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NMSK Exam 2: Neuro > Antiepileptic Drugs > Flashcards

Antiepileptic Drugs Flashcards

1
Q

Membrane depolarization leads to enhanced ________ receptor function & reduced _______ function. Epileptic seizures involve neurons firing at higher frequency than normal.

A

Membrane depolarization leads to enhanced excitatory (⬆︎ glutamate and aspartate) receptor function & reduced GABA function

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2
Q

4 mechanisms of AEDs (Anti-Epileptic Drugs)

A
  1. Supress excitatory (glutamate) transmission
  2. Enhance inhibitory (GABA) transmission
  3. Block low-threshold T-type Ca2+ channels
  4. Novel mechanism
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3
Q

How can we suppress excitatory (glutamate) transmission?

A
  1. Supress VGNav channels
  2. Supress ligand-gated AMPA/NMDA channels
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4
Q

Antiepileptic drugs that block pre-synaptic VGNa2+ by prolonging fast- inactivation state.

A
  • 1-3) Carbamazepine, Oxcarbazepine, Eliscarbazepine
  • 4-6) Lacosamide, Rufinamide, Zonisamide
  • 7) Lamotrigine
  • 8) Phenytoin
  • 9) Topiramate
  • 10) Valproic acid
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5
Q

Which AED is unique in that it can prolonging fast inactivationAND enhancing slow inactivation of VGNav2+ channels?

A

Lacosamide

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6
Q

AMPA-R ANT

MOA

A
  • 1. Topiramate
  • 2. Perampanel

MOA = bind to post-synaptic AMPA receptor and block glutamate binding; channel doesn’t open –> AP does not propogate downstream

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7
Q

NMDA-R ANT

MOA

A

Felbamate

  • MOA = bind to post-synaptic NMDA-R and block glutamate binding; channel doesn’t open –> AP does not propogate downstream
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8
Q

Describe VGNa channels during depolarization

A
  1. Resting state:
    1. Activation gate = CLOSED,
    2. Inactivation gate = OPEN
  2. Open state:
    1. Both gates OPEN
  3. Fast-inactivated state (cannot be reactived)
    1. Activation gate = OPEN
    2. Inactivation gate = CLOSED
  4. Inactivated-closed state
    1. Both gates CLOSED
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9
Q

The pharmacological activity of AED Nav channel blockers is _______ and ________-dependent

A

State and Use-dependent

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10
Q

AED’s binding site is at the _________ side Nav channel ‘pore’

A

Inside; activation gate must be open

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11
Q
  • If the _________ gate is open, AEDs can NTR pore and bind.
  • Which states can this occur?
A
  • Activation gate
  • Open state and Fast-inactivated state
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12
Q

Why do the AED’s that are VGNav+ blockers act preferentially on the neurons involved in epileptic seizures?

A

The probability of Na+ blockade is proportional to FREQUENCY of Nav channel opening and dose, The neurons involved in epilepsy will be firing at ⬆︎ frequency than normal, allowing more chances for these drugs to slip right in and bind

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13
Q

How can we enhance inhibitory (GABA) transmission?

A
  1. Presynaptic: Block GABA reputake or metabolism
  2. Post-synaptic: Poteniate GABA-A-R Cl-currents
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14
Q
  • Nothing bound to GABAA -R = ____________.
  • Binding to GABAA–R = ______________.
A
  • Nothing bound to post-synaptic GABAA -R = inactive Cl- channel closed.
  • Binding to post-synaptic GABAA–R = Cl- channel opens => hyperpolization = ⬇︎ AP propagation
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15
Q

MOA of the AED, Tiagabine?

A
  1. Blocks pre-synaptic reuptake of GABA by blocking the GABA transporter, GAT-1 =>⬆︎ GABA => bing to post-synaptic GABAA-R => hyperpolarization => ⬇︎ AP propogation
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16
Q

MOA of Valproic Acid

A
  1. ⬆︎ activity of glutamic acid decarboxylase => ⬆︎ presynaptic GABA
  2. Inhibit GABA-T, which typically metabolizes GABA
  3. Inhibit SSD (Succinic Semialdehyde Decarboxylase), which typically metabolized GABA
  4. *T-type Ca2+ channel ANT
  5. Prolongs fast inactivation of Na channels
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17
Q

MOA of Vigabatrin

A
  1. Inhibit GABA-T => prevents metabolism of GABA
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18
Q

Which 2 AED’s inhibit the metabolism of GABA by inhibiting GABA-T?

A

1. Valproic acid

2. Vigabatrin

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19
Q

Post-synpatic GABA-A AGO (enhance transmission)

MOA of each

A
  1. Barbituates (PB) (phenobarbital & primidone)
    1. Bind to allosteric site on GABA-A R => ⬆︎ DURATION of Cl- channel opening
  2. Benzos (Lorazepam, Diazepam, Clonazepam)
    1. Bind to allosteric site on GABA-A-R => potentiate effects of GABA by ⬆︎ FREQUENCY of Cl- channel opening
  3. Topiramate
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20
Q

Which drug in the barbiturate family gets metabolized to phenobarbital in the body?

A

Primidone

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21
Q

Of the GABA-A-R AGO used as AED’s which is more lethal at higher doses and why?

A
  • Barbituates (PB) are more lethal bc GABA INdependent
  • Benzodiazepines are GABA-dependent
22
Q

MOA of Topiramate

A
  1. GABA-A -R- AGO: ⬆︎ frequency of (+)
  2. AMPA-R ANT
  3. Fast inactivation of Navchannels
23
Q

Which type of ion channel causes the 3-Hz spike and wave activity in the thalamus, which is the hallmark of absence (petit mal) seizures?

A

T-type Ca2+ channels

24
Q

What type of drugs are useful for controlling absence/petit mal seizures?

A

T-type Ca2+ channels blockers, which cause 3 Hz spike and wave activity in thalamus

25
**T-type Ca2+ channel ANT** target \_\_\_\_\_\_
**CTX - thalamus oscillation**
26
Which **narrow spectrum drug** is only used for **absence seizures** and **_only_** limits excitation of Ca2+ channels?
**Ethosuximide**
27
**3 T-type Ca2+ channels ANT**
1. **Ethosuxamide** 2. **Valproic acid** (other axns) 3. **Zonisamide** (also prolongs fast inactivation of Na+ channel)
28
What is a complication of using **Zonisamide** as an AED in some patients?
Is a **sulfonamide** and people may have **allergies**
29
Which 2 AED's both are T-type Ca2+ channels ANT and prolong fast inactivation of Nav channels?
**1. Valproic acid** (also GABA-T inhibition) ## Footnote **2. Zonisamide**
30
**SV2A (Synaptic Vesicle 2A) Protein Blockers** (on presynaptic neuron)
1. **Levetiracetam** 2. **Brivaracetam**
31
**α2δ subunit of P/Q type Ca2+ Channel Blockers** (on presynaptic neuron)
1. **Gabapentin** 2. **Pregabalin**
32
**K+ Channel Openers** (on _pre_ AND _post_-synaptic neuron)
1. **Ezogabine**
33
What drug was FDA approved to treat Dravet Syndrome and Lennox Gaustaut Syndrome? MOA
**Cannabidiol (Epidiolex**) + used in combo w other AEDs: does NOT bind to CBD-R
34
**Warning** and **risks** of ALL AEDs
* **1. Abrupt withdrawal =\> status epilepticus** * **2. Suicidal behavior and ideation**
35
Issues with Phenytoin (3)
1. **Zero-order (saturable) pharmacokinetics:** ⬆︎ dosage can exceed Vmax 2. Induces CYP-450 enzymes =\> many drug-drug interactions 3. Gingival hyperplasia 4. Hypocalcemia/ Vit. D deficit/ Osteoporosis
36
* **Osteopenia/Osteoporosis** is a side effect associated with chronic administration of which 4 AED's? * What do these drugs induce?
* **1. Carbamazepine** * **2. Phenytoin** * **3. Phenobarbital** * **4. Valproic acid** \*These drugs induce _CYP450-dependent vitamin D catabolism_
37
**Carbamazepine** issues
1. **Induces of CYP-450 enzymes =\> drug interactions** 2. Causes **auto-induction (self-metabolism) =\> loss of efficacy and recurrance of seizures** 3. **Hematological toxicities**: leukopenia/ neutropenia/ thrombocytopenia
38
What other drug, besides Carbamazepine, induces its own metabolism?
**Lamotrigine (25%),** but to much less extebt
39
Before administering which AED is a **CBC** **required** as this drug has potential side effects including leukopenia, neutropenia, and thrombocytopenia?
**Carbamazepine**
40
What analogue of carbamazepine was formulated which has **fewer CNS/hematological SE's** and is a **less-potent CYP450 inducer?**
**Oxcarbazepine**
41
**Phenobarbital** issues
1. Coma, respiratory depression, fatality-risk 2. CYP450 inducer (drug interactions 3. CNS depressant 4. Hypocalcemia/ Vit. D deficit/ Osteoporosis
42
Which AED is only prescribe-able via **REMS (Risk-Evaluation and Mitigation Strategy)** program; why?
**Vigabatrin** - May cause progressive, **permanent**, **bilateral**, concentric **vision loss**
43
Which 4 AED's **induce CYP450,** which can have SERIOUS consequences in patients?
* **1. Carbamazepine** * **2. Phenytoin** * **3. Phenobarbital** * **4. Valproate**
44
What are 3 major AED-drug interactions associated with the CYP450 inducers?
1. ⬆︎ clearance of **oral contraceptives** --\> 2-4 fold rise in OHC failure rate; risk for unplanned pregnancy 2. ⬆︎ clearance of **warfarin** --\> less anticoagulation; ⬆︎ risk for arterial/venous thrombosis 3. ⬆︎ clearance of **HIV meds** --\> ⬆︎ risk for HIV replication
45
Which 2 AED's **inhibit** **conjugation/metabolism** of drugs by UGT causing **accumulation of parent drug** (esp. each other when used together)?
1. **Valproic acid** 2. **Lamotrigine**
46
Which 3 AED's **induce conjugation** of drugs by UGT causing a **⬇︎ of parent drug** (i.e., when given with valproic acid will ⬇︎ levels of valproic acid)?
**1) Phenytoin** **2) Carbamazepine** **3) Phenobarbital**
47
Which AED are 65-95% cleared by the kidney; thus, if we have renal insufficiency, doses have to be adjusted bc will ⬆︎ in blood?
1. Levetiracetam 2. Topiramate 3. Oxcarbazepine 4. Gabapentin / Pregabalin 5. Vigabatrin
48
What are some of the example causes of **Status Epilepticus, a MEDICAL MRGNC?**
1. Abrupt withdrawl of AED's, BZD's, Opioid's, Alcohol 2. - Brain mass/trauma 3. - Infection 4. - Fever
49
What is the initial therapy for convulsive **status epilepticus** (i.e., the first IV, alternative drug, and if no IV access)?
_- In first IV:_ - **Lorazepam** - Alternative - **Diazepam** \*Wait 3-5 minute for response then additional lorazepam PRN _- If no IV access:_ - **Midazolam** IM injection In 2nd IV: Fosphenytoin, phenytoin, valproic acid, levetiracetam
50
If treating convulsive status epilepticus adult and first IV treatment does not work, what are the AED's used in the **second IV treatment?**
1. **- Fosphenytoin** 2. **- Phenyotin** 3. **- Valproic acid** 4. **- Levetiracetam**
51
After inititial therapy in status epileptiuc and metabolic abnormalties are corrected, what is the 2nd therapy\>
1. Repeat Fosphenytoin if given before or any other 1st line drug not already given 2. Intubation, mechanical ventilation 3. Continous monitor of BP, cardiac monitoring 4. Prep for continous midazolam or propofol infusion

NMSK Exam 2: Neuro (15 decks)

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