Flashcards in Pharmacology Of Seizures & Epilepsy Deck (67):
Acquired or inherited malfunction of neuronal ion channels or neurotransmitter systems disrupting normal electrical activity in brain
Are anti-epilepsy drugs (AEDs) effective?
AEDs can stop seizures from occurring in 2/3 of pts, but they do not cure epilepsy.
There are >32 AEDs available for therapy.
About 25% of pts discontinue their medication because of significant side effects
Seizure free with:
1st drug: 47%
2nd drug: 13%
3rd drug or multidrugs: 4%
36% not seizure free
Drugs used to treat epilepsy target neurotransmitter systems in order to suppress excitatory, i.e. Glutamate transmission, and/or enhance inhibitory, GABA transmission. Side effects?
Because glutamate and GABA are ubiquitous neurotransmitters throughout CNS, side effects of these therapies involve a broad array of brain mechanisms, from regulation of homeostasis to alteration in higher brain functions
What are the generalized onset seizures?
Myotonic, atonic, clonic
Tonic/clonic (also partial onset)
What are the partial onset seizures?
Tonic/clonic (also generalized onset)
What drug treats absence seizures?
What drugs treat the myotonic, atonic, clonic seizures?
What drugs treat the tonic/clonic seizures?
Generalized: phenytoin, phenobarbital
Partial onset: carbamazepine
What are the broad spectrum AEDs?
What are the narrower spectrum AEDs?
What drugs treat simple and complex seizures?
AEDs antagonize excitation by targeting ___ and ____
Voltage-gated Na+ ion channels (Nav)
Low-threshold (T type) Ca2+ channels
What AEDs antagonize voltage-dependent Na+ channels?
Describe inactivation of voltage-gated Na+ channels
Within a few milliseconds, the channels close from inside of neuron and go into a fast inactivated state from which they cannot be reactivated, directly or instantly.
Describe repolarization of voltage-gated Na+ channels
Na+ channels return to resting potential.
During prolonged depolarization and repetitive neuronal activity, Na+ channel goes into slow inactivated state by closing pore from inside
Process happens on second-to-minute time scale
Which AEDs prolong fast inactivation state of voltage-gated Na+ ion channels?
Traditional AED: penytoin, carbamazepine
New AEDs: lamotrigine, oxcarbazepine
Which AEDs enhance slow inactivation of voltage-gated Na+ channels?
New AED: lacosamide
Voltage-gated Na+ channels generate rapid, transient inward currents that drive what?
Upstroke of action potentials of neurons and other excitable cells
Describe neuron action potential: Na+ channels during depolarization and repolarization
1. Resting state: -70V. Activation gate closed. Inactivation gate open.
2. Open state: 0V. Activation and inactivation gates open
3. Fast-inactivated state: +25V. Activation gate open. Inactivation gate closed.
3. Fast-inactivated state
4. Inactivated closed state: -70V. Activation and inactivation gates closed
1. Resting state
Voltage-gated Na+ channels are targets for drugs, used to treat epilepsy, seizures, pain, and cardiac arrhythmias.
Drugs used to treat these disorders exhibit little or no selectivity for these channel subtypes.
True or False?
Subunits of voltage-gated Na+ channels undergo conformational changes during action potential.
True or False
Describe AEDs' binding to voltage-gated Na+ channels
AEDs' binding site is at interior side of the voltage-gated Na+ channel pore
If activation gate opens, AEDs can access pore
If activation gate closes, AEDs cannot access pore
Pharmacological activity of AED voltage-gated Na+ channel blockers is state or use-dependent
Probability of a voltage-gated Na+ channel blockade is proportional to what? Relevance?
Proportional to frequency of Nav channel opening and dose
Epileptic seizures involve neurons firing at a higher frequency than normal
Therefore, Nav blockers act preferentially on neurons involved in disease
Describe how phenytoin and carbamazepine modulate voltage-gated Na+ channels
Phenytoin and carbamazepine are state-dependent agents that slow the recovery of Nav ion channels from inactivation
Phenytoin is most effective at depolarized membrane potentials and high-frequency action potential firing. This state-dependence causes minimal effects on cognitive functions (low-frequency firing)
Carbamazepine binds Nav less effectively, but with a much faster rate than phenytoin, making carbamazepine more effective in blocking high-frequency firing.
These differences may correlate with different clinical responses
Describe how lamotrigine modulates voltage-gated Na+ channels
Similar to that of phenytoin and carbamazepine (voltage and use dependence)
However, lamotrigine also acts on other molecular targets, such as N- and P-type voltage-gated Ca2+ channels in cortical neurons and neocortical potassium currents
Therefore, its anti-epileptic action is not identical
Describe the effect of lacosamide on Na+ channels and explain how this distinguishes it from other AEDs that target Na+ channels
Lacosamide is a novel AED that effectively treats partial seizures
It stabilizes the slow-inactivated state (-70V, both gates closed), while other AEDs act primarily on fast-inactivation state (+25V, inactivation gate closed)
In a prolonged train of depolarizing stimuli, lacosamide is more effective at reducing amplitudes and frequency of sustained repetitive firing spikes when the stimulus was prolonged to tens of seconds as opposed to less than 1 sec.
By contrast, AEDs like phenytoin, carbamazepine, and lamotrigine exert their action over a substantially shorter time scale
Describe voltage-sensitive Ca2+ channels (VSCC)
VSCC mediate Ca2+ ions entry into excitable cells
There are 3 types of neuronal Ca2+ channels: L, N, and T
Describe the T-type Ca2+ channels
These mediate 3 Hz spike and wave activity in thalamus, which is the *hallmark of absence (petit mal) seizures
AEDs that inhibit these T-type Ca2+ channels are particularly useful for controlling absence seizures
What do antagonists of T-type Ca2+ channels target? What drug is ONLY used to treat absence (petit mal) seizures?
Targets cortex-thalamus oscillation
Narrow spectrum AED ethosuximide
-only used for absence seizures
-only limits excitation (Ca2+ channel)
For many years, valproate was the only broad-spectrum agent available and is still considered first-line therapy by many experts for generalized onset seizures
Has intolerable adverse effects: weight gain, tremor, hair loss, and lethargy
Has also been associated with neural tube defects in offsrping of women who take it during pregnancy
Describe the MOA of zonisamide
Zonisamide is a sulfonamide derivative that is chemically and structurally unrelated to other anticonvulsants
Its primary mechanisms of action are:
1. Blocking voltage-dependent Na+ channels
2. Blocking T-type Ca2+ channels
What drug inhibits GABA reuptake (transporters)?
What drug inhibits GABA metabolism (GABA-T)?
Inhibit reuptake: Tiagabine
Inhibit metabolism: Vigabatrin
List the drugs that enhance postsynaptic GABAergic neuronal transmission
Phenobarbital (and related barbiturate)
Primidone (active metabolite = phenobarbital)
What are phenobarbital's complications?
Powerful, nonspecific CNS depression
Can cause significant sedation
Can cause lethal respiratory depression
Has abuse & addiction potential
These liabilities led to development of benzodiazepines
Describe postsynaptic GABAergic transmission
1. GABAa receptor unoccupied = inactive Cl- channels closed
2. GABAa receptor sub-units occupied = Cl- channel opens
3. Hyperpolarization blunts AP propagation
Describe benzodiazepines MOA at postsynaptic GABAa Cl- channel
Benzodiazepines (BZD) bind to distinct site -> allosteric change potentiates GABA binding ->Cl- channels open with greater frequency
Describe barbiturates MOA at postsynaptic GABAa Cl- channel and toxicity
Phenobarbital (PB) binds to distinct site and increases duration of Cl- channel opening
Toxicity: high doses of barbiturates are GABA independent
Lethality PB>BZD (GABA dependent)
What drugs are indicated for treatment of status epilepticus?
Benzodiazepines (diazepam or lorazepam)
Describe status epilepticus
Epileptic seizures can occur without convulsions (absence seizures). Seizures can occur without epilepsy:
Drug withdrawal (alcohol, benzodiazepines, opioids, AEDs)
Stimulant abuse (cocaine)
During natural disasters
Medical emergency (40-50,000 deaths/yr and thousands more of brain damage/yr)
Describe treatment of status epilepticus
Goal: Stop seizure/EEG bursts
Initial treatment: GABAergic agents that increase inhibition
IV lorazepam/diazepam ~5 min
If seizure doesn't stop, Fosphenytoin IV, which is a Na+ channel antagonist
Benzodiazepine drug of choice for myoclonic seizures and subcortical myoclonus
Sedative effect and tolerance are similar to those of other benzodiazepines
Very effective in emergency treatment of status epilepticus, like diazepam, and can be given IV or rectally
What are the drugs that have multiple MOA?
Topirimate: voltage-gated Na+ channels, ligand-gated Na+ channels (AMPA/glutamate receptor - receptor antagonist that prevents depolarization), increases GABA, potentiates GABAa receptors (agonist)
Valproic acid (valproate, divalproate): voltage-gated Na+ channels, T-type Ca2+ channels, increases GABA
Mech and key points of gabapentin?
Binds to voltage-dependent Ca2+ channels
No significant drug interactions
Mech and key points of leviteracetam
Binds to synaptic vesicle protein SV2A, blunts glutamate release
Well-tolerated, no CYP interaction
Mech and key points of pregabalin
100% renal clearance
Mech and key points of ezogabine
Opens voltage-gated K+ channels
Causes urinary retention
Why do doctors choose different drugs for same type of seizure?
Seizure type is one determinant of drug utility
Pharmacokinetic properties (absorption, distribution, metabolism, elimination) are also a determinant of compliance, toxicity, and adverse effects, particularly interactions with other drugs administered together with AEDs
Describe the complications with phenytoin
Zero-order pharmacokinetics (doubling dose does not necessarily double serum level. Dose adjustment difficult)
Inducer of hepatic CYP 450 enzymes
Distinct toxicities: gingival hyperplasia, hirsutism, hypocalcemia, osteoporosis
Describe complications with carbamazepine
Inducer of hepatic CYP 450 enzymes
Aplastic anemia (rare but often fatal) - idiosyncratic
Leukopenia, neutropenia, thrombocytopenia (infections, bruising)
Describe osteopenia/osteoporosis side effects
Serious side effects associated with chronic administration of carbamazepine, phenytoin, phenobarbital, and valproic acid
These drugs induce cytochrome P450-dependent vitamin D catabolism, and thereby reduce circulating vitamin D levels
Resultant decreased absorption of intestinal Ca2+ can trigger compensatory PTH-mediated responses that demineralize bone to maintain systemic Ca2+ homeostasis
Describe drug level monitoring of carbamazepine
Levels must be monitored early in therapy
Dosage increases up to 15 to 20 mg/kg per day may be necessary after 2-3 months because of CYP450 autoinduction.
Serum levels should be checked every 2 months until successive determinations are constant.
Levels should be checked if dosages are changed or other antiepileptic drugs are added to regimen
Describe AED-drug interactions: oral contraceptives
Starting carbamazepine can increase clearance of oral contraceptives (estrogen) metabolized by CYP isoenzymes
4-fold risk in OCP failure rate.
Risk for unplanned pregnancy
AED-drug interactions: oral anti-coagulants
Starting carbamezpine can increase clearance of warfarin (oral anti-coagulant) metabolized by CYP isoenzymes
Too rapid coagulation. Elevated risk for arterial/venous thrombosis
Describe ADME of new AEDs
Mixed clearance renal-hepatic
Topiramate, oxcarbazepine, levetiracetam, zonisamide
Renal clearance >50% of total
Generally, newer AEDs have fewer problems attributable to drug interactions associated with hepatic metabolism. However, can still have serious toxicities
Analogue of carbamazepine but with advantage of fewer adverse effects due to its lack of formation of active metabolite
Metabolism of oxcarbazepine occurs in liver, but with minimal effects to CYP450 enzymes. Advantageous in pts who require multiple drugs
Compare breakdown of OXCBZ and CBZ
OXCBZ -> reductase -> monohydroxyOXCBZ ->. Glucuronides
CBZ -> CYP3A4 -> active 10,11-CBZ epoxide (toxicity) -> epoxide hydrolase -> 10,11-diol glucuronides
What causes hyponatremia associated with both oxcarbazepine and carbamazepine?
Due to increased responsiveness of collecting tubules to antidiuretic hormone and is considered to be example of syndrome of inappropriate secretion of antidiuretic hormone (SIADH)
Describe renal clearance of gabapentin and pregabalin
100% renal clearance
Renal insufficiency requires dose adjustment
Life-threatening warning of carbamazepine
Allergic reaction (Stevens-Johnson syndrome)
Life-threatening warning of lamotrigine
Allergic reaction (Stevens-Johnson syndrome)
What hepatic enzyme do valporate and lamotrigine inhibit?
They inhibit conjugation of drugs by UGT enzymes, causing accumulation of parent drug (each other when used together, which they often are)
Serious adverse effects of levetiracetam
Serious adverse effects of oxcarbazepine
Hyponatremia (more common in elderly)
Serious adverse effects of tiagabine
Serious adverse effects of topiramate
Open angle glaucoma
Hypohidrosis (mainly children)
Serious adverse effects of zonisamide
Hypohidrosis (mainly children)