
-
- Well absorbed orally (peak 1-4 hrs)
-
- IV administration redistribution
-
- Diazpam rapid redistribution (1 hr)
-
- Diazepam 99%, Clonazepam 85% bound to plasma protein
-
- N-desmethyldiazepam (metabolite) is less active than diazepam
partial agonist
-
- Diazepam and NDD hydroxylated to active metabolite oxazepam t
1/2is 1 to 2 days
-
- Clonazepam reduction of nitro group to inactive 7-amino
derivatives
-
- Lorazepam conjugation with glucoronic acid t 1/2is 14hrs
58. Benzodiazepines contd.
-
- Long term use of Clonazepam drowsiness and lethargy tolerance
to antiseizure effects
-
- Muscular incoordination and ataxia
-
- Hypotonia, dysarthria and dizzziness
-
- Behavoiural abnormalities in children aggression,
hyperactivity, irritability and difficulty in concentration
-
- Increased bronchial and salivary secretions
59. Benzodiazepines contd.
-
- Cloonazepam in absence seizure and myoclonic seizure in
children (1 to 6 months)
-
- Dose initial 1.5mg/day, children 0.01 to 0.03mg/kg/day
-
- Status epilepticus Diazepam Lorazepam may be used as
alternative
60. Benzodiazepines contd. 61. Gabapentin
- GABA molecule covalently bound to a cyclohexane ring
- Originally designed to be centrally active GABA agonist rapid
transfer across BBB
- Pharmaqcological Effects:
-
- Inhibits hindlimb extension in ME seizure
-
- Inhibits clonic seizures induced by PTZ
-
- Efficacy is equal to valproic acid but different from
carbamazepine and phenytoin
62. Gabapentin contd.
-
- Probably, promotes nonvesicular release of GABA
-
- Binds a protein in cortical membrane similar to L type of
voltage sensitive Ca++ channel
-
- But, do not alter Ca++ currents
-
- Does not reduce repetitive firing of action potentials
63. Gabapentin contd.
-
- Not metabolized in humans
-
- Not bound to plasma proteins and excreted unchanged in
urine
-
- No known drug interaction
-
- Partial seizures with or without secondary generalization in
addition to other drugs
-
- 900-1800mg/day is equivalent to 300 mg/day of carbamazepine if
used alone
-
- Usual starting dose is 300mg/day
- Adverse effects:somnolence, dizziness, ataxia etc.
64. Lamotrigine
- Phenyltriazine derivative
- Originally, as antifolate agent
- Pharmacological Effects and Mechanisms:
-
- Suppresses tonic hindlimb extension in ME seizure
-
- Partial and secondarily generalized in kindling
-
- No action on PTZ seizures
-
- Delays recovery from inactivation of Na+ channels carbamazepine
and phenytoin
-
- Effective against partial and secondarily generalized
seizures
-
- Broad spectrum activity action in areas other than Na+
channels
-
- Inhibition of glutamate release
65. Lamotrigine contd.
-
- Completely absorbed from GIT and metabolized by
glucoronidation
-
- Plasma half-life 15 to 30 hrs
-
- Phenobarbitone, carbamazepine and phenytoin reduces half
life
-
- Valproate increases plasma concentration but its concentration
reduces
-
- Together with Carbamazepine increase in 10,11-epoxide and
toxicity
- Uses:Monotherapy and add on therapy in simple partial and
secondarily generalized seizures
66. Topiramate
- Sulfamate substituted monosaccharide
- Pharmacological effects and MOA:
-
- Broad spectrum antiseizure drug
-
- Carbonic anhydrase inhibitor
-
- Antiseizure activity against PTZ, ME seizure and partial and
secondarily generalized tonic-clonic kindling
-
- Multiple actions Na+ channel, K+ channel, GABA A , AMPA-kainate
subtypes of glutamate
-
- Rapidly absorbed orally, 10-20% bound to plasma protein,
excreted unchanged in urine
-
- Metabolized by hydroxylation, glucoronidation and
hydrolysis
-
- Reduction in estradiol level
67. Major DrugInteractions
-
- With P.barbitone unpredictable overall reaction
-
- With Carbamazepine increases each other`s metabolism
-
- With Valproate displaces phenytoin from protein binding
-
- Mainly significant interactions are due to displacement of
protein binding - sulfonamides
-
- Increase in metabolism of other drugs like primidone,
phenytoin, ethosuximide, valproic acid, and clonazepam
-
- Phenobarbitone and Phenytoin increases its metabolism
-
- Significant interactions are due to enzyme induction
68. Major Drug Interactions contd.
-
- Due to Protein binding and inhibition of metabolism
-
- Phenytoin is displaced from binding
-
- Inhibits metabolism of phenobarbitone, phenytoin and
carbamazepine
-
- Valproate inhibits metabolism and clearance
69. Other uses of AEDs:
- Gabapentin, carbamazepine neuropathic pain
- Lamotrogine, carbamazepine bipolar disorder
- Valproate, topirimate, gabapentin migraine
- Diazepam Tetanus, eeclampsia and convulsant drug poisoning
70. Treatment of Epilepsies
-
- Control and prevent all seizure activity (seizure - freedom and
improvement in quality of life!)
-
- To search the cause of epilepsy
-
- Attempts to remove the causes
-
- Symptomatic treatment with antiepileptic drugs
-
- To consider status epilepticus as medical emergency and treat
efficiently and promptly
- Choice of Drugs:According to the seizure types.
71. Treatment of Epilepsies Drug choices - Diazepam rectal
0.5mg/kg Febrile convulsions Phenytoin IV Phosphenytoin IV Diazepam
Lorazepam Status epilepticus Lamotrigine Topiramate Valproate
Myoclonic Gabapentin Lamotrigine Phenytoin, Carbamazepine and
Valproate Complex partial seizure with or without generalization
Ethosuximide Valproate Absence seizure Phenobarbitone and Valproate
Carbamazepine, Phenytoin and Valproic acid Generalized tonic-clonic
or simple partial seizure 2 nd choice 1 stchoice Seizure types 72.
Treatment of Epilepsies contd.
- 3. Initiation of treatment:
-
- Initiate therapy even if it is isolated tonic-clonic seizure
with family history of seizure, abnormal neurological examination,
abnormal EEG and an abnormal MRI
-
- Substitute another drug if fails
-
- Combination therapy only when all monotherapy fail
-
- Therapeutic monitoring of drugs dose adjustments
73. Treatment of Epilepsies contd.
-
- Prolong therapy life long/3yrs after last seizure
-
- Withdrawal childhood epilepsy, absence of family history,
primarily generalized tonic-clonic seizure and normal EEG
74. Treatment of Epilepsies contd.
- Antiepileptics and pregnancy
-
- Drugs should not be stopped if conceive status epilepticus
-
- Fits during pregnancy birth defects, mental retardation
etc.
-
- Folic acid and vit.K supplementation
- Care during attacks:tonic-clonic seizures
75. Generalized Onset Seizures
- Tonic-clonic, myoclonic, and absence seizures:1st line drug is
usuallyvalproate
- Generalized seizures:Phenytoin and carbamazepine are effective
on tonic-clonic seizures but not other types of seizures
- Absence seizures:Valproate and ethosuximide are equally
effective in children, but only valproate protects against the
tonic-clonic seizures that sometimes develop.
- Risk of hepatoxicity with valproateshould not be used in
children under 2
76. Partial Onset Seizures
-
- Phenytoin and carbamazepine may be slightly more effective
- With secondary generalization
-
- First-line drugs are carbamazepine and phenytoin (equally
effective)
-
- Valproate, phenobarbital, and primidone are also usually
effective
- Phenytoin and carbamazepinecan be used together (but both are
enzyme inducers)
77.
- Adjunctive (add-on) therapy: newer drugs felbamate, gabapentin,
lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate,
and zonisamide
- Phenytoin and carbamazepine failure:Lamotrigine, oxcarbazepine,
felbamate approved for monotherapy
- Refractory partial seizures: Topirimate can be effective.
Partial Onset SeizuresNew Drugs 78. Status Epilepticus
- Defn.:Continuous seizure activity for more than 30 minutes, or
2 or more seizures without recovery of consciousness. Recurrent
tonic-clonic convulsions without recovery in between
- Goal of therapy:rapid termination of seizure activity more
difficult to control permanent brain damage
- Prompt treatment with effective Drugs
- Attentionto hypoventilation and hypotension
79. Status Epilepticus contd.
- Diazepam 10mg IV bolus injection (2mg/min)
-
- Fractional dose at every 10 min. or titrated dose by slow
infusion
- Followed by Phenobarbitone IM/IV (100-200mg) or Phenytoin slow
IV in saline (25-50mg/min)
- Resistant cases (refractory): IV anaesthetics
- General supportive measures
80. Attentions
- Selection of an appropriate antiseizure agent
81. Thank You