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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

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
3D printing drugs
Keppra first FDA approved cool because you could potentially make a tablet of any dose using this method
26
Target: Voltage-gated sodium channels
Carbamazepine, lamotrigine, lacosamide
27
Target: Voltage-gated calcium channels (T-type)
Ethosuximide
28
Target: Voltage-gated potassium channels
Retigabine (ezogabine)
29
Target: SV2A
Levetiracetam | Brivaracetam
30
Target: a2d
Gabapentin, gabapentin enacarbil, pregabalin
31
Target: AMPA receptor
Perampanel
32
Sodium Channel structure
24 transmembrane domains Channels made up of Alpa and Beta subunits Voltage sensing domain is responsible for opening and closing channel
33
Hodgkin-Huxley Model
Closed - Open - Activated Closed when some domains of subunits are "down" and open when domains move "up"
34
Most common Sodium channels in CNS
Nav 1.2 also 1.1, and 1.6 1.3 is only in development, not much in adults
35
Pathophysiology of Nav channels
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
Brivaracetam (Briviact)
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
Gabapentin (Neurontin)
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
Perampanel (Fycompa)
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
Negative allosteric Modulators
Bind to allosteric site and LOWER THE POTENCY AND/OR EFFICACY of the agonist that binds at the orthosteric site NAM
40
Positive allosteric Modulators
Bind to the allosteric site and INCREASE THE POTENCY AND/OR EFFICACY of the agonist that binds at the orthosteric site PAM
41
Silent allosteric Modulators
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
Retigabine (Ezogabine, Potiga, Trobalt)
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
Barbiturates
Effective agents partial and generalized seizures, easy to OD Ex. Phenobarbital, primidone, mephobarbital
44
Benzodiazepines
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
Chlordiazepoxide (Librium)
First Benzo Sedative, hypnotic, anxiolytic, anti-convulsant effects Subject to abuse and has many side effects
46
Clonazepam
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
Cannabidiol (Epidiolex)
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
Stiripentol (Diacomit)
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
GABAa receptor channels
Need Alpha and Beta together to make GABA site. Need 5 subunits to make a receptor, different combos have different properties
50
Benzodiazepines mechanism of action
Allosteric modulators at GABAA receptors
51
Barbiturates mechanism
Positive allosteric modulators, Agonist at GABAA receptors Antagonist at AMPA/Kainate receptors Minor effects on CAv channels, glycine and nAChRs
52
First line Anti-seizure
Clobazem and valproic acid
53
Second line Anti-seizure
stiripentol, topiramate, ketogenic diet
54
Third line Anti-seizure
clonazepam, levetiracetam, zonisamide, ethosuximide, VNS
55
Contraindicated
carbamazepine, oxcarbazepine, lamotrigine, phenytoin, and vigabatrin
56
How does decreased Na+ current lead to disease?
These channels cause changes in inhibitory neurons, by decreasing inhibition it makes it impossible to bring excitatory signals under control
57
KCNQ
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
Hm1a toxin
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
Considerations for development of future AEDs
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
GABA synthesis
Glutamine -> Glutamate -> GABA Vigabatrin inhibits GABA conversion into Succinate Semialdehyde, increasing GABA levels
61
M- current (KCNQ channels)
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
Benzodiazepine binds to....
Between alpha/gamma subunits GABAa receptor
63
Barbiturate binds to...
Between alpha/beta subunits GABAa receptor
64
Most common risk factors epilepsy
No identified risk factors followed by family history related
65
How to terminate action potentials
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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