Pharmacology Of Seizures & Epilepsy Flashcards Preview

Neuro II Final > Pharmacology Of Seizures & Epilepsy > Flashcards

Flashcards in Pharmacology Of Seizures & Epilepsy Deck (67):
1

Describe epilepsy

Acquired or inherited malfunction of neuronal ion channels or neurotransmitter systems disrupting normal electrical activity in brain

2

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

3

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

4

What are the generalized onset seizures?

Absence
Myotonic, atonic, clonic
Tonic/clonic (also partial onset)

5

What are the partial onset seizures?

Simple
Complex
Tonic/clonic (also generalized onset)

6

What drug treats absence seizures?

Ethosuximide
(Generalized onset)

7

What drugs treat the myotonic, atonic, clonic seizures?

Benzodiazepines
Clonazepam
(Generalized onset)

8

What drugs treat the tonic/clonic seizures?

Generalized: phenytoin, phenobarbital
Partial onset: carbamazepine

9

What are the broad spectrum AEDs?

Valproate
Lamotrigine
Topirimate
Levetiracetam
Zonisamide

10

What are the narrower spectrum AEDs?

Phenytoin
Phenobarbital
Carbamazepine
Gabapentin
Pregabalin
Oxcarbazepine
Lacosamide
Tiagabine
Vigabatrin
Ezogabin

11

What drugs treat simple and complex seizures?

(Narrower spectrum)
Carbamazepine
Gabapentin
Pregabalin
Oxcarbazepine
Lacosamide
Tiagabine
Vigabatrin
Ezogabin

12

AEDs antagonize excitation by targeting ___ and ____

Voltage-gated Na+ ion channels (Nav)
Low-threshold (T type) Ca2+ channels

13

What AEDs antagonize voltage-dependent Na+ channels?

Phenytoin
Carbamazepine

Lamotrigine
Oxcarbazepine
Zonisamide

14

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.

15

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

16

Which AEDs prolong fast inactivation state of voltage-gated Na+ ion channels?

Traditional AED: penytoin, carbamazepine
New AEDs: lamotrigine, oxcarbazepine

17

Which AEDs enhance slow inactivation of voltage-gated Na+ channels?

New AED: lacosamide

18

Voltage-gated Na+ channels generate rapid, transient inward currents that drive what?

Upstroke of action potentials of neurons and other excitable cells

19

Describe neuron action potential: Na+ channels during depolarization and repolarization

Depolarization:
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.

Repolarization:
3. Fast-inactivated state
4. Inactivated closed state: -70V. Activation and inactivation gates closed
1. Resting state

20

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?

True

21

Subunits of voltage-gated Na+ channels undergo conformational changes during action potential.
True or False

True

22

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

23

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

24

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

25

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

26

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

27

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

28

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

29

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)
-Non-sedating drug

30

Describe valproate

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

31

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

32

What drug inhibits GABA reuptake (transporters)?
What drug inhibits GABA metabolism (GABA-T)?

Inhibit reuptake: Tiagabine

Inhibit metabolism: Vigabatrin

33

List the drugs that enhance postsynaptic GABAergic neuronal transmission

Phenobarbital (and related barbiturate)
Primidone (active metabolite = phenobarbital)
Benzodiazapines (diazapam/lorazepam)

34

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

35

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

36

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

37

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)

38

What drugs are indicated for treatment of status epilepticus?

Benzodiazepines (diazepam or lorazepam)

39

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)
Poisons (strychnine)
Brain tumor
High fever
During natural disasters

Medical emergency (40-50,000 deaths/yr and thousands more of brain damage/yr)

40

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

41

Describe clonazepam

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

42

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

43

Mech and key points of gabapentin?

Binds to voltage-dependent Ca2+ channels
No significant drug interactions

44

Mech and key points of leviteracetam

Binds to synaptic vesicle protein SV2A, blunts glutamate release
Well-tolerated, no CYP interaction

45

Mech and key points of pregabalin

Multiple mech
100% renal clearance

46

Mech and key points of ezogabine

Opens voltage-gated K+ channels
Causes urinary retention

47

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

48

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

49

Describe complications with carbamazepine

Inducer of hepatic CYP 450 enzymes
Aplastic anemia (rare but often fatal) - idiosyncratic
Leukopenia, neutropenia, thrombocytopenia (infections, bruising)
Hypocalcemia, osteoporosis

50

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

51

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

52

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

53

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

54

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

55

Describe oxcarbazepine

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

56

Compare breakdown of OXCBZ and CBZ

OXCBZ -> reductase -> monohydroxyOXCBZ ->. Glucuronides

CBZ -> CYP3A4 -> active 10,11-CBZ epoxide (toxicity) -> epoxide hydrolase -> 10,11-diol glucuronides

57

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)

58

Describe renal clearance of gabapentin and pregabalin

100% renal clearance
Renal insufficiency requires dose adjustment

59

Life-threatening warning of carbamazepine

Allergic reaction (Stevens-Johnson syndrome)
Aplastic anemia

60

Life-threatening warning of lamotrigine

Allergic reaction (Stevens-Johnson syndrome)

61

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)

62

Serious adverse effects of levetiracetam

None

63

Serious adverse effects of oxcarbazepine

Hyponatremia (more common in elderly)
Rash

64

Serious adverse effects of tiagabine

Stupor

65

Serious adverse effects of topiramate

Nephrolithiasis
Open angle glaucoma
Hypohidrosis (mainly children)

66

Serious adverse effects of zonisamide

Rash
Renal calculi
Hypohidrosis (mainly children)

67

Which old AEDs are Class D teratogens?

Valproic acid (valproate) - spina bifida, atrial septal defect, cleft palate, hypospadias, polydactyly
Carbamazepine
Phenytoin