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Module 8 > Epilepsy + Pharmacology of Antiepileptic Drugs > Flashcards

Epilepsy + Pharmacology of Antiepileptic Drugs Flashcards

1
Q

what are epileptic seizures

A

disturbance of neuronal environment lowering the threshold for electrical activity

excessive and/or hypersynchronous electrical activity in the cerebral cortex

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2
Q

what does an epileptic seizure result in

A

paroxysmal episodes of abnormal consciousness, motor activity, sensory input and/or autonomic function

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3
Q

how do epileptic seizures arise

A
  1. inadequate neuronal inhibition
  2. excessive neuronal excitation
  3. combination of the above
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4
Q

how does inadequate neuronal inhibition cause epileptic seizures

A

abnormality of inhibitory neurotransmitters –> GABA = major inhibitory neurotransmitter

primary loss of inhibitory neurons

decreased neuromodulation by serotonin, dopamine, or noradrenaline

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5
Q

how does excessive neuronal excitation cause epileptic seizures

A

abnormality of excitatory neurotransmitters –> L-glutamate = major excitatory neurotransmitters

increased acetylcholine

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6
Q

what is the normal neuronal cell physiology

A
  1. cell membrane is hyperpolarized
  2. membrane potential is determined by influx/efflux of ions through voltage gated channels (extracellular sodium >>> intracellular, extracellular potassium <<< intracellular)
  3. action potentials are created by a reduction in the cell membrane potential
  4. increased permeability of voltage gated channels to sodium results in depolarization (sodium flows into cell)
  5. at the axon terminal this depolarization results in opening of calcium channels
  6. calcium enters cell resulting in release of neurotransmitters
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7
Q

how are seizures terminated

A
  1. input from subcortical areas
  2. development of lactic acidosis
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8
Q

what are the purpose of antiepileptic drugs

A
  1. prevent excessive or hypersynchronous neuronal activity
  2. avoid spread of seizure activity within brain
  3. protects brain from the excitoxic effects of seizures and neuronal damage
  4. delary or halt the progression of seizures over time
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9
Q

what are the major CNS targets for AED (3)

A
  1. GABA
  2. glutamate
  3. voltage-gated channels (Na, Ca, Cl)
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10
Q

what do AED’s need to be in order to be effect

A

highly lipid soluble to penetrate CNS

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11
Q

what is the effects of AED’s

A

hyperpolarize the inside of the cell

  1. GABA binding sites: open the Cl channel
  2. benzodiazepine binding sites: increases the binding of GABA
  3. barbiturate binding site: increases the duration of GABA-dependent chloride channel opening
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12
Q

what are major classes of veterinary AEDs (11)

A
  1. barbiturates: phenobarbital
  2. benzodiazepines: diazepam, midazolam, clonazepam, clorazepate
  3. impitoin: pexion
  4. bromide: potassium bromide
  5. fatty acids: sodium valproate
  6. fructose derivatives: topiramate
  7. GABA analogs: gabapentin, pregabalin
  8. hydantoins: phenytoin
  9. pyrimidinediones; primidone
  10. pyrrolidines: levetiracetam
  11. sulfonamides: zonisamide
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13
Q

how doe cases with epileptic seizures present

A
  1. occasional brief seizures (few mins long)
  2. emergencies during severe seizures –> clusters of short seizures with minimal to no recovery between seizures (cluster seizure = more than 1 in a 24 hour period) and status epilepticus = prolonged seizure lasting more than 20-30 mins
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14
Q

how are epileptic seizures managed

A
  1. addressing any underlying cause
  2. irrespective of the cause: symptomatic control of the seizures with medications
  3. symptomatic control with:
  • chronic ongoing therapy for dogs with occasional brief seizures
  • immediate, short-term emergency therapy for dogs presenting during status epilepticus ro a severe cluster of seizures
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15
Q

what are the aims of treatment for chronic epileptic seizures

A

treatment unlikely to abolish seizures

  1. reduce freq, severity and duration
  2. delay progression of seizures
  3. minimize side effects
  4. minimize demands on owner
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16
Q

what medications are most effective in treating chronic seizures

A

clinical effect is based on maintaining an effective serum concentration

*drugs that are eliminated slowly

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17
Q

what are suitable medications for chronic therapy

A
  1. phenobarbital
  2. imepitoin
  3. potassium bromide
  4. diazepam
  5. levetiracetam
  6. zonisamide
  7. gabapentin
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18
Q

what are exception to using standard anti-epileptic drugs

A

extra-cranial causes

  1. hepatic encephalopathy
  2. hypoglycemia
  3. multiple toxic causes: carbamates, methaldehyde, organophosphates
  4. ion imbalance: hypocalcemia
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19
Q

what medications do we chose for chronic epilepsy in dogs

A

initial therapy: phenobarbital or imepitoin

in dogs regractory to Pb add potassium bromide (KBr) in addition to Pb

in dogs refractory to this combination therapy: add or change to levetiracetam, zonisamide or gabapentin

initial therapy in dogs with hepatic impairment: potassium bromide or levetiracetam

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20
Q

how is chronic epilepsy treated in cats

A

initial therapy: phenobarbital, levetiracetum or diazepam (imepitoin also safe to use in cats)

refractory to a single medication try the other or try a combination of the two

DO NOT USE KBr IN CATS

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21
Q

when do you start maintenance treatment

A

ideally as soon as animal develops epileptic seizures –> definitely if there is more than 1 seizure per month

or if:

  1. owner objects to their freq
  2. very severe seizure or a cluster of seizures (irrespective of freq)
  3. seizures are increasing in freq or severity
  4. underyling progressive disorder is identified
  5. objective post-ictal signs (aggression)
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22
Q

how must clients be educated

A

daily antiepileptic treatment may reduce seizure severity, freq or both, but absence of seizures is difficult to achieve

medication aims at controlling seizures

side effects are common initially

side effects may be more severe than seizures

owners must keep a diary of seizure events

withdrawal effects: may precipitate seizures

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23
Q

what is the mechanism of action of phenobarbital

A

variety of actions, not all of which are fully understood, but major mode of action is probably mediated through GABA

  1. enahances the activity of GABA, the major inhibitory CNS neurotransmitter and thereby increases neuronal inhibition
  2. reduces neuronal excitability through interaction with glutamate receptors
  3. inhibits voltage gated Ca channels
  4. competitive binding of chloride channel picrotoxin site
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24
Q

what are the pharacokinetics of phenobarbital (absorption, distribution, metabolism, elimination half life, serum concentrations)

A

1. absorption: rapid oral absorption, high bioavailability (86-96%)

2. distribution: widely distributed, lower lipid solubility than other barbiturates and slower penetration of CNS than other barbiturates

3. metabolism: primarily hepatic metabolism (25% excreted unchanged by kidneys)

4. elimination half life: 30h-90h in dogs and 3h-83h in cats

5. serum concentrations: doses should be guided by serum concentration and not oral dose –> concentrations will decrease with chronic therapy and therefore doses will need to increase

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25
Q

what is serum concentration

A

measured serum concentration is most important not the administered oral dose

therapeutic range = serum concentration providing optimal seizure control while minimizing side effects

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26
Q

what is steady serum state

A

5 elimination half lives

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27
Q

what is the steady serum state in phenobarbital

A

7 days to 2 weeks in phenobarbital

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28
Q

what is the steady serum state in bromide

A

3 months (up to 6)

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29
Q

what occurs as serum concentration increases

A

sub-therapeutic –> therapeutic –> toxic

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30
Q

what is the loading dose

A

use to increase serum conc. to steady state faster

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31
Q

what does the loading dose require

A

administration of the 5x maintenance dose

must take into account possible side effects associated with administration of such a high dose

*because of side effects loading doses are restricted to emergency use

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32
Q

how are phenobarbital serum concentrations monitored

A

timing of sample collection relative to time of dose admin is not important at starting doses

timing is clinically relevant at high doses in dogs –> collect blood sample at same time relative to time of drug admin

less hepatic induction in cats: timing is less important

serum separation tubes may falsely reduce the serum phenobarbital conc. –> DON’T USE

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33
Q

what are the adverse effects of phenobarbitals

A

divided into those initially (most dogs develop tolerance after 2-4 weeks) and those assoicated with long term therapy

  1. initially: polyuria, polydipsia, polyphagia, transient sedation or less commonly hyperexcitability, transient ataxia
  2. less commonly: blood dyscrasias (including neutropenia, anemia, thrombocytopenia), usually as idiosyncratic or allergic response that resolves with cessation of therapy
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34
Q

what are the adverse effects associated with longer term therapy phenobarbital

A

1. hepatic toxicity: reduced by maintaining serum concentrations with the therapeutic range, by avoiding combinations of hepatotoxic therapies and by monitoring serum biochemistry every 6 months

induction of hepatic enzymes (ALP and ALT) –> no hepatic enzyme induction in cats

2. mild reduction in serum albumin

3. increased metobolism of thyroid hormones and suppression of TSH

4. induction of hepatic microsomal p450 enzyme systems

35
Q

how is hepatic function monitored

A

induction of hepatic enzymes these are a poor guide to hepatic impairement

bile acid assay is the best guide to hepatic function in animals on Pb therapy, particularly a significantly elevated pre- and post-prandial bile acid assay

dramatic elevation of ALP and ALT: greather than would be expected with enzyme induction should raise concern

dramatic or sustained hypoalbuminemia

36
Q

what is the routine monitoring of patients on treatment for epileptic seizures

A
  1. regulary (6 monthly) monitoring of serum phenobarbital levels
  2. regular (6-12 monthly) monitoring of hepatic and bone marrow function (hematology, biochemistry and bile acid assay)
37
Q

what are indications of phenobarbital treatment failure

A
  1. low serum concentration (dose too low, poor owner compliance, interference with absorption)
  2. drug interaction
  3. incorrect diagnosis
  4. a second disease causing seizures
  5. refractory epilepsy: 25-40% of dogs with priamry epilepsy
38
Q

what is refractory epilepsy

A

seizures refractory to phenobarbital –> add another maintenance drug

39
Q

what are examples of maintenance drugs in refractory epilepsy

A
  1. bromide (potassium or sodium salt)
  2. imepitoin (pexion)
  3. levetriracetam
  4. zonisamide
  5. gabapentin
  6. long acting phenytoin
  7. long acting benzodiazepam: clorazepate dipotassium
40
Q

what is the mechanism of action of potassium bromide

A

interaction with chloride channels

  1. Cl channels regulated by GABA –> hyperpolarize the neuronal membrane making it more stable
  2. bromide crosses the Cl channels in preference to Cl –> smaller hydrated diameter
  3. facilitates effect of neurotransmitters acting on GABA channel by hyperpolarizing the cell membrane
  4. bromide may act synergistically with phenobarbital
41
Q

what are the pharmacokinetics (absorption, distribution, metabolism, elimination half life, serum concentration)

A

1. absorption: absorbed from small intestine (peak 1.5 hours), not protein bound

2. distribution: extracellular space, eliminated slowly due to marked renal reabsorption (increased dietary salt will increase elimination)

3. metabolism: no hepatic metabolism (combined with absence of protein binding useful for dogs with hepatic disease)

4. elimination half life: 25 days, requires 3-4 weeks of therapy to achieve therapeutic effect and 3-4 months to achieve steady state

5. serum concentration: drug doses should be guided by serum concentration and not oral dose

42
Q

what are the adverse effects of potassium bromide

A
  1. initially: vomiting and anorexia (often will resolve if a different formula used –> capsules, suspension, powder, tablets, syrup or if medication used with food)
  2. ataxia and sedation
  3. asthma in over 50% of cats (can be fatal –> contraindictated)
  4. pancreatitis
  5. pruritis
43
Q

what are the uses of bromide in dogs

A

sole anticonvulsant if Pb is contraindicated

with Pb in refractory epilepsy (preferably only when Pb is at top end of therapeutic range)

44
Q

what is the mechanism of action of Pexion

A

partial agonist at benzodiazepin recognition site of GABA receptor

potentiates GABA receptor mediated inhibitory effects on neurons

also has weak calcium channel blocking effect

45
Q

what are the pharmacokinetics (absorption, distribution, metabolism, elimination half life)

A

1. absorption: >92% absorbed, peak absorption around 2 hours, bioavailability varies with food so relation with feeding should be consistent

2. distribution: wide, rapidly crosses BBB, not protein bound, no accumulation once steady state reached

3. metabolism: metabolized prior to elimination (urine and feces)

4. elimination half life: 1.5-2 hours

46
Q

what are the adverse effects of Pexion

A

not yet fully known –> polyphagia, hyperactivity, polyuria, polydipsia, somnolence, hypersalivation, vomiting, ataxia, apathy, diarrhea, decreased sight and sound sensitivity reported at beginning of treatment

fewer than phenobarbital fewer adverse events

47
Q

what are the uses of pexion

A

reducing frequency of generalized seizures due to idiopathic epilepsy in dogs

efficacy as an add on therapy not demonstrated

after 20wks considered as effective as phenobarbitone

no loss of anticonvulsant acitivty, no increase in liver enzymes

48
Q

what are the use of levetiracetam (keppra)

A

add on medication in refractory dogs or as sole anticonvulsant in cats

useful in animal with hepatic impairment

49
Q

what is the mechanism of levetiracetam (keppra)

A

unknown

50
Q

what are the pharmacokinetics of levetiracetam (keppra)

A

rapidly absorbed, minimally protein bound and around 90% renal excretion

51
Q

what is the elimination half life of levetiracetam (keppra)

A

dogs: 2.3-3.6hrs
cats: 5.3hrs

52
Q

what are the serum concentration of levetiracetam (keppra)

A

not useful in guiding therapy

53
Q

what are the adverse effects of levetiracetam (keppra)

A

sedation

occasionally restlessness, vomiting and ataxia in dogs

54
Q

what are the use of zonisamide (zonegran)

A

add on medication in refractory dogs

55
Q

what is the mechanism of action of zonisamide (zonegran)

A

unknown

56
Q

what is the pharmacokinetics of zonisamide (zonegran)

A

rapidy absorbed and low protein binding

mostly excreted unchanged in urine (around 20% undergoes hepatic metabolism)

no induction of hepatic enzymes

57
Q

what is the elimination half life of zonisamide (zonegran)

A

dogs: 15 hours (dramitically reduced if given concurrently with drugs that induce hepatic microsomal enzyme systems)

58
Q

what is the serum concentration of zonisamide (zonegran)

A

not useful in guiding therapy

59
Q

what are the adverse effects of zonisamide (zonegran)

A

sedation, ataxia, anorexia

contraindicated in dogs with hypersensitivity to sulphonamides and caution if there is concurrent renal or hepatic impairment

60
Q

what are the uses of gabapentin

A

add on medication in refractory dogs, esp those with severe clusters of seizures

61
Q

what are the mechanism of action of gabapentin

A

unknown

but thought to inhibit CNS voltage-gated sodium channels

may enhance GABA release

62
Q

what are the pharmacokinetics of gabapentin

A

rapidly absorbed and not protein bound

metabolized to N-methylhabapentin with around 1/3 renally excreted (in dogs)

63
Q

what is the elimination half life of gabapentin

A

3-4 hours in dogs

64
Q

what are serum concentrations in gabapentin

A

not useful in guiding therapy

65
Q

what are the adverse effects of gabapentin

A

sedation

GIT irritation

66
Q

what are status epilepticus seizures

A

1 epileptic seizure lasting more than 5 mins or

2 or more epileptic seizures without a break within a 5 min period

67
Q

what are cluster seizures

A

2 or more generalized epileptic seizures in 24 hours

68
Q

what are the aims of treatment for emergency severe seizures

A
  1. abolish the acute seizure episode
    - emergency treatment only for the duration of the severe episode
    - if ongoing underlying cause then the animal may also demonstrate chronic seizures that may require control with chronic therapy
69
Q

what medications are the most effective for treatment of severe emergency seizures

A

short acting medications and don’t achieve a maintained serum concentration

short-acting nature means that higher doses can be used with a lower risk of overdose

drugs are not suitable for maintenance therapy (except diazepam in cats)

70
Q

what are the medications suitable for emergency therapy

A
  1. diazepam
  2. midazolam
  3. levetiracetam (particularly cluster seizures)
  4. phenobarbital loading dose (rapidly increase blood levels)
  5. pentobarbitone
  6. propofol infusion
  7. potassium bromide loading dose
71
Q

what are the phamacokinetics of diazepam

A

maintenance medication in cats, emergency medication only in dogs

wide margin of safety

anticonvulsant effect following IV admin 2-3 mins

half life of over 3 hours –> CNS concentrations decline rapidly and anticonvulsant effect only lasts around 20 minutes in dgos (repeated treatment)

72
Q

what are the pharmacokinetics of midazolam

A

wide margin of safety and broad therapeutic index

rapid elimination (half life = 53-77 mins)

73
Q

what are cluster seizures

A

2 or more generalized epileptic seizures in 24 hours

74
Q

how are cluster seizures managed

A

in severe seizures and in addition to maintenance therapy can use additional pulse therapy during the cluster with –> levetiracetam (keppra)

rectal diazepam

gabapentin

75
Q

what is the aim when treating cluster seizures

A

reduce number of seizures in a cluster

76
Q

what is the medication of choice in treating cluster seizures

A

levetiracetam (keppra)

at end of cluster stop the additional drug, all the time the dog remains on its normal maintenance therapy

most clusters last between 24-72 hours

reduce the dose if the dog appears too sedated

77
Q

what are the aims of managing status epilepticus

A
  1. stop seizures, use short acting anticonvulsat drugs
  2. supportive care
  3. follow up maintenance anticonvulsant therapy
  4. obtain diagnostic samples
78
Q

what is the specific short acting therapy of diazepam for status epilepticus

A

2-3 mins to clinical effect

repeat up to three times

79
Q

how is phenobarbital used in naive animals for status epilepticus

A

initial loading dose 12mg/kg IV

blood conc of 65-100 umol/l

clinical effect in 20 min

if animal not too sedated: further boluses at 3mg/kg to take total dose to 18-24mg/kg

80
Q

what is the treatment of phenobarbitol in status epilepticus of animals already on Pb

A

already have blood levels –> large bolus will result in toxic levels

single bolus of 3mg/kg to slightly increase levels (blood sample for Pb level first)

potassium bromide loading dose

81
Q

what is the bromide loading regime in status epilepticus

A

dogs going into status epilepticus in the presnce of therapuetic levels of pb

oral or rectal loading dose

rectal dose may cause severe diarrhea

200mg/kg daily for 5 days, divided into 4-6 doses

single loading dose of 600 to 1000mg/kg, divided into multiple doses

monitor level post load and one month later

82
Q

what if the seizures continue in status epilepticus

A

sedate or GA for 12-36 hours

constant diazepam infusion

constant midazolam infusion

levetiracetam infusion

propofol coma

83
Q

what is the supportive care in status epilepticus if sedated or GA

A

maintain normal body temp

maintain patient airway

turn patient every 2-4 hours

monitor vital parameters

broad spectrum antibiotic

Module 8 (43 decks)

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