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ANTISEIZURE DRUGS
OR
Antiepileptic drugs
Epilepsy Chronic disorder characterized by recurrent seizures
Seizures is a sudden, excessive, abnormal discharge of cerebral neurons
Causes of seizures Heredity – major contributing factor may occur due to infection, neoplasm or head injury Environmental causes-alteration in blood gases, pH,
electrolytes, or glucose availability
Seizure classified into two broad groups
Partial: simple or complex
Generalized: absence, tonic, clonic, tonic-clonic, myoclonic, febrile
PARTIAL SEIZURES
Simple partial seizures (without loss of consciousness) confined to a single locus in brain abnormal activity in one limb or muscles With autonomic symptoms (nausea, blood pressure
changes,...)
Complex partial seizures (with loss of consciousness) Simple partial followed by a loss of consciousness Impaired consciousness from the onset Exhibits complex sensory hallucination Motor dysfunction may involve chewing movements,
diarrhea or urination
Generalized seizures
Electrical discharge spread to both hemisphere May be convulsive (shaken repeatedly) or non
convulsive Immediate loss of consciousness occurs Types
generalized tonic-clonic (grand mal) seizures
absence (petit mal) seizurestonic seizuresatonic seizuresclonic and myoclonic seizuresfebrile seizures
======================= Partial Seizures localized onset of attack ascertained, either by
clinical observation or by EEG – attack begins in a specific locus in brain
Simple Partial seizures – least complicated, characterized by minimal spread of abnormal discharge, normal consciousness and awareness are preserved – pt may have a sudden onset of clonic jerking of an extremity lasting 60-90 secs; residual weakness lasts for 15-30 mins after attack.
Pt completely aware of attack, can describe it in detailEEG may show an abnormal discharge highly localized to the involved portion of brain
=======================Complex Partial seizures – localized onset, discharge becomes more widespread (usually bilateral) and almost always involves limbic systemmost (not all) CPS arise from one of the temporal lobes, possibly because of the susceptibility of this area to insults such as hypoxia or infection
Clinically, pt may have a brief warning followed by an alteration of consciousness during which some pts may stare and others may stagger or even fallMore, however, demonstrate fragments of integrated motor behavior called automatisms for which pt has no memoryafter 30-120 secs, pt makes a gradual recovery to normal consciousness but may feel tired or ill for several hours after attack
Generalized Seizures Tonic-clonic seizures
characterized by tonic phase continuous rigidity of all extremities
clonic phase massive jerking of body ( rapid contraction and relaxation)
Tongue or cheek bitten, urinary incontinence common Seizure followed by period of confusion and exhaustion
due to depletion of energy
Absence seizure (petit mal) Typical absence seizures consists of staring for a
few seconds (altered consciousness) then returning to full function, as if nothing occurred
Brief duration (< 10 secs) ass with mild clonic jerking of eyelids, patient
stares & exhibit rapid eye blinking begin in childhood or adolescence and may occur
up to hundreds of times a day
The patient has no recollection of the event.
Myoclonic seizures Myoclonic jerking – seen in generalized tonic-
clonic seizures, partial seizure, absence seizures, and infantile spasms
Short episode of muscle contractions
Occurs due to permanent nurologic damage due to hypoxia, uremia, encephalitis or drug poisoning
Atonic seizures
sudden loss of postural tone, if standing pt falls suddenly and may be injured, if seated, may suddenly drop forward
Infantile spasms characterized clinically by brief recurrent
myoclonic jerks of body with sudden flexion or extension of the body and limbs
90% of affected pts have their 1st attack before age of 1 yr
Most pts mentally retarded cause infection, kernicterus and hypoglycemia
Febrile fits Frequently occurs in young children (6 months- 6
yrs) during high grade fever Characterized by tonic clonic convulsions of short
duration (1 to 5 min), eye rolling & unresponsiveness
Benign, do not cause death, nurologic damage, injury, or learning disorder
Status epilepticus Continuous, rapid, recurrent seizures
Antiepileptic drugs
Primary drugs Phenytoin Carbamazepine Clonazepam (BZ) Clorazepate (BZ) Diazepam (BZ) Ethosuximide Lorazepam (BZ) Phenobarbital Primidone Valproic acid
Adjunct drugs Fel bamate Gaba pentin Lamo trigine Leve tira cetam Tiaga bine Topira mate Zoni samide Viga batrin
Pathophysiology of Seizures
Increased CNS excitability
Membrane depolarization Increased excitatory input Decreased inhibitory (GABA) input
Strategies in Treatment
Stabilize membrane by blockade of voltage gated channels (Na & Ca) prevent depolarization by action on ion channels
Increase GABAergic transmission
Decrease Excitatory glutamate transmission
Classification of Anticonvulsants
Action on Ion Channels
Enhance GABA
Transmission
Inhibit glutamate
Transmission
Na+:
Phenytoin, Carbamazepine, Lamotrigine
Topiramate
Valproic acid
Ca++:
Ethosuximide
Valproic acid
Benzodiazepines
Barbiturates
Valproic acid
Gabapentin
Vigabatrin
Topiramate
Felbamate
Felbamate
Topiramate
Phenytoin Diphenylhydantoin – oldest antiseizure drug
Mechanism of action. Blocks voltage gated Na+ channels in inactive state,
slows recovery blocks repetitive firing of action potentials, promotes
stabilization of membrane, reduce propagation of abnormal impulse in brain
At higher dose blocks Ca 2+ conductance Interfere with release of neurotransmitters
norepinephrine, acetylcholine Produces drowsiness and lethargy
Phenytoin /Clinical use
Highly effective in Partial seizures (simple and complex) Tonic-clonic seizures Status epilepticus Arrhythmia
Not effective in absence seizures
Phenytoin /Adverse effects Depression of CNS Sedation, Nystagmus,
diplopia and ataxia, confusion & hallucination Reversible Gingival hyperplasia and hirsutism GIT nausea & vomitingLong term use Coarsening of facial features occurs in children Mild peripheral neuropathy deep tendon
reflexes in lower extremities Osteomalacia due to abnormalities of vitamin D
metabolism
Phenytoin /Adverse effects Megaloblastic anemia due to folate
deficiency Inhibition of antidiuretic hormone
secretion Hyperglycemia and glycosuria
insulin secretion Teratogenic effects fetal
hydantoin syndrome includes cleft lip, cleft palate, congenital heart disease, growth retardation and mental deficiency
Phenytoin/ Drug Interactions
Phenytoin metabolism decrease by Cimetidine, isoniazid, Chloramphenicol, dicumarol, sulfonamide
Phenytoin metabolism increase by Carbamazepine
Carbamazepine
M.O.A By blocks sodium channels reduce the
propagation of abnormal impulses inhibits high-frequency repetitive firing in neurons decrease synaptic transmission, inhibits uptake
and release of NE from brain postsynaptic action of GABA potentiated
Carbamazepine /Clinical use
Drug of choice in all partial seizures Highly effective in tonic–clonic seizures Trigeminal neuralgia Use in Manic depressive patient to decrease
the symptoms
Carbamazepine Adverse effects
Respiratory depression Drowsiness, vertigo, diplopia, blurred vision,
ataxia & coma Irritating to stomach n & v may occurs Serious liver toxicity hyponatremia and water intoxication Idiosyncratic blood dyscrasias,including fatal
cases of aplastic anemia and agranulocytosis Is an enzyme inducer
Drugs inhibiting metabolism of Carbamazepine
Cimetidine Diltiazem Erythromycin Isoniazid Propoxyphene
Phenobarbital clinically useful as antiseizure drugs
phenobarbital, mephobarbital, metharbital,
Mechanism of Action Elevate seizure threshold Limits the spread of seizure discharge in brain Binds to a regulatory site on GABA receptor,
prolonging the openings of Cl- channels Blocks excitatory responses induced by glutamate
Phenobarbital/ clinical uses
Doc in children with febrile fits Effective in simple partial seizures Recurrent tonic clonic seizures Relieve anxiety insomnia
Phenobarbital adverse effects Sedation Ataxia Nystagmus Vertigo N &v Morbilliform rash (measles like) Agitation & confusion Rebound seizures can occur on discontinuation of
drug
Primidone
2-deoxyphenobarbital Metabolized to Phenobarbital and phenyl-
ethyl-malonamide All 3 are active anticonvulsants M.O.A. – similar to Phenobarbital Effective against partial and tonic clonic
seizures
Valproic acid
Drug of choice for myoclonic seizures Effective in tonic clonic & absence seizures Block sodium channels & enhance
GABAergic transmission Adverse effects N, V, ataxia, sedation,
tremors, rash & alopecia
Ethosuximide
Inhibit T-type calcium channels in brain reduce propagation of abnormal electrical activity
First choice in absence seizures
Benzodiazepines Benzodiazepines are safest antiepileptic drugs Clonazepam use for chronic treatment of
absence & myoclonic seizures Chlorazepate effective in partial seizures Diazepam & lorazepam drug of choice in
acute treatment of status epilepticus (interrupt repeated seizures)
A/E sedation, drowsiness, fatigue, ataxia, respiratory and cardiac depression
Adjunct antiepileptic drugs
Newer agents Use as add on therapy in refractory
epilepsies Also effective as monotherapy
Lamotrigine
M.O.A. –blocks sodium channels, voltage activated calcium channels & decreased synaptic release of glutamate
Add on therapy, monotherapy for partial seizures, absence and myoclonic seizures in children
Dizziness, headache, diplopia, nausea, somnolence, and skin rash – potentially life-threatening dermatitis develops in 1-2% of pediatric pts
Felbamate
Broad spectrum Use only in refractory cases (may cause
aplastic anemia & hepatic failure) block sodium channels & inhibits glycin &
glutamate transmission Effective in partial seizures
Gabapentin Amino acid, analog of GABA, effective against
partial seizures M.O.A. – in spite of its close structural
relationship to GABA, it appears not to act on GABA receptors, interfere with voltage gated calcium channels
Used in Partial and G tonic clonic seizures, diabetic neuropathic pain, postherpetic neuroralgia in adults
To-pira-mate
Effective in refectory partial and secondary generalized seizures
M.O.A. Blocks voltage dependent sodium channels Potentiate inhibitory effect of GABA,
acting at a site different from BNZs or barbs
Ti-aga-bine M.O.A. – inhibitor of GABA uptake Prolongs inhibitory action of synaptically released
GABA Indicated for adjunctive treatment of partial
seizures
Zonisamide
Primary site of action is on sodium channel Also act on voltage dependent calcium
channels Effective against partial and G tonic clonic
seizures, also against infantile spasms and certain myoclonias
S/E – drowsiness, cognitive impairment, serious skin rashes
Levetiracetam
M.O.A. – unknown Effective for the treatment of refectory
partial seizures S/E – somnolence, asthenia, dizziness
Acetazolamide
Inhibits carbonic anhydrase Mild acidosis in brain – mech by which
drug exerts its antiseizure activity Used for all types of seizures Use severely limited by rapid development
of tolerance usually within weeks
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