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Pharmacology > L5 Anticonvulsant Drugs > Flashcards

L5 Anticonvulsant Drugs Flashcards

1
Q

What are the 6 common AEDs (anti-epileptic drugs)?

A
  1. Carbazepine
  2. Phenytoin
  3. Sodium Valproate
  4. Lamotrigine
  5. Levetiracetam
  6. Topiramate

Christmas Pudding Smells Less Lovely Tomorrow

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2
Q

When is Carbamazepine indicated?

A

Partial or generalised tonic clonic seizure.

Not absence or myoclonic (may worsen these)

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3
Q

When is Phenytoin indicated?

A

Status epilepticus, partial or generalised tonic clonic.

Not absence or myoclonic. (not first line)

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4
Q

When is Sodium Valproate and Lamotrigine indicated?

A

Partial or generalised (all types)

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5
Q

When is Levetiracetam indicated?

A

Partial and generalised tonic clonic, myoclonus, and possibly absences

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6
Q

When is Topiramate indicated?

A

Partial and generalised tonic clonic

(not for absences and myoclonus)

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7
Q

What is epilepsy?

A

The epileptic brain generates recurrent seizures (hypersynchronous excessive, abnormal, discharges from neurones) without provocation

2 unprovoked seizures = epilepsy

  • Abnormal structure / function (genetics)
  • Multiple manifestations of seizures
  • Common and serious condition.
  • 30% are medically refractory (I.e. Not seizure free after 2 sequential drugs)
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8
Q

What are the 3 main types of generalised seizures?

A
  1. Generalised Tonic Clonic Seizure (GTCS) (Widespread seizure activity causing impaired consciousness)
  2. Absence
  3. Myoclonic (myoclonus)
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9
Q

Which drugs promote inhibition in normal synaptic transmission?

A

Topiramate

Benzodiazepines

Valporate

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10
Q

Which drugs reduce excitation in synaptic transmission?

A

Phenytoin

Carbamazepine

Lamotrigine

Valproate Topiramate

Levetiracetam

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11
Q

What are the key aspects of AED treatment?

A
  • Seizures freedom, without adverse effects
  • Robust first single drug - may be life!
  • Smallest dose.
  • Trial and error!
  • Treatment usually started after 2nd seizure, or first with high risk of recurrence.
  • 6 months off driving if stopping meds.

(investigate with an MRI/ECG after first seizure)

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12
Q

What are the principles of selecting an appropriate AED?

A

•Type (Partial or generalised) / syndrome.

•Spectrum of efficacy

  • Comorbidities (migraine, bipolar)
  • Tolerability (compliance/formulation)

•Pharmacokinetics/pharmacodynamics

•Speed of titration

•Cost, blood tests, frequency of administration.

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13
Q

Carbamazepine

  1. What is the mechanism of action (what can it also be used for?
  2. What is another name for it?
A
  1. Sodium channel blocker. (Hepatic metabolism - strong CYP3A4 inducer - reduces conc of anticoagulants, analgesia, antivirals, steroids, statins, oral contraceptive pill, immunosuppresants.
  • Auto-induction (weeks-months) of liver enzymes can fall by 50%. Not a predictable effect.
  • Also used for neuropathic pain. Use slow release preparation if possible (tolerability is issue)
  1. Tegretol
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14
Q

Carbamazinipine

  1. What are some dose dependent side effects?
  2. What is the main side effect?
  3. What are some warnings?
  4. What interactions does it have?
A
  1. Dose dependent - diplopia, ataxia, sedation, fatigue.
  2. Hyponatraemia - SIADH : increases ADH release.
  3. bone marrow suppression, hypersensitivity, hepatic derangement, rash
  4. will need a higher dose of OCP. Beware with other sodium channel blockers - compounding of side effects
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15
Q

Phenytoin

  1. What is it’s mechanism of action?
  2. What are the acute side effects?
  3. What are the chronic side effects?
  4. Idiosyncratic side effects?
A
  1. Sodium Channel Blocker
  2. dizziness, ataxia, fatigue, diplopia (double vision), nystagmus, rash, sedation at high levels.
  3. gum hyperplasia, coarse face, hirsutism, osteopenia (enhanced Vit. D metabolism), low folate, and peripheral neuropathy
  4. fever, rash, lymphadenopathy, teratogenic

Particularly Nasty Side Effects

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16
Q

Phenytoin

  1. What is the therapeutic range of Phenytoin?
  2. Describe the elimination kinetics
    1. At high concentrations
    2. At low concentrations
      3.
A
  1. 10-20ug/ml
    1. Zero order kinetics: Fixed amount metabolised per unit time - higher concentrations
    2. First order elimination kinetics: fixed % of drug is metabolised per unit time
17
Q

Phenytoin

  1. Is a hepatic enzyme inducer- what implications will this have?
  2. What is the concentration of phenytoin increased by?
  3. What can the concentration be decreased by?
  4. In what form is it in in the blood? What displaces it?
A
  1. Reduced effects of warfarin, and of other anticonvulsants (eg. carbamazepine), and of oral contraceptive pill.
  2. Enzyme Inhibitors
  3. carbamazepine and antacids (i.e other enzyme inducers)
  4. 90% protein bound. Valproate displaces and inhibits metabolism - increases free phenytoin and toxicity
18
Q

Sodium Valproate

  1. What are the mechanisms of action?
  2. What is it used for?
  3. What does it also act upon?
  4. What is a major issue?
  5. With what does it need careful titration with?
  6. What are the side effects?
A
  1. Multiple: Sodium/calcium channel blocker, ^GABA, decreases Glutamate
  2. Versatile AED: myoclonic, atonic, GTCS, partial seizures.
  3. Hepatic metabolism
  4. Teratogenicity. (In pregnancy also)
  5. Lamotrigine
  6. Generally well tolerated , however
  • Hyperammonemic encephalopathy
  • Hepatic and pancreatic failure
  • Dose related tremor
  • Weight gain, PCOS (polycystic ovary syndrome)
  • Alopecia (hair loss)
  • Thrombocytopenia (low platelets)

7.

19
Q
  1. What is the number 1 drug for most seizure types?
  2. Why?
  3. What is it used for?
  4. What are the common side effects?
A
  1. Levetiracetam
  2. Few side effects and no significant interactions
  3. Effective for partial, generalized convulsive and also for myoclonic seizures, and possibly absence seizures.
  4. irritability, anxiety, fatigue, dizziness, behavioral changes and rarely psychosis. Rare hepatic failure•Rash uncommon. Not cognitively hugely problematic.
20
Q

Levetiracetam

  1. What is it’s mechanism of action?
  2. What is the half life
  3. How is it excreted?
A
  1. Acts via SV2A ligand - blocks synaptic vesicle release at the synapse. Rapid and complete absorption. Little effect from food.
  2. Elimination half-life is 7 h. Steady-state concentrations at 2d. BD dosing. (twice daily)
  3. RENALLY EXCRETED as unchanged drug
  • Protein binding clinically insignificant (10%).
  • CYP-independent metabolism (24%). Not an inhibitor or substrate of CYP450 enzymes, and has few drug-drug interactions.
21
Q

Which AED is safe in pregnancy?

A

Lamotrigine

22
Q

Lamotrigine

  1. What is it’s mechanism of action?
  2. What is it useful for?
  3. What is it’s tolerance like?
  4. What are the side effects?
  5. What are the interactions?
A
  1. Similar to other sodium channel modulators.
  2. Active for absence seizures. (Partial or generalised (all types)) Mood stabilising effects
  3. Well tolerated typically. Idiosycratic rash/Stevens-Johnson syndrome can be fatal .
  4. Rash incidence minimized by slow titration. Stop if develop rash.

•Other side effects:

  • Insomnia
  • Less cognitive effect
  1. Interactions with OCP (pill can reduce levels of Lamotrigine, breakthrough seizures), other AEDs
23
Q

Topiramate

  1. What are the modes of action?
  2. What is required due to tolerability?
  3. How is it eliminated?
  4. What are the side effects?
  5. What else is it used for?
A
  1. Multiple modes of action: Sodium/calcium channel blocker, increases GABA, decreases Glutamate
  2. Slow titration
  3. Enzyme inducer and inhibitor. Hepatic elimination.
  4. sedation, anorexia, and weight loss. Psychiatric. Word finding difficulties. Kidney stones, and acute angle closure glaucoma. Likely teratogen.
  5. Migraines
24
Q

With the Ageing Population, what needs to be considered when prescribing AEDs?

A

Psychiatric issues - Avoid levetiracetam/topiramate. Could use valproate, Carbamazepine as mood stablisers. Lamotrigine has use for bipolar.

Bone health - Usually enzyme inducing drugs e.g. valproate.Vit D catabolism. Monitor DEXA. (bone scan to assess for osteoporosis) (Dual

Obesity - Valproate (50% in first 1-2 months, Hyperinsulinaemia, insulin resistance, PCOS) Carbamazepine.

•Topiramate - appetite suppresant,weight loss.

25
Q

Epilepsy and Pregancy

  1. What are the drugs of choice?
  2. Which drug’s levels drop during pregnancy?
  3. Which drugs have the highest malformation rate?
  4. What effect is associated with Valproate in particular?
  5. What is recommended throughout?
A
  1. Levetiracetam and lamotrigine
  2. Lamotrigine
  3. Valproate in polytherapy has highest malformation rate. (spina bifida, ASD, cleft palate, craniosynostosis)
  4. Neurodevelopmental delay (Low IQ)
  5. Folate 5mg throughout
26
Q
  1. What are the symtpoms of AED Hypersensitivity syndrome?
  2. What is it most likely with?
A
  1. Rash, temps, tender nodes, hepatitis (50% mortality), eosinophilia, pharyngitis, organ failure.
  2. Aromatic AEDs Phenytoin/Carbamazepine
  • Cross reactivity.
  • Rare. Potentially fatal (10%)
  • First 1-8 weeks of exposure.
27
Q

Outline the treatment of Status Epilepticus

What dose is intially required and of what?

A

Timely with robust doses.

  • T = 5m : 4 mg Lorazepam. Repeat once at 10-15m. (max 0.1mg/kg)
  • T = 15m : Phenytoin 20mg/kg. 50mg/min. Slower if contraindicated/elderly.
  • T = 15m : call ICU. Anaesthetic drugs required.

(Propofol, midazolam, thiopentone. (beyond scope of this lecture)

28
Q

What is status epilepticus?

A

5 minutes of continuous seizure activity, or of briefer seizures with no recovery of consciousness in between times.

(New operational definition)

29
Q

Benzodiazepines

  1. Which are used in status epilepticus?
  2. What is their mechanism of action?
  3. What are the routes of administration?
  4. Which is the preferred benzodiazepine?
A
  1. Diazepam, Midazolam, Lorazepam
  2. GABA agonists
  3. Multiple routes. IV most definitive. IM in pre hospital status epilepticus.
  4. Lorazepam (best pharmacokinetic profile)
30
Q

What occurs with prolonged seizure activity?

A

Increase in NMDA receptors presented on the synaptic membrane

As seizure goes on, exitataory mechanisms become much more robust. Body setting itself up for a continuous seizure

(Less inhibitory signalling and excess excitatory transmission occurs in propagation of seizure activity)

31
Q

(What happens with repeat doses of diazepam?)

A
32
Q
  1. What are the three Benzodiazepines used in the treatment of epilepsy?
  2. Which has the shortest distribution half life? (minutes)
  3. Which has the longest distribtion half life?
  4. Which has the shortest elimination half life (hours)
  5. Which has the longest elimination half life, what is it, and what are the implications?
A
  1. Diazepam, Lorazepam, Midazolam
  2. Midazolam
  3. Lorazepam
  4. Midazolam
  5. Diazepam, >30 hours, patient can go into a coma
33
Q

How can monitoring serum levels be useful?

A
  • Useful in phenytoin (variable & dose dependent) (Correct for albumin and valproate use.)
  • Seizure freedom occurs at levels lower than reference range.
  • Identify level associated with seizure freedom for individual. Treat the patient, not the levels.
  • Check compliance
34
Q

What are the three most important drugs to know about?

A

Sodium Valproate

Lamotrigine

Carbamazepine

35
Q

What are the side effects associated with Phenytoin?

A

P - P450 interactions

H - Hirsutism

E - Enlarged Gums

N - Nystagmus

Y - Yellow/browning of the skin

T - Teratogenic

O - Osteomalacia

I - Interferes with folate metabolism

N - Neuropathies

Pharmacology (26 decks)

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