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Pharmacology > CNS: Antiepileptic drugs > Flashcards

CNS: Antiepileptic drugs Flashcards

1
Q

Seizures

A

clinical manifestation of an abnormal and excessive excitation and synchronization of a population of cortical neurons

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2
Q

Epilepsy

A

Chronic disorder characterized by spontaneous recurrent seizures

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3
Q

Convulsions

A

Involuntary, paroxysmal skeletal muscle contractions

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4
Q

Partial Seizure Simple

A

Limited motor or sensory signs, consciousness intact

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5
Q

Partial Seizure Complex

A

Consciousness Impaired

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6
Q

Secondary Generalized

A

Symptoms increase until resembling a generalized seizure

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7
Q

Generalized Seizures

Absence/Petit Mal

A

Sudden brief loss of consciousness

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8
Q

Generalized Seizures

Myoclonic Seizures

A

Sudden, brief, shocklike contractions of muscles

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9
Q

Generalized Seizures

Clonic seizures

A

Rhythmic, synchronized contractions throughout the body, loss of consciousness

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10
Q

Generalized Seizures

Tonic Seizures

A

Generalized, sustained muscle contractions throughout the body, loss of consciousness

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11
Q

Generalized Seizures

Tonic-Clonic/Grand Mal

A

Major convulsions of entire body, loss of consciousness

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12
Q

Generalized Seizures

Atonic seizures

A

Sudden loss of muscle tone in the head and the neck; consciousness may be maintained or loss briefly

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13
Q

Status Epilepticus

A

More than 30 minutes of continuous seizure activity Two or more sequential seizures spanning this period without full recovery between seizures Medical emergency Diazepam, lorazapam IV (fast, short acting) Followed by phenytoin, fosphenytoin, or phenobarbital (longer acting) when control is established

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14
Q

Rationale for Drug treatment

A

Antiepileptic drug Decreases the frequency and/or severity of seizures in people with epilepsy Treats the symptom of seizures not the underlying epileptic condition Goal – maximize quality of life by minimizing seizures and ADEs Effective in 60% of patients with epilepsy (seizure free), 20% experience drastic reduction in seizures

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15
Q

Pharmacokinetics/Dynamics

A

Good oral absorption and bioavailability Most metabolized in liver but excreted unchanged in kidneys Classic AEDs generally have more severe CNS sedation than newer drugs Because of overlapping mechanisms of action, best drug can be chosen based on minimizing side effects in addition to efficacy

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16
Q

Classifications of AED: Classical

A

Phenytoin Phenobarbital Primidone Carbamazepime Ethosuximide Valproate (valproic acid)

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17
Q

Classification of AED: Newer

A

Lamotrigine Felbamate Topiramate Gabapentin/pregabalin Tiagabine Vigabatrin Oxycarbazepine Levetiracetam Fosphenytoin

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18
Q

Side effects of AED

A

Sedation – especially with barbiturates

Cosmetic – phenytoin, steven johnson’s syndrome (rare)

Weight gain – valproic acid, gabapentin

Weight loss – topiramate

Reproductive function – valproic acid

Cognitive – topiramate

Behavioral – felbamate, leviteracetam

Allergic - many

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19
Q

Epilepsy-Basic Neurophysio: Causes of Hyperexcitabiltiy

A

excitatory post synaptic potentials (EPSPs)

inhibitory post synaptic potentials (IPSPs)

changes in voltage gated ion channels

alteration of local ion concentrations

20
Q

Epilepsy-Glutamate

A

The brain’s major excitatory neurotransmitter Two groups of glutamate receptors Ionotropic—fast synaptic transmission Three subtypes – AMPA, kainate, NMDA Glutamate-gated cation channels Metabotropic—slow synaptic transmission G-protein coupled, regulation of second messengers (cAMP and phospholipase C) Modulation of synaptic activity Modulation of glutamate receptors Glycine, polyamine sites, zinc, redox site

21
Q

Epilepsy GABA

A

Major inhibitory neurotransmitter in the CNS Two types of receptors GABAA—post-synaptic, specific recognition sites, linked to CI- channel

GABAB —presynaptic autoreceptors that reduce transmitter release by decreasing calcium influx, postsynaptic coupled to G-proteins to increase K+ current

22
Q

Cellular Mechanisms of Seizure Generation

A

Excitation (too much) Ionic—inward Na+, Ca++ currents Neurotransmitter—glutamate, aspartate

Inhibition (too little) Ionic—inward CI-, outward K+ currents Neurotransmitter—GABA

23
Q

Targets for AEDs

A

↑ inhibitory neurotransmitter system such as GABA ↓ excitatory neurotransmitter system – glutamate

Block voltage-gated inward positive currents – Na+ or Ca++ ↑ outward positive current – K+

Many AEDs have multiple MOAs

24
Q

Dicarbamates Felbamate (Felbatol®)

A
  • Indicated for treatment of partial seizures in adults and children generalized absence seizures (Lennox-Gastaut syndrome) in children Potent AED lacking sedative effect (unlike all other AEDs)
  • ADEs GI issues Rare but fatal aplastic anemia => restricted for use only in extreme refractory epilepsy
25
Q

Topiramate (Topamax®)

A
  • Used for partial seizures, as an adjunct to tonic-clonic seizures (add-on or alternative to phenytoin)
  • MOA Acts on AMPA receptors, blocking the glutamate binding site, but also blocks kainate receptors and Na+ channels, and enhances GABA currents
  • ADEs Paresthesia – ‘pins and needles’ Fatigue Taste change Weight loss Difficulty concentrating
26
Q

Benzodiazepenes

A
  • Clonazepam (Klonopin®) Used for absence seizure (sometimes myoclonic)
  • Most specific ADE among benzos – selective for GABAa Sedating, may lose effectiveness to development of tolerance
  • Diazepam (Valium®) and Lorazepam (Ativan®) Used as first-line treatment for status epilepticus (delivered IV – fast acting) Sedating Cause ataxia Behavioral changes
27
Q

BarbituratesPhenobarbital, Primidone (Mysoline®)

A
  • Used for partial seizures, especially in neonates, first class of drugs
  • MOA: ↑ inhibitory effects of GABA
  • ADEs: Very strong sedation, cognitive impairment, behavioral changes, folate deficiency, vitamin K deficiency, skin problems Tolerance may arise, risk of dependence Primidone is metabolized to phenobarbital Induce CYP450 enzymes Seldom used due to side effects
28
Q

Tiagabine (Gabitril®)

A
  • Interferes with GABA reuptake Used for treatment of partial seizures
  • ADEs: Decreased concentration Dizziness, somnolence, nervousness Chest pain, hypertenstion, edema, syncope, vasodilation Alopecia Speech disorder
29
Q

Vigabatrin

A
  • Irreversible inhibitor of GABA amino-transferase – enzyme responsible for the degradation of GABA => GABA released at synaptic site => enhances inhibitory effects U
  • seful for treatment of partial seizures and tonic-clonic seizures as an alternative agent ADEs – sedation, dizziness, weight gain
30
Q

Na+ Channels as AED Targets

A
  • Neurons fire at high frequencies during seizures Action potential generation is dependent on Na+ channels
  • Use-dependent or time-dependent Na+ channel blockers reudce high frequency firing without affecting physiological firing
31
Q

AEDs That Act Primarily on Na+Channels

A

Phenytoin, Carbamazepine – Block voltage-dependent sodium channels at high firing frequencies—use dependent

Oxcarbazepine – Blocks voltage-dependent sodium channels at high firing frequencies – Also effects K+ channels

Zonisamide – Blocks voltage-dependent sodium channels and T-type calcium channels

32
Q

Hydantoins, Phenytoin (Dilantin®), Fosphenytoin (Cerebyx®)

A

First-line for partial seizures Some use for tonic-clonic seizures

MOA: Blocks voltage-dependent sodium channel at high firing frequencies Highly protein bound Induces P450 enzyme system

ADEs: GI irritation, sedation, gingival hyperplasia, hirsutism, nystagmus, ataxia, dysarthria Fosphenytoin – prodrug for phenytoin (used as IM injection)

33
Q

Iminostilbenes Carbamazapine (Tegretol®)

A

Tricyclic antidepressant used for partial seizures and some use in tonic-clonic seizures

MOA: Similar to phenytoin Induces P450 enzyme system => induces its own metabolism

ADEs: Sedating, agranulocytosis and aplastic anemia, leukopenia, hyponatremia, cardiac arrhythmias, CHF

34
Q

Iminostilbenes Oxcarbazapine (Trileptal®)

A

Newer agent – related to carbamazapine Approved for monotherapy in partial seizures

MOA: Same as carbamazapine May also augment K+ channels Some CYP450 induction

ADEs: Sedating but less toxic than carbamazapine

35
Q

Zonisamide (Zonergan®)

A

Used as add-on for partial and generalized seizures

MOA Blocks voltage-dependent sodium channels and T-type calcium channels

ADEs Serious skin rash Suicidal ideation Metabolic acidosis Anemia, leukopenia

36
Q

Ca2+ Channels as Targets

A

General Ca2+ channel blockers have not proven to be effective AEDs. Absence seizures are caused by oscillations between thalamus and cortex that are generated in thalamus by T-type (transient) Ca2+ currents

37
Q

Succinimides Ethosuximide (Zarontin®)

A

MOA Acts specifically on T-type channels in thalamus, and is very effective against absence seizures ADEs GI disturbances Less sedating Movement disorders Skin rashes

38
Q

Gabapentin (Neurontin®), Pregabalin (Lyrica®)

A

Used in add-on therapy for partial and tonic-clonic seizures

MOA Act specifically on calcium channel subunits called α2δ1.

It is unclear how this action leads to their antiepileptic effects, but inhibition of neurotransmitter release may be one mechanism

ADEs Less sedating

39
Q

K+ Channels

A

K+ channels have important inhibitory control over neuronal firing in CNS—repolarizes membrane to end action potentials K+ channel agonists would decrease hyperexcitability in brain So far, the only AED with known actions on K+ channels is valproate

40
Q

Carboxylic Acids proate (Valproic Acid®)

A

First-line for generalized seizures, also used for partial seizures

MOA Acts on K+ channels to decrease hyperexcitability in the brain

Also blocks Na+ channels and enhances GABAergic transmission Highly protein bound Inhibits CYP450

ADEs CNS depressant GI disturbances Hair loss Weight gain Teratogenic Hepatotoxic

41
Q

Regulation of Neurotransmitter Release

A

Several AED have actions that result in the regulation of neurotransmitter release from the presynaptic terminal, such as lamotrigine, in addition to their noted action on ion channels or receptors

Levetiracetam appears to have as its primary action the regulation of neurotransmitter release by binding to the synaptic vesicle protein SV2A

42
Q

Levetiracetam (Keppra®)

A

Add-on therapy for partial seizures

MOA regulation of neurotransmitter release by binding to the synaptic vesicle protein SV2A

ADEs CNS depression

43
Q

Lacosamide (Vimpat®)

A

Used for partial-onset seizures as adjunctive therapy MOA Enhances the number of Na+ channels entering into the slow inactivated state

Regulates and reduces the long-term availability of Na+ channels

ADEs N/V/D Diplopia Dose adjust in patients with mild or moderate hepatic impairment or severe renal impairment

44
Q

Drug Interactions of AEDs

A

Many AEDs are notable inducers of cytochrome P450 enzymes and a few are inhibitors

Of the classic AEDs, phenytoin, carbamazipine, phenobarbital, and primidone are all strong inducers of cytochrome P450 enzymes

Valproate inhibits cytochrome P450 enzymes

45
Q

Treatment Considerations of AEDs

A

Most AEDs undergo complete or nearly complete absorption when given orally

Fosphenytoin (prodrug) may be administered intramuscularly if intravenous access cannot be established in cases of frequent repetitive seizures Diazepam (available as a rectal gel) has been shown to terminate repetitive seizures and can be administered by family members at home

Phenytoin, fosphenytoin, phenobarbital, diazepam, lorazepam and valproate are available as IV preparations for emergency use

Most AEDs are metabolized in the liver (P450) by hydroxylation or conjugation. These metabolites are then excreted by the kidney.

Gabapentin undergoes no metabolism and is excreted unchanged by the kidney

Monotherapy is preferred: better patient compliance, less adverse effects Add-on therapy is often necessary to eliminate “break-through” or refractory seizures

46
Q

Considerations in Rehabilitation

A

Thorough medical history is a must! Monitor patient progress – keeping dosages within therapeutic window Schedule sessions around the time of day when side effects such as H/A, dizziness, sedation, GI disturbance are mild Ataxia might impair patient’s ability to participate in various functional activities (if persistent – start coordination exercises) Interventions that might exacerbate skin conditions should be avoided Depending on the seizure triggers, some patients might do better in quieter environments at the time of day when chance of seizure is minimal

Pharmacology (12 decks)

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