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Pharmacology > !Antiepileptic Agents > Flashcards

!Antiepileptic Agents Flashcards

1
Q

What is a seizure

A

Transient alteration of behavior due to disordered, synchronous, and rhythmic firing or populations of brain neurons
-a disorder of neuronal excitability

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2
Q

Epilepsy

A

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

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3
Q

Partial seizures

A

Beginning vocally in a cortical site

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4
Q

Simple partial seizure

A

Preservation of consciousness

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5
Q

Complex partial seizure

A

Impairment of consciousnesss

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6
Q

Generalized seizure

A

Can occur after starting as a partial sz
Involves both hemispheres widely from the outset
—thalamus+cerebral cortex propogation

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7
Q

Manifestation seizures

A

Determined by functions normally served by cortical site where seizures arises

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8
Q

What are the types of generalized seizures

A

Absence seizures
Myoclonic seizure
Tonic clonic seizure

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9
Q

Membrane depolarization leads to enhanced __ receptor function and reduced __ function

A

Excitatory (glutamate aspartate)

GABA

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10
Q

What happens in the presynaptic terminal of GABA neuron

A

Glutamate is turned to GABA by GAD then stored in vesicles

GABA is turned to succinic semi-aldehyde by GABAT

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11
Q

What happens when GABA leaves the presynaptic terminal (either through GAT-1 or vesicle release)

A

Bind GABAA on post synaptic and extrasynaptic on postsynaptic neuron

Also

Enters astrocytes where it is turned to succin semi-aldehyde by GABA-T

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12
Q

Antiepileptic drugs (AEDs) act on what

A

Voltage gated Nav channels

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13
Q

What happens when AED bind voltage gated Nav channels

A

Generate rapid, transient inward currents driving action potential upstroke (excitable neuronal cells)

Cause neuronal action potential

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14
Q

Within a few milliseconds, the Nav channels close form inside the neuron and go into a __ __ state from which they cannot be deactivated..directly or instantly

A

Fast inactivated

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15
Q

Nav channels return to resting potential. After depolarization and repetitive neuronal activity, the Nav channel goes into a __ ___ state by closing the pore from the INSIDE

A

Slow inactivated

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16
Q

Nav resting state

A

-70 V

Activation gate closed

Inactivation gate open

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17
Q

Nav open state

A

Activation gate open
Inactivation gate open

0V

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18
Q

Fast inactivated state

A

Open activation gate

Closed inactivation gate

+25 V

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19
Q

Inactivated closed state

A

Closed activation gate
Closed inactivation gate

-70V

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20
Q

Resting state

A

Closed activation state
Open inactivation state

-70V

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21
Q

Where do AED bind the Nav receptor

A

At the interior side channel pore

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22
Q

If activation gate is open AED can ___ pore

A

Access

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23
Q

If inactivation gate is closed, AED ___ access pore

A

Cannot

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24
Q

Open is depolarized or depolarizing

A

Depolarizing

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25
Q

Fast inactivated state is depolarized or depolarizing

A

Depolarized

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26
Q

What states is the activation gate closed

A

Resting and inactivated closed

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27
Q

What states is the activation gates open

A

Resting state, open state, fast inactivated state

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28
Q

AED lamotrigine

A

Holds the fast inactivated state shut

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29
Q

The probability of a Nav blockade is proportional to the frequency of Nav channel opening and the _-

A

Dose

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30
Q

Epileptic seizures involve neurons firing at __ frequency than normal

A

Higher

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31
Q

Nav blockers act preferentially on neurons involved in __

A

Disease

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32
Q

Effects of AED

A

Prolong fast inactivation

Enhance slow inactivation

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33
Q

Which AED prolong fast inactivation state of Nav ion channels

A

Carbamazepine, oxcarbazine, lamotrigine, phenyoin, rufinamide, topiramate, valproic acid, zonisamide, and lacosamide

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34
Q

Which AED enhance slow inscativation of Nav chennsl

A

Lacosamide
(Reduces amplitude and frequency of sustained repetitive firing spikes when stimulus was prolonged to tens of seconds as opposed to less than 1 second (as with fast activators)

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35
Q

Lacosamide

A

Bind Nav

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36
Q

Which drugs bind Nav on presynaptic terminal

A

Phenytoin, carbamazepine, lamotrigine, LACOSAMIDE, zonisamide, oxcarbazepine, topiramate, valproic acid

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37
Q

What drugs are AMPA receptor antagonists

A

Topiramate and perampanel

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38
Q

What are AMPA receptors

A

Ligand gated ion channels Glu binding causes depolarization

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39
Q

Name a NMDA receptor antagonist

A

Felbamate

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40
Q

What is NMDA

A

Ligand gated ion channels Glu binding causes depolarization

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41
Q

When the GABA receptor is unoccupied, the Cl channel is___

A

CLOSED inactivated

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42
Q

When GABA receptor is occupied the Cl channel is ___

A

Open

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43
Q

What happens when GABAA receptor occupied

A

Hyperpolarization blunts AP propagation

44
Q

What drugs stop the biosynthesis of GABA in the presynaptic neuron(L-glu to GABA by glutamic acid decarboxylase)

A

Vigabatrin

Valproic acid

45
Q

What does vigabatrin do

A

Stop GABAT

46
Q

What does valproic acid strop

A

GABA-T and SSD

47
Q

What drug stops the reuptake of GABA by the terminal by GAT-1

48
Q

What is GAT-1

A

Actually for reuptake

49
Q

What drugs enhance post synaptic GABA-Eric neuronal transmission

A
  1. barbiturates (phenobarbital/primidone)
  2. benxodiazapines (lorazepam/diazepam/clonazepam)
  3. Topiramate
50
Q

Benzodiazepines

A

Bind to a distinct site->allosteric change potentiation GABA binding->Cl channels open with greater frequency

51
Q

Barbiturates

A

Bind to a distinct site and increases the duration of Cl channel opening

52
Q

Toxicity barbiturates

A

High doses of barbiturates are GABA independent

Lethality PB>benzodiazepines

53
Q

Lethality PB_BZd

54
Q

Barbiturates is ___ and benzodiazepine is ___

A

GABA independent

GABA dependent

55
Q

Barbiturates lethality

A

Respiratory depression

Coma

56
Q

Topiramate

A

GABAA agonist-

Increases frequency of GABAA receptor activation (AND fast inactivation of Nav channels AND AMPA-receptor antagonist)

57
Q

What are neuronal T type Ca channels

A

Mediate 3 Hz spike and wave activity in the thalamus

58
Q

Hallmark of what is of 3-Hz spike and wave activity in thalamus by T type Ca channels

A

Absence (Petit mal )seizures

59
Q

AED inhibit T type Ca channels

A

Useful for controlling absence seizures

60
Q

How treat absence seizures

A

Antagonist of T type Ca channels to target cortex-thalamus oscillation

61
Q

Ethosuximide

A

Narrow spectrum
Only used for absence seizures
Only limits Ca excitation (Ca channel)

62
Q

Ethosuximide, valproic acid, zonisamide

A

Antagonists of T type Ca channels

Prolong fast inactivation of Nav channels (valproic and zonisamide)

GABA-T inhibitor (valproic acid)

63
Q

What does levetiracetam

A

Books SV2A which allows release of synaptic vesicles of GAB from neuron presynaptic

64
Q

What do gabapentin and pregabalin do

A

Block a2delta subunit of P/Q-type Ca channel on presynaptic neuron

65
Q

What does retigabine do(only available in EU)

A

Block KCNQ K channel on pre and post synaptic which causes efflux of K

66
Q

What factors do physicians use to select AED

A 
FDA indications 
Side effects/toxicity profile
Pharmacokinetics-adherence (prevalence of significant medication non adherence in epilepsy has been reported to vary between 26 and 79%
Drug drug interactions 
Routes of administration 
Cost
67
Q

Broad warning risk of all AED

A

Abrupt withdrawal of antiepileptic medication may precipitate status epilepticus
Suicidal behavior and ideation

Suggests that the risk apples to all AED used for any indication

68
Q

Phenytoin pharmacokinetics

A

Zero order-dose titration upward may exceed Vmax of patient

69
Q

Phenytoin serum drug level monitoring

A

10-20 mg

Come >50 mcg/mL
Circulatory/respiratoy depresssion and death >95 mcg/mL

70
Q

Phenytoin is an inducer go what

A

CYP-450

Frequent drug drug interactions

71
Q

Toxicities of phenytoin

A 
Gingival hyperplasia (oral hygiene vital0
Hypothyroidism
CV risk (arrhythmia/hypotension 
Hypocalcemia/vit D deficits/osteoporosis **
72
Q

Osteopenia/osteoporosis are SE associated with

A

Carbamazepine, phenytoin, phenobarbital,valproic acid

73
Q

Why do carbamazepine, phenytoin, phenobarbital, and valproic acid cause osteopenia/osteoporosis

A

Induce CYP450 dependent vitamin D catabolism, thereby reduce circulating vitamin D levels. Resultant decreased absorption of intestinal Ca can trigger compensatory PTH mediated responses that demineralization bone to maintain systemic Ca homeostasis

74
Q

Carbamazepine serum monitoring level

A

4-12 mcg/mL

75
Q

Carbamazepine is an inducer of what

A

CYP 450 enzymes
Frequent drug drug interactions
Induces auto induction (self metabolism)

76
Q

Toxicities carbamazepine

A

Hematologic also:leukopenia/neutropenia/thrombocytopenia

Hypocalcemia/vitamin D deficit/osteoporosis

77
Q

CBZ induces its own ____

A

Metabolism (also lamotrigine does this)

78
Q

After 14 days of CBZ (and sometimes lamotrigine) CYP is increased. What does this cause

A

CBZ more metabolized and decrease in efficacy and could get recurrence of seizures

79
Q

Oxcarbazepine

A

Analogue of carbamazepine with fewer CNS/hematologic always SE;s due to formation of an alternative active metabolite, and is a less potent CYP450 inducer (dose dependent) (AE cross sensitivity 30%)

80
Q

Ox-CBZ turned into 10-monohydroxy ox-CBZ (s-licarbazine) by what

81
Q

10-monohydroxy ox-CBZ (S-licarbazine) is turned to glucuronide with what

A

Conjugation

82
Q

What happens when CYP3A4 reacts with CBZ

A

CBZ-10,11 epoxied (active and TOXIC)

83
Q

What happens when CBZ-10,11 epoxied reacts with epoxied hydroplane

A

10,11-diol and glucuronides

84
Q

Eslicarbazepine

A

A prodrug converged to S-licarbazine

85
Q

Phenobarbital serum drug level monitoring

A

10-40mcg.mL

Coma/respiratoy depression >50mcg/mL

Fatality risk >80 mcg.mL

86
Q

Phenobarbital is an inducer of what

A

CYP-450

Frequent drug drug interactions

87
Q

Toxicities of phenobarbital

A

CNS depressant

Hypocalcemia/vitamin D deficit/osteoporosis

88
Q

Vigabatrin is prescribable only by what

A

REMS program

89
Q

Toxicities of vigabatrin

A

Progressive, permanent, bilateral, concentric vision loss

D/C after mac of 3 months if no effective response

90
Q

Drug drug interactions associated with hepatic CYP450 induction

A

Carbamazepine, phenytoin, phenobarbital, valproate

91
Q

AED inducers can increase clearance of __ __ metabolized by CYP isoenzymes

A

Oral contraceptives

2-4 fold rise in OHC failure rate risk for unplanned pregnancy

92
Q

What birth control can you use with AED inducers

A

Long lasting reversible contraceptives including copper or levonorgestrel IUDs and etonogestrel implants

93
Q

AED inducers can increase clearance of ___ metabolized by CYP

A

Warfarin

Less anticoagulation elevated risk for arterial/venous thrombosis

94
Q

AED inducer can increase clearance of __ medication metabolized by CYP isoenzymes

A

HIV

Elevated risk for HIV replication

95
Q

Valproic acid and lamotrigine inhibit what

A

Conjugation of drugs by glucuronosyltransferases (UGT) causing accumulation of parent drug (espicially each other when used together)

96
Q

Phenytoin, carbamazepine and phenobarbital induce what

A

Conjugation of drugs by glucuronosyltransferases (UGT) causing reduction or parent drug (when given with valproic acid)

97
Q

Mixed clearance newer AED

A

Minimize drug interactions

98
Q

Renal clearance of newer AED minimized drug interactions . What drugs

A

Levetiracetam/topiramate/oxcarbazepine/gabapentin/pregabalin/vigabatrin

99
Q

65-100% renal clearance of these drugs. Renal insuffiency causes what

A

Dose adjustment

100
Q

Status epilepticus-a medical emergency

A

A seizure that persists for a sufficient length of time or is repeated frequently enough that recovery between attacks does not occur

101
Q

Causes of status epilepticus

A

Abrupt withdrawal of AEDs, BZds, opoids, alcohol, brain mass/trauma, infection, fever

102
Q

Initial therapy of epilepticus in adults

A

In 1st IV
-lorazepam .1mg/kg IV or 4mg IV (max 2 mg/minute)

Alternatives
-diazepam .15 mg/kg IV up to 10 mg per dose (max 5 mg/minute)

Wait 1 minute for response then additional lorazepam PRN

If no IV
Midazolam 10 mg IM is weight >40 kg

In second IV
Fosphenytoin 20mg/kg PE at 100 to 120 mg PE/minute OR
Phenytoin 20mg/kg at 25 to 50 mg/minutes OR
Valproic acid 30 mg/kg at 10 mg/kg/minute
Levetiracetam 40 to 60 mg/kg (maximum 4500 mg) over 15 minutes

103
Q

Second line therapy for treatment of convulsive status

A

Repeat fosphenytoin if given previously or choose among first line drugs not already given

Intubation, mechanical ventilation

Continuous blood pressure, cardiac monitoring

Prepare for continuous midazolam or propofol infusion

Then midazolam, propofol, pentobarbital

104
Q

Parenteral benzodiazepine choices initial regimen

A

Lorazepam, diazepam, midazolam, clonazepam

105
Q

Non sedation antiseizure choices (initial regimen )

A

Phenytoin, fosphenytoin, valproate, levetiracetam, lacosamide

106
Q

How treat status epilepticus

A

Initial therapy
-lorazepam or diazepam
Wait a minute for response then additional lorazepam

If no IV
Midazolam

In second IV
Fosphenytoin, or phenytoin, or valproic acid, or levetiracetam

Then correct metabolic abnormalities

Then repeat fosphenytoin incubate

Then prepare for continuous midazolam or propofol infusion

Start midazolam, propofol or pentobarbital

Pharmacology (52 decks)

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