2 Anticonvulsants Flashcards
What are seizures exactly?
Abnormal discharges of electrical activity in cerebral neurons
Neurological disorder characterized by recurrent seizures
Epilepsy
1% of the world’s pop has it
Seizures typically originate in what part of the brain?
Cerebral cortex
What causes seizures?
Can be... Neurological disease Head trauma Infection Tumors Drugs High fevers
About 50% have unknown origins
What are the different classifications of seizure?
Partial (originates in one are of the brain)
• Simple
• Complex
• Partial with 2˚ general
Generalized (involves whole brain) • Absence • Tonic-clonic • Myoclonic • Atonic
Name that seizure!
Focal
Brief (20-90 sec)
Grimacing, focal clinic jerking of an extremity
No loss of consciousness
Simple partial
Name that seizure!
Focal Longer (<2 min) Altered or loss of consciousness Temporal lobe Automatic movements
Complex partial
Name that seizure!
Starts focal —> general
Loss of consciousness
Muscle contractions alternating with relaxation
Partial with secondary generalized tonic-clonic
Name that seizure!
Arise from reciprocal firing of thalamus and cortex
Generalized seizures
Name that seizure!
Initial tonic rigidity (15-30s) Subsequent tremor Eventually clonic jerking (60-120s) LOC Patient stuporous and confused
Tonic-clonic (grand mal)
Name that seizure!
Sudden onset
Brief (10-30s)
Loss of awareness but not consciousness
May be some mild clonic movements
Absence (petit mal)
Name that seizure!
Brief spasm or rigidity
Often secondary to other seizure disorders
Myoclonic
Name that seizure!
Sudden loss of postural tone
Patient can fall done
Atonic
No drugs - they have to wear a helmet
What are the two targets for anticonvulsant medications?
Increase GABA activity (b/c blockade of GABA receptors causes seizures)
Decrease excitatory glutamate activity (b/c activation of glutamate NMDA receptors can lead to seizures)
Mechanisms for increasing GABA activity for the treatment of seizures
Block GABA reuptake (Tiagabine)
Inhibit GABA metabolism (Vigabatrin)
Stimulate GABA-a receptors (Benzos and barbs)
Bind to synaptic vesicular protein SV2A (Levetiracetam)
Mechanisms for decreasing glutamate activity for the treatment of seizures
Common targets: Voltage-gated Na+ and Ca2+ channels (Phenytoin, ethosuximide)
Other targets: SV2A, K+ channels, NMDA and AMPA receptors
To treat absence seizures, drugs need to target…
Ca2+ channels
Ethosuximide is really the only drug that does
How does inhibition of Na+ channels work to treat seizures?
Voltage gated Na+ channels become inactive after each firing
Inactivation state is prolonged so the action potential does not fire as rapidly
Targets rapidly firing neurons
No effect on normal neurons
Where do drugs that inhibit Na+ channels to inhibit glutamate activity bind?
INTRAcellularly (have to cross the membrane)
What are the general principles to remember for anticonvulsant therapy?
Most drugs will stop seizures without side effects - 50% of patients
Monitor plasma drug levels and use SINGLE DRUG if possible
Common side effects - GI, CNS disturbances
• Teratogenic
• Hypersensitivity (Stevens-Johnson syndrome)
Most anticonvulsant drugs are metabolized by CYP450s but these three INDUCE CYP450s
Phenytoin
Carbamazepine
Phenobarbital
What is the main difference between Phenytoin (Dilantin) and Fosphenytoin (Cerebyx)?
Phenytoin is not injectable (not water soluble)
Fosphenytoin is injectable
Uses for Phenytoin and Fosphenytoin
Partial seizures and generalized tonic-clonic seizures
NOT effective for absence seizures
Phenytoin/Fosphenytoin MOA
Prolongs the inactivation of Na+ channels to decrease glutamate activity
Phenytoin and Fosphenytoin are elimated by ______ kinetics at low doses but ______ at therapeutic and high doses
1st order
Zero order
Because of this, small changes in dose/elimination can cause BIG changes in plasma levels
Phenytoin is likely to have interactions with…
Drugs that alter CYP450s
It is metabolized by, induces, AND inhibitors CYP450s!
Side effects of phenytoin
Nystagmus, diplopia, ataxia, sedation
GINGIVAL HYPERPLASIA***
Long term:
• Coarsening of facial features
• Mild peripheral neuropathy
• Abnormal vitamin D metabolism
Skin rash - d/c!!! (Risk of SJS)***
Pregnancy Category D
What are the primary uses for Carbamazepine (Tegretol)
DRUG OF CHOICE for PARTIAL seizures**
Generalized tonic-clonic seizures
Bipolar disorder
TRIGEMINAL NEURALGIA
Carbamazepine (Tegretol) increases metabolism of …
Multiple anticonvulsants
Haloperidol***
Oral contraceptives***
Metabolism of Carbamazepine (Tegretol) is increased by _________ and inhibited by __________
Phenobarbital, Phenytoin
Cimetidine, fluoxetine, and VALPROIC ACID
Side effects of Carbamazepine (Tegretol)
Diplopia, ataxia, GI upset, drowsiness
Aplastic anemia and agranulocytosis
Highest potential for STEVENS JOHNSON SYNDROME of the anticonvulsants
Pregnancy Category D
Patients with _________ are more likely to develop Stevens Johnson Syndrome when taking Carbamazepine
HLA-B 1502
Genetic screening is REQUIRED prior to prescribing
MOA for Lamotrigine (Lamictal)
Inactivation of Na+ channels; decreases glutamate activity
May also inhibit Ca2+ channels
Uses for Lamotrigine (Lamictal)
Partial seizures**
May be effective against myoclonic and absence seizures in children
Bipolar disorder
What pharmacokinetic details do we need to know about Lamotrigine (Lamictal)?
Inducers of CYP450s (phenytoin, carbamazepine, phenobarbital) will increase metabolism
Half-life double by valproic acid
Side effects of Lamotrigine (Lamictal)
CNS - dizziness, HA, diplopia, ataxia, somnolence
GI - nausea and vomiting
Skin rash and Stevens-Johnson Syndrome
Pregnancy Category C (better than the others but still not good)
How is Topiramate (Topamax) used?
Partial and generalized tonic-clonic seizures
May also be effective for absence seizures
Migraine prevention***
MOA for Topiramate (Topamax)
Blocks Na+ channels and decreases glutamate activity
Also has some activity at Ca2+ channels
Potentialities GABA receptors and inhibits glutamate receptor
May inihibit spread of seizures
Topiramate (Topamax) may increase metabolism of ________.
Contraceptives
Side effects of Topiramate (Topamax)
Dizziness, sedation, nervousness, confusion
ACUTE MYOPIA/GLAUCOMA
Uses for Levetiracetam (Keppra)
Partial, myoclonic, and tonic-clonic seizures
MOA for Levetiracetam (Keppra)
Binds synaptic vesicular protein (SV2A) —> decreased glutamate and increased GABA release
Pharmacokinetics for Levetiracetam (Keppra)
Oral absorption is rapid - peak blood concentrations in 1-2h
1/2 life of 6-8h, longer in elderly
Side effects of Levetiracetam (Keppra)
Dizziness, somnolence, ataxia, and asthenia
__________ has minimal drug interactions so is a good option for multidrug therapy
Levetiracetam (Keppra)
MOA for Phenobarbital (Luminal)
Prolongs opening of chloride channel at GABA receptor —> alters Na+ and Ca2+ conductance at high concentrations
Uses for phenobarbital (luminal)
Partial seizures
Generalized tonic-clonic seizures
Potential for abuse those so use with caution
Phenobarbital _______ CYP450s
Induces —> increased metabolism of phenytoin and carbamazepine
Uses for Gabapentin (Neurontin)
ADJUNCT for partial and generalized tonic-clonic seizures
Neuropathic pain**
Bipolar disorder (off label)
MOA for Gabapentin (Neurontin)
GABA analog***
May augment GABA release
Pharmacokinetics of Gabapentin (Neurontin)
1st order elimination by the kidneys
Short half-life, taken 3x/day
Side effects of Gabapentin
Sleepiness, dizziness, ataxia, fatigue, tremor, H/A
Pregnancy Cat C
_______ has negligible drug interactions, so it’s a good 2nd drug for multidrug therapy
Gabapentin
What is Pregabalin (Lyrica) and how is it used?
GABA analog - structurally related to GABA
Binds to alpha-2-delta subunit of voltage-gated Ca2+ channels inhibiting excitatory neurotransmitter release
Used for generalized anxiety disorder***
Other uses: neuropathic pain, fibromyalgia, post-op pain
Side effects of Pregabalin (Lyrica)
Peripheral edema, dizziness, fatigue, weight gain, xerostomia***, ataxia, blurred vision, GI disturbances
TERATOGENIC
Adjunct treatment for partial seizures that works by inhibiting reuptake of GABA (GAT-1) to enhance GABA activity
Tiagabine (Gabitril)
Side effects of Tiagabine (Gabitril)
Nervousness, difficulty concentrating, depression
Dizziness, tremor, rash (rare but d/c if happens)
Pregnancy Cat C
How is Vigabatrin (Sabril) used?
Refractory complex partial seizures
Infantile spasm (West’s syndrome)
MOA for Vigabatrin (Sabril)
IRREVERSIBLY inhibits GABA transaminase (GABA-T) to decrease GABA metabolism and enhance activity
Short half-life but b/c of MOA drug effects are prolonged and do not correlate with plasma levels
Side effects of Vigabatrin (Sabril)
Visual field problems and retinal damage**
Agitation, confusion
Drug of choice for absence seizures
Ethosuximide (Zarontin)
MOA for Ethosuximide (Zarontin)
Inhibits low-threshold (T-type) Ca2+ channels
Inhibits ‘pacemaker’ for rhythmic cortical diamanté
Side effects of Ethosuximide (Zarontin)
GI irritation, lethargy, fatigue, HA, dizziness
HICCUPS**
Stevens Johnson Syndrome (very rare)
Metabolism is inhibited by VALPROIC ACID
Uses for Valproic Acid (Depakene)
Absence AND general tonic-clonic seizures (MIXED seizures)
Bipolar disorder
Prophylaxis of migraine
MOA for Valproic Acid (Depakene)
Blocks Ca2+ channels and Na+ channels
May enhance GABA activity
Pharmacokinetics for Valproic Acid (Depakene)
Absorption is prolonged by food
1/2life of 9-18h
INHIBITS ITS OWN METABOLISM at low doses
Valproic acid inhibits metabolism of …
Phenytoin
Phenobarbital
Carbamazepine
Side effects of Valproic Acid
Nausea, abdominal pain, heartburn, weight gain, sedation, tremor, alopecia
HEPATOTOXICITY - monitoring of liver function is REQUIRED
Pregnancy Cat D
How is Clonazepam (Klonopin) used as an anticonvulsant?
Absence seizures, myoclonic seizures, and infantile spasms (West Syndrome)
MOA for Clonazepam (Klonopin)
It’s a Benzo
Stimulates GABA receptor and enhances GABAergic inhibition
Side effects of Clonazepam (Klonopin)
Sedating
Tolerance to anti-seizure effect
Pregnancy Cat D
Drug of choice for Status Epilepticus
Diazepam (Valium) and Lorazepam (Ativan)
Both are benzos
MOA for benzos
Stimulates GABA channel
All the anticonvulsants have some degree of teratogenicity but valproic acid increases the risk of …
Spina Bifida
Withdrawal from anticonvulsants can lead to…
Rebound increase in seizure activity
Overdose of anticonvulsants
CNS depression but rarely lethal
Need high drug plasma levels
Respiratory depression most common effect of large overdose
Do NOT treat with CNS stimulants
Which anticonvulsants increase the risk for Stevens Johnson Syndrome?
Drugs that block Na+ channels - Phenytoin, Lamotrigine, CARBAMEZAPINE, Valproate
Patients should be screened for HLA-B 1502
Failure rate of contraceptives is ____ for patients on anticonvulsants versus _____ in the general population
3.1% v 0.7%
Birth defects are ____ as likely when on anticonvulsants as opposed to general population rate
2x
Congenital heart defects and neural tube defects are most common
