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Drug Action III > Seizures (Med Chem) - Block 1 > Flashcards

Seizures (Med Chem) - Block 1 Flashcards

1
Q

What is the desired mechanism for seizure drugs?

A
  1. Suppress formation or spread of abnormal electrical discharges
  2. Modify ion conductance
  3. Increase inhibitory GABA transmission
  4. Decrease excitatory glutamine activity
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2
Q

Differentiate the AED gens?

A

First generations – very efficacious but complicated PK, many DDIs and increased incidence of adverse effects
Second generations – unique MOAs, better tolerability. Often used first in pharmacotherapy
Third generations – Reserved for failure of other agents or as adjunctive therapies because of cost, limited long-term experience

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3
Q

Patient who have unsatisfactory control are considered to be?

A

Drug resistant

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4
Q

Does AED cure epilepsy?

A

AED treats sx not the underlying pathology

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5
Q

What is the ideal AED?

A

TO suppress sz without sedation or CNS ADRs
Status epilepticus: Rapid onset after parenteral inj
Prophylaxisis: Long duration after PO with constant therapeutic levels

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6
Q

Describe the SAR of AEDs?

A
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7
Q

What is the resting potential?

A

-50 to -80 mV

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8
Q

Describe the action of Na+ channels from closed to open?

A

NaCl is greater concentrations outside, K is inside:
1. Neurons are depolarized -> NaCl undergoes a conformationalchange -> closed to open conduction -> Na flux
2. <1 ms, enters inactivated state by closure of inactivation gate (requires repolarization to activate again)
3. Stabilize and prolong inactive stae of Na channels (inactive bind > active binding)

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9
Q

Describe the repolarization phase

A
  1. Max depol leads to Na inactivation gate closure and voltage sensitive K gates open
    * K exits cell and internal negativity of neuron is restored
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10
Q

Describe the hyperpolarization phase?

A
  1. K+ close close slowly -> excessive K+ efflux
  2. Neuron is insensitive to additional stimulus during (relative refractory period)
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11
Q

What kind of sz are commonly treated by AED?

A

Focal and focal impaired awareness (secondary generalized) sz

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12
Q

AED acts in a ____ manner?

A

Use-dependent:
* Neurons that fire rapidly are especially susceptble
* Little effect on absence sz and sometimes increase frequency

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13
Q

ADRs of phenytoin?

A

Toxicity begins at >20 ug/mL but serious toxicity is rare:
1. Gingivial hyperplasia
2. Teratogen

Classified as aromatic anticonvulsanr

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14
Q

What type of drugs can cause drug induced hypersensitivity such as rash, agranulocytosis, thrombocytopenia, SJS, and hepatitis?

A

Aromatic anticonvulsants

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15
Q

Describe the PK properties of phenytoin?

A
  1. Nonlinear
  2. Heavy PPB
  3. Induces several CYP

IM: pH 11.5 (charged at phsy pH) can see crystallization at site (erraptic absorption)
PO: Bioava. varies for fromulations from different manufacters
Metabolism can get saturated

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16
Q

Fosphenytoin

MOA, PK, Advantages, Disadvantages

A

MOA: prodrug of phenytoin
PK: Constent plasma concentratios after IM/IV (IM is more soluble, steady, and better absorbtion)
Advatnages: More tolerable and safe, stable, IM, faster infusion rate
Disadvantages: Rate and doe-related paresthesias and pruritis

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17
Q

Carbmazepine

Brand, ADR, PK

A

Tegretol
ADR: Idiosyncratic rashes, osteomalacia, aplastic anemia, agranulocytosis, hypersensitivity
PK: Induces CYP3A4/UGTs and its own metabolism (months the achieve steady state)

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18
Q

Oxcarbazepine

Brand, MOA, ADR, PK

A

Trileptal
MOA: Action on Ca and K channels
ADR: CNS, rash
* Hyponatremia, hypersensitivity (less common)
* Lacks reactive metabolite but still aromatic

PK: Induces CYP3A4/5 and UGT and inhibits CYP2C19
* Does not induce own metabolism

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19
Q

How does eslicarbazepine differ from oxcarbazepine?

A

Same active metabolite as oxcarbazepine but faster conversion

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20
Q

Lamotrigine

Brand, MOA, ADR, PK, Interactions

A

MOA: reduces glutaminergic excitatory transmission and inhibits neuronal nicotinic Ach receptors
ADRs: insomnia, dermatitis/rash (aromatic)
* Cleft palate in pregnancy

PK: Half life decreases in the presence of enzyme-inducing AED
Interactions: Increased levels by valproate (inhibits N-glucoronidation)

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21
Q

Valproic Acid

MOA, ADR, Interactions

A

MOA: Blocks low-threshold T-type Ca2+ channel and NMDA receptor mediated excitation, may increase inhibitory effect of GABA (inhibit degradative enzymes or reuptake)
* pKa = 4.7 -> ionized at physiological pH -> ion = pharmacologically active moiety

ADR: hepatotoxicity, teratogenicity, pancreatitis
Interactions: Phenytoin, phenobarbital

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22
Q

What are the types of valproic acid derivatives?

A

Divalproex sodium (Depakote): enterically coated (minimize GI effects)
Valproate sodium: IV

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23
Q

Hepatotoxicity from reactive metabolite of valproic acid from what structure?

A

Terminal alkene

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24
Q

Topiramate

Brand, MOA, ADR, Interactions

A

Topamax
MOA: enhance GABAA-mediated chloride flux, possible antagonist at AMPA and KA receptors
ADR: Renal stones (carbonic anhydrase inhibition)
Interactions: Induces CYP3A4 and inhibits CYP2C19. Can lessen effectiveness of OCP

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25
What are hydantoins?
1. Phenytoin (Dilantin) 2. Fosphenytoin 3. Carbamazepine (Tegretol) 4. Oxcarbazepine (Trileptal) 5. Eslicarbazepine 6. Lamotrigine (Lamictal) 7. Valproic Acid + Derivatives
26
Carbonic anhydrase inhibitors SAR? Types?
1. Topiramate (Topamax) 2. Zonisamide 3. Rufinamide 4. Lacosamide (Vimpat) 5. Cenobomate
27
Zonisamide | MOA, ADR, PK
**MOA:** Blocks T-type Ca channels and CAI **ADR:** Renal stones, SJS * CI with sulfonamide allergy
28
Rufinamide | ADR, PK, Interactions
**ADR:** CNS sedatve, GI, rebound sz, QT ointerval shortening **PK:** Give with food for better absorption **Interactions:** Weak inhibitor of CYP2E1 and weak inducer of CYP3A4
29
Lacosamide | Brand, ADR
Vimpat **ADR:** CNS, cardiac arrhythmias (mild PR interval prolongation)
30
Cenobomate | MOA, ADR
**MOA:** allosteric modulator of GABAa **ADR:** CNS, physical dependence
31
Describe the importance of glutamate?
Provides excitatory neutransmission via NMDA and AMPA/KA recepotors: 1. Activation of channels -> sodium and calcium influx + potassium efflux -> depolarization 2. Responsible for neuron-to-neuron spread of excitation 3. Inhibition -> inhibit generation of seizure activity and/or terminates at early stages of development
32
To prevent unacceptable behavioral AE glutamate antagonist must have ___?
Specific antagonists should not be used and agents shoulg have **pleiotropic** effects
33
Felbamate | MOA, ADR, Interactions
**MOA:** Alters gating behavior of NMDA receptor, potentiates GABAA conductance, inhibits sodium and calcium channels **ADR:** BBW of aplastic anemia and severe hepatotoxicity due to terminal alkene **Interactions:** Inhibits CYP2C19
34
Perampanel | MOA, ADR, PK
**MOA:** Noncompetitive AMPA-type glutamate receptor antagonist **ADR:** Behavioral (aggression, hostility, irritability and anger) * BBW for psychiatric and behavioral changes **PK:** Doesn't reach ss for 2-3 wks
35
MOA of CCB? Type of sz?
T-type calcium currents = pacemakers for normal brain activity * Generates thalamic oscillatory currents involved in absence seizures * Works against this
36
Ethosuximide | Indication, ADR
**Indication:** absence sz (exacerbate other sz) **ADR:** GI, CNS, Idiosyncratic hypersensitivity rx
37
What is the function of High Voltage Activated (HVA) Calcium Channels?
Control entry of calcium into presynaptic terminal and regulate neurotransmitter release Drugs that inhibits HVA have pleiotropic effects
38
Gabapentin | Brand, MOA, Indication, ADR, PK, Interactions
Neurontin **MOA:** Inhibits α-2-δ subunit of P/Q-type calcium channels * No GABA-mimetic activity but raises brain GABA levels **Indication:** focal and generalized tonic-clonic seizures * Can exacerbate myoclonic and absence sz **ADR:** CNS **PK:** Bioavailability decreases with increasing dose (saturation) **Interactions:** Antacids decrease absorption
39
Pregabalin | MOA, ADR, PK
**MOA:** 3-10x more potent than gabapentin **ADR:** CNS, life-threatening rash with respiratory sx * Requires tapering **PK:** Linear and more predicatable
40
What is the function of synaptic vesicle protein 2A? What drugs affect it?
Synaptic vesicle integral membrane protein: Positive effector of synaptic vesicle exocytosis Drugs **reduce release of glutamate** during trains of high-frequency activity
41
Levetiracetam | Brand, MOA, ADR, PK
Keppra and XR **MOA:** inhibit calcium currents and decrease potassium efflux SV2A **ADR:** CNS depression **PK:** broad therapeutic window
42
What is brivaracetam?
20x greater affinity than levetiracetam and metabolized by CYP2C19
43
What is GABA?
Predominant inhibitory neurotrasmitter in the brain
44
What is the function of GABA enhancements?
1. Binds to GABAA and GABAB Drugs suppress the formation and/or spread of abnormal electrical discharges
45
What is the difference between GABAa and b?
A: on chloride ion channels, GABA binding causes chloride influx and neuronal hyperpolarization B: linked to potassium and calcium channel activity
46
Examples of GABA enhancers?
Tiagabine Vigabatrin Barbiturates * Phenobarbital (Luminal) * Primidone * Stiripentol Benzodiazepines *
47
Tiagabine | MOA, ADR, PK
**MOA:** Binds to GABA transporter 1 (GAT1) -> blocks uptake of GABA into neuros and glia -> enhances GABA-mediated inhibition **ADR:** development of nonconvulsive status epilepticus * CNS **PK:** Take with food to avoid adverse effects
47
Vigabatrin | MOA, ADR
**MOA:** Inhibits GABA transaminase (GABA-T) – metabolizes GABA in synapses * Irreversible inhibitor from terminal alkene **ADR:** CNS sedation, CI if mental illness is present, BBW of irreversible bilateral visual field constriction
48
What are the properties of barbiturates?
1. Binds to site on GABAa receptor and increase mean open duration 2. Very narrow therapeutic range 3. Inducers of many CYP450s 4. Lipophilic (distribute well into brain, long half-lives, absorbed well BUT slowly)
49
Phenobarbital | Brand, Indication, ADR, INteractions
Luminal **Indication:** Parenterally as sodium salt for emergency situations **ADR:** CNS sedation tolerance, physical dependence, aromatic (hypersensitivity) **INteractions:** Severe CNS depression with alcohol or benxodiazepines (Induces CYP450s and UGT)
50
Primidone | ADR, PK, Interactions
**ADR:** CNS depression, megaloblastic anemia (folic acid def) **PK:** Metabolized to phenobarbital **Interactions:** MOAIs, alcohol, benzo
51
Stiripentol | MOA, ADR, PK, Inhibitos
**MOA:** Barbiturate-like effect – increases duration of opening **ADR:** CNS, GI **PK:** Nonlinear **Interactions:** Potent inhibitor of CYP3A4, 1A2, 2C19
52
Mechanism of benzodiazepines?
Enhance effect of GABA on GABAA chloride channel (increase affinity for GABA): * Increase frequency of opening * Leads to hyperpolarization, counteracts depolarizing effect of excitatory neurotransmission
53
Barbs vs Benzo?
Barbs can cause death and coma with increased dose
54
Benzodiazepines | Indications, ADRs, Interactions
**Indications:** Acute seizures **ADR:** Sedative effects, tolerance can develop **Interactions:** Can enhance action of other CNS depressants, alcohol * Using with opioids can cause profound sedation, respiratory depression, coma and death
55
Diazepam | Brand, Indication, PK
Valium **Indications:** rectal gel refractory patients with epilepsy and parenterally for status epilepticus * PO is less effective and tolerance develops fast * IV: enters brain fast because lipophilic – but redistributes quickly -> status epilepticus can return **PK:** Metabolized by CYP3A4 and CYP2C19
56
Clorazepate | PK
Metabolized to active metabolite of diazepam -> similar properties
57
Clonazepam | Brand, PK
Klonopin **PK:** Very potent but tolerance develops frequently and side effects are common
58
Lorazepam | Brand, Indication, PK
Ativan **Indication:** IV/IM: more effective than diazepam and IV phenytoin * lower risk of continuing seizures **PK:** Not metabolized by CYP3A4 unlike other benzos
59
Clobazam | Brand, MOA, PK
Onfi, Sympazan **MOA:** 1,5-benzodiazepine as opposed to 1,4- but similar MOA and adverse effects **PK:** Inhibitor of CYP2D6
60
Cannabadiol | ADR, PK
**ADR:** Somnolence, decreased appetite, diarrhea, fatigue **PK:** Oil-based solution (PO): given in sesame oil or high fat meals
61
Biggest complaint about AED?
CNS effects: drowsiness, dz, somoliensce
62
Hematologic ADRs? Drugs that cause?
Fever, sore throat, bruising, bleeding, blood dyscrasia * Carbamazepine * Phenytoin * Felbamate * Ethosuximide
63
Skin ADR? Drugs?
Rash, Stevens-Johnson Syndrome * carbamazepine * lamotrigine * phenytoin * phenobarbital * pregabalin * zonisamide
64
Drugs that cause hepatotoxicity?
1. Phenytoin 2. Valproate 3. Felbamate
65
Drugs that cause kidney stones?
Topiramate Zonisamide
66
Drugs that cause anydrosis, heat stroke?
Topiramate, zonisamide
67
Drugs that cause glacoma?
Topiramate
68
Drugs that cause peripheral vision loss?
Vigabatrin
69
Drugs that cause cardiac Sx?
QT interval ahortening: rufinemide PR interval prolongation: Lacosamide
70
Nonconvulsive status epilepticus drug?
Tiagabine
71
What is SJS?
Severe potentially life threatening allergic rx (blisters and erosions)
72
Who are at risk for SJS?
HLA-B*1502 allele
73
Drugs that cause SJS?
1. Phenobarbital 2. Carbamazepine 3. Lamotrigine
74
How do you maintain bone health whilst taking anticonvulsants?
Supplement with Ca++
75
BBW of carbamazepine?
Aplastic anemia, agranulocytosis, serious dermatological reactions
76
BBW of felbamate?
Aplastic anemia, hepatic failure
77
BBW of lamitrigine?
Serious rash (Stevens-Johnson syndrome)
78
BBW of valproic acid?
Hepatotoxicity, teratogenicity, pancreatitis
79
Clobazam BBW?
Concomitant use with opioids
80
Peranpanel BBW?
Severe psychiatric and behavioral reactions
81
Phenytoin BBW?
Cardiovascular risk with rapid infusion
82
Vigamatrin BBW?
Permanent vision loss
83
AEDs that don't affect CYP450s?
Gabapentin Pregabalin Lamotrigine Tiagabine Levetiracetam Zonisamide
84
What is the preferred contraceptive for women taking enzyme inducing AEDs?
IUD
85
AED with hypersensitivity issues?
Aromatic
86
AED with hepatotoxic/reactive issues?
terminal alkene

Drug Action III (23 decks)

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