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Pharmacology 2 > 3.4 Antiepileptics > Flashcards

3.4 Antiepileptics Flashcards

1
Q

absence seizures

A

ethosuximide first, then valrpoate and clonazepam

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2
Q

myclonic seizures

A

valproate and clonazepam

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3
Q

febriel seizures

A

diazepam

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4
Q

status epilepticus

A

lorazepam or diapepam, fosphenytoin or phenytoin, alt. phenoboarbital

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5
Q

simple partial siaures

A

phenytoin, carbamazepine, alt penobarbital, primidone,

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6
Q

complex partial seizures

A

phenytoin, carbamazepine, alt. Primidone

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7
Q

loldes nonsedative antiseizure drug

A

phenytoin

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8
Q

penytoin action

A

blocks Na channels in their inactivated state (prolonging it) and slows its rate of recovery, prevents seizure propagation

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9
Q

Na channel acts in

A

resting(channed doesn_t move - activation (M) gate closed, inactivate gate opnes) open/activated (activation gate opens, sodium moves), inactivated (after deopolarizaiton inactivation (H) gate closes and channel blocked)

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10
Q

phenytoin other mechanism

A

at very high concentrations, phenytoin can block voltage dependent Ca cannels and interfere with the release of excitatory neurotransmitters

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11
Q

phenytoin is not a

A

not a generalized CNS depressant however, produces some degree of drowsiness and lethargy without producing hypnosis

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12
Q

Phenytoin absorption

A

slow and veriable

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13
Q

Phenytoin kinetics

A

non-linear (follows zero order kinetic elimination) – disproportiate increases with every inc in dose

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14
Q

phenytoin half life

A

12 to 24hrs at therapuetic dose but then at high dose it will be 60 hrs

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15
Q

Phenytoin daility dose

A

daily dose can produce large increases in the plasma concentration resuling in toxicity —->NEEDS PLASMA MONITORING (therapeutic range is 10-20ug/mL)

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16
Q

Phenytoin and enzyme induction

A

inducers of CYP450 like most antiepileptics

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17
Q

Status epilepticus and Phenytoin

A

given in the IV form of fosphenytoin, a produrg bc it has better pharmacokinetic and toxicity profile

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18
Q

Dose related toxicity to Phenytoin

A

CNS depression (lethargy, fatigue, drowsiness, nystagmus, ataxia, diplopia), gingival hyperplacia (gum hypertrophy***very imp) – occurs in about 20% of all pts during chronic therapy due to altered collagen metabolism, can be minimized with good oral hygien (Ca blockers can also casue gingival hyperplasia), hirsutism, coarsing of facial features occur in young pts (unpleasant in women), acne, megaloblastic anemia (pehnytoing interferes with folate absorption and increases its excretion), Aplastic anemia (immune -mediated–check CBC –they are succeptible to infection), behaviour changes (confusion, hallucination, drowsiness), osteomalacia (phenytoin desensitized target tissues to Vit D and interferes with Ca metabolism), inhibition of ADH release and inhib of insulin release (hyperglycemia, glycosuria–>hypovelemia), in pregnancy (teratogenic effect) –fetal hydantoin syndrom) cleft lip, cleft palate, growth retardation, microcephaly (possibly due to an epoxide metabolite of phenytoin)

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19
Q

Phenytoin is an inducer so

A

it induces metabolism of other anti-epileptics, anticoagulatns, oral contraceptives (steroids), levodopa, Vit D,

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20
Q

Inhibition of the metabolism of Phenytoin

A

chloramphenicol, dicumarol, cimetidine, sulfonamides

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21
Q

therapeutic uses of phenytoin

A

generalized tonic-clonic seizures, partial seizures (both simple and complex), status epilepticus (IV fosphenytoin), trigeminal neuralgia (occasionally)

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22
Q

fosphenytoin

A

prodrug of phytoin, rapily converted to pheytoin in plasma, IV can be used as a substute for phenytoin

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23
Q

fosphenytoin compared with phenytoin

A

fosphenytoin allows more rapid loading, IM adminsitration and IV administration with minimal vascular erosion –Phenytoin sodium should never be give IM as it can cause tissue damage and necrosis. Fosphenytoin can be used to control seizures during neurosurgery and status epilepticus

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24
Q

carbamazepine

A

prolongs the inactivated Na channel (identical to phenytoin) and inhibits high freq repetitive firing in neurons

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25
Q

carbamazepine absorption

A

slow oral abs

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26
Q

carbamazepine metabolism

A

metabolized in liver by oxidation –epoxide derivative (active metaboliet leading ot toxicity)

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27
Q

carbamazepine inducer

A

enzyme inducer of CYP450–auto induction

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28
Q

carbamazepine t 1/2

A

10 to 20hrs, reduced with repeated used

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29
Q

adverse effects of carbamazepine

A

dialational hypnatremia (due to inc ADH secretion), exfoliative dermatitis (unique to carbamazepine), fetal malformations (teratogenic) cleft lip, palate, spinabifida (more classic)

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30
Q

therapuetic uses of carbamazepine

A

partial/generalized epilepsy, trigeminal neuralgia (neuropathic pain), maniac depressive psychosis (bipolar disorder)

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31
Q

carbamazepine contraindications

A

should not be sued for pts with absence seizures bc it amy cause an inc in seizures, the mechanisms underlying carbamazepine aggravation of absence seizures are uncertain but are thought to involve enhancement of neuronal activity withing thalamocortical circuity

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32
Q

Oxcarbazepine

A

is a prodrug whose actions are similar to those of carbamazepine, with improved toxicity profile. Oxc dos not produce the epoxide metabolite wich is largely responsible for the adverse effects of carbamazepine. Less potent inducer of hepatic microsomal enzymes than carbamazepine. antiseizure efficacy and is comparable with that of carbamazepine, phenytoin and valproic acid

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33
Q

disadvantage of oxcarbazepine

A

more reports of hyponatremia with oxcarbazepine, eps in pts at risk

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34
Q

Phenobarbital

A

has specific anticonvulsant action at low dose – GABA a facilitatory action, anti glutamate action (those medated by activation of AMPA rec), Ca entry reduction, at high dos also blocks Na conductance like phenytoin

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35
Q

phenobarbital kinetics

A

long half life, enzyme induction, increases porphyrin synthesis - contraindicated in porphyrias, tolerance and dependence

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36
Q

barbiturates toxidity

A

hangover effect, impairment of finemotor skills, tolarance (PK and PD) and dependenc (physical and psychological)

37
Q

primidone

A

this drug is also metabolized to phenobarbital and the main action is through it—M/a like phenobarbital also resembles pheytoin M/a

38
Q

valproate (sodium valproate)

A

antiseizure properties discovered serendispitously, broad spectrum anticonvulsant, effective in Manic depressive psychosis and acute mania, and migrane

39
Q

valproate mechanism of action

A

prolongs inactivation of Na channel (simialr to pehytoing and carbamazepien) hence blocks sustained high-freq repetitive firing of neurons, inhibition of degredation of gaba by inhibiting GABA transaminase, blocks t-type Ca channels

40
Q

valproate abs

A

good, metabolize d by liver

41
Q

valproate inhibition

A

enzyme inhibitor inhibitng CYP450

42
Q

divalproex sodium

A

a combination of sodium valproate and valproic acid, is reduced to valproate when reaches GIT, better GI tolerance hence preferred by pts

43
Q

adverse effects of valproate

A

gi eefcts (nausea, vomiting, abdominal pain and heart burn) and alopecia, hepatotoxicity (from toxic metabolites) Idiosyncracy) –> severe (may be fatal) Liver function test should be done in the first 6 to 12 monts of therapy, thromocytopenia and inhibition of platelet aggregation causes bleeding (idiosyncrasy), rashes, pancreatitis, neural tube defects (spinabifida -teratogenic), stimulation of appetiteld

44
Q

valproate therapeutic uses

A

broad spectrum antiepileoptic, generalized and partial seizures, absence seizures (second choice), myoclonic seizures, MDP and acute mania (bipolar disorder) migraine prophylaxis

45
Q

benzodiazepienes for antiepileptics

A

lorazepam, diazepam, clonazapam

46
Q

conazepam

A

absence and myoclonic seizures

47
Q

status epileptic benzos

A

lorazepam, diazepam

48
Q

benso disadvantages

A

sedation and tolerance with long term use

49
Q

ethosuximide

A

primary action on thalamic neurons which are involved in absence seizures, acts by supression of T type Ca channles

50
Q

Ethosuximide acts by

A

suppression of the T Ca curren (primarily in thalamic neurons)

51
Q

Ethosuximide is used in

A

absence seizures

52
Q

Ethosuximide adverse effects

A

GI disturbances (Nausea and vomiting ; 40%) fatigue dizziness and agranulocytosis (RARE)

53
Q

Phensuximide and methsuximide

A

congerners with limited utility, used in absence seizures, Phensuximide is generally less effective and Methsuximide is more toxic than Ethosuximide

54
Q

Gabapentin

A

analog of Gaba, precise mechanism of action is not known but increases gaba effects by altering gaba metabolism and inc gaba levels in brain (does not bind with gaba receptors)

55
Q

gabapentin use

A

partial refractory seizures, neuropathic pain (cush as post herpetic neuralgia), A/E most common –Fatigue, somnolence, dizziness and atxia

56
Q

pregabalin

A

analog of gabapentin, binds to voltage gated Ca channel and reduces release of excitatory neurotransmitters (such as glutamate, NE, substance P, and calcitonin gene-related (CGRP))

57
Q

Adjunct antiepiletics

A

gabapentin, pregabalin, felbamate, lamotrigine, vigabatrin, tiagabine, topiramate

58
Q

pregabalin use

A

used to treat partial seizures and also approved fo use in treating post herpetic neuralgia and diabetic peripheral neuropathy

59
Q

pregabalin majro adverse effects

A

dizziness, dryness of mouth, blurred vision, somnolence, ataxia, weight gain

60
Q

felbamate

A

broad spectrum of anticonvulsant action, has multiple propsoed mechanisms (block voltage Na channels, block NMDA glut rec, block Ca channels, potentiation of Gaba actions

61
Q

felbamate risks

A

aplastic anemia and hepatic failure, reserved for use in refractory epilepsis (particulary Lennox-Gastaut syndrome)

62
Q

Lamotrigine

A

blocks Na channels, high voltage-dependent Ca channels, effective in a wide variety of seizure disorders (partial seizures, generalized seizures, absence seizures, Lennox gastaut syndrome) approved in bipolar disorder

63
Q

Lamotrigine half-life

A

24-35h, decreases by carbamazepine and phenytoin, increases by >50% by valproate, dosages should be reduced if given with valproate

64
Q

Lamotrigine adverse effects

A

hepatotoxicity, stevens-Johnson Syndrome

65
Q

vigabatrin

A

a gamma vinyl analog of GABA, irreversible inhibitor of Gaba transaminase, used in infantile spasms and partial epilepsy

66
Q

Adverse effects of vigabatrin

A

visual field defects (must undertake baseline visual test), asthenia, depression, and psychosis

67
Q

Tiagabine

A

inhibits gaba uptake into the neuron by blocking the gaba transporter

68
Q

tiagabine

A

used for partial epilepsy

69
Q

tiagabine adverse effects

A

dizziness, astenia, nervousness, tremor, diarrhea, and depression (mild to moderate in severity and transient)

70
Q

Topiramate

A

broad-spectrum anticonvulsant, delays the recovery of the inactivated Na channels, enhances Gaba activity by binding to the Gaba receptor, blocks the activation of AMPA receptors

71
Q

Topiramate use

A

used as add on therapy for partial seizures

72
Q

Topiramate adverse effects

A

ataxia, fatigue, nervousness and memory dysfunction (thinking abnormally, word-finding difficulties), acute myopia, glaucoma, and renal stones

73
Q

Levetiracetam

A

binds to the synaptic vesicular protein SV2A, may modify the synaptic release of glutamate and Gaba through action on vesicular function

74
Q

Levetiracetam use

A

in refractory partial epilepsy, myoclonic seizures, and primary generalized tonic-clonic seizures in adults and children. Somnolence, asthenia, dizziness, and ataxia are the adverse effects

75
Q

Zonisamide

A

sulfonamide derivtive, prolongs the inactivated state of Na channel, inhibits Ca T currents, add on thereapy for partial and generalized seizures

76
Q

Zonisamide adverse effects

A

drowsiness, fatigue and coordination difficulties (most common)

77
Q

Acetazolamide

A

carbonic anhydrase inhibitor, used for seizures during menses (catamenial epilepsy) and absence seizures

78
Q

what is the drawback to acetazolamide

A

tolerance in the drawback

79
Q

Status epilepticus

A

an emergency and must be treated immediately, refers to continuous seizures or repetitive, discrete seizures with impaired consciousness. Anticonvulsant therapy should then begin without delay

80
Q

Status epilepticus management

A

to attend to any acute cardiorespiratory problems or hyperthermia, establish venous access, to perform a brief medical and neurologic examination

81
Q

3 most commonly used classes fo drugs for the initial treatment of status epilepticus

A

benzodiazepines (IV diazepam/IV Lorazepam), Hydantoins (IV Fosphenytoin/IV Phenytoin), Barbitu

82
Q

Pregnancy and Epilepsy

A

Phenytoine, Carbamazepine, Valproate, Lamotrigine, and phenobarbital have been associated with teratogenicity, however the potential harm of uncontrolled seizures on the mother and fetus is considered greater than the teratogenic effects of antiepileptic drugs

83
Q

current recommendation for pregnant women

A

pregnant women be maintained on effective drug therapy, when possible it is prudent to have the pt on montherapy at the lowest effective does, especially during the first trimester, also folate supplementation and Vit K supplementation

84
Q

folate supplementation

A

pt should also take folate (1 to 4 mg/d) since the antifolate effects of anticonvulsants are thought to play a role in the development of neural tube defects)

85
Q

vit K supplementation

A

oral vit K in the last 2 weeks of pregnancy and vit K at birth to the neonate

86
Q

Contraception and AEDs

A

special care should be taken when prescribing antiepileptic medications for women who are taking oral contraceptive agents. Carbamazepine, phenytoin, phenobarbital, and topiramate can significantly decrease the effects of oral contraceptives via enzyme induction na dother mechanisms. pt should be advised to consider alternative forms of contraception

87
Q

Withdrawla of AEDS

A

best treatable seizures - childhood seizures, consider withdrawal if complet control of seizures at least for 2 years, slow withdrawal withing 12 months, rapid withdrawal leads to status epilepticus, recurrance rate of seizures is 40%

88
Q

AED therapuetic strateges

A

AEDs treatment individualization is most important, specifically different pt groups (eg children, women of child bearing potential, and the elderly) may be better suited to receive one AED than another, Anti-epileptic drugs are most effective and have the least adverse effects when they are used as monotherapy. the drug should not be abruptly withdrawn in controlled seizures as seizures may occur on withdrawal, hence the initial drug should not be discontinued prior to the substitution of an alternative drug, some antiepileptic drugs have teratogenic potential (needs reduction or termination of therapy during pregnancy or planned pregnancy; however, maternal sezures also present significant risk to the fetus. TDM - very effective and important in maximizing the treatment and minimizing the adverse effects

Pharmacology 2 (12 decks)

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