Mkgrady8 Neuro 5 Anticonvulsant Drugs

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what is epilepsy

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Epilepsy is a periodic disturbance of CNS function that is recurrent and which is associated with excessive neuronal discharge for which the behavioral consequence is SEIZURE; Epilepsies are common and frequently devastating disorders which affect approximately 2.5 million people in the United States alone. There are many etiologic factors that can result in epileptic seizures. The specific symptoms will depend upon the portion of the CNS involved. Classification is based on symptomatology and EEG patterns. Accurate diagnosis is essential, since drug therapy is selective for a particular type

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simple partial seizures

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Various signs and symptoms, including convulsions, depending upon the cortical area involved; WITHOUT IMPAIRMENT OF CONSCIOUSNESS. Convulsions may be confined to a single limb or muscle group, or there may be specific and localized sensory disturbances

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complex partial seizures

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Attacks of confused behavior with impairment of consciousness; a wide variety of clinical manifestations. Associated with bizarre generalized EEG activity during seizure, but evidence of temporal lobe abnormalities in many cases (temporal lobe or psychomotor seizures)

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partial seizures secondarily generalized

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Partial seizures that become generalized.

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generalized tonic-clonic (grand mal) seizures

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Major convulsions; usually a sequence of maximal tonic spasm of all body musculature followed by synchronous clonic jerking and prolonged depression of all central functions

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absence (petit mal) seizures

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Brief (usually less than 10 seconds but not more than 45 seconds) and abrupt loss of consciousness associated with high-voltage, bilaterally synchronous, 3-per-second spike-and-wave pattern in the EEG; usually some symmetrical clonic motor activity.

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partial seizure types: causes

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account for ~60% of all epilepsies. The etiology most commonly consists of a lesion in some part of the cortex, such as a tumor, malformation,or due to damage caused by trauma or stroke: Cerebral Pathology: Tumors, trauma, intracranial infections, cerebrovascular diseases (congenital vascular malformation, subdural hematoma, cerebral emboli, stroke, hypertensive encephalopathy), perinatal brain damage (anoxia, birth trauma), degenerative disorders and lipidosis, and allergic encephalitis; Cellular mechanisms are uncertain but may involve: vascular abnormalities resulting in focal ischemia; loss of inhibitory neurons; development of super sensitivity; abnormal excitability due to loss of dendritic spines; proliferation of scar tissue; deficiency in synthesis of inhibitory transmitters; and deficiency in Na+-K+ ATPase activity; Factors that can favor the development of seizures are over hydration and hyponatremia, dehydration, hypernatremia, hyperosmolality, hypocalcemia, hypomagnesemia, hypoglycemia, hypoxia, respiratory alkalosis, fever, sleep deprivation,B6 deficiency, excess glucocorticoids, estrogen therapy, renal failure, eclampsia of pregnancy, phenylketonuria, drug toxicity (phenothiazines, antihistamines, tricyclic antidepressants, local anesthetics, many others), barbiturate or alcohol withdrawal, heavy metal intoxication, etc; In many cases, seizures are treated by correcting the specific problem. Treatment with antiepileptic drugs may also be necessary

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generalized seizure types: causes

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account for ~40% of all epilepsies and the etiology isusually genetic. In recent years more than a dozen single-gene mutations have been identified which are linked to an epileptic phenotype. Mutations of genes encoding voltage- and ligand-gated ion channels that alter the intrinsic properties and/or synaptic function are believed to be the principal causal factor

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seizure mechanism: ion channel level

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Pharmacological studies have resulted in a general conceptual mechanism of seizure, that seizure results from defective synaptic transmission between neurons. Either a reduction in inhibitory synaptic activity or enhancement of excitatory synaptic activity may trigger a seizure

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seizure mechanism: neuronal level

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"Epileptic" neurons show paroxysmal depolarizing shifts of membrane potential associated with high frequency bursts, loss of IPSPs, and synchronous discharge of surrounding cells. There may be depolarization of axon terminals with antidromic bursting.

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seizure mechanism: environmental

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Environmental changes result in triggering of seizure focus and/or facilitate spread of abnormal activity from the focus to normal cells. With sufficient spread, the entire brain is involved, resulting in a tonic-clonic (grand mal) seizure and unconsciousness.

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seizure mechanism: posttetanic potentiation

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enhancement of synaptic transmission during rapid, repetitive stimulation. May contribute to circulating seizure activity within an area, there by maintaining the seizure.

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status epilepticus

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Continuing or recurring seizures without restoration of consciousness between seizures.If clonic-tonic, then a medical emergency which must be treated; Causes: fever, brain damage in the neonatal period, acute encephalopathies, meningitis, toxic encephalopathy, WITHDRAWAL OF ANTIEPILEPTIC MED, barbiturate abstinence

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generalized mechanisms of anticonvulsant action

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Elevation of the threshold for discharge of "epileptic" neurons in the seizure focus; Prevention of the spread of seizure activity to normal neurons; The ideal antiseizure drug would suppress all seizures without causing any side-effects. Unfortuneately, the drugs currently available do not control seizure activity in all patients and cause side-effects which range in severity from minimal impairment of CNS activity to death from aplastic anemia or hepatic failure; It is generally held that complete control of seizures can be achieved in about 50% of patients and that another 25% can be improved significantly

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treatment of tonic-clonic or partial seizures:

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carbamazepine; phenytoin; phenobarbital; valproic acid

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treatment of absence seizures:

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ethosuximide; valproic acid

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treatment of absence, myoclonic, or atonic seizures

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valproic acid

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treatment of status epilepticus

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diazepam; phenytoin; phenobarbital

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what can phenytoin be used for

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generalized tonic clonic (grand mal), simple partial seizures, complex partial seizures, status epilepticus; BUT NOT ABSENCE SEIZURES (does nothing for these)

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how does phenytoin work

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Significant anticonvulsant action without generalized CNS depression; Limits development of maximum seizure activity; limits high-frequency repetitive firing of neurons; prevents spread of seizure process to normal tissue; stabilizes neuronal membranes and blocks posttetanic potentiation; Mechanism of action= Slows the rate of recovery of voltage-activated Na channels from inactivation (doesn't stop it like an anesthetic); because the action of phenytoin on Na channels is use dependent it does not lead to generalized CNS depression and sedation; may exacerbate absence (petit mal) seizures

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main side effect of phenytoin

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hirsutism (excessive hair growth)

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carbamazepine: what is it used for, how does it work

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generalized tonic clonic, simple partial, and complex partial; NOT EFFECTIVE IN ABSENCE SEIZURES; works exactly the same way as phenytoin

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phenobarbital: what is it used for, how does it work

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generalized tonic clonic and simple partial, complex partial, status epilepticus; binds and activates GABA receptors so that more CL- enters the neurons which hyperpolarizes the neuron so makes it less likely to fire

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phenobarbital: the main side effect

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sedation so it slows down your normal cognition as well which isn't exactly pleasant (this doesn't happen with phenytoin); also DROWSINESS

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ethosuximide: what is it used for and how does it work

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DOC FOR UNCOMPLICATED ABSENCE (PETIT MAL) SEIZURES AND IS INEFFECTIVE IN ALL OTHER SEIZURES; reduces low-threshold calcium currents or T currents in neurons in the thalamus. The thalamus plays an important role in the generation of a 3 Hz spike wave rhythm which are typical of absence seizures. It is currently believed that by blocking T-currents ethosuximide inhibits absence seizures

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valproic acid: what is it used for and how does it work and main side effect

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absence, generalized tonic clonic, myoclonic and atonic, mixed, and partial seizures; like phenytoin it slows the recovery from inactivation of Na channels, like ethosuximide it induces a small reduction in the T currents important in absence seizures, inhibits enzymes which are responsible for degrading GABA and therefore may potentiate GABAAR currents by allowing the concentration of GABA to remain elevated; can cause HEPATIC TOXICITY AND PANCREATITIS

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benzodiazepines: name to know, what are they used for, how do they work

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diazepam; terminating STATUS EPILEPTICUS; binds to GABA receptors increasing their openings (distinct from barbiturates in that they increase the frequency of GABAAR channel openings without effecting the duration of the channel open time)

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gabapentin: how does it work

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increases the release of GABA presynaptically so hyperpolarization

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lamotrigine: how does it work

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same as carbamazepine

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fosphenytoin: how does it work

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it breaks down to phenytoin

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felbamate: how does it work

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GABA

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vigabatrin: how does it work

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inhibits degredation of GABA

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tonic clonic (grand mal): treatment

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carbamazepine, phenytoin, valproate; alternate phenobarbital or primidone

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partial seizures: treament

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carbamazepine or phenytoin; alternate valproic acid, phenobarbital, primidone, gabapentin, lamotrigine

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absence (petit mal): treament

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ethosuximide or valproate; alternate clonazepam or lamotrigine

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atypical, absence, myoclonic, tonic: treatment

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valproate; alternate= clonazepam

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status epilepticus: treatment

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diazepam, phenytoin, pehnobarbital; alternate= lorazepam, clonazepam, paraldehyde, lidocaine