Transcript Antiseizure Drugs

Antiseizure Drugs
By
S. Bohlooli, PhD
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.
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
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.
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.
- 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 Nmethyl-D-aspartate and glutamate neurons).
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).
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.
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, nonrepetitive firing.
• 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.
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
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
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.
Chemical strucutre
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
- < 2% by the kidney.
Total Clearance: concentration-dependent
Half-life: concentration-dependent
plasma concentrations < 10 mcg/mL: 6-24 hours
plasma concentrations > 10 mcg/mL: 48-72 hours
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
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)
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 (?)
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.
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.
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
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
> 40
None
Lethargy, stupor
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
Chemical structure
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
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
CARBAMAZEPINE TOXICITY
Central nervous system
- Diplopia, ataxia, vertigo, headache, blurring of vision (common, doserelated).
- 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.
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.
THERAPEUTIC USES
Epilepsy
- It is the first choice drug for partial seizures and for generalized tonicclonic seizures.
- In complex partial seizures carbamazepine prevents the attacks in 6065% 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.
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
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.
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
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
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)
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
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.
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
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
> 60
None
Coma
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.
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 GABAaminotransferase? 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.
Chemical structure
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
- > 95% by the liver (some metabolites are active)
EXCRETION - < 5% by the kidney
Total Clearance: » 7.5 mL/min (70 Kg)
Half-life: » 14 hours
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)
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)
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)
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.
CONTRAINDICATIONS AND
PRECAUTIONS
- Children below 2 years of age
- Hepatic disfunction, hepatic disease
- Hypoalbuminemia (protein binding may be
reduced)
- Thrombocytopenia, blood discrasias
- Pregnancy
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.
Chemical structure
ETHOSUXIMIDE PHARMACOKINETICS
ABSORPTION
- Oral bioavailability: > 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
ETHOSUXIMIDE TOXICITY
(the overall incidence of adverse effects is low)
Central nervous system
- Drowsiness, fatigue, headache, dizziness, euphoria (mild, doserelated 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).
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.
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
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: > 90%
- Bound in plasma: 0%.
- Biotransformed to dimethadione, an active metabolite with an extremely long halflife (» 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).
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.
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
- > 99% by the liver (many metabolites are active)
EXCRETION
- < 1% by the kidney.
Total Clearance:
mL/min(70 Kg) » 26
Half-life: » 45 hours
(half-life of active metabolites: » 100 hours)
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)
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: > 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.
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: > 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.
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.
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.
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
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.
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.
PLASMA LEVEL OF COMMONLY USED ANTIEPILEPTIC
DRUGS
Drug
Carbamazepine
Phenytoin
Phenobarbital
Primidone
Valproic acid
Ethosuximide
Clonazepam
Diazepam
Effective level
(mcg/ml)
4-12
10-20
10-30
5-10
30-100
40-100
0.05-0.07
0.6-1.0
Toxic level
(mcg/ml)
>9
> 20
> 40
> 10
> 100
> 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.