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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
Q

What are hydantoins?

A
  1. Phenytoin (Dilantin)
  2. Fosphenytoin
  3. Carbamazepine (Tegretol)
  4. Oxcarbazepine (Trileptal)
  5. Eslicarbazepine
  6. Lamotrigine (Lamictal)
  7. Valproic Acid + Derivatives
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26
Q

Carbonic anhydrase inhibitors SAR? Types?

A
  1. Topiramate (Topamax)
  2. Zonisamide
  3. Rufinamide
  4. Lacosamide (Vimpat)
  5. Cenobomate
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27
Q

Zonisamide

MOA, ADR, PK

A

MOA: Blocks T-type Ca channels and CAI
ADR: Renal stones, SJS
* CI with sulfonamide allergy

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28
Q

Rufinamide

ADR, PK, Interactions

A

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

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29
Q

Lacosamide

Brand, ADR

A

Vimpat
ADR: CNS, cardiac arrhythmias (mild PR interval prolongation)

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30
Q

Cenobomate

MOA, ADR

A

MOA: allosteric modulator of GABAa
ADR: CNS, physical dependence

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31
Q

Describe the importance of glutamate?

A

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

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32
Q

To prevent unacceptable behavioral AE glutamate antagonist must have ___?

A

Specific antagonists should not be used and agents shoulg have
pleiotropic effects

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33
Q

Felbamate

MOA, ADR, Interactions

A

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

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34
Q

Perampanel

MOA, ADR, PK

A

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

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35
Q

MOA of CCB? Type of sz?

A

T-type calcium currents = pacemakers for normal brain activity
* Generates thalamic oscillatory currents involved in absence seizures
* Works against this

36
Q

Ethosuximide

Indication, ADR

A

Indication: absence sz (exacerbate other sz)
ADR: GI, CNS, Idiosyncratic hypersensitivity rx

37
Q

What is the function of High Voltage Activated (HVA) Calcium Channels?

A

Control entry of calcium into presynaptic terminal and regulate neurotransmitter release

Drugs that inhibits HVA have pleiotropic effects

38
Q

Gabapentin

Brand, MOA, Indication, ADR, PK, Interactions

A

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
Q

Pregabalin

MOA, ADR, PK

A

MOA: 3-10x more potent than gabapentin
ADR: CNS, life-threatening rash with respiratory sx
* Requires tapering

PK: Linear and more predicatable

40
Q

What is the function of synaptic vesicle protein 2A? What drugs affect it?

A

Synaptic vesicle integral membrane protein: Positive effector of synaptic vesicle exocytosis

Drugs reduce release of glutamate during trains of high-frequency activity

41
Q

Levetiracetam

Brand, MOA, ADR, PK

A

Keppra and XR
MOA: inhibit calcium currents and decrease potassium efflux SV2A
ADR: CNS depression
PK: broad therapeutic window

42
Q

What is brivaracetam?

A

20x greater affinity than levetiracetam and metabolized by CYP2C19

43
Q

What is GABA?

A

Predominant inhibitory neurotrasmitter in the brain

44
Q

What is the function of GABA enhancements?

A
  1. Binds to GABAA and GABAB

Drugs suppress the formation and/or spread of abnormal electrical discharges

45
Q

What is the difference between GABAa and b?

A

A: on chloride ion channels, GABA binding causes chloride influx and neuronal hyperpolarization
B: linked to potassium and calcium channel activity

46
Q

Examples of GABA enhancers?

A

Tiagabine
Vigabatrin
Barbiturates
* Phenobarbital (Luminal)
* Primidone
* Stiripentol

Benzodiazepines
*

47
Q

Tiagabine

MOA, ADR, PK

A

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
Q

Vigabatrin

MOA, ADR

A

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
Q

What are the properties of barbiturates?

A
  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
Q

Phenobarbital

Brand, Indication, ADR, INteractions

A

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
Q

Primidone

ADR, PK, Interactions

A

ADR: CNS depression, megaloblastic anemia (folic acid def)
PK: Metabolized to phenobarbital
Interactions: MOAIs, alcohol, benzo

51
Q

Stiripentol

MOA, ADR, PK, Inhibitos

A

MOA: Barbiturate-like effect – increases duration of opening
ADR: CNS, GI
PK: Nonlinear
Interactions: Potent inhibitor of CYP3A4, 1A2, 2C19

52
Q

Mechanism of benzodiazepines?

A

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
Q

Barbs vs Benzo?

A

Barbs can cause death and coma with increased dose

54
Q

Benzodiazepines

Indications, ADRs, Interactions

A

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
Q

Diazepam

Brand, Indication, PK

A

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
Q

Clorazepate

PK

A

Metabolized to active metabolite of diazepam -> similar properties

57
Q

Clonazepam

Brand, PK

A

Klonopin
PK: Very potent but tolerance develops frequently and side effects are common

58
Q

Lorazepam

Brand, Indication, PK

A

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
Q

Clobazam

Brand, MOA, PK

A

Onfi, Sympazan
MOA: 1,5-benzodiazepine as opposed to 1,4- but similar MOA and adverse effects
PK: Inhibitor of CYP2D6

60
Q

Cannabadiol

ADR, PK

A

ADR: Somnolence, decreased appetite, diarrhea, fatigue
PK: Oil-based solution (PO): given in sesame oil or high fat meals

61
Q

Biggest complaint about AED?

A

CNS effects: drowsiness, dz, somoliensce

62
Q

Hematologic ADRs? Drugs that cause?

A

Fever, sore throat, bruising, bleeding, blood dyscrasia
* Carbamazepine
* Phenytoin
* Felbamate
* Ethosuximide

63
Q

Skin ADR? Drugs?

A

Rash, Stevens-Johnson Syndrome
* carbamazepine
* lamotrigine
* phenytoin
* phenobarbital
* pregabalin
* zonisamide

64
Q

Drugs that cause hepatotoxicity?

A
  1. Phenytoin
  2. Valproate
  3. Felbamate
65
Q

Drugs that cause kidney stones?

A

Topiramate
Zonisamide

66
Q

Drugs that cause anydrosis, heat stroke?

A

Topiramate, zonisamide

67
Q

Drugs that cause glacoma?

A

Topiramate

68
Q

Drugs that cause peripheral vision loss?

A

Vigabatrin

69
Q

Drugs that cause cardiac Sx?

A

QT interval ahortening: rufinemide
PR interval prolongation: Lacosamide

70
Q

Nonconvulsive status epilepticus drug?

A

Tiagabine

71
Q

What is SJS?

A

Severe potentially life threatening allergic rx (blisters and erosions)

72
Q

Who are at risk for SJS?

A

HLA-B*1502 allele

73
Q

Drugs that cause SJS?

A
  1. Phenobarbital
  2. Carbamazepine
  3. Lamotrigine
74
Q

How do you maintain bone health whilst taking anticonvulsants?

A

Supplement with Ca++

75
Q

BBW of carbamazepine?

A

Aplastic anemia, agranulocytosis, serious dermatological reactions

76
Q

BBW of felbamate?

A

Aplastic anemia, hepatic failure

77
Q

BBW of lamitrigine?

A

Serious rash (Stevens-Johnson syndrome)

78
Q

BBW of valproic acid?

A

Hepatotoxicity, teratogenicity, pancreatitis

79
Q

Clobazam BBW?

A

Concomitant use with opioids

80
Q

Peranpanel BBW?

A

Severe psychiatric and behavioral reactions

81
Q

Phenytoin BBW?

A

Cardiovascular risk with rapid infusion

82
Q

Vigamatrin BBW?

A

Permanent vision loss

83
Q

AEDs that don’t affect CYP450s?

A

Gabapentin
Pregabalin
Lamotrigine
Tiagabine
Levetiracetam
Zonisamide

84
Q

What is the preferred contraceptive for women taking enzyme inducing AEDs?

A

IUD

85
Q

AED with hypersensitivity issues?

A

Aromatic

86
Q

AED with hepatotoxic/reactive issues?

A

terminal alkene

Drug Action III (23 decks)

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