Psychotropic - Anti Convulsant

Drugs for Special Population
Dr. Jarir At Thobari, MSc, PhD, FISPE
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Anticonvulsants
Dr. Jarir At Thobari, MSc, PhD, FISPE

Outline
• Introduction
• Why do we treat seizures
• How do we select anticonvulsant
medications
• Adverse Effects
• Drug Interactions
• Anticonvulsants in Pregnancy & Children

Epidemiology of Seizure
• 450 million people worldwide suffer from these
disorders –
• One in four people will be affected at some point
during their lifetime. In the South-East Asia Region
of WHO
• 27 percent of disability is due to neuropsychiatric
disorders, including epilepsy
• 3rd most common neurologic disorder
– After Stroke and Alzheimer’s

Seizure Occurrence
• Up to 10% of the population will experience a
single seizure during their lifetime
– majority due to an acute reversible cause: fever,
metabolic changes, drug intoxication/withdrawal.
• Since seizures don’t recur in these patients after

the provoking factor has been corrected, they
don’t have a diagnosis of epilepsy.
• A diagnosis of epilepsy is made after a patient

has had 2 or more unprovoked seizures

What was the cause of the seizure?
• Epileptic seizures are symptoms due to a

variety of causes
• Determining the underlying cause has

implications for both treatment and
prognosis

Causes epileptic seizures
Idiopathic (Genetic) - 50% of cases
– Childhood and Juvenile absence epilepsy
– Benign rolandic epilepsy of childhood
– Juvenile myoclonic epilepsy (JME)
Symptomatic - 50% of cases

– Malformations of brain developmental
– Tuberous Sclerosis
– Brain Infection
– Stroke
– Traumatic brain injury
– Tumor

Normal CNS Function

Hyperexcitability reflects both increased
excitation and decreased inhibition
Inhibition
Excitation
GABA
glutamate
aspartate
Clinical Factors Associated With Genetic Versus
Symptomatic Epilepsy
Idiopathic Epilepsy Symptomatic Epilepsy
1. Normal development  Developmental Delay
2. Normal neurological examination  History of brain injury
3. Family history of epilepsy  Abnormal Neurological Exam
4. No history of brain injury  Other congenital malformations
(e.g. head trauma, meningitis)
 Characteristic EEG abnormalities

Why Do We Treat Seizures?
• Prevent Falls & Injuries

• Employment & Education
• Psychosocial well-being
– Anxiety
– Embarrassment
– Loss of self-control
– Driving
– Life-style restriction

Overall Incidence of Convulsive Disorders:
Increased frequency at extremes of age
Incidence Per 100,000 Patient Years
300
250 Alcohol
Other provoked
Epilepsy
200 Single
150 Total
100
50
0
0 20 40 60 80 100
Age
Hauser, W. A. et al. (1995). Epilepsia, 34(3), 453-458.

* *
* *
* *
White (2005). American Epilepsy Proceedings.

GABA Biosynthesis & Breakdown
(so many drug targets)
GAD: glutamic acid decarboxylase converts

glutamate to GABA
VGAT: vesicular GABA transporter
GAT-1, GAT-2: membrane GABA transporter
found on neurons & astrocytes
GAT-3: membrane GABA transporter found on
astrocytes
GABA-T: GABA Aminotransferase, begins
conversion of GABA to succinic semialdehyde
(SSA)
Meyer & Quezner (2008). Psychopharmacology, Chapter 7.

Mechanisms of Action: GABA-ergic AEDs

Medications
• New
• Very Old – Clobazam (FrisiumR)
– Bromides (1861) – Lamotrigine (LamictalR)
– Topiramate (TopamaxR)
– Vigabatrin (SabrilR)
• Old • Even Newer
– Phenobarbital (1912) – Levetiracetam (KeppraR)
– Phenytoin (DilantinR)(1936) – Oxcarbazepine (TrileptalR)
– Diazepam (ValiumR)(1960’s) • The Newest
– Lacosamide (VimpatR)
– R
Carbamazepine (Tegratol ) (1974)
– Rufinamide (Banzel R)
– Valproic Acid (DepakoteR) (1978) – Ezogabine (PotigaR)

When do you consider starting
treatment?
• After first unprovoked seizure 50% of

patients will have a 2nd seizure. This needs
to be balanced against the potential side-
effects and cost of medication.
• In general treatment is started after the 2nd

seizure.

How effective are medications?
• 70% of patients will respond

– (1st or 2nd drug)
• If 2 appropriate drugs fail

– 3rd drug: approximate 5% success rate
• If 3rd drug fails: “ refractory epilepsy”

– Other treatments
• Ketogenic diet
• Epilepsy Surgery

Goals of Treatment
• Complete Suppression of Seizures
– with NO side-effects
• Maintain/Restore patients lifestyle

Principles of AED therapy
1. Select most appropriate drug
• Seizure type
• Epilepsy Syndrome
• Individual patient factors
– adverse effect, cost, patient-lifestyle
– dosing schedule
– Co-morbidities

2. Optimize Dosage
– start low dose, titrate up to maximum dose
– Minimize initiation related side-effects
– End Point:
• seizures controlled or side-effects occur

• Drug level monitoring
– Target blood drug level
• Helpful in guiding dose adjustments
– Treat the INDIVIDUAL

• NOT the therapeutic range

Adverse Effects
• Initiation & Dose related adverse effects
• Idiosyncratic “allergic” reactions

Adverse Effects
• Initiation & Dose related adverse effects
– Important to recognize
– Seldom are serious – reversible
• Decreasing medication
• Discontinuing medication

Valproic Acid (DepakoteR)
• Advantages • Disadvantages
– Well tolerated – Weight gain
– Broad spectrum – Tremor
– No effect on BCP – Hair thinning
– Platelet dysfunction
– Drug interactions
– “allergic” reactions
– Avoid in Pregnancy

Lamotrigine (LamictalR)
– Effective – Allergic Rash
– Well-tolerated – Titrate Slowly
– Twice daily

Idiosyncratic “allergic” reactions
• Unpredictable
• NOT dose-dependent
• Usually occur early in the course of
treatment
• Range: Mild-> severe
• Rare: 1 in 20,000 – 50,000

• Skin Rash
– Usually within 4 – 6 weeks
– Titrate dose up slowly
– Mild - Severe
• Reversible if discontinued early!!
– AED: lamotrigine 1:1000-2000
– Others: phenytoin, carbamazepine, phenobarbital

• Liver
– Usually occurs early in treatment
– Can be reversible if medication is stopped early
• Blood
– Symptoms:
• Bleeding, bruising, persistent infections

Carbamazepine (TegratolR)
– Effective – Dizziness/unsteady
– Well tolerated – “allergic” reaction
– Drug Interactions
– May exacerbate seizures
• Myoclonic, absence

Carbamazepine
• Rare serious & potentially fatal skin
reactions:
• 1 to 6 per 10, 000 patient
• Asian Ancestry: risk 10 times higher

Carbamazepine
• Genetic Marker
– Inherited variant of a gene (HLA-B 1502 allele), an immune system
gene
– Patients with this variant are at a higher risk
– It is possible to screen: blood test
• Asian Ancestry: prevalence of this allele

• High Risk: (10-15%)
– China (Han Chinese), Thailand, Malaysia, Indonesia, Philippines, Taiwan
• Moderate Risk: (5-10%)
– South Asia
• Low Risk: ( <1%)
– Japanese or Korean

Carbamazepine
• Note:
– If already on carbamazepine for months
• Unlikely to experience serious reaction
– Patients with positive results may not get this
reaction
– Serious skin reactions can still occur in
patients who test negative
– Regardless of ethnicity
• Monitor for signs and symptoms

Phenytoin
• One of the oldest and most widely used anticonvulsants.
• Mechanism uncertain, but probably related to effect on
Na+ channels.
• May be administered orally or IV.
• Pharmacokinetics are complex:
– oral absorption is good but rate is variable.
– highly protein-bound - important to note that usual
laboratory test measures total, not free phenytoin
– metabolism is primarily hepatic. Exhibits saturation
kinetics, so that small increment in dose can produce
an abrupt rise in equilibrium concentration.
– half-life averages 22 hours but highly variable; bid
dosing usually satisfactory

Phenytoin
• Pharmacokinetics are complex:
– induces hepatic metabolism of other
anticonvulsants as well as anticoagulants
– Acute toxicity of oral form is usually nystagmus,
ataxia and diplopia; sedation may also occur.
– Chronic administration causes hirsuitism, gingival
hyperplasia, cerebellar dysfunction, and peripheral
neuropathy
– Hypersensitivity with fever, rash which may
progress to exfoliation (Stevens-Johnson
syndrome) is relatively infrequent, but requires
discontinuation of the drug in most cases.

Phenytoin (DilantinR)
– Effective – Therapeutic levels
– Broadspectrum – Drug interactions
– Chew tabs, capsules – “Allergic” reactions
– Intravenous
– Inexpensive
– Once daily

Phenytoin (1938)
• History: less sedative than

phenobarbital
• MOA: decreased recovery of
voltage gated Na+ channels from
inactivation
• PK: 3A4 inducer
• Adverse Events: lethargy
(transient), gingival hyperplasia
Goodwin & Gillman (2011). p. 588.
Sharma & Dasroy (2000). NEJM, 342, 325.

Phenytoin & Category D
• ↓ growth AED Syndrome?
• Facial Abnormalities
– nasal hypoplasia
– maxilla hypoplasia
– flat philtrum
• ↓ IQ (variable)
• ↓ K+
Howe et al. (1995). American Journal of Medical Genetics, 58, 238-248.

Topiramate (TopamaxR)
– Effective – Cognitive effects
– “off label” – Kidney Stones
• Migraine – Weight Loss
– No “allergic” reactions
– Twice daily

Levetiracetam (KeppraR)
– Effective – Mild fatigue
– No drug interactions – Psychosis (0.6%)
• Including OCP – Cost
– Well tolerated
• No “allergic” reactions
– Can titrate fast

Clobazam (FrisiumR)
– Effective – Drowsiness
– Well tolerated – Unsteadiness
– Once or twice daily – Rare
• Behavior changes

Lacosamide (VimpatR)
– Effective for focal – Drowsiness
seizures – Headache
– Rare
• Heart arrhythmia
• Rash
• Suicidal behavior

Rufinamide (BanzelR)
– Effective in Lennox- – Drowsiness
Gastaut Syndrome – Headache
– Loss of appetite
– Rare
• Heart arrhythmia
• Rash
• Suicidal behavior

Ezogabine (PotigaR)
– Effective for focal seizures – Three times daily dosing
– Well tolerated – Drowsiness
– Dizziness
– Urinary Retention
– Rare
• Bluish Pigmentation
– Skin
– Sclera
– Retina

Why do drug interactions occur?
• Increase breakdown of other drugs
• Decrease breakdown of other drugs

Drug Interactions: Birth Control Pill
• Reduce Effectiveness • No Effect
– Carbamazepine – Clobazam
– Oxcarbazepine – Clonazepam
– Phenobarbital – Ethosuximide
– Phenytoin – Gabapentin
– Topiramate – Levetiracetam
– Valproic Acid
• Lamotrigine

Stopping AED Therapy
• Need to continue AED therapy should be re-
evaluated after 2 years seizures free.
• Factors favoring low risk recurrence

– Minimum 2 years seizure free
– Normal EEG
– Normal Neurological Examination
– Ease of controlling seizures
• Slow withdrawal of medications:

– over 2-3 months

Anticonvulsants and Pregnancy
• > 90% of women with epilepsy will have a
healthy baby
• Slightly higher risk for congenital

malformations
– General population: 2-3%
– Untreated epilepsy: 2-5%
– All anticonvulsant drugs: 4-7%

Anticonvulsants and Pregnancy
• Planned Pregnancy
– Talk to doctor
• Ideally one drug at lowest possible dose

– Monotherapy: 4.5% vs polytherapy 7%
• Folic Acid
– 0.4mg/day all women of child baring age
– Higher dose (4-5mg/day): women with epilepsy of
child baring age

Drug Therapy For Neonatal Seizures
Standard Therapy
AED Initial Dose Maintenance Dose Route
Phenobarbital 20mg/kg 3 to 4 mg/kg per day lV, lM, PO

Phenytoin 20 mg/kg 3 to 4 mg/kg per day lV, POª
Fosphenytoin 20 mg/kg phenytoin 3 to 4 mg/kg per day lV, lM
equivalents
Lorazepam² 0.05 to 0.1 mg/kg Every 8 to 12 hours lV
Diazepam²´ 0.25 mg/kg Every 6 to 8 hours lV
AED= andtiepileptic drug; lV= intravenous; lM= intramuscular; PO= oral

ªOral phenytoin is not well absorbed.
²Benzodiazepines typically not used for maintenance therapy.
³Lorazepam preferred over diazepam.

Conclusion
• Epilepsy is common
• We treat seizures to prevent injury and
maintain active lifestyle
• We select anticonvulsant medications
– Seizure types, drug profile, individual factors
• Adverse Effects
• Drug Interactions
• Anticonvulsants and Pregnancy

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Drugs for Special Population

Dr. Jarir At Thobari, MSc, PhD, FISPE

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Dr. Jarir At Thobari, MSc, PhD, FISPE

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

• Since seizures don’t recur in these patients after

• A diagnosis of epilepsy is made after a patient

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

• Epileptic seizures are symptoms due to a

• Determining the underlying cause has

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Symptomatic - 50% of cases

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Idiopathic Epilepsy Symptomatic Epilepsy

1. Normal development  Developmental Delay

2. Normal neurological examination  History of brain injury

3. Family history of epilepsy  Abnormal Neurological Exam

4. No history of brain injury  Other congenital malformations

(e.g. head trauma, meningitis)

 Characteristic EEG abnormalities

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

• Prevent Falls & Injuries

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

White (2005). American Epilepsy Proceedings.

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

GAD: glutamic acid decarboxylase converts

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

• After first unprovoked seizure 50% of

• In general treatment is started after the 2nd

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

• 70% of patients will respond

• If 2 appropriate drugs fail

• If 3rd drug fails: “ refractory epilepsy”

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

• Maintain/Restore patients lifestyle

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

– Minimize initiation related side-effects

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

– Treat the INDIVIDUAL

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

• Idiosyncratic “allergic” reactions

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

– AED: lamotrigine 1:1000-2000

– Others: phenytoin, carbamazepine, phenobarbital

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

• Asian Ancestry: risk 10 times higher

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

• Asian Ancestry: prevalence of this allele

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM