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Pharmacology and Medical Chemistry I > Exam 3 - Lecture 23 and 25, Anticonvulsants > Flashcards

Exam 3 - Lecture 23 and 25, Anticonvulsants Flashcards

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1
Q

Epilepsy

A

Greek “to be seized”

A group of syndromes characterized by recurrent, unprovoked seizures

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2
Q

Seizure

A

Latin “to take possession of”. An abnormal, excessive hyper synchronous discharge of a population of (cortical) neurons

Focal = partial

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3
Q

Convulsion

A

Sudden, irregular, involuntary muscle contraction

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4
Q

Epileptogenesis

A

The process by which a “normal” brain becomes epileptic

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5
Q

Refractory epilepsy

A

Epilepsy remains uncontrolled following prescription of 2 different drugs. Also called intractable or pharmacoresistant

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6
Q

Symptomatic epilepsy

A

Results from a known/ suspected CNS disorder

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7
Q

Idiopathic epilepsy

A

No known cause, possibly genetic

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8
Q

Cryptogenic epilepsy

A

The disease etiology is unknown

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9
Q

Generalized tonic-clonic seizure

A

(classic seizure phenotype)

~20-30% of patients

Tonic Phase -> Clonic Phase -> Post-ictal confusional Fatigue

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10
Q

Ictal State

A

The seizure

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11
Q

Postictal State

A

State of altered consciousness after a seizure. Lasts 5 - 30 min, characterized by drowsiness, confusion, nausea, hypertension, headache or migraine and other disorienting symptoms

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12
Q

Simple Partial seizures

A

~ 10 to 15% of patients

Auditory - Hiss or ringing in ears
Visual - See flashes of light, blurring etc
Somatosensory - Tingling of face, side of body
Focal Motor - Tonic-clonic movements of upper/lower limb
Autonomic - Sweating, flushing
Grimacing
Head and eyes turned opposite sides

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13
Q

Complex Partial Seizures

A

~20 - 50% of patients “Grand Mal”

Dysphasia
Olfactory Hallucinations
Formed visual hallucinations - seeing a tree that’s not there
Formed auditory hallucinations - hearing music etc
Dreamy state, blank face
Psychomotor phenomena - chewing movement, wetting lips
Impairment of consciousness - cognitive, affective symptoms

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14
Q

Sudden unexpected death in epilepsy

A

SUDEP

Defined as the sudden and unexpected, non-traumatic and non-growing death of a person with epilepsy, without a toxicological or anatomical cause of death detected during the post-mortem examination

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15
Q

SUDEP Risk Factors

A

Males, mostly younger because don’t survive to older age

Severe refractory seizures
Poor compliance
Young age and early age of seizures onset
Biologically male
Being asleep during seizure
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16
Q

SUDEP mechanism

A

Seizure in brain causes a chain reaction, causing issues with heart rate and breathing.

Causes apnea (stop breathing), Arrhythmia and Asystole (No contraction) of heart

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17
Q

How is epilepsy treated

A

Anti-convulsant/seizure/epileptic drugs
Surgery - specific focal lesions vs corpus callostomy
Ketogenic diet - no carbs, burn fat release ketones
Implanted device - Vagus nerve or deep brain stimulator

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18
Q

Properties of an ideal anti epileptic drug

A

Highly effective, low incidence of toxicity
Effective against more than one seizure type
Long lasting, long half life
Non-sedating
Inexpensive
No tolerance, particularly to anticonvulsant effect

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19
Q

Categories of AED

A 
SV40 binders
Ion channel ligands
Barbiturate
Benzodiazepines
Novel AEDs
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20
Q

Carbamazepine (Tegretol)

A

MoA: Sodium Channel Blocker, state dependent
Low efficacy inhibitor of 5HT reuptake

FDA approved for: Partial seizures, Generalized tonic-clonic seizures, Mixed seizures, Trigeminal neuralgia, Mania in bipolar disorder

Side effects: DRESS syndrome (Drug reaction with eosinophilia and systemic systems) or DIHS (drug-induced hypersensitivity syndrome). Suicidal tendency, hyponatremia, Spina bifida

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21
Q

Lamotrigine (Lamictal)

A

MoA: Sodium channel blocker, state dependent binds when channel is moving between closed-open-inactive

Indications: Focal seizures, Tonic-clonic seizures, Lennox Gastaut syndrome, Recurrent depressive episodes in bipolar disorder

Side effects: in >10% of patients, Nav1.7 channels activate nerves, leading to a rash. Arrhythmias rare but possible in case of OD. Long list of side effects

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22
Q

Valproic Acid (Depakene)

A

MoA:
Enhances Na channel inactivation (state dependent, likes to hold in inactive state), Low efficacy block of Cav3 channels, No effect on GABAA receptor function

Side effects:
Frequent GI (16%), anorexia, nausea, vomiting
CNS: sedation, ataxia, tremor (not common)

Toxicity:
Rare, fulminant hepatits (liver death) often fatal
Combo with clonazepam has caused absence status epileptics (rare)

Effective in many seizure models and clinical seizure types

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23
Q

Lacosamide (Vimpat)

A

MoA:
Enhances Na inactivation, state dependent…likes to hold in inactive state.
Binds to collapse-in response mediator protein 2 (crmp-2)

Approved for:
adjunct partial onset seizures in 17yr +
Patients with diabetic neuropathic pain
oral or injectable dosage forms
effective as add on in refractory partial seizures

Side effects: headache, drowsiness, blurred vision and tremor

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24
Q

Levetiracetam (Keppra)

A

Novel MoA:
Binds Vesicle protein SV2A, stereoselective
Pyrrolidine s-enantiomer of a protest nootropic agent

FDA approved for:
Partial-onset seizure, Myclonic seizure, Tonic-clonic seizure

Side effects:
Psychosis, Suicidal ideation, somnolence (drowsiness), Asthenia (lack of strength), Dizziness….low incidence of side effects

Dose not interact metabolically with other AEDs

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25
Q

3D printing drugs

A

Keppra first FDA approved

cool because you could potentially make a tablet of any dose using this method

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26
Q

Target: Voltage-gated sodium channels

A

Carbamazepine, lamotrigine, lacosamide

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27
Q

Target: Voltage-gated calcium channels (T-type)

A

Ethosuximide

28
Q

Target: Voltage-gated potassium channels

A

Retigabine (ezogabine)

29
Q

Target: SV2A

A

Levetiracetam

Brivaracetam

30
Q

Target: a2d

A

Gabapentin, gabapentin enacarbil, pregabalin

31
Q

Target: AMPA receptor

A

Perampanel

32
Q

Sodium Channel structure

A

24 transmembrane domains

Channels made up of Alpa and Beta subunits

Voltage sensing domain is responsible for opening and closing channel

33
Q

Hodgkin-Huxley Model

A

Closed - Open - Activated

Closed when some domains of subunits are “down” and open when domains move “up”

34
Q

Most common Sodium channels in CNS

A

Nav 1.2 also 1.1, and 1.6

1.3 is only in development, not much in adults

35
Q

Pathophysiology of Nav channels

A

You want drug to target specific sodium channel, since there are sodium channels all over the body

Ex… targets 1.2 and also 1.7 (expressed in bunch of other spots) or 1.5 (which is in heart)

36
Q

Brivaracetam (Briviact)

A

MoA:
Binds to vesicle protein SV2A; stereoselective, reducing neurotransmitter release

FDA approved for:
Partial seizures
Alternative to levetiracetam if adverse effects observed

Adverse effects:
Somnolence (drowsiness)
Asthenia (lack of strength)
Dizziness
Nausea
Coadmin with carbamazepine or phenytoin increase their efficacy, potentially reducing tolerance
37
Q

Gabapentin (Neurontin)

A

MoA:
Binds to a2d subunit of voltage-gated Ca2+ channels to inhibit channel function
Subunits of pre-synaptic P/Q type Ca2+ channels
Reduces presynaptic neurotransmitter release
DOES NOT INTERACT WITH GABA-PHYSIOLOGY

FDA approved for:
Partial seizures
Neuropathic pain
Trigeminal neuralgia
RLS
Adverse effects:
Dizziness
Fatigue
Ataxia
Suicidal Tendency
Addiction
38
Q

Perampanel (Fycompa)

A

MoA:
Non-competitive antagonist at post-synaptic AMPA receptors
AMPA-receptors are glutamatergic ion channels

FDA approved for:
Partial seizures
Tonic-clonic seizures
Patients over 12 years old

Adverse effects:
Fetal Damage
Black box warning - homicidal ideation (have to monitor in hospital first before being sent home)
OD can cause euphoria

39
Q

Negative allosteric Modulators

A

Bind to allosteric site and LOWER THE POTENCY AND/OR EFFICACY of the agonist that binds at the orthosteric site

NAM

40
Q

Positive allosteric Modulators

A

Bind to the allosteric site and INCREASE THE POTENCY AND/OR EFFICACY of the agonist that binds at the orthosteric site

PAM

41
Q

Silent allosteric Modulators

A

Also called neutral allosteric ligands, bind to the allosteric site of a receptor and have NO effect on efficacy/potency of the orthostric ligand.

They prevent NAMS and PAMS from interacting with receptor

42
Q

Retigabine (Ezogabine, Potiga, Trobalt)

A

MoA:
Activates M-current (mediated by Kv7 [KCNQ] voltage-gated potassium channels)

Activation of channels increases K flux and stabilizes the resting potential of the neurons below the firing threshold. RTG activates the channels and inhibits the seizures.

FDA approved:
Partial seizures

Off-label use:
Migraine
Trigeminal neuralgia
Neuropathic pain

Adverse effects:
Dizziness and vertigo
Fatigue
Blue skin discoloration
Slurred speech
43
Q

Barbiturates

A

Effective agents partial and generalized seizures, easy to OD

Ex. Phenobarbital, primidone, mephobarbital

44
Q

Benzodiazepines

A

Effective against limited forms of partial or generalized seizures and status epilepticus.

Ex. Clonazepam, lorazepam, diazepam, midazolam, clorazepate, clobazam

Most widely prescribed and used

45
Q

Chlordiazepoxide (Librium)

A

First Benzo

Sedative, hypnotic, anxiolytic, anti-convulsant effects

Subject to abuse and has many side effects

46
Q

Clonazepam

A

Fewest side effects, best tolerated

MoA benzos:
Allosteric modulators GABA Rs

Low efficacy block of Cav3 channels
Suppresses seizure focus and enhances surround inhibition

Side effect:
related to CNS depression

Effective for:
Absence and myoclonic seizures

Issues:
Extensive anticonvulsant tolerance

47
Q

Cannabidiol (Epidiolex)

A

MoA:
Low affinity for CB- receptors
Antagonist at GPR55, inverse agonist at GPR3,6,12
Allosteric modulator at mu and d opioid receptors
Blocks Nav channels

FDA approved for:
Lennox Gaustaut Syndrome
Dravet Syndrome
Epilepsy in tuberous sclerosis complex

Adverse reactions:
Somnolence (drowsiness)
Decreased appetite
Diarrhea
Sleep distrurbance
48
Q

Stiripentol (Diacomit)

A

MoA:
Increases GABAergic signaling (Unclear if it is a direct effect on GABAA-Rs, increased release of GABA or maintenance of GABA levels in synaptic cleft)

FDA approved for:
Dravet Syndrome, particularly as add on to valproate
Not known if useful in adolescents or adults

Adverse effects:
Somnolence
Decreased appetite
Ataxia 
Sleep disturbance
Neutopenia
Aggressive, irritable behavior (in children)
49
Q

GABAa receptor channels

A

Need Alpha and Beta together to make GABA site.

Need 5 subunits to make a receptor, different combos have different properties

50
Q

Benzodiazepines mechanism of action

A

Allosteric modulators at GABAA receptors

51
Q

Barbiturates mechanism

A

Positive allosteric modulators,
Agonist at GABAA receptors
Antagonist at AMPA/Kainate receptors
Minor effects on CAv channels, glycine and nAChRs

52
Q

First line Anti-seizure

A

Clobazem and valproic acid

53
Q

Second line Anti-seizure

A

stiripentol, topiramate, ketogenic diet

54
Q

Third line Anti-seizure

A

clonazepam, levetiracetam, zonisamide, ethosuximide, VNS

55
Q

Contraindicated

A

carbamazepine, oxcarbazepine, lamotrigine, phenytoin, and vigabatrin

56
Q

How does decreased Na+ current lead to disease?

A

These channels cause changes in inhibitory neurons, by decreasing inhibition it makes it impossible to bring excitatory signals under control

57
Q

KCNQ

A

6 transmembrane proteins

Mutations in KCNQ2 or 3:
can lead to pediatric epilepsies or deafness…unsure if its due to loss or gain of function

can also lead to SUDEP

58
Q

Hm1a toxin

A

comes from a spider

decreases seizure frequency and improves survival in mice. reduce seizures and live longer

Binds to voltage sensing domain Na channel

59
Q

Considerations for development of future AEDs

A

Considerations:
Experimental models
Druggable targets
Alternatives to pharmacological intervention?
How to design clinical trial….. hard to do tests if you need to keep patient on whatever AED they are already taking

Possibilites
Computational approach to SAR based on structural biology
Completely novel drug scaffolds

60
Q

GABA synthesis

A

Glutamine -> Glutamate -> GABA

Vigabatrin inhibits GABA conversion into Succinate Semialdehyde, increasing GABA levels

61
Q

M- current (KCNQ channels)

A

Chanel needs PIP2 for activation

Hydrolysis of PIP2 decreases M-current, resting membrane potential depolarizes (voltage goes up)

Acetylcholine inhibits channels, by acting on PIP2

K+ current helps regulate excitability, reducing K+ current makes it easier for action potentials to fire…making it easier for seizures to start

62
Q

Benzodiazepine binds to….

A

Between alpha/gamma subunits GABAa receptor

63
Q

Barbiturate binds to…

A

Between alpha/beta subunits GABAa receptor

64
Q

Most common risk factors epilepsy

A

No identified risk factors followed by family history related

65
Q

How to terminate action potentials

A

Block Nav channels
Block neurotransmitter release
Blocks postsynaptic receptor activation
Increase opening of Kv channels

Pharmacology and Medical Chemistry I (30 decks)

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