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Drugs acting on CNS

Epilepsy

• It is a condition due to too many brain cells over excited in a given time
• Group of disorder characterized by paroxysmal cerebral dysrhythmia
manifesting as brief episodes of seizures
• Types :
• Generalized – neuronal overactivity widespread
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Generalised tonic clonic seizures (GTCS) – grand mal
Absence seizures – petit mal
Atonic seizures
Myoclonic seiures
Infantile spasms

• Partial – neuronal overactivity in one part of brain
• Simple partial – without loss of consciousness
• Complex partial –with loss of consciousness

Let’s read this scenario
• A 12 year old boy was a known case of epilepsy who is currently
receiving treatment with sodium valproate
...
There he was given Diazepam per rectally which caused
his seizure to be arrested
...
Enhancement of GABA action – Cl- channel opening
• Barbitrates, benzodiazepines – facilitate GABA function
• Gabapentin – GABA analogue
• Vigabatrin, valproate – inhibit GABA breakdown by GAA transaminase

2
...
Inhibition of Ca2+ channel function
• Ethosuximide, trimethadione

Carbamazepine
• MoA
• Chemically related to tricyclic antidepressant ; pharmacologically to phenytoin
• Clinical benefit in treatment of
• Partial seizures
• Mania and manic depression, bipolar disorder
• Trigeminal neuralgias

• Properties of carbamazepine
• Given orally
• It is a strong inducer of hepatic enzymes
• Some metabolites also have antiepileptic properties

• What are the unwanted effects with their use?
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Drowsiness, dizziness and ataxia, vertigo
Severe mental and motor disturbances
Water retention – hyponatraemia
Gastrointestinal and cardiovascular side effects
Bone marrow depression (neutropenia), hypersensitivity (rashes,
photosensitivity, hepatitis)
• Acute intoxication – coma, convulsion, collapse
• Hepatic enzyme induction
• accelerates the metabolism of many drugs – phenytoin, oral contraceptives, warfarin and
corticosteroids

Phenytoin
• MoA
• Stabilization of neuronal membrane – prolong inactive state of Na+ channels
• Prevents repetitive detonation of normal brain cells
• High frequency discharges are reduced

• Properties
• Given orally, >80% plasma protein bound
• Metabolized in liver – excreted as glucoronide
• Variable plasma concentration – use with other drugs affects its plasma protein
binding as well as hepatic clearance
• Complex pharmacology and many side effects has limited its use today

• What are the problems with phenytoin use?
• In therapeutic use
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Gum hypertrophy
Hirsuitism, acne, hypersensitivity reactions
Megaloblastic anemia
Osteomalacia, hyperglycemia
Teratogenesis – fetal hydantoin syndrome

• At high plasma levels
• Cerebellar and vestibular manifestation – ataxia, vertigo, diplopia, nystagmus
• Drowsiness, behavioral alteration, confusion
• Cardiac arrhythmias, hypotension

Valproate
• MoA
• Frequency dependent Na+ channel inactivation
• GABAergic inhibition – by increasing GABA levels and inhibiting catabolism by GABA
transaminase
• Inhibit T type Ca2+ channels

• Properties and uses
• Broad spectrum anticonvulsant action effective in all types of seizures – main se in
generalized seizures
• Also in
• Partial seizures
• Myoclonic and atonic seizures
• Mania and bipolar disorder

• What are the side effects with valproate use?
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They have relatively low toxicity
Anorexia, vomiting, heartburn
Alopecia, thinning and curling of the hair
Dose related drowsiness, ataxia, tremors
Serious – hepatotoxicity, hepatitis
Teratogenic – spina bifida and other neural tube defects

Ethosuximide
• MoA
• Reduction of propagation of abnormal electrical activity in brain
• By inhibiting T type Ca2+ channels
• Blocks high voltage current

• Use

• Effective in treatment of absence seizures

• Side effects

• Nausea and anorexia, lethargy and dizziness
• Precipitate tonic–clonic seizures in susceptible patients
• Rare – severe hypersensitivity reactions

Phenobarbitone
• MoA
• Action on GABA-A receptors- inhibition of neuronal activity
• Additional effects on Ca2+ channels and glutamate release
• High anticonvulsant activity – increase seizure threshold, limit spread

• Limitations
• Sedative effect
• Long term use – behavioral abnormalities, diminution of intelligence,
impairment of learning and memory (so not used now)
• Megaloblastic anaemia, hypersensitivity reactions, osteomalacia – can occur
• Respiratory and cardiovascular depression

Benzodiazepines
• MoA : potentiate GABAergic inhibition
• Used in management of both acute seizures as well as in status epilepticus
• Clonazepam has additional Ca2+ channel blocking actions

• Agents
• Lorazepam, diazepam, clonazepam – intravenously
• Diazepam – per rectally

• Side effects
• Sedation, dullness
• Withdrawal symptoms – exacerbation of seizures if drug stopped suddenly

• Other uses
• Absence seizures, adjuvant in other forms of seizures

Newer antiepileptics
• Vigabatrin
• Irreversible inhibitor of the GABA-metabolising enzyme GABA transaminase
• Use – mainly in infantile spasms
• Side effects – depression, psychotic disturbances and hallucinations

• Lamotrigine

• Drug that resembles phenytoin and carbamazepine in its pharmacological effects
• Use in absence seizures as well as in other unrelated psychiatric disorders
• Side effects – nauseaa, dizziness, ataxia, hypersensitivity reactions

• Gabapentin / pregabalin
• GABA analogues used in management of partial seizures
• Side effects – sleepiness, headache, fatigue, dizziness, weight gain

• Topiramate
• Multiple mechanisms
• Blocking sodium and calcium channels
• Enhancing the action of GABA
• Weakly inhibiting carbonic anhydrase

• Mainly used as add-on therapy in refractory cases of partial and generalised seizures

• Levetiracetam
• Cognitive enhancer with antiepileptic properties
• Side effects – headaches, inflammation of the nose and throat, sleepiness, vomiting and
irritability

• Antiepileptics in pregnancy
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Lamotrigine
Sodium valproate in I trimester
Carbamazepine is relatively safe
Monotherapy is preferred
Folic acid 5mg is taken to prevent neural tube defects

Antiepileptics and clinical use
• Generalized tonic–clonic seizures – Valproate
• Other drugs – phenytoin , carbamazepine
• , Use of a single drug is preferred

• Partial (focal) seizures – carbamazepine
• Others – valproate
• Alternatives – clonazepam, phenytoin, gabapentin, pregabalin, lamotrigine

• Absence seizures – ethosuximide
• Other drugs – valproate, lamotrigine

• Myoclonic seizures and status epilepticus – diazepam IV or rectally
• Others
• Neuropathic pain – carbamazepine, gabapentin
• Mood stabilizers in mono or bipolar affective disorder – carbamazepine, valproate



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