Psychiatry drugs pdf - غير معروف

ANTI-EPILEPTIC DRUGS

Dr.Nasser A. H. Al-Harchan

Asst. Prof. of Pharmacology

College of Medicine

Baghdad University

introduction

Seizure

• Seizures

are

sudden,

transitory,

and

uncontrolled episodes of brain dysfunction
resulting from abnormal discharge of neuronal
cells with associated motor, sensory or
behavioral changes.

Epilepsy

• A group of chronic CNS disorders

characterized by recurrent seizures.

Classification of Epileptic Seizures

I. Partial (focal) Seizures

A. Simple Partial Seizures
B. Complex Partial Seizures
C. Partial with secondary generalized tonic

classic seizure

II. Generalized Seizures

A. Generalized Tonic-Clonic Seizures
B. Absence Seizures
C. Myoclonic Seizures

Pathological Basis

Abnormal electrical discharge in the brain

Coordinated activity among neurons depends on a
controlled balance between excitation and inhibition

Any local imbalance will lead to a seizure

Imbalances occur between glutamate-mediated
excitatory neurotransmission and gamma-
aminobutyric acid (GABA) mediated inhibitory
neurotransmission

Generalised epilepsy is characterised by disruption
of large scale neuro-networks in the higher centres.

Strategies in Treatment

• Stabilize membrane and prevent

depolarization by action on ion channels

• Increase GABAergic transmission

• Decrease EAA (Excitatory Amino Acid)

Transmission

Classification of Anticonvulsants

Classical

• Phenytoin
• Phenobarbital
• Primidone
• Carbamazepine
• Ethosuximide
• Valproic Acid
• Trimethadione

Newer

• Lamotrigine
• Felbamate
• Topiramate
• Gabapentin
• Tiagabine
• Vigabatrin
• Oxycarbazepine
• Levetiracetam
• Fosphenytoin
• Others

Phenytoin

• Limited water solubility – not given i.m.
• Slow, incomplete and variable absorption.
• Extensive binding to plasma protein.
• Metabolized by hepatic ER by hydroxylation.

Chance for drug interactions.

• Therapeutic plasma concentration: 10-20 µg/ml
• Shift from first to zero order elimination within

therapeutic concentration range.

Phenytoin – Toxicity and

Adverse Events

Acute Toxicity

• High i.v. rate: cardiac arrhythmias ±

hypotension; CNS depression.

• Acute oral overdose: cerebellar and

vestibular symptoms and signs:

nystagmus, ataxia, diplopia vertigo.

Chronic Toxicity

• Dose related vestibular/cerebellar effects
• Behavioral changes
• Gingival Hyperplasia
• GI Disturbances
• Sexual-Endocrine Effects:

– Osteomalacia
– Hirsutism
– Hyperglycemia

Phenytoin – Toxicity

Chronic Toxicity

• Folate Deficiency - megaloblastic anemia
• Hypoprothrombinemia and hemorrhage in newborns
• Hypersenstivity Reactions – could be severe. SLE,

fatal hepatic necrosis, Stevens-Johnson syndrome.

• Pseudolymphoma syndrome
• Teratogenic
• Drug Interactions: decrease (cimetidine, isoniazid) or

increase (phenobarbital, other AED’s) rate of
metabolism; competition for protein binding sites.

Phenytoin – Toxicity and

Adverse Events

Carbamazepine (Tegretol)

• Second - most commonly prescribed

anticonvulsant

• Structurally related to tricyclic

antidepressants

• Uses:

– partial and tonic-clonic seizures
– neuropathic pain management
– Schizophrenia, bipolar disorder

• May be used in combination with Dilantin

or Phenobarbital

Ø all types except absence seizures; particularly useful for

generalized tonic-clonic, simple and complex partial

Ø inhibition of voltage-gated Na

channels

Ø oral, slow and erratic, 75% plasma protein bound; t

1/2

=36 hrs

initially, decreasing to 20 hrs following continuous therapy
(autoinduction), active metabolite excreted

Ø diplopia and ataxia, GI upset, hypersensitivity, serious toxicity

including aplastic anemia, agranulocytosis

Ø drug interactions are many, related to the hepatic enzyme

inducing properties of carbamazepine

Carbamazepine (Tegretol)

• Toxicity similar to phenytoin
• Adverse effects

– CNS:

• Restlessness, irritability, agitation
• Dizziness, confusion, ataxia, encephalopathy

– Renal

• Renal failure, urinary frequency
• Water retention (stimulates ADH)

– Visual changes

Carbamazepine (Tegretol)

• Agranulocytosis
• Lupus
• Arrhythmia & cardiac conduction

abnormalities

• Toxicity: bone marrow depression, hepatic

dysfunction, visual changes

Carbamazepine (Tegretol)

• Numerous drug interactions
• Erratically absorbed, better absorption on

full stomach

Phenobarbital

• The only barbiturate with selective anticonvulsant effect.
• Bind at allosteric site on GABA receptor and ↑ duration

of opening of Cl channel.

• ↓

Ca-dependent release of neurotransmitters at high doses.

• Inducer of microsomal enzymes – drug interactions.
• Toxic effects: sedation (early; tolerance develops); nystagmus &

ataxia at higher dose; osteomalacia, folate deficiency and vit. K
deficiency.

• In children: paradoxical irritability, hyperactivity and behavioral

changes.

• Deoxybarbiturates: primidone: active but also converted to

phenobarbital. Some serious additional ADR’s: leukopenia,

SLE-like.

Valproic Acid

• Effective in multiple seizure types.
• Blocks Na and Ca channels. Inhibits GABA

transaminase. Increases GABA synthesis.

• Toxicity: most serious: fulminant hepatitis. More

common if antiepileptic polytherapy in children <
2 years old. (?) Toxic metabolites involved.

• Drug interactions: inhibits phenobarbital and

phenytoin metabolism.

Ethosuximide

• Second - most commonly prescribed Drug of

choice for Absence. Blocks Ca++ currents (T-
currents) in the thalamus.

• Not effective in other seizure types
• GI complaints most common
• CNS effects: drowsiness lethargy).
• Has dopamine antagonist activity (? In seizure

control) but causes Parkinsonian like symptoms.

• Potentially fatal bone marrow toxicity and skin

reactions (both rare)

Benzodiazepines

• Diazepam (Valium) IV, IM
• Lorazepam (Ativan) IV

– Used to terminate status epilepticus
– Close medical supervision & resuscitative

equipment should be available

qpotentiates GABAA receptor function via a distinct

allosteric binding site on the protein termed the
benzodiazepine receptor. ↑ frequency of opening of Cl
channel.

Benzodiazepines

Ø diazepam (i.v.)- drug of choice for the treatment of status

epilepticus

Ø clonazepam and clorazepate- long-term treatment of absence,

myoclonic,

akinetic

and

atonic

seizures;

tolerance

anticonvulsive

action

limits

clinical

usefulness

benzodiazepines

Ø potentiates GABA

receptor function via a distinct allosteric

binding site on the protein termed the benzodiazepine receptor

Ø oral, t

1/2

: clonazepam=1 day; clorazepate=2 hrs; i.v. diazepam=1-

2 days); very high plasma protein binding, N-desmethyldiazepam

1/2

=3 days) is active metabolite of diazepam and clorazepate,

clonazepam is primarily reduced to inactive metabolites

Ø sedation, ataxia; hyperactivity and irritability in children; high

therapeutic index, low incidence of toxicity

Ø additive or synergistic effects with other sedative hypnotics

Enhancers of GABA Transmission

• Gabapentin: Developed as GABA analogue.

Mechanism: Increases release of GABA by
unknown mechanism.

• Vigabatrin: Irreversible inhibitor of GABA

transaminase. Potential to cause psychiatric
disorders (depression and psychosis).

• Tiagabine: decreases GABA uptake by

neuronal and extraneuronal tissues.

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