Anticonvulsants Flashcards
What is a seizure?
A failure of conscious intent to control brain function.
What are convulsions?
Failure to inhibit motor output
What are absence seizures?
Inability to generate motor output
T/F Seizures may be idiopathic or secondary to various conditions.
TRUE
When would chronic pharmacological treatment be warranted?
If the seizure was of an unknown cause and recurring (epilepsy). Similar therapy may be needed in the aftermath of a known cause.
What are the 3 stages typically seen in seizures?
(1) Focal discharge (paroxysmal depolarization)
(2) Spread
(3) Termination
What is the prevalence of epilepsy?
about 1-2%, second most common neurological disorder (after stroke)
What are the three ways in which anticonvulsants work?
(1) Decrease excitation: glutamate receptors and glutamate release (calcium channels)
(2) Increase inhibition: GABA receptors GABA synthesis and release
(3) Decrease impulse generation and propogation: Na channels (K channels)
What are the main causes of provoking seizures?
- Things that are stressful
- Dehydration
- Sleep deprivation
- Head injury
- Infection
- Fever
- Intoxication of drugs
- Space occupying lesions in the brain
Anticonvulsants: Mechanism of action
- Seizure spread through brain depends on action potentials (sodium channels) and release of excitatory transmitters (mostly glutamate) (calcium channels). It is prevented by inhibitory neurotransmitters, especially GABA
Anti-seizure drugs suppress spread of abnormal electrical activity (rather than eliminate its cause) by these 4 things:
(1) Blocking actions potentials (sodium channel block)
(2) Increasing the inhibitory tone of the brain (increasing GABA transmission)
(3) Reducing neurotransmitter release (calcium channel block)
(4) Reducing excitatory neurotransmission (decreasing glutamate neurotransmission)
What are the two types of partial seizures?
Simple partial and Complex partial
What are the major manifestations of simple partial seizures? (2)
(1) Various manifestations, depending upon the affected brain region
(2) Key feature is preservation of consciousness
What are the major manifestations of complex partial seizures? (4)
(1) Localized onset followed by widespread discharges (usually bilateral)
(2) Confused behavior, impairment of consciousness
(3) Most arise form the temporal lobe
(4) Almost always involves the limbic system
What are the two types of generalized seizures?
Tonic-clonic (Grand mal) and Absence (Petit mal)
What are the major manifestations of tonic-clonic seizures? (2)
(1) Major convulsions (tonic body muscle spasms followed by synchronous clonic jerking)
(2) Prolonged depression of all central functions after seizures (postictal depression)
What are the major manifestations of absence seizures? (4)
(1) Sudden onset, abrupt cessation (usually less than 10 sec)
(2) Brief loss of consciousness, sometimes with motor involvement
(3) Occurs in childhood and often disappears during maturation; may be frequent
(4) Characteristic 3 Hz spike and wave EEG
What are the animal models take home messages for the exam? (3)
(1) Some models may relate to epilepsy if the animals have spontaneous recurrent seizures (seizure prone genetic strain, “kindled” animals)
(2) Most models related better to acute seizures, either partial or general
(3) Animal models are most useful for screening for new drugs or testing drug combination
What are the Anticonvulsants that are sodium channel blockers? What are they generally effective against?
(1) Phenytoin
(2) Carbamazepine
(3) Lamotrigine
- generally effective against partial seizures and generalized tonic clonic seizures
T/F (Sodium channel blockers) Anticonvulsants inhibit high frequency seizure activities without affecting normal action potentials.
TRUE; specifically bind to and prolong the inactivated state of voltage-activated sodium channels
What are the common side effects of sodium channel blockers?
(1) Nystagmus
(2) Diplopia
(3) Ataxia
What are the anticonvulsant drugs that enhance GABA neurotransmission?
(1) GABAa receptor modulators (postsynaptic)
- barbituates (phenobarbital)
- benzodiazepines (diazepam, lorazepam)
(2) Drugs that increase synaptic GABA levels (presynaptic)
- valproic acid, tiagabine, gabapentin
What are the calcium channel blockers? What do they do?
- ethosuximide and valproic acid: inhibit “T-type” calcium channels that are enriched in thalamic neurons and involved in the generation of rhythmic action potentials responsible for absence seizures
- lamotrigine: inhibits another type (high voltage activated) or calcium channels
What are the 3 drugs that decrease glutamate neurotransmission?
(1) Valproic acid
(2) Topiramate
(3) Lamotrigine
- decrease glutamate neurotransmission, but these drugs have other anticonvulsant mechanisms as well
T/F Anti-seizure drugs only provide symptomatic therapy.
TRUE; pharmacological cure for epilepsy is not available. Prevention of seizures varies in efficacy
What do you have to do in order to minimize toxic effects?
Monitor blood concentrations
Reduction in dosage should be gradual or instantaneous?
GRADUAL to avoid seizure recurrence
T/F Multiple drug therapies are not common.
FALSE; they are common, especially due to the fact that some types of epilepsy are difficult to control (it allows a primary agent to be used at lower dosages if side effects are limiting)
Carbamazepine, phenytoin, phenobarbital: Drug interactions
All induce a variety of cytochrome P450 enzymes which increases the metabolism of each other
Valproic acid: drug interactions
Inhibits CYP enzymes that increases the plasma concentration of phenytoin, carbamazepine, and phenobarbital
Which drugs are high protein binding?
Phenytoin, valproic acid
Why is it pure petit-mal drugs (i.e. ethosuximide) are contraindicated for other types of seizures and vice versa?
The wrong drug-type increases the likelihood of seizure recurrence and status epilepticus
What is status epilepticus? What should it be treated with?
- one continuous seizure or recurrent seizures without regaining consciousness for greater than 30 minutes (5 min)
- treated with lorazepam or diazepam
T/F Many anticonvulsants appear to increase the likelihood of birth defects. Therefore, you should withdraw drugs at least 6 months before.
TRUE; phenytoin, carbamazepine, valproic acid, topiramate
- monotherapy may have to do because it is safer than untreated epilepsy
- folate supplement with pregnancy
Phenytoin: Mechanism of action
Binds to and prolongs the inactivated state of voltage gated sodium channels
Phenytoin: Acute toxicities
nystagmus, ataxia, diplopia
Phenytoin: long term side efects
gingival hyperplasia (>20%), hirsutism, teratogen
T/F Phenytoin has a high therapeutic index.
FALSE; gradual dose increase, blood drug monitoring (therapeutic plasma level: 10-20 micrograms/mL)
What is the pharmacokinetic properties of Phenytoin?
First order kinetics at low concentration but maximum capacity of the liver to metabolize phenytoin is saturated at low therapeutic range resulting in saturation kinetics (first order)
What is considered the drug of choice for controlling partial seizures and generalized tonic-clonic seizures? What is its mechanism of action?
Carbamazepine; sodium channel blocker
T/F Carbamazepines induce CYP enzymes
TRUE
Carbamazepine: Side effects
(1) Dipolopia
(2) Ataxia
(3) Skin rash
(4) Aplastic anemia*
(5) Agranulocytosis*
* - rarely occur
Phenobarbital: mechanism of action
- Binds to allosteric regulatory site on GABAa receptor and enhances GABA mediated Cl influx
- induces microsomal enzymes
T/F Benzodiazepines are used for long-term therapies.
FALSE; used for status epilepticus IV (kinetics as well as tolerance prevents long-term therapy)
Ethosuximide: mechanism of action
Blocks T-type calcium channels
Ethosuximide: uses
effective for absence (pur petit mal drug) and lacks the hepatotoxicity of valproate
What is the drug of choice for absence seizure?
Ethosuximide
Ethosuximide: adverse effect
- gastric distress (idiosyncratic side effects are extremely rare)
- hepatotoxicity major concern
- reduces serum protein binding of some drugs
- inhibits CYP enzymes: increases plasma concentration of phenobarbital and phenytoin
- teratogen: spina bifida
Valproic acid: uses
First drug effective against both absence and tonic-clonic seizures
Valproic acid: mechanism of action
blocks sodium channels and T-type calcium channels
Gabapentin: mechanism of action
appears to increase GABA transmission by unknown mechanism
T/F Gabapentin is metabolized in the liver.
FALSE; no known drug interaction
Lamotrigine: Mechanism of action
(1) blocks voltage sensitive sodium channels
(2) inhibits calcium channels
(3) inhibits glutamate release
Lamotrigine: uses
broader spectrum: even absence
Lamotrigine: adverse effects
(1) diplopia
(2) skin rash
Topiramate: Mechanism of action
(1) inhibits sodium channels
(2) modulates GABAa receptors
(3) blocks glutamate receptors
Topiramate: uses
- broad spectrum: even absence
- also useful for preventing migrane headaches
Tigabine: Mechanism of action
blocks reuptake of GABA into nerve terminals and glia by inhibiting GABA transporter, GAT-1
Tigabine: side effects
generally mild
