Antiseizure Drugs

1
Antiseizure Drugs

• By
• S. Bohlooli, PhD

2
SEIZURE DISORDERS

• Seizures are self sustained (but self-limiting)
  episodes of neural hyperactivity.
• - During a seizure some neurons of the brain
  begin to fire in massive synchronized bursts (a
  paroxysmal high-frequency, or synchronous
  low-frequency, high voltage electrical
  discharge).
• .- Convulsive seizures, the most common form of
  attacks, begin with tonic or clonic jerking of
  all extremities with loss of consciousness.

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• Etiology
• - Hyperpyrexia (acute infections, heat stroke,
  etc)
• - CNS infections (meningitis, encephalitis, AIDS,
  brain abscess, neurosyphilis, rabies, falciparum
  malaria, toxoplasmosis, etc)
• - Expanding brain lesions (neoplasm, intracranial
  hematoma, etc)
• - Brain defects (congenital, developmental)
• - Cerebral trauma (skull fractures, birth injury,
  etc)
• - Cerebral hypoxia (Adams-Stokes syndrome,
  anesthesia, carotid sinus hypersensitivity, CO
  poisoning, etc)
• - Cerebral edema (hypertensive encephalopathy,
  etc)
• - Cerebral infarct or hemorrhage
• - Metabolic disturbances (hypoglycemia,
  hypoparathyroidism, etc)
• - Toxic agents (cocaine, antihistamines,
  tricyclic antidepressant, salicylates, xanthines,
  atropine-like drugs, etc lead, solvents,
  insecticides, etc.)
• - Abstinence syndrome (alcohol, barbiturates,
  etc)
• - Anaphylaxis

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EPILEPSY

• Definition
• Epilepsy is a chronic recurrent disorder of
  cerebral function characterized by spontaneous,
  sudden brief attack of altered consciousness,
  motor activity, sensory phenomena or
  inappropriate behavior. The disorder is always
  associated with abnormalities in the EEG.

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• Pathogenesis
• - A portion of dysfunctional tissue in the brain
  discharges synchronously in response to
  endogenous or exogenous stimuli.
• - The spread of the discharge to other parts of
  the brain results in convulsive phenomena.
• - In primary generalized epilepsy the seizures
  are generalized from the outset, beginning as a
  diffuse synchronous discharge affecting all
  cerebral areas simultaneously.

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• - Seizures themselves do not equal epilepsy.
  Given a sufficient stimulus even a normal brain
  can discharge in a diffusely synchronous fashion
  and produce a seizure.
• This chronic low seizure threshold may result
  from several mechanisms including
• a) changes in intrinsic voltage-dependent
  membrane current.
• b) attenuation or loss of pre and/or postsynaptic
  inhibition (mainly due to a genetic or
  postpathologic hypofunction of GABA neurons).
• c) increased effectiveness of excitatory synapses
  (mainly due to a genetic or postpathologic
  hyperfunction of N-methyl-D-aspartate and
  glutamate neurons).

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CLASSIFICATION OF EPILEPTIC SEIZURES

• PARTIAL SEIZURES
• (focal, local)
• Simple partial seizures (focal cortical)
• - Specific motor, sensory, autonomic, or
  psychomotor focal phenomena without loss of
  consciousness (the symptom of each seizure type
  is often an index of the site of brain
  dysfunction)
• Complex partial seizures (psychomotor, temporal
  lobe)
• - Stereotyped purposive movements and bizarre
  behavior accompanied by, mental distortion,
  complex sensory hallucinations, disturbed
  consciousness and strong emotional responses.
• Partial seizures secondary generalized
• - These seizures begin locally bur they rapidly
  spread throughout the entire brain (loss of
  consciousness is usually immediate).

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GENERALIZED SEIZURES

• Generalized tonic-clonic seizures (grand mal)
• - Unconsciousness with dramatic tonic-clonic
  convulsions, followed by a period of confusion
  and exhaustion.
• Absence seizures (petit mal)
• - Brief period (10-30 sec) of unconsciousness,
  with eye or muscle fluttering at a rate of 3/sec,
  and with or without loss of muscle tone.
• Atonic (akinetic) seizures
• - Brief periods of complete loss of postural tone
  with sagging of the head or falling.
• Myoclonic seizures
• - Isolated myoclonic jerks that may reoccur for
  several minutes.
• Infantile spasms (West's syndrome)
• - Very brief (5-10 sec) sudden flexion of the
  arms, forward flexion of the trunk, and extension
  of the legs. The syndrome is accompanied by a
  progressive mental retardation.

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ANTISEIZURE DRUGS

• The inhibition of seizure activity in the CNS is
  accomplished without major disturbances in the
  normal electrical activity.
• In fact antiseizure drugs inhibit sustained,
  high-frequency, repetitive firing much more
  effectively than low-frequency, non-repetitive
  firing.

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• Antiseizure drugs do not cure epilepsy they just
  suppress seizures on a temporary basis. Therefore
  most patients must take them daily for life.
• Antiseizure drugs frequently cause adverse
  effects that are usually mild. However most
  antiseizure drugs may cause occasionally
  life-threatening adverse reactions.

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The mechanisms of action of antiseizure drugs are
still not well understood but have been found to
concern mainly

• a) voltage-operated ion channels
• b) inhibitory and excitatory synaptic functions

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Chemical class Generic name Trade name
Hydantoins Phenytoin Mephenytoin Ethotoin Dilantin, etc Mesantoin Peganone
Iminostilbenes Carbamazepine Oxcarbazepine Tegretol
Barbiturates and Desoxybarbiturates Phenobarbital Mephobarbital Methabarbital Primidone Luminal, etc Mebaral Gemonil Mysoline
Valproates Valproic acid Sodium valproate Depakene Depakote
Succinimides Ethosuximide Phensuximide Methsuximide Zarontin Milontin Celontin
Oxazolidinediones Trimethadione Paramethadione Tridione Paradione
Benzodiazepines Diazepam Lorazepam Clonazepam Clorazepate Valium, etc Ativan Klonopin Transene
GABA-ergic drugs Gabapentin Vigabatrin Tiagabine Neurontin Sabril Gabitril
Others Acetazolamide Felbamate Lamotrigine Topiramate Diamox Felbatol Lamictal Topamax
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PHENYTOIN PHARMACODYNAMICS

• Mechanism of action
• - Frequency-dependent and voltage-dependent
  blockade of inactivated Na channels (likely the
  main mechanism).
• - Blockade of post-tetanic potentiation.
• - Blockade of Ca channels (after high doses)
• - Alteration of synaptic concentrations of many
  neurotransmitters (after high doses).
• Effects
• - Prevention of the spread of excitation from
  seizure focus (the excessive discharge of the
  neurons of the focus is not prevented and
  therefore aura and EEG alterations are not
  eliminated)
• - Cerebellar-vestibular stimulation (with high
  doses)
• the drug is not a general CNS depressant and can
  cause excitation in several brain neurons
• - Analgesic effect in some type of neuropathic
  pain.

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Chemical strucutre
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PHENYTOIN PHARMACOKINETICS

• ABSORPTION
• - Oral bioavailability 90 (absorption speed
  depends on pharmaceutical preparation)
• - Oral Tmax 3-12 hours.
• DISTRIBUTION
• - Bound in plasma 90
• - Vd (70 Kg) 45 L
• - Concentration in the cerebrospinal fluid is
  equal the unbound concentration in plasma
• BIOTRANSFORMATION
• - 98 by the liver (biotransformation rate is
  low).
• EXCRETION
• - lt 2 by the kidney.
• Total Clearance concentration-dependent
• Half-life concentration-dependent
• plasma concentrations lt 10 mcg/mL 6-24
  hours
• plasma concentrations gt 10 mcg/mL 48-72
  hours

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PHENYTOIN INTERACTIONS PHENYTOIN INTERACTIONS PHENYTOIN INTERACTIONS
PC of phenytoin are increased by PC of phenytoin are decreased by Phenytoin decreases PC of
Chloramphenicol(2) Cimetidine (2) Warfarin (2) Isoniazid (2) Estrogens (2) Sulfonamides (3) Phenylbutazone (3) Valproic acid (2)(3) Fluoxetin (2) Alcohol (1) Carbamazepine (1) Barbiturates (1)(4) Rifampin (1) Quinidine (1) Estrogens (1) Corticosteroids(1) Methadone (1) Levodopa (1) Carbamazepine (1) Theophylline (1) Vit D (1)
PC plasma concentrations (1) stimulation of metabolism (induction of P-450 system) (2) inhibition of metabolism (3) displacement from plasma proteins (4) inhibition of intestinal absorption PC plasma concentrations (1) stimulation of metabolism (induction of P-450 system) (2) inhibition of metabolism (3) displacement from plasma proteins (4) inhibition of intestinal absorption PC plasma concentrations (1) stimulation of metabolism (induction of P-450 system) (2) inhibition of metabolism (3) displacement from plasma proteins (4) inhibition of intestinal absorption
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PHENYTOIN TOXICITY (1)

• Central nervous system
• - Nystagmus (frequent), diplopia, ataxia,
  dyskinesia, vertigo, tremor, hyperreflexia,
  blurring of vision.
• - Hyperactivity, nervousness, silliness.
• - Sedation, drowsiness (rare)
• - Peripheral neuropathy (7-30 of patients
  treated for long time)
• - Phenytoin encephalopathy (with high drug plasma
  levels). It may include abnormal facial and arm
  movements, staggering, mental confusion,
  delirium, hallucinations, increased frequency of
  seizures.
• Cardiovascular system
• - Cardiovascular collapse, cardiac arrhythmias
  (when administered IV for emergency treatment)

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PHENYTOIN TOXICITY (2)

• Gastrointestinal system
• - Anorexia, nausea and vomiting, epigastric pain.
• - Gum hyperplasia (30-40 of patients)
• - Cholestatic jaundice
• - Acute hepatic necrosis (very rare)
• Endocrine system
• - Hyperglycemia (blockade of insulin secretion)
• - Osteomalacia (due to increased metabolism of
  vit D and reduced intestinal Ca absorption)
• Hematopoietic system
• - Megaloblastic anemia (rare)
• - Thrombocytopenia, leukopenia, pancytopenia
  (rare)
• - Agranulocytosis, aplastic anemia (very rare)
• - Hypoprothrombinemia (increased metabolism of
  vit K)
• - Limphoadenopathy, pseudolymphoma
• - Malignant lymphoma (?), Hodgkin's disease (?)

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PHENYTOIN TOXICITY (3)

• Other systems
• - Skin hyperpigmentation, hirsutism (mainly in
  women)
• - Coarsening of facial features (in children)
• - Nephritis, myopathy (rare)
• Allergic skin reactions
• - Skin rashes, erythema multiforme
• - Exfoliative dermatitis, Stevens-Jonson
  syndrome, lupoid syndrome (very rare)
• Pregnancy
• - Risk of malformations increases 2-3 fold
• - A "fetal hydantoin syndrome" (cleft lip, cleft
  palate, congenital heart disease, slowed growth
  and mental deficiency) has been described.

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PHENYTOIN THERAPEUTIC USES

• THERAPEUTIC USES
• Epilepsy
• - It is a drug of choice for all form of epilepsy
  of cortical origin (generalized tonic-clonic
  seizures, simple and complex partial seizures,
  etc) and for the emergency treatment of status
  epilepticus.
• - Absence, myoclonic and akinetic seizures often
  may worsen in patients treated with phenytoin.
• Trigeminal and related neuralgias
• - Carbamazepine remain the preferred agent for
  these conditions but phenytoin is the second
  choice drug and can achieve good results.
• Cardiac arrhythmias
• - Rarely used, except in arrhythmias due to
  digitalis toxicity.

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PHENYTOIN CONTRAINDICATIONS

• - Absence seizures, myoclonic seizures, atonic
• seizures
• - Cardiac disease (A-V block, sinus bradycardia,
• cardiac failure)
• - Serious hepatic disease
• - Diabetes mellitus
• - Leukopenia, thrombocytopenia, lymphadenopathy,
• lymphomas
• - Porphyria (acute intermittent, variegata)
• - Pregnancy

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RELATIONSHIPS BETWEEN PLASMA CONCENTRATION OF PHENYTOIN AND THERAPEUTIC AND ADVERSE EFFECTS RELATIONSHIPS BETWEEN PLASMA CONCENTRATION OF PHENYTOIN AND THERAPEUTIC AND ADVERSE EFFECTS RELATIONSHIPS BETWEEN PLASMA CONCENTRATION OF PHENYTOIN AND THERAPEUTIC AND ADVERSE EFFECTS
Plasma levels (mcg/mL) Therapeutic effects Adverse effects
8-15 Complete (or partial) control of attacks in most patients Negligible
20-29 As above Nystagmus, vertigo, blurring of vision
30-39 As above Ataxia and other symptoms of overdose toxicity
gt 40 None Lethargy, stupor
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CARBAMAZEPINE PHARMACODYNAMICS

• Chemistry
• - A tricyclic compound closely related to
  tricyclic antidepressants
• - Its spatial conformation however is very
  similar to that of phenytoin.
• Mechanism of action
• - Frequency-dependent and voltage-dependent
  blockade of inactivated Na channels.
• - Decreased synaptic transmission (after high
  doses)
• Effects
• - Prevention of the spread of excitation from
  seizure focus (the excessive discharge of the
  neurons of the focus is not prevented and
  therefore aura and EEG alterations are not
  eliminated)
• - Cerebellar-vestibular stimulation (with high
  doses)
• the drug is not a general CNS depressant and can
  cause excitation in several brain neurons
• - Analgesic effect in some type of neuropathic
  pain.
• - Antidiuretic effect (likely due to enhancement
  of ADH action on the kidney).
• - Mild antimuscarinic effects.
• - Strong induction of hepatic microsomal enzymes

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Chemical structure
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CARBAMAZEPINE PHARMACOKINETICS

• ABSORPTION
• - Oral bioavailability 90
• - Oral Tmax 6-8 hours.
• DISTRIBUTION
• - Bound in plasma 75
• - Vd (70 Kg) 80 L
• - Concentration in the cerebrospinal fluid is
  equal to unbound concentration in plasma
• BIOTRANSFORMATION
• - 99 by the liver (biotransformation rate is
  slow)
• EXCRETION -1 By the kidney
• Total Clearance 90 mL/min(70 Kg)
• Half-life acute administration 36 hours
• chronic administration 20 hours

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CARBAMAZEPINE INTERACTIONS CARBAMAZEPINE INTERACTIONS CARBAMAZEPINE INTERACTIONS
PC of carbamazepine is increased by PC of carbamazepine is decreased by Carbamazepine decreases PC of
Verapamil(2) Warfarin (2) Isoniazid (2) Erythromycin (2) Valproic acid (2) Fluoxetin (2) Carbamazepine (1) Barbiturates (1) Phenytoin (1) Haloperidol (1) Theophylline (1) Estrogens (1) Warfarin (1) Corticosteroids(1) Primidone (1) Ethosuximide (1) Valproic acid (1) Clonazepam (1) Tricyclic antidepressants(1)
PC plasma concentration (1) stimulation of metabolism (induction of P-450 system) (2) inhibition of metabolism PC plasma concentration (1) stimulation of metabolism (induction of P-450 system) (2) inhibition of metabolism PC plasma concentration (1) stimulation of metabolism (induction of P-450 system) (2) inhibition of metabolism
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CARBAMAZEPINE TOXICITY

• Central nervous system
• - Diplopia, ataxia, vertigo, headache, blurring
  of vision (common, dose-related).
• - Sedation, drowsiness (after high doses).
• - Confusion, agitation, hallucinations (after
  high doses).
• - Increased frequency of seizures (rare).
• Cardiovascular system
• - Cardiac arrhythmias.
• - Worsening of coronary disease (rare).
• - Heart failure, after long treatments (rare).
• Gastrointestinal system
• - Anorexia, nausea and vomiting, abdominal pain.
• - Xerostomia, constipation.
• Cholestatic hepatitis (very rare).
• Urinary system
• - Water retention and hyponatremia, after long
  treatments.

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CARBAMAZEPINE TOXICITY

• Hematopoietic system
• - Megaloblastic anemia.
• - Thrombocytopenia, leukopenia (2 of patients).
• - Pancytopenia, agranulocytosis, aplastic anemia
  (very rare).
• Other systems
• - Osteomalacia (after long treatments).
• Allergic skin reactions
• - Skin rashes, urticaria, photosensitivity.
• - Exfoliative dermatitis, Stevens-Johnson
  syndrome, lupoid syndrome (very rare).
• Pregnancy
• - The risk of malformations (craniofacial
  defects, fingernail hypoplasia, delay of
  development) increases 2-3 fold if the drug is
  given during pregnancy.

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• THERAPEUTIC USES
• Epilepsy
• - It is the first choice drug for partial
  seizures and for generalized tonic-clonic
  seizures.
• - In complex partial seizures carbamazepine
  prevents the attacks in 60-65 of patients.
• - The antiepileptic effect can undergo tolerance
  in 10-20 of patients.
• - Absence, myoclonic and akinetic seizures often
  may worsen in patients treated with
  carbamazepine.
• Trigeminal and related neuralgias.
• Carbamazepine is the first choice drug for
  trigeminal neuralgia (result are good in 70 of
  patients). In refractory cases the addition of
  phenytoin can be useful.
• Bipolar affective disorder
• - As an alternative to lithium for the therapy of
  acute mania and the prophylactic treatment of
  bipolar disorder.
• Diabetes insipidus
• - Rarely used to treat pituitary diabetes
  insipidus. The drug is not effective in
  nephrogenic diabetes insipidus, which indicates
  that functional V2 receptors are required for the
  antidiuretic effect.

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• CONTRAINDICATIONS AND PRECAUTIONS
• - Absence seizures, myoclonic seizures, atonic
• seizures
• - Cardiac disease (A-V block, sinus bradycardia,
• cardiac failure, myocardial infarction))
• - Serious hepatic disease
• - Alcoholism
• - Blood dyscrasias
• - SIADH
• - Pregnancy

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PHENOBARBITAL PHARMACODYNAMICS

• Chemistry
• - The drug belongs to the barbiturate class. Its
  three dimensional conformation however is very
  similar to that of phenytoin.
• Mechanism of action
• - Enhancement of GABA-mediated inhibition (the
• opening of Cl- channels is prolonged by
• facilitating GABA action)
• - Direct opening of Cl- channels (after high
  doses).
• - Reduction of glutamate-mediated excitation
• (blockade of AMPA receptors).
• - Blockade of Na and Ca channels (at high
  doses)
• Effects
• - Suppression of the excessive discharge of the
  seizure focus
• - Prevention of the spread of excitation from
  seizure focus.
• - All other effects of the barbiturate class.

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PHENOBARBITAL PHARMACOKINETICS

• ABSORPTION
• - Oral bioavailability 100
• - Oral Tmax 4-12 hours.
• (absorption rate depends on food and on
  pharmaceutical preparation)
• DISTRIBUTION
• - Bound in plasma 50
• - Vd (70 Kg) 40 L
• - Bound and free drug concentrations in brain are
  equal to those in plasma
• BIOTRANSFORMATION
• - 75 by the liver (biotransformation rate is
  low)
• EXCRETION
• - By the kidney 25 (acid urine)
• up to 75 (in alkaline urine)
• Total Clearance 4.5 mL/min(70 Kg)
• Half-life adults 100 hours
• children 50 hours

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BARBITURATE INTERACTIONS BARBITURATE INTERACTIONS
PC of barbiturates are Barbiturates decreases PC of
increased by Valproic acid (2) decreased by Barbiturates (1) Phenytoin (1) (3) Carbamazepine (1) Theophylline (1) Estrogens (1) Warfarin (1) (3) Corticosteroids (1) Quinidine (1) Propranolol (1) Calcium channel blockers (1)
PC plasma concentrations (1) stimulation of metabolism (2) inhibition of metabolism (3) inhibition of intestinal absorption PC plasma concentrations (1) stimulation of metabolism (2) inhibition of metabolism (3) inhibition of intestinal absorption
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BARBITURATE TOXICITY

• Central nervous system
• - Sedation, lassitude, drowsiness (the most
  frequent complains), impairment of fine motor
  skills
• - Agitation and confusion (especially in aged
  people)
• - Nystagmus, diplopia, vertigo, ataxia
• (after high doses)
• - Paradoxical excitement (especially in children)
• - Muscular hypotonia, dysmetria, decreased
  cutaneous reflectivity, tremor, foot clonus,
  Babinski's sign (after long treatment with high
  doses)
• - Drug dependence (not with phenobarbital)
• Gastrointestinal system
• - Nausea and vomiting, abdominal pain, diarrhea.
• Respiratory system
• - Respiratory depression (after high doses)
• - Coughing, laryngospasm (after iv injection)

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BARBITURATE TOXICITY

• Hematopoietic system
• - Megaloblastic anemia (rare)
• - Hypoprothrombinemia
• - Leukopenia, thrombocytopenia, pancytopenia
  (rare)
• - Agranulocytosis, aplastic anemia (very rare)
• Other systems
• - Osteomalacia (after long treatments).
• - Attack of acute porphyria (in porphyremic
  patients)
• Allergic reactions
• - Asthma, angioneurotic edema, fever.
• - Skin rashes, urticaria, eczematous or bullous
  dermatitis.
• - Exfoliative dermatitis, Stevens-Jonson
  syndrome, lupoid syndrome (very rare).
• Pregnancy
• - The risk of malformations increases 2-3 fold if
  barbiturates are given during pregnancy.
• - Hemorrhage in the newborn

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• THERAPEUTIC USES
• Epilepsy
• - It is a second choice drug for simple partial
  seizures, for generalized tonic-clonic seizures
  and for status epilepticus.
• - Absence, myoclonic and akinetic seizures often
  may worsen in patients treated with
  phenobarbital.
• Febrile convulsions in children
• - Sometime still used for the long-term
  prophylaxis in risk children (that is children
  who have their first seizure before 18 month of
  age, who have significant neurological
  abnormalities, etc).
• - Today, uncertainties regarding the efficacy of
  prophylaxis, combined with substantial side
  effects of the drug in children, strongly argue
  against its use.
• Neonatal hyperbilirubinemia
• - Used to induce microsomal enzymes that
  conjugate bilirubin.

37

• CONTRAINDICATION AND PRECAUTIONS
• - Absence seizures, myoclonic seizures, atonic
  seizures
• - Porphyria (acute intermittent, variegata)
• - Previous history of serious allergic reactions
  to barbiturates
• - Serious respiratory or liver diseases
• - Patients with severe pain
• - Pregnancy

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RELATIONSHIPS BETWEEN PLASMA CONCENTRATION OF PHENOBARBITAL AND THERAPEUTIC AND ADVERSE EFFECTS RELATIONSHIPS BETWEEN PLASMA CONCENTRATION OF PHENOBARBITAL AND THERAPEUTIC AND ADVERSE EFFECTS RELATIONSHIPS BETWEEN PLASMA CONCENTRATION OF PHENOBARBITAL AND THERAPEUTIC AND ADVERSE EFFECTS
Plasma levels (mcg/mL) Therapeutic effects Adverse effects
15 Minimum concentrations for febrile convulsions Negligible
10-35 Control of grand mal or simple partial seizures Sedation ,ataxia and nystagmus can appear but generally undergo tolerance
35-50 As above Overt symptoms of overdose toxicity
gt 60 None Coma
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PRIMIDONE PHARMACOLOGY

• Chemistry
• - A desoxybarbiturate very similar to
  phenobarbital.
• Pharmacodynamics
• - Mechanism of action and effects are similar to
  those of phenobarbital (the drug however has an
  anticonvulsant action independent of its
  conversion to active metabolites).
• Pharmacokinetics
• - Oral bioavailability 100 oral Tmax 3
  hours.
• - Converted in liver into two active metabolites
  
• 1) phenobarbital (10-20)
• 2) phenylethylmalonamide (50-70).
• - Half-life primidone 8 hours.
• phenylethylmalonamide 16 hours
• Toxicity
• - Sedation and drowsiness occur early in
  treatment
• - Toxicity is very similar to that of
  phenobarbital
• Therapeutic uses and contraindications
• - As alternative drug in partial and tonic-clonic
  seizures.
• - Contraindications are the same as for
  phenobarbital.

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PHARMACODYNAMICS OF VALPROIC ACID

• Chemistry
• - Valproic acid is the dipropylacetic acid.
  Salts, ester and amides of this acid also are
  active antiepileptic agents.
• Mechanism of action
• - Increased GABA content in the brain (inhibition
  of GABA-aminotransferase? Facilitation of
  glutamic acid decarboxylase?).
• - State-dependent blockade of inactivated Na
  channels.
• - Increased membrane K conductance (at high
  doses)
• likely valproate works by several mechanisms but
  the precise mode of action remain uncertain
• Effects
• - Valproate can be considered a broad spectrum
  antiepileptic drug (see therapeutic uses)
• - It is less sedating than other antiseizure
  drugs.
• - It inhibits the biotransformation of several
  drugs including phenytoin, phenobarbital and
  carbamazepine.

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Chemical structure
42
PHARMACOKINETICS OF VALPROIC ACID

• ABSORPTION
• Oral bioavailability 100- Oral Tmax 2 hours.
• DISTRIBUTION
• Bound in plasma 95-
• Vd (70 Kg) 9 L
• - Concentration in the cerebrospinal fluid is
  equal to unbound concentration in plasma
• BIOTRANSFORMATION
• - gt 95 by the liver (some metabolites are
  active)
• EXCRETION - lt 5 by the kidney
• Total Clearance 7.5 mL/min (70 Kg)
• Half-life 14 hours

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TOXICITY OF VALPROIC ACID

• Central nervous system
• - Fine hand tremor (frequent with high doses)
• - Sedation (when given with other CNS
  depressants)
• - Nervousness, excitation, aggressiveness (rare)
• - Headache, ataxia, nystagmus , diplopia,
  dysarthria, dizziness, hallucinations (with high
  doses).
• Gastrointestinal system
• - Anorexia, nausea and vomiting, abdominal cramps
• heartburn (common, dose-related).
• - Weight gain, increased appetite (uncommon).
• - Fulminant hepatitis (rare)
• - Acute pancreatitis (very rare)

44
TOXICITY OF VALPROIC ACID

• Other systems
• - Transient hair loss, skin rashes, pruritus,
  photosensitivity, erythema multiforme.
• - Thrombocytopenia, inhibition of platelet
  aggregation.
• - Transient elevation of hepatic enzymes in
  plasma (in up to 40 of patients)
• - Menstrual disturbances (up to 20 of patients)
• Pregnancy
• - Increased incidence of spina bifida (the risk
  of neural tube defect may be increased 20 fold)

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VALPROATE HEPATITIS

• - The occurrence is 1 in 37000 patients if the
  drug is given alone, but 1 in 6500 patient if
  other drugs are administered concurrently.
• - Children below 2 years of age (or with mental
  retardation or congenital neurological disease)
  are especially at risk.
• - Hepatitis appears usually after two months of
  therapy, but it may show after few days or after
  six months.
• - Increase in hepatic enzymes has no prognostic
  value since it is very common in patients taking
  valproate.
• - Hepatitis is always serious, often lethal.
• - The pathologic lesion consists in a
  microvescicular steatosis without any signs of
  inflammation.
• - Pathogenesis is unknown (probably idiosyncratic)

46

• THERAPEUTIC USES
• Epilepsy
• - It is the best drug available to control
  myoclonic seizures (results are good and
  sometimes excellent) and atonic seizures (results
  are sometimes rather good)
• - It is considered a drug of choice (together
  with carbamazepine and phenytoin) for
  tonic-clonic seizures.
• - It is considered a drug of choice (together
  with ethosuximide) in absence seizures (for
  uncomplicated absence seizures ethosuximide is
  preferred because of valproate hepatotoxicity)
• - It is the preferred drug in patients with
  absence seizures and concomitant grand mal
  seizures.
• - It is considered less effective than (or
  equally effective as) carbamazepine and phenytoin
  (but more effective than phenobarbital and
  primidone) in simple and complex partial
  seizures.
• - It is an alternative drug in infantile spasms.
• Bipolar affective disorder
• - As an alternative to lithium for the therapy of
  acute mania and the prophylactic treatment of
  bipolar disorder.
• Migraine prophylaxis
• - It has been approved by FDA for the prevention
  of migraine attack. There is no evidence that it
  might be useful in treatment of acute migraine.

47

• CONTRAINDICATIONS AND PRECAUTIONS
• - Children below 2 years of age
• - Hepatic disfunction, hepatic disease
• - Hypoalbuminemia (protein binding may be
  reduced)
• - Thrombocytopenia, blood discrasias
• - Pregnancy

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ETHOSUXIMIDE PHARMACODYNAMICS

• Chemistry
• - Ethosuximide is the more effective and less
  toxic among the three antiepileptic succinimides
  (ethosuximide, methsuximide and phensuximide).
• Mechanism of action
• - Blockade of voltage-sensitive T type Ca
  channels in thalamic neurons (the T type Ca
  current is thought to provide a pacemaker current
  in thalamic neurons responsible for generating
  the rhythmic cortical discharge of an absence
  attack)
• Effects
• - Suppression of the excessive discharge of the
  thalamic seizure focus.
• - Prevention of the spread of excitation into
  thalamic-cortico-thalamic circuits.

49
Chemical structure
50
ETHOSUXIMIDE PHARMACOKINETICS
ABSORPTION - Oral bioavailability gt 90 - Oral Tmax 3-7 hours.
DISTRIBUTION - Bound in plasma 0 - Vd (70 Kg) 45 L - Concentration in CSF is equal to concentration in plasma
BIOTRANSFORMATION - 75 by the liver (metabolites are inactive)
EXCRETION - 25 by the kidney.
Total Clearance mL/min(70 Kg) 13
Half-life adults 45 hours children 30 hours
51
ETHOSUXIMIDE TOXICITY

• (the overall incidence of adverse effects is low)
• Central nervous system
• - Drowsiness, fatigue, headache, dizziness,
  euphoria (mild, dose-related effects)
• - Vertigo, ataxia, nystagmus (after high doses).
• - Restlessness ,agitation, anxiety,
  aggressiveness, inability to concentrate (in
  children with a prior history of psychiatric
  disturbances)
• Gastrointestinal system
• - Anorexia, nausea and vomiting, hiccup,
  diarrhea, abdominal cramps (common, dose-related
  effects)
• Hematopoietic system
• - Leukopenia, thrombocytopenia, pancytopenia
  (rare)
• - Agranulocytosis, aplastic anemia (very rare)
• Allergic skin reactions
• - Skin rashes, urticaria (rare)
• - Stevens-Johnson syndrome (very rare).

52

• THERAPEUTIC USES
• - It is the preferred drug in absence seizures,
  where it completely prevents the attacks in 60
  of patients and diminishes their frequency in
  20-30 of patients.
• - It is considered a second choice drug in
  myoclonic and atonic seizures.

53

• CONTRAINDICATIONS AND PRECAUTIONS
• - Tonic-clonic seizures (if given alone.
  Therefore in case of absence seizures associated
  with grand mal seizures the drug must be given
  together with carbamazepine or phenytoin).
• - Serious hepatic or renal diseases
• - Pregnancy

54
PHARMACOLOGY OF TRIMETHADIONE AND PARAMETHADIONE
Pharmacodynamics - These drugs are oxazolidinediones, that is they contain an heterocyclic oxazolidine ring. - Their mechanism of antiepileptic action is very similar to that of succinimides. Trimethadione pharmacokinetics - Oral bioavailability gt 90 - Bound in plasma 0. - Biotransformed to dimethadione, an active metabolite with an extremely long half-life ( 240 hour) Toxicity - Sedation, hemeralopia. - Exfoliative dermatitis, lupoid syndrome, hepatitis, nephrotic syndrome, myasthenic syndrome, fulminating aplastic anemia. - Fetal malformations (the teratogenic risk is high). Therapeutic uses - As alternative drugs in absence seizures. (rarely used today because of their potential for serious toxicity).
55
BENZODIAZEPINES AS ANTISEIZURE DRUGS
Chemistry - All benzodiazepines have antiseizure properties but some selectivity seems to exist (certain compounds appear more effective than others in specific seizure types). Diazepam and clonazepam are the most used. Mechanism of action - Enhancement of GABA-induced increased frequency of bursts of openings of chloride channels. Effects - Prevention of the spread of excitation from seizure focus - All other effects of benzodiazepine class. Therapeutic uses - Clonazepam is a first choice drug in myoclonic seizures and a second choice drug in absence seizures and infantile spasms - Unfortunately the antiseizure effect of benzodiazepines undergoes tolerance after 1-6 months of therapy. - Diazepam is the drug of choice to treat acute convulsive episodes irrespective to the cause. - Diazepam, rectally administered at the onset of fever, is the drug of choice to prevent recurrent febrile seizures in children.
56
DIAZEPAM PHARMACOKINETICS
ABSORPTION - Oral bioavailability 100 - Intramuscular bioavailability unreliable.
DISTRIBUTION - Bound in plasma 99 - Vd (70 Kg) 77 L - Initially concentrated in brain but rapidly redistributed in other tissues (redistribution half-time 1 hour)
BIOTRANSFORMATION - gt 99 by the liver (many metabolites are active)
EXCRETION - lt 1 by the kidney.
Total Clearance mL/min(70 Kg) 26
Half-life 45 hours (half-life of active metabolites 100 hours)
57
ADVERSE EFFECTS OF BENZODIAZEPINES
Central nervous system - Sedation, drowsiness, asthenia (common, dose-related adverse effects) - Lethargy, ataxia, hypotonia, dysarthria, dizziness, vivid or disturbing dreams (after high doses). - Hangover effects (after high doses) - Hyperactivity, irritability, aggressiveness (rare, more frequent in children) - Anterograde amnesia (after high doses) - Psychological and physical dependence. Respiratory system - Respiratory depression (only after high IV doses in risk patients) Other systems - Dry mouth, metallic taste, nausea, diarrhea. - Menstrual irregularities, sexual disturbances. Pregnancy - Small increase in the risk of cleft lip or cleft palate. - "Floppy baby syndrome" (if given to the mother during labor)
58
PHARMACOLOGY OF GABAergic DRUGS
GABAPENTIN Mechanism of action - It is still poorly understood. Likely the drug enhances GABA release from nerve terminals. Pharmacokinetics - Oral bioavailability gt 60 - No biotransformation. Secretion by the kidney. - Half-life 6 hours. Toxicity - Drowsiness (19), dizziness (17), fatigue (11) - Ataxia (12 ), nystagmus (8), tremor (7), dysarthria, diplopia, amnesia. - Xerostomia (2), constipation (1.5). Therapeutic uses - Second choice drug for simplex or complex partial seizures and grand mal seizures. - Second choice drug for neuropathic pain.
59
VIGABATRIN Pharmacodynamics (The drug is still investigational in USA) - The drug is an irreversible inhibitor of GABA-aminotransferase (the enzyme responsible for degradation of GABA) Pharmacokinetics - Oral bioavailability gt 80 - Half-life 7 hours. Toxicity - Sedation, drowsiness, dizziness, weight gain. - Agitation, confusion. - Depression, psychosis (rare). Therapeutic uses - Second choice drug for in partial seizures and infantile spasms.
TIAGABINE - An inhibitor of GABA reuptake. - Second choice drug for both partial and genralized tonoc-clonic seizure.
60
CARBONIC ANHYDRASE INHIBITORS AS ANTISEIZURE DRUGS
Chemistry - Acetazolamide, a sulfonamide diuretic, is the prototype for the carbonic inhibitors. Pharmacodynamics - Inhibition of carbonic anhydrase increases the carbon dioxide content in the brain. - Decrease in tissue pH seems to inhibit Na entrance into the cells. - Anticonvulsant effects (which are similar to those of carbon dioxide) rapidly undergo tolerance. Toxicity - Skin rashes, drowsiness, paresthesias. - Bone-marrow suppression, interstitial nephritis, (rare) Therapeutic uses - As an alternative drug in all type of seizures (efficacy is low and tolerance limit the use). - In epileptic women who have exacerbation of seizures at the time of menses.
61
DRUG THERAPY OF INFANTILE SPASMS
- Infantile spasms are an epileptic syndrome very difficult to treat. - Drugs of choice are ACTH and corticosteroids (prednisone, dexamethasone, etc.). ACTH seems more effective but the subject remains controversial. - The mechanism of action of corticosteroids or ACTH in the treatment of infantile spasms is unknown. - Corticosteroids therapy often must be discontinued because of adverse effects. - Alternative drugs for infantile spasms are benzodiazepines (clonazepam, nitrazepam), vigabatrin and valproic acid. - The therapy of infantile spasms is able to reduce the number of attack in 40-50 of patient but it rarely improves the progression of mental retardation.
62
THERAPEUTIC INDICATIONS FOR ANTISEIZURE DRUGS THERAPEUTIC INDICATIONS FOR ANTISEIZURE DRUGS THERAPEUTIC INDICATIONS FOR ANTISEIZURE DRUGS
Types of epilepsy Preferred drugs Alternative drugs
Tonic-clonic seizures Carbamazepine Valproic acid Phenytoin Phenobarbital Primidone Gabapentin Tiagabine
Simple partial seizures Carbamazepine Phenytoin Valproic acid Phenobarbital Primidone Vigabatrin Gabapentin Lamotrigine Topiramate
Complex partial seizures Carbamazepine Phenytoin Valproic acid Primidone Vigabatrin
Absence seizures Ethosuximide Valproic acid Clonazepam Trimethadione
Myoclonic and Atonic seizures Valproic acid Clonazepam Ethosuximide
Status Epilepticus Diazepam (1) Lorazepam (1) Phenytoin (2) Phenobarbital(2)
Infantile spasms ACTH Corticosteroids Clonazepam Vigabatrin Valproic acid
Febrile seizures Diazepam
() drugs are listed in order of preference (1) acute management (2) preventive management () drugs are listed in order of preference (1) acute management (2) preventive management () drugs are listed in order of preference (1) acute management (2) preventive management
63
GENERAL PRINCIPLES FOR THE THERAPY OF EPILEPSIES (1)
- The initial choice of the drug must be based on diagnosis (mainly founded upon anamnesis and EEG record) and spectrum of adverse effects of the drug. - In most instances medication should be started with a single drug (the one that is considered first choice for the type of seizure to be treated). - Initial dosage should be low in order to avoid unwanted effects (many adverse effects undergo tolerance). Loading dosage should be employed only if the urgency for control of seizures exceeds the risk of adverse effects. - Since most antiseizure drugs have a long half-life the steady-state will be reached only after some days of treatment. - It is very important that maintenance dose should be the minimum effective dose. Therefore the dosage should be increased gradually until seizure are controlled or toxicity makes further increase inadvisable.
64
GENERAL PRINCIPLES FOR THE THERAPY OF EPILEPSIES (2)
- If the initial drug does not control seizures a trial with another agent from a different chemical class should be attempted before considering a multidrug regimen. The second drug should be introduced before the first drug is discontinued. - A combined drug treatment is required in case of refractory seizures or mixed seizures. Polytherapy however increases the likelihood of toxicity and of complex drug interactions. - Most crucial for successful management is the regularity of medication since faulty compliance is the most frequent cause for failure of therapy. - If the patient has had no seizures (including EEG seizures) for 2 years, drugs may be withdrawn to see weather the seizure threshold has normalized. - Withdrawal should always be done gradually over a period of weeks or months in order to avoid the risk of increased seizure frequency and severity.
65
PLASMA LEVEL OF COMMONLY USED ANTIEPILEPTIC DRUGS PLASMA LEVEL OF COMMONLY USED ANTIEPILEPTIC DRUGS PLASMA LEVEL OF COMMONLY USED ANTIEPILEPTIC DRUGS
Drug Effective level (mcg/ml) Toxic level (mcg/ml)
Carbamazepine Phenytoin Phenobarbital Primidone Valproic acid Ethosuximide Clonazepam Diazepam 4-12 10-20 10-30 5-10 30-100 40-100 0.05-0.07 0.6-1.0 gt 9 gt 20 gt 40 gt 10 gt 100 gt 150 --- ---
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ANTISEIZURE DRUG TOXICITY GENERAL FEATURES
- The therapeutic index for most antiepileptic drugs is low, and toxicity is not uncommon. - Toxicity is mainly dose-dependent since antiseizure therapy is often long term, the probability of adverse effect is rather high. - For antiepileptic drugs relationships between blood levels and therapeutic (or toxic) effects have been characterized to a particular high degree. Monitoring of plasma concentrations is therefore the best way to control overdose toxicity. - Many CNS and ANS adverse effects undergo tolerance and therefore they can be minimized by gradually increasing the dose. - Most antiepileptic drugs can cause adverse effects upon the CNS cerebellar-vestibular disorders are especially frequent. - Abrupt withdrawal of an antiepileptic drug is the most common cause of status epilepticus. - All antiseizure drugs (especially if given in combination) may lead to behavioral and cognitive disturbances mainly in children. The occurrence of such disturbances seems more frequent with phenytoin and phenobarbital. - Several lethal cases of overdose toxicity of anticonvulsants are reported in literature. Most of these cases result from skin, liver or hematopoietic disorders. - Children born to mothers taking antiepileptic drugs have an increased risk (perhaps 2-3 fold) of congenital malformations. The risk increases if two or more drugs are taken concurrently. - The formation of epoxide intermediates during the biotransformation of antiseizure drugs has been implicated in the induction of fetal malformations.