30-60 h
Side effects Sedation,Ataxia,Confusion,Depression,Dizziness
Behavioral changes,Tolerance,Dependence
Interactions Level increased by valproic acid
Clobazam
Principal
Use
Lennox-Gastaut syndrome
MOA GABA-A receptor agonist
Typical Dose 10–40 mg/d; bid
Half Life
A group of chronic CNS disorders characterized by recurrent 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.
A group of chronic CNS disorders characterized by recurrent 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.
the causes, pathophysiology, clinical manifestations, diagnosis and treatment of epilepsy has been discussed in detail with the perspective of a subject called pathophysiology in both medical sciences as well as the pharmaceutical sciences
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Electrophysiological assessment of neuromuscular transmissionRahul Kumar
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the causes, pathophysiology, clinical manifestations, diagnosis and treatment of epilepsy has been discussed in detail with the perspective of a subject called pathophysiology in both medical sciences as well as the pharmaceutical sciences
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Definition of psychosis, Causes of psychosis, Symptoms of psychosis, Classification of anti psychotic drugs, Mechanism of action, Pharmacokinetics, Adverse effects, Therapeutic uses, Contraindications, New inventions
Presented by
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Author: Danielle Cassidy, Pharm.D., BCPS
Audience: Third year pharmacy students at University of Colorado School of Pharmacy
Background: describes common causes of seizures, differentiates dosing of antiepileptic drugs in pediatrics vs. adults, common risk factors associated with febrile seizures, treatment of febrile seizures, treatment of status epilepticus (inpatient & outpatient), & how to dispense/counsel parents on the administration of Diastat.
Contents
Definition of Seizure and Epilepsy
Epidemiology
Classification of seizure
Pathophysiology of seizures
Evaluation Patients Presenting with Seizure
Focal seizure and related epilepsy syndromes
Generalized seizures and Epilepsy syndromes
Treatment of seizures and Epilepsy
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"epilepsy-it is a brain disorder in which the person has repeated convulsions over a period of time. Epilepsy occurs when permanent changes in the brain tissue cause it to be excitable or jumpy. The brain sends out abnormal signals. Mindheal homeopathy is more effective in the treatment of epilepsy then conventional medicine."/>
Effective treatment for epilepsy in Mindheal Homeopathy clinic ,Chembur, Mumb...Shewta shetty
"epilepsy-it is a brain disorder in which the person has repeated convulsions over a period of time. Epilepsy occurs when permanent changes in the brain tissue cause it to be excitable or jumpy. The brain sends out abnormal signals. Mindheal homeopathy is more effective in the treatment of epilepsy then conventional medicine."/>
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2. Contents
• History
• Definition
• Mechanism – Neurophysiology
• Etiology
• C/F
• Investigations
• Treatment
• Epilepsy syndromes
• Status and Refractory epilepsy
• Epilepsy in Women
3. History
• 400 B.C.:
• The Greek physician Hippocrates writes the first book
on epilepsy, On the Sacred Disease.
• Refuting the idea that epilepsy is a curse or a
prophetic power, Hippocrates proves the truth: It's a
brain disorder. "It is thus with regard to the disease called
Sacred: it appears to me to be nowise more divine nor more
sacred than other diseases, but has a natural cause like other
affections. . ."
4. History
• 70 A.D.:
• In the Gospel According to Mark (9:14-29), Jesus Christ
casts out a devil from a young man with epilepsy:
"Teacher, I brought you my son, who is possessed by a spirit that
has robbed him of speech. Whenever it seizes him, it throws him to
the ground. He foams at the mouth, gnashes his teeth, and
becomes rigid. I asked your disciples to drive the spirit out, but
they could not." (NIV)
5. History
• 1859-1906:
• Under the leadership of three English neurologists—
• John Hughlings Jackson
• Russell Reynolds
• Sir William Richard Gowers
• the modern medical era of epilepsy begins. In a study,
Jackson defines a seizure as "an occasional, an excessive, and
a disorderly discharge of nerve tissue on muscles." He also
recognizes that seizures can alter consciousness,
sensation, and behavior.
6. History
• 1929
• A German psychiatrist named Hans Berger announced to
the world
• that it was possible to record electric currents generated on the
brain, without opening the skull, and to depict them graphically
onto a strip of paper.
• Berger named this new form of recording as the
electroencephalogram (EEG).
7. Definitions
• Seizure : (Latin sacire, "to take possession of") -
paroxysmal event due to
– abnormal, excessive, hypersynchronous discharges
from an aggregate of CNS neurons.
• Epilepsy : ( Greek word epilambanein, meaning to attack
or to seize )
– clinical phenomenon rather than a single disease, in
which a person has recurrent seizures due to a
chronic, underlying process.
Harrisons 17th edi
8. Disease Burden
• Epilepsy is affecting at
least 50 million people
worldwide.
• Epilepsy accounts for 1%
of the global burden of
disease
• It knows no geographical,
racial or social
boundaries.
9. Mechanism - Neurophysiology
• Influx of Na+ and outflow of K+ contribute to membrane
depolarization and generation of the action potential
• Influx of Ca++ tends to further depolarize the cell
• Cl− influx hyperpolarizes the membrane and inhibits action
potentials
10. The dynamic target of seizure control in the management of
epilepsy is achieving balance between the factors that influence
the excitatory postsynaptic potential (EPSP) and those that
influence inhibitory postsynaptic potential (IPSP).
11. Some antiepileptic drugs stabilize the inactive configuration of
the sodium (Na+) channel, preventing high-frequency neuronal firing.
12. Low-voltage calcium (Ca2+) currents (T-type) are responsible for the
rhythmic thalamocortical spike and wave patterns of generalized absence
seizures. Some antiepileptic drugs lock these channels, inhibiting the
underlying slow depolarizations necessary to generate spike-wave bursts.
13. The GABA-A receptor mediates chloride (Cl-) influx, leading to
hyperpolarizationof the cell and inhibition. Antiepileptic drugs
may act to enhance Cl- influx or decrease GABA metabolism.
15. B-Slide 15
Epilepsy—Basic
Neurophysiology
The brain’s major excitatory neurotransmitter
Two groups of glutamate receptors
– Ionotropic—fast synaptic transmission
– Metabotropic—slow synaptic transmission
Modulation of glutamate receptors by
Glycine, polyamine sites, Zinc, redox site
16. B-Slide 16
Epilepsy—Basic
Neurophysiology
The brain’s major inhibitory neurotransmitter
Two types of receptors
– GABAA— post-synaptic, specific recognition sites, linked
to CI-
channel
– GABAB —presynaptic autoreceptors that reduce
transmitter release by decreasing calcium influx,
postsynaptic coupled to G-proteins to increase K+ current
17. B-Slide 17
Basic Mechanisms Underlying Seizures
and Epilepsy
Feedback and
feed-forward
inhibition,
illustrated via
cartoon and
schematic of
simplified
hippocampal circuit
Babb TL, Brown WJ. Pathological Findings in Epilepsy. In: Engel J. Jr. Ed.
Surgical Treatment of the Epilepsies. New York: Raven Press 1987: 511-540.
18. B-Slide 18
Normal CNS Function
Excitation
Inhibition
glutamate,
aspartate
GABA
Modified from White, 2001
22. International League against Epilepsy (ILAE)-1981
1. Partial seizures
a. Simple partial seizures (with motor, sensory, autonomic/
psychic signs)
b. Complex partial seizures
c. Partial seizures with secondary generalization
2. Primarily generalized seizures
a. Absence (petit mal)
b. Tonic-clonic (grand mal)
c. Tonic
d. Atonic
e. Myoclonic
3. Unclassified seizures
a. Neonatal seizures
b. Infantile spasms
23.
24. GTCS
• Initially tonic contraction of muscles throughout the body
• Muscles of expiration and larynx at the onset -produce a
loud moan or "ictal cry.“
• Respirations are impaired, secretions pool in the
oropharynx, and cyanosis develops.
• Contraction of the jaw -biting of the tongue
• A marked enhancement of sympathetic tone leads to
increases in HR, BP and pupillary size.
• After 10–20 s, the tonic phase of the seizure typically
evolves into the clonic phase, produced by the
superimposition of periods of muscle relaxation on the tonic
muscle contraction.
• The periods of relaxation progressively increase
25. GTCS – post ictal
• The postictal phase - unresponsiveness, muscular
flaccidity, and excessive salivation that can cause
stridorous breathing and partial airway obstruction.
• Bladder or bowel incontinence may occur
• Patients gradually regain consciousness over minutes
to hours, and during this transition there is typically
a period of postictal confusion
• Patients subsequently complain of headache, fatigue,
and muscle ache that can last for many hours.
26. There is a patient with H/o Suspected seizure…
• Ensure ABC
• Is it a seizure ? History and Examination
28. There is a patient with H/o Suspected seizure…
• Ensure ABC
• Is it a seizure ? History and Examination
• Is he a known Epileptic ? On Treatment ?
• Proceed with Investigations – as guided by History and
Examination,
• Blood ( Metabolic / Drug levels )
• EEG, Imaging ( CT / MRI )
29. You have diagnosed it is a seizure…then ?
• If it is First episode of unprovoked seizure ?
30. Treatment of the first unprovoked seizure
• 1. Prolonged focal seizure
• 2. First seizure presenting as status epilepticus
• 3. Presence of neurological deficit, hemiparesis,
mental retardation, cerebral palsy etc.
• 4. Family history of seizures among parents, siblings
or children.
• 5. EEG / CT / MRI abnormality
• 6. High risk jobs (Professional or other activities
that may endanger life during a seizure)
• 7. The individual and family do not accept the
expected risk of recurrence ( 35 - 40 % )
•Epilepsy society of India
31. Antiepileptic Drugs
• Which are they
• Goal of Treatment
• Principels of treatment
• Selection of Drug
• Duration of Treatment
• When to stop
• Non medical Treatment
32. Antiepileptic Drug Therapy
• Goals
• Completely prevent seizures without causing any
untoward side effects
• Preferably with a single medication
• Dosing schedule that is easy for the patient to
follow
33. Antiepileptic Drug Therapy
• Principles
• Start with a single conventional antiepileptic drug
• Start with a low dose
• If ineffective / poorly tolerated, then monotherapy
using another AED can be tried
• Combination Therapy
34. Conventional or First line drugs
• Phenytoin (PHT)
• Phenobarbitone (PHB)
• Carbamazepine (CBZ)
• Oxcarbazepine (OXC)
• Valproate (VPA)
35. New or Second line drugs
• Ethosuximide
• Gabapentin
• Lomotrigine
• Vigabatrin
• Topiramate
• Tiagabine
• Zonisamide
• Clonazepam
• Clobazam
39. Phenytoin – PHT ( 1938 )
Principal
Use
Tonic-clonic (grand mal)
Focal-onset
MOA Block Sodium Channels, also Ca Channels
Typical Dose 300–400 mg/d (3–6 mg/kg, adult; 4–8 mg/kg, child); qd-bid
Half Life 24 h (wide variation, dose- dependent)
Side effects Dizziness,Diplopia,Ataxia,Incoordination,Confusion,
Gum hyperplasia,Lymphadenopathy,Hirsutism,Osteomalacia
Facial coarsening,Skin rash
Interactions Level increased by isoniazid, sulfonamides, fluoxetine
Level decreased by enzyme-inducing drugsa
Altered folate metabolism
40. Fosphenytoin ( Pro drug )
Principal
Use
Tonic-clonic (grand mal)
Focal-onset
MOA Block Sodium Channels, also Ca Channels
Typical Dose IV Preparation, can be given 3 times faster,
Half Life
Side effects Better Tolerated
Interactions
41. Carbamazepine – CBZ (1974 )
Principal
Use
Partial
Tonic-clonic
MOA Block Sodium Channels
Typical Dose 600–1800 mg/d (15–35 mg/kg, child); bid-qid
Half Life 10–17 h
Side effects Ataxia,Dizziness,Diplopia,Vertigo,
Aplastic anemia,Leukopenia,GI irritation,Hepatotoxicity
Hyponatremia
Interactions Level decreased by enzyme-inducing drugsa
Level increased by erythromycin, propoxyphene,
INH,cimetidine, fluoxetine
42. Oxcarbazepine - OXC
Principal
Use
Focal-onset
MOA Block Sodium Channels
Typical Dose 900–2400 mg/d (30–45 mg/kg, child); bid
Half Life 10–17 h (for active metabolite
Side effects Lessed Side effects
Interactions Lesser Interactions
43. Phenobarbital - PHB
Principal
Use
Tonic-clonic
Focal-onset
MOA Bind GABA-A receptors,blocks Na, Ca, opens Cl, depress
glutamate
Typical Dose 60–180 mg/d (1–4 mg/kg, adult); (3–6 mg/kg, child); qd
Half Life 90 h (70 h in children)
Side effects Sedation.Ataxia,Confusion,Dizziness,Decreased libido,
Depression,skin rashes
Interactions Level increased by valproic acid, phenytoin
44. Valproic acid - VPA
Principal
Use
drug of choice for primary GTCS,
Absence,Atypical absence,Myoclonic,Focal-onset
MOA increase synthesis of GABA , may Block Na channel
Typical Dose 750–2000 mg/d (20–60 mg/kg); bid-qid.start 250 mg/d with a
maintenance dose of 500-1500 mg/d.
Half Life 15 h
Side effects Ataxia,Sedation,Tremor
Hepatotoxicity,Thrombocytopenia,GI,Weight gain,
Transient alopecia,Hyperammonemia, low IQ in infants born
Interactions Level decreased by enzyme-inducing drugsa
45. Lamotrigine - LTG
Principal
Use
Focal-onset,Tonic-clonic,Atypical absence,Myoclonic
Lennox-Gastaut syndrome
MOA Block Sodium Channels
Typical Dose 150–500 mg/d; bid
Half Life 25 h,14 h (with enzyme-inducers)
59 h (with valproic acid)
Side effects Dizziness,Diplopia,Sedation,Ataxia,Headache,
Skin rash,Stevens-Johnson syndrome
Interactions Level decreased by enzyme-inducing drugsa and OCP,
Level increased by valproic acid
46. Ethosuximide
Principal
Use
Absence (petit mal)
MOA Block Sodium Channels
Typical Dose 750–1250 mg/d (20-40 mg/kg); qd-bid
Half Life 60 h, adult
30 h, child
Side effects Ataxia,Lethargy,Headache
Interactions Gastrointestinal irritation,Skin rash
Bone marrow suppression
47. Gabapentin
Principal
Use
Focal-onset
MOA Block Sodium Channels
Typical Dose 900–2400 mg/d; tid-qid
Half Life 5–9 h
Side effects Sedation,Dizziness,Ataxia,Fatigue,
GI,Weight gain,Edema
Interactions No known significant interactions
48. Tiagabine ( TGB )-1998
Principal
Use
adjunctive therapy in refractory partial epilepsy
MOA GABA uptake inhibitor
Typical Dose 32–56 mg/d; bid-qid
Half Life 7–9 h
Side effects Confusion,Sedation,Depression,Dizziness,Speech or
language problems,Paresthesias,Psychosis, Gi
Interactions Level decreased by enzyme-inducing drugsa
49. Topiramate
Principal
Use
Focal-onset,Tonic-clonic
Lennox-Gastaut syndrome
MOA increase synthesis of GABA , may Block Na channel, inhibit
Glutamate, inhibit carbonic anhydrase
Typical Dose starting dose 25 mg/d;increased biweekly increments of 25-
50 mg. Maintenance dose is 200-600 mg/d in 2 divided
doses.
Half Life 20–30 h
Side effects Psychomotor slowing,Sedation,Speech or language problems
Fatigue,Paresthesias, Renal stones,Glaucoma,Weight loss
Hypohydrosis
Interactions Level decreased by enzyme-inducing drugsa
50. Zonisamide - ZNS
Principal
Use
Focal-onset
MOA Block Sodium Channels
Typical Dose 200–400 mg/d;qd-bid
Half Life 50–68 h
Side effects Sedation,Dizziness,Confusion,Headache,Psychosis,Anorexia
Renal stones,Hypohydrosis
Interactions Level decreased by enzyme-inducing drugsa
52. Clonazepam
Principal
Use
Absence,Atypical absence
Myoclonic, ( with Anxiety )
MOA GABA-A receptor agonist, May block Na Channels
Typical Dose 1–12 mg/d (0.1–0.2 mg/kg); qd-tid
Half Life 24–48 h
Side effects Ataxia,Sedation,Lethargy
Interactions Level decreased by enzyme-inducing drugsa
53. Vigabatrin - VGB
Principal
Use
Absence,Atypical absence
Myoclonic, ( with Anxiety )
MOA Inhibit GABA Transaminase
Typical Dose 500 mg twice daily, and is increased by 250-500 mg every 1-
2 weeks to a maximum dose of 4000 mg/d.
Half Life 4-8 hrs
Side effects Drowsiness,depression (5%), agitation (7%), confusion and,
rarely, psychosis.
Interactions VGB can reduce plasma concentration of Phenytoin by 25%
54. Clobazam
Principal
Use
partial epilepsy, Lennox-Gastaut syndrome or primary or
secondarily generalized ( as adjunctive )
MOA agonist action at the GABA-A receptor, May Block Sodium
and Ca Channels
Typical Dose 10-20 mg/d , OD
Half Life 10-50 hours
Side effects Sedation tolerance, dizziness, ataxia, blurred vision, diplopia,
irritability, depression, muscle fatigue
Special
Indications
Catamenial epilepsy, prophylaxis for some situations, such
as traveling
55. When to Discontinue Therapy
• 70% of children and 60% of adults who have their seizures
completely controlled with antiepileptic drugs can
eventually discontinue therapy
• Normal IQ / EEG/ CT / MRI /
• Seizure free interval / Occupation
56. Treatment of Refractory Epilepsy
• There are currently no clear guidelines for rational
polypharmacy
• Combine first-line drugs
• Later add newer drug such as levetiracetam or topiramate
57.
58.
59.
60.
61.
62.
63. Women with epilepsy
• Proper contraception ( Progest Depots or OCP’s with
High Estrogen content )
• Preconceptional counselling
• 90 % can have Normal Pregnancy and labour and child
• fetal abnormalities in children born to mothers with
epilepsy is increased by 5–6%
• No preference to any drugs
• Avoid Valproate , Carbamazepine
• Use Monotherapy
• Start Folic acid 10 mg/d
64. Women with epilepsy
• Check AFP, and for Neural tube defects
• Vit K 20 mg i.m at 34 and 36 wks
• Institutional Delivery
• Avoid pptating factors – sleep deprivation, Hypoglycemia,
pain, Drug Interactions during labour
• Vit K 1 mg i.m to new born
• May require reduction in dose postpartally
• Contraception
• Concentration in breat milk- 80% for ethosuximide, 40–60% for
phenobarbital, 40% for carbamazepine, 15% for phenytoin, and 5%
for valproic acid
65. Women with epilepsy
• Catamenial Epilepsy :
• increase in seizure frequency around the time of menses
• Acetazolamide (250–500 mg/d) may be effective as
adjunctive therapy in some cases when started 7–10 days
prior to the onset of menses and continued until bleeding
stops
66. Morbidity / Mortality
• Trauma
• Burns
• Social Stigma
• Most deaths are accidental due to impaired consciousness.
However,
• Sudden unexpected death in epilepsy (SUDEP) may occur
• Mechanism of death is controversial, cardiac arrhythmias,
pulmonary edema, and suffocation during an epileptic
seizure
67.
68.
69.
70. Refractory Epilepsy
• Options for management of refractory epilepsy:
• Future strategies
• Second line drugs
• Surgery
• Gama knife
• Seizure prediction and prevention
• Neural stimulation (Vagus, TMS, DBS)
• Gene therapy
• Stem cell therapy
Editor's Notes
Neurotransmitters are substances that are released by the presynaptic nerve terminal at a synapse
and subsequently bind to specific postsynaptic receptors for that ligand. Ligand binding results in channel
activation and passage of ions into or out of the cells. The major neurotransmitters in the brain are
glutamate, gamma-amino-butyric acid (GABA), acetylcholine (ACh), norepinephrine, dopamine, serotonin,
and histamine. Other molecules, such as neuropeptides and hormones, play modulatory roles that modify
neurotransmission over longer time periods (Slide 6).
Neurotransmitters are substances that are released by the presynaptic nerve terminal at a synapse
and subsequently bind to specific postsynaptic receptors for that ligand. Ligand binding results in channel
activation and passage of ions into or out of the cells. The major neurotransmitters in the brain are
glutamate, gamma-amino-butyric acid (GABA), acetylcholine (ACh), norepinephrine, dopamine, serotonin,
and histamine. Other molecules, such as neuropeptides and hormones, play modulatory roles that modify
neurotransmission over longer time periods (Slide 6).
Neurotransmitters are substances that are released by the presynaptic nerve terminal at a synapse
and subsequently bind to specific postsynaptic receptors for that ligand. Ligand binding results in channel
activation and passage of ions into or out of the cells. The major neurotransmitters in the brain are
glutamate, gamma-amino-butyric acid (GABA), acetylcholine (ACh), norepinephrine, dopamine, serotonin,
and histamine. Other molecules, such as neuropeptides and hormones, play modulatory roles that modify
neurotransmission over longer time periods (Slide 6).
Interneurons (e.g., basket cells) are generally considered to be local-circuit cells which influence the activity of nearby neurons. Most principal neurons form excitatory synapses on post-synaptic neurons, while most interneurons form inhibitory synapses on principal cells or other inhibitory neurons. Feed-forward inhibition occurs when an inhibitory neuron receives collateral innervation from an excitatory projection neuron. Since the inhibitory neuron is activated closely in time with the principal cell, feed-forward inhibition serves to inhibit over-activation of the principal cell by the projection neuron. Recurrent inhibition can occur when a principal neuron forms synapses on an inhibitory neuron, which in turn forms synapses back on the principal cells to achieve a negative feedback loop. In this type of feedback inhibition, the excited principal cell recurrently excites interneurons to inhibit the firing of neighboring principal cells, thus preventing the pool of target principal neurons from becoming synchronously over-activated. Slide 4 illustrates schematically both types of inhibition in a local interneuron-granule cell dentate gyrus circuit.
However, recent work suggests that some interneurons appear to have rather extensive axonal projections, rather than the local, confined axonal structures previously suggested. In some cases, such interneurons mayprovide a very strong synchronization or pacer activity to large groups of neurons.