View
225
Download
2
Tags:
Embed Size (px)
Citation preview
Antiseizure drugs
Dr M Mosaddegh
Overview
• Seizures are sudden episodes of neurological dysfunction caused by abnormal electrical activity of the brain
• Seizures are common• 1% of the population will have a seizure
EpilepsyA 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.
• Brain Trauma• Encephalitis• Drugs• PKU• Photo epilepsy• Birth trauma• Withdrawal from
depressants• Tumor• Hypoxia• Idiopathic
• High fever(Febrile convulsion)• Hypoglycemia• Extreme acidosis• Extreme alkalosis• Hyponatremia• Hypocalcemia• Infection e.g.
meningitis, brain abscess, viral encephalitis
Causes for Acute Seizures
I. Partial (focal) SeizuresA. Simple Partial SeizuresB. Complex Partial Seizures
II. Generalized SeizuresC. Generalized Tonic-Clonic SeizuresD. Absence SeizuresE. Tonic SeizuresF. Atonic SeizuresG. Clonic and Myoclonic Seizures
F. Infantile Spasms
Classification of Epileptic Seizures
9
• Earlier studies suggested that many patients respond to monotherapy but fewer and fewer patients respond to combination therapy.
AED Response – Established AEDs
Monotherapy
70% controlled*
30% poorly managed
30% controlled* on 2 drugs
Combinations of two or more drugs provide little more benefit
* Controlled was defined as adequately managed but not necessarily seizure-free
I. Partial (Focal) Seizures
A. Simple Partial SeizuresB. Complex Partial Seizures
Scheme of Seizure SpreadSimple (Focal) Partial
Seizures
Contralateral spread
A. Simple Partial Seizures (Jacksonian)• Involves one side of the brain at onset.• Focal w/motor, sensory or speech disturbances.• Confined to a single limb or muscle group.• Seizure-symptoms don’t change during seizure.• No alteration of consciousness.EEG: Excessive synchronized discharge by a small group of
neurons. Contralateral discharge.
I. Partial (Focal) Seizures
Scheme of Seizure Spread
Complex Partial Seizures
Complex Secondarily Generalized Partial Seizures
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).
• Wide variety of clinical manifestations.• Consciousness is impaired or lost.
EEG: Bizarre generalized EEG activity with evidence of anterior temporal lobe focal abnormalities. Bilateral.
I. Partial (focal) Seizures
II. Generalized Seizures
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.
II. Generalized Seizures (con’t)A. Generalized Tonic-Clonic Seizures
Recruitment of neurons throughout the cerebrum
Major convulsions, usually with two phases:1) Tonic phase2) 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, Absence Seizures are non-convulsive
II. Generalized Seizures (con’t)A. Generalized Tonic-Clonic Seizures
Tonic phase:- 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.
II. Generalized Seizures (con’t)A. Generalized Tonic-Clonic Seizures
Clonic phase:- Alternating contraction and relaxation, causing a reciprocating movement which could be bilaterally symmetrical or “running” movements.
EEG: Characterized by groups of spikes on the EEG and periodic neuronal depolarizations with clusters of action potentials.
Scheme of Seizure Spread
Generalized Tonic-Clonic Seizures
Both hemispheres areinvolved from outset
Neuronal Correlates of Paroxysmal Discharges
Generalized Seizures
Neuronal Correlates of Paroxysmal Discharges
B. Absence Seizures (Petite Mal)• Brief and abrupt loss of consciousness.• Sometimes with no motor manifestations.• Usually symmetrical clonic motor activity
varying from occasional eyelid flutter to jerking of the entire body.
• 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.
II. Generalized Seizures
B. Absence Seizures (Petite Mal) (con’t)• Often begin during childhood (daydreaming attitude,
no participation, lack of concentration).• A low threshold Ca2+ current has been found to
govern oscillatory responses in thalamic neurons (pacemaker) and it is probably involve in the generation of these types of seizures.
EEG: Bilaterally synchronous, high voltage 3-per-second spike-and-wave discharge pattern.
spike phase: neurons generate short duration depolarization and a burst of action potentials. No sustained depolarization or repetitive firing.
II. Generalized Seizures
Scheme of Seizure Spread
Primary GeneralizedAbsence Seizures
Thalamocortial relays are believed
to act on a hyperexcitable
cortex
Neuronal Correlates of Paroxysmal Discharges
Generalized Absence Seizures
Scheme of Seizure Spread
II. Generalized Seizures (con’t)
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.
II. Generalized Seizures (con’t)E. Clonic and Myoclonic Seizures• Clonic Seizures: Rhythmic clonic contractions of all
muscles, loss of consciousness, and marked autonomic manifestations.
• Myoclonic Seizures: Isolated clonic jerks associated with brief bursts of multiple spikes in the EEG.
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.
Primary
Types of s
(focal)
Treatment of Seizures
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
Treatment of Seizures
Strategies:• Modification of ion conductances.
• Increase inhibitory (GABAergic) transmission.
• Decrease excitatory (glutamatergic) activity.
Actions of Phenytoin on Na+ Channels
A. Resting State
B. Arrival of Action Potential causes depolarization and channel opens allowing sodium to flow in.
C. Refractory State, Inactivation
Na+
Na+
Na+
Sustain channel in this conformation
GABAergic SYNAPSE
Drugs that Act at the GABAergic Synapse
• GABA agonists• GABA antagonists• Barbiturates• Benzodiazepines• GABA synthesizing
enzymes• GABA uptake inhibitors• GABA metabolizing
enzymes
GAD
GAT
GABA-T
GLUTAMATERGIC SYNAPSE
• Excitatory Synapse.• Permeable to Na+, Ca2+
and K+.• Magnesium ions block
channel in resting state.• Glycine (GLY) binding
enhances the ability of GLU or NMDA to open the channel.
• Agonists: NMDA, AMPA, Kianate.
Mg++
Na+
AGONISTS
GLU
Ca2+
K+
GLY
Chemical Structure of Classical Antiseizure Agents
X may vary as follows:
Barbiturates - C – N -Hydantoins - N –Oxazolidinediones – O –Succinimides – C –Acetylureas - NH2 –*
*(N connected to C2)
Small changes can alter clinical activity and site of action.e.g. At R1, a phenyl group (phenytoin) confers activity against partial seizures, but an alkyl group (ethosuximide) confers activity against generalized absence seizures.
“Older” AEDs• Phenobarbital 1912• Phenytoin 1938• Primidone 1952• Ethosuximide 1960• Carbamazepine 1974• Valproate 1978
Newer AEDS
• felbamate 1993• gabapentin 1994• lamotrigine 1995• topiramate 1996• tiagabine 1998• levetiracetam 1999• oxcarbazepine 2000• Zonisamide 2000• pregabalin 2005
Treatment of Seizures1) Hydantoins: phenytoin2) Barbiturates: phenobarbital3) Oxazolidinediones: trimethadione4) Succinimides: ethosuximide5) Acetylureas: phenacemide6) Other: carbamazepine, lamotrigine, vigabatrin,
etc.7) Diet8) Surgery, Vagus Nerve Stimulation (VNS).
• Most classical antiepileptic drugs exhibit similar pharmacokinetic properties.
• Good absorption (although most are sparingly soluble).
• Low plasma protein binding (except for phenytoin, BDZs, valproate, and tiagabine).
• Conversion to active metabolites (carbamazepine, primidone, fosphenytoin).
• Cleared by the liver but with low extraction ratios.• Distributed in total body water.• Plasma clearance is slow.• At high concentrations phenytoin exhibits zero order
kinetics.
Treatment of Seizures
Treatment of SeizuresStructurally dissimilar drugs:
• Carbamazepine• Valproic acid• BDZs.
New compounds:• Felbamate • Gabapentin• Lamotrigine• Tiagabine• Topiramate• Vigabatrin
Pharmacokinetic Parameters
TREATMENT OF SEIZURESDrugs Seizure disorderCarbamazepine or Valproate orPhenytoin orPhenobarbital
Tonic-clonic(Grand mal)Drug of Choice
Topiramte Lamotrigine (as adjunct or alone) Gabapentin (as adjunct)
Alternatives:
Carbamazepine or Topiramte or Phenytoin or Valproate
Partial (simple or complex) Drug of choice
Phenobarbital Lamotringine (as adjunct or alone) Gabapentin (as adjunct )
Alternatives:
Treatament cont,dValproate or Ethosuximide
Absence ( petit mal) Drug of choice
ClonazepamLamotrigine
Alternatives:
Valproate Myoclonic, Atonic Drug of choice
Clonazepam Alternatives:
Diazepam, i.v.or Phenytoin, i.v. or Vaproate
Status EpilepticusDrug of choice
Phenobarbital, i.v Alternatives:Diazepam, rectal*Diazepam ,i.vValproate
Febrile Seizures
* Preferred
• Up to 80% of patients can expect partial or complete control of seizures with appropriate treatment.
• Antiepileptic drugs suppress but do not cure seizures
• Antiepileptics are indicated when there is two or more seizures occurred in short interval (6m -1 y)
• An initial therapeutic aim is to use only one drug (monotherapy)
Treatment:
Treatment ( Cont. )• Advantage of monotherapy: • fewer side effects, decreased drug-drug interactions, better
compliance, lower costs• Addition of a second drug is likely to result in significant
improvement in only approx. 10 % of patients.
Treatment ( Cont. ) • when a total daily dose is increased, sufficient time
(about 5 t 1l2) should be allowed for the serum drug level to reach a new steady-state level.
• The drugs are usually administered orally
• The monitoring of plasma drug levels is very useful
• Precipitating or aggravating factors can affect seizure control by drugs
Treatment ( Cont. )• The sudden withdrawal of drugs should be avoided withdrawal may be considered after seizure- free
period of 2-3 or more years
• Relapse rate when antiepileptics are withdrawn is 20 -40 %
When to Withdraw Antiepileptic Drugs?
Normal neurological examination Normal IQ Normal EEG prior to withdrawal Seizure- free for 2-5 yrs or longer NO juvenile myoclonic epilepsy
Patients not meeting this ideal profile in all points, withdrawal may be encouraged after careful assessement of the individual patient.
The Cytochrome P-450 Enzyme System
Inducers Inhibitors
phenobarbital valproate
primidone topiramate (CYP2C19)
phenytoin oxcarbazepine (CYP2C19)
carbamazepine felbamate (CYP2C19)
felbamate (CYP3A) (increase phenytoin, topiramate (CYP3A) phenobarbital)oxcarbazepine (CYP3A)
Phenytoin
Pharmacokinetics• Well absorbed when given orally, however, it is also
available as iv. (for emergency) • 80-90% protein bound• Induces liver enzymes (Very Important)• Metabolized by the liver to inactive metabolite• Metabolism shows saturation kinetics and hence t ½
increases as the dose increased• Excreted in urine as glucuronide conjugate• Plasma t ½ approx. 20 hours• Therapeutic plasma concentration 10-20 µg/ml (narrow)• Dose 300-400 mg/day
Phenytoin ( Cont. )Mechanism of Action: Membrane stabilization by blocking Na & Ca influx
into the neuronal axon.or inhibits the release of excitatory amino acids via
inhibition of Ca influx
Clinical Uses: Used for partial Seizures & generalized tonic-clonic
seizures. But not effective for absence Seizures .Also can be used for Rx of ventricular fibrillation.
Side effects:Dose Related:• G.I.T upset• Neurological like headache, vertigo,
ataxia, diplopia, nystagmus• Sedation
Side effects of Phenytoin ( Cont. )
Non-dose related:• Gingival hyperplasia• Hirsutism• Megaloblastic anaemia• Hypersensitivity reactions (mainly skin rashes and
lesions, mouth ulcer) • Hepatitis –rare• Fetal malformations- esp. cleft plate• Bleeding disorders (infants)• Osteomalacia due to abnormalities in vit D
metabolism
• Side effects of phenytoin ( Cont.)
• Pharmacokinetic Interactions
– Inhibitors of liver enzymes elevate its plasma levels e.g. Chloramphenicol, INH,cimetidine.
– Inducers of liver enzymes reduce its plasma levels e.g. Carbamazipine; Rifampicin, phenobarbital.
Fosphenytoin
• A Prodrug. Given i.v. or i.m. and rapidly converted to phenytoin in the body.
• Avoids local complications associated with phenytoin: vein irritation, tissue damage, pain and burning at site, muscle necrosis with i.m. injection, need for large fluid volumes.
• Otherwise similar toxicities to phenytoin.
CARBAMAZEPINE Its mechanism of action and clinical uses are similar to that
of phenytoin. However, it is also commonly used for Rx of mania and trigeminal neuralgia.
Pharmacokineticsavailable as an oral form only Well absorbed 80 % protein bound Strong inducing agent including its own (can lead to failure of
other drugs e.g. oral contraceptives, warfarin, etc.Metabolized by the liver to CBZ 10.11-epioxide(active) and
CBZ -10-11-dihydroxide (inactive)
Pharmacokinetics of CBZ( Cont. )• Excreted in urine as glucuronide conjugate
• Plasma t1/2 approx. 30 hours
• Therapeutic plasma concentration 6-12 µg/ml (narrow).
• Dose 200-800 mg/day (given BID as sustained release form)
• Side Effects of Carbamazepine: • G.I upset• Drowziness, ataxia and headache; diplopia• Hepatotoxicity- rare• Congenital malformation (craniofacial anomalies &
neural tube defects).• Hyponatraemia & water intoxication.• Late hypersensitivity reaction (erythematous skin rashes,
mouth ulceration and lymphadenopathy. • Blood dyscrasias as fetal aplastic anemia (stop
medication); mild leukopenia (decrease the dose)
Pharmacokinetic interactions of CBZ
• Inducers of liver enzymes reduce its plasma level e.g. Phenytoin; Phenobarbital; Rifampicin
• inhibitors of liver enzymes elevate its plasma levels e.g. erythromycin,INH ,verapamil; Cimetidine
Phenobarbital Mechanism of Action:• Increases the inhibitory neurotransmitters
(e.g: GABA ) and decreasing the excitatory transmission.
• Also, it also prolongs the opening of Cl- channels.
• Absorption: rapid• Half-life: 53-118 hours (long)•
Phenobarbital• Partial seizures, effective in neonates• Second-line drug in adults due to more severe CNS
sedation• Adverse effects: CNS sedation but may produce
excitement in some patients. Skin rashes if allergic. Tolerance and physical dependence possible.
• Interactions: severe CNS depression when combined with alcohol or benzodiazapines. Stimulates cytochrome P-450
Primidone• Partial seizures• Mechanims—see phenobarbital• Absorption: Individual variability in rates. Not highly
bound to plasma proteins.• Metabolism: Converted to phenobarbital and phenylethyl
malonamide, 40% excreted unchanged.• Half-life: variable, 5-15 hours. • Adverse effects: CNS sedative• Drug interactions: enhances CNS depressants, drug
metabolism, phenytoin increases conversion to PB
Vigabatrin (restricted)
Pharmacological effects:Drug of choice for infantile spasms, Use for partial seizures and West’s syndrome.
• Not bound to proteins ,Not metabolized and excreted unchanged in urine
• Plasma t1/2 4-7 hrsSide effects: Visual field defects, psychosis and depression
(limits its use).
VIGABATRIN (-vinyl-GABA)
• 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
Lamotrigine Pharmacological effects Resembles phenytoin in its pharmacological effects Well absorbed from GIT Metabolised primarily by glucuronidation Does not induce or inhibit C. P-450 isozymes ( its metabolism is
inhibitted by valproate ) Plasma t 1/2 approx. 24 hrs.• Mechanism of Action: Inhibits excitatory amino acid release (glutamate & aspartate )
by blockade of Na channels.• Side effects: • Skin rash, somnolence, blurred vision, diplopia, ataxia,
headache, aggression, influenza – like syndrome
LAMOTRIGINE (Lamictal)
• Add-on therapy with valproic acid (w/v.a. conc. have be reduced => reduced clearance).
• Low plasma protein binding• Effective in myoclonic and generalized
seizures in childhood and absence attacks.
• Involves blockade of repetitive firing involving Na channels, like phenytoin.
Toxicity:• Dizziness• Headache• Diplopia• Nausea• Somnolenc
e• Life
threatening rash “Stevens-Johnson”
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
Gabapentin• Structural analogue of GABA .May increase the
activity of GABA or inhibits its re-uptake. Pharmacokinetics: Not bound to proteins Not metabolized and excreted unchanged in urine• Does not induce or inhibit hepatic enzymes (similar
to lamotrigine) • Plasma t ½ 5-7 hours
GABAPENTIN• Used as an adjunct in partial and
generalized tonic-clonic seizures.• 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.
Topimerate• Add-on for refractory partial or generalized seizures. Effective as monotherapy for partial or generalized seizures, Lennox-Gastaut syndrome.
• Use-dependent blockade of Na+ channels, increases frequency of GABAA channel openings, may interfere with glutamate binding to AMPA/KA receptor
• Half-life: 20-30 hours (long)• Adverse effects: CNS sedative• Drug interactions: Stimulates CYP3A and inhibits CYP2C19,
can lessen effectiveness of birth control pills
Topiramate ( Cont. )
Clinical Uses:Recently, this drug become one of the safest antiepileptics which can be used alone for partial and generalized tonic-clonic, and absence seizures.
TIAGABINE (Gabatril)• Adjunctive therapy in partial and
generalized tonic-clonic seizures• Bioavailability > 90 %• Highly protein bound ( 96% )• Metabolized in the liver• Plasma t ½ 4 -7 hrs• Mode of action: • inhibits GABA uptake and
increases its level
Toxicity:• Abdominal pain and
nausea (must be taken w/food)
• Dizziness• Nervousness• Tremor• Difficulty concentrating• Depression• Asthenia• Emotional liability• Psychosis• Skin rash
Zonisamide
Pharmacokinetics:• Well absorbed from GIT
(100 %) • Protein binding 40% • Extensively metabolized in
the liver• No effect on liver enzymes• Plasma t ½ 50 -68 hrsClinical Uses:Add-on therapy for partial
seizuresSide Effects:Drowsiness, ataxia ,
headache, loss of appetite,nausea& vomiting, Somnolence .
Levetiracetam• Add-on therapy for partial seizures• Binds to synaptic vesicle protein SV2A, may
regulate neurotransmitter release• Half-life: 6-8 hours (short)• Adverse effects: CNS depresssion• Drug interactions: minimal
Ethosuximide• Absence seizures• Blocks T-type Ca++ currents in thalamus• Half-life: long—40 hours• Adverse effects: gastric distress—pain, nausea,
vomiting. Less CNS effects that other AEDs, transient fatigue, dizziness, headache
• Drug interactions: administration with valproate results in inhibition of its metabolism
VALPROATE (Depakene)• Fully ionized at body pH, thus active
form is valproate ion.• Mechanism of action, similar to
phenytoin. • levels of GABA in brain.• Facilitates Glutamic acid
decarboxylase (GAD).• Inhibits the GABA-transporter in
neurons and glia (GAT).• [aspartate]Brain?• May increase membrane potassium
conductance.
Toxicity:• Elevated liver enzymes
including own.• Nausea and vomiting.• Abdominal pain and
heartburn.• Tremor, hair loss, • Weight gain.• Idiosyncratic hepatotoxicity.• Negative interactions with
other antiepileptics.• Teratogen: spina bifida
• Inhibits metabolism of several drugs such as Carbamazepine; phenytoin, Topiramate and phenobarbital.
• Clinical Use:–Very effective against absence, myoclonic
seizures.–Also, effective in gen. tonic-clonic siezures
(primarly Gen)– Less effective as compared to carbamazepine
for partial seizures– Like Carbamazepine also can be used for Rx of
mania
• Side Effects of Sod. valproate:• Nausea, vomiting and GIT disturbances (Start
with low doses)• Increased appetite & weight gain • Transient hair loss.• Hepatotoxicity • Thrombocytopenia• Neural Tube defect (e.g. Spina bifida) in the
offspring of women. (contraindicated in pregnancy)
Status EpilepticusStatus 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.
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.
DIAZEPAM AND LORAZEPAM
• Given I.V.• Lorazepam may be longer acting.• Have muscle relaxant activity.• Allosteric modulators of GABA
receptors.• Potentiate GABA function by
increasing the frequency of channel opening.
Toxicity• Sedation• Children may
manifest a paradoxical hyperactivity.
• Tolerance
Treatment of Seizures
PARTIAL SEIZURES ( Simple and Complex, including secondarily generalized)
Drugs of choice: Carbamazepine Phenytoin
Valproate
Alternatives: Lamotrigine, phenobarbital, primidone, oxcarbamazepine.
Add-on therapy: Gabapentin, topiramate, tiagabine, levetiracetam, zonisamide.
Treatment of Seizures
PRIMARY GENERALIZED TONIC-CLONIC SEIZURES (Grand Mal)Drugs of choice: Carbamazepine
Phenytoin Valproate*
Alternatives: Lamotrigine, phenobarbital, topiramate, oxcartbazepine, primidone, levetiracetam.
*Not approved except if absence seizure is involved
Treatment of SeizuresGENERALIZED ABSENCE SEIZURES
Drugs of choice: Ethosuximide Valproate*
Alternatives: Lamotrigine, clonazepam, zonisamide, topiramate (?).
* First choice if primary generalized tonic-clonic seizure is also
present.
Treatment of SeizuresATYPICAL ABSENCE, MYOCLONIC, ATONIC*
SEIZURESDrugs of choice: Valproate
ClonazepamLamotrigine**
Alternatives: Topiramate, clonazepam, zonisamide, felbamate.
* Often refractory to medications.
**Not FDA approved for this indication. May worsen myoclonus.
Treatment of Seizures
INFANTILE SPASMS
Drugs of choice: Corticotropin (IM) or Corticosteroids (Prednisone)
Zonisamide
Alternatives: Clonazepam, nitrazepam, vigabatrin, phenobarbital.
Treatment of Seizures in PregnancyPhenytoin PhenobarbitalCarbamazepine Primidone
They may all cause hemorrhage in the infant due to vitamin K deficiency, requiring treatment of mother and newborn.
They all have risks of congenital anomalies (oral cleft, cardiac and neural tube defects).
Teratogens: Valproic acid causes spina bifida. Topiramate causes limb agenesis in rodents and hypospadias in male infants.
Zonisamide is teratogenic in animals.
INTERACTIONS BETWEEN ANTISEIZURE DRUGS
With other antiepileptic Drugs:- Carbamazepine with
phenytoin Increased metabolism of carbamazepinephenobarbital Increased metabolism of epoxide.
- Phenytoin withprimidone Increased conversion to phenobarbital.
- Valproic acid withclonazepam May precipitate nonconvulsive status
epilepticusphenobarbitalDecrease metabolism, increase toxicity.phenytoin Displacement from binding, increase
toxicity.
ANTISEIZURE DRUG INTERACTIONS
With other drugs:antibiotics phenytoin, phenobarb, carb.anticoagulants phenytoin and phenobarb
met.cimetidine displaces pheny, and BDZsisoniazid toxicity of phenytoinoral contraceptives antiepileptics metabolism.salicylates displaces phenytoin and v.a. theophyline carb and phenytoin may
effect.
Table 2. Proposed Mechanisms of Antiepileptic Drug Action
↓Na+ ↓Ca+ ↓K+ ↑ Inh. ↓Excitatorychannels channels channels transmission transmission
________________________________________________________________________________Established AED’sPHT +++CBZ +++ESM +++PB + +++ +BZD’s +++VPA + + ++ +
New AED’sLTG +++ +OXC +++ + +ZNS ++ ++VGB +++TGB +++GBP + + ++FBM ++ ++ ++ ++TPM ++ ++ ++ ++LEV + + +________________________________________________________________________________+++ primary action, ++ possible action, + probable action.From P. Kwan et al. (2001) Pharmacology and therapeutics 90:21-34. [Data from Upton (1994), Schachter (1995), McDonald and Kelly (1995), Meldrum (1996), Coulter (1997), and White (1999).]
Weight Issues• Risk of weight gain– Valproate – Gabapentin and
pregabalin
• “Risk” of weight loss– Topiramate – Zonisamide – Felbamate
Drugs that decrease efficacy of oral contraceptives
• Phenytoin • Carbamazepine • Phenobarbital• Primidone • Topiramate at
higher doses• Oxcarbazepine
Lifestyle changes to minimize seizures
• Avoid sleep deprivation
• Avoid alcohol• Treat fevers quickly• Occasional patients
should avoid specific factors such as strobe lights, etc
• Pill boxes/reminders
Herbal meds reported to worsen seizures
• Bearberry• Black cohosh• Borage• Damiana• Echinacea• Ephedra*• Ergot• Evening Primrose Oil• Gingko (prob safe)• Ginseng• Goldenseal• Green Tea• Guarana
• Histalet Forte• Kava Kava• Ma Huang*• Metabolife• Monkshood• Phen-Fen*• Sage• St. John’s Wort• Uva-Ursi• Water-hemlock• European water hemlock• Wormwood• Yohimbe
Herbal meds with significant interactions with seizure meds
• Chamomila• Choke cherry• Comfrey• Dillapiol• Echinacea• Eucalyptus Oil• Grapefruit juice• Licorice• Mentat• Nicotinamide• Paeoniae radix
• Piperine• Psyllium• Pyrrolizidine• Sage• St. John’s Wort• Septilin• Shankapushpi• Sho-seiryu-to• Wild cherry