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Pharmacology > Antiepileptic Drugs > Flashcards

Antiepileptic Drugs Flashcards

1
Q

Epilepsy

A

-dogs (most common idiopathic epilepsy)
-cats
-horses (foals)
-birds (parrots common)

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2
Q

Risk characterization

A

=Hazard x Exposure
(Severity x likelihood)

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3
Q

Risks associated with anti epileptic drugs

A

-Adverse effects

  • Cost (of medication and therapeutic monitoring/bloodwork)
    -client effort (life long administration)
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4
Q

Risks associated without anti-epileptic drug therapy

A

-Progression of seizures and eventual euthanasia

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5
Q

Veterinarians role as risk Manager

A
  1. Discuss therapeutic options with client
  2. Understand what client is willing to accept
    -Acceptance of seizures incidents (elimination is not feasible, but reduction of seizure frequency/severity is goal)
    -Acceptance of adverse drug events, and TDM, cost, compliance
    **note some owners more worried about one than the other
  3. Tailor drug regimen to best manage risks
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6
Q

Communication of AED therapy

A
  1. Before therapy is started, discuss:
    -Goals of AED therapy
    -Expected adverse effects
    -Schedule therapeutic drug monitoring and blood work
  2. While on AED therapy:
    -check on adverse events
    -monitor
    -adjust therapy
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7
Q

Objective of Anticonvulsants

A

**Pathogenesis not well understand

Objective is to raise the seizure threshold by stabilizing neuron membrane potential

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8
Q

Possible mechanisms of Anticonvulsant therapy

A
  1. enhance inhibitory neurotransmitters
    eg. GABA, glycine
  2. Reduce excitatory neurotransmitters
    eg. Glutamate
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9
Q

Hyperpolarization

A

Occurs by:

  1. activating post synaptic K or Cl channels

OR

  1. Reducing pre and post synaptic Na/Ca channels
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10
Q

Why is anticonvulsant therapy challenging?

A
  1. Individual response is unpredictable
    -subpopulation of dogs are refractory to therapy
  2. No cure
    -chronic administration
    -side effects
    -tolerance (PK or PD)
  3. Poor compliance
  4. Therapeutic drug monitoring may be needed to ensure efficacy/safety
    -tough sell to clients but also allows you the opportunity to optimize dose regimen for individual therapy
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11
Q

Tolerance to drug

A

-Work initially and then seizures begin to come back

“The animal is termed to have developed a tolerance to the drug”

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12
Q

Premature death and epilepsy

A

-epilepsy implies an increased risk of premature death (1-2 yrs after diagnosis)

-often the prognosis of epilespy depends on vet experience, therapeutic success, owners motivation

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13
Q

Vet used licensed Anticonvulsant drugs

A
  1. Phenobarbitol (Canada)
  2. Phenobarb, KBr, Primidone
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14
Q

Other drugs used as anti-convulsant

A
  1. Benzodiazepines- during seizures, not for prevention
  2. Levetiracetam (Kepra?), GABA-type drugs
  3. Imepitoin, Zonisamide, CBD
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15
Q

Efficacy of seizure control from drugs

A

Phenobarbitol: up to 85%

KBr: slightly lower

**no comparative studies; not sure if newer drugs are more effective

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16
Q

Phenobarbitol

A

*controlled drug; human generics available

-Barbiturate with anti-epileptic effects when used at sub-anesthetic doses

-Unknown mechanism: may be less excitatory (Ach, Glu, NE) or more inhibitory (GABA)

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17
Q

Other barbiturates

A

-Pentobarbital= euthanasia

-Thiopental= anesthesia

**All controlled drugs!

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18
Q

Adverse effects of Phenobarbitol in dogs

A
  • Sedation/lethargy

-PU/PD from potentially decreased urinary smooth muscle tone

-Polyphagia (avoid obesity= PB distributes into fat)

-Ataxia (should diminish over 10-15days)

-Some Blood dyscrasias

-Decreased in T4 concentration…be aware of hyperthyroidism

-Hepatotoxicity

-Drug interactions (CYP enzyme induction… NOT INHIBITION)

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19
Q

Hepatotoxicity from Phenobarbitol

A
  1. Large increase in ALP and some increase in ALT
    *Liver enzymes more than 3x normal
  2. Abnormal bile acid stimulation test
  3. Decreased albumin, urea, cholesterol
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20
Q

Drug interactions with phenobarbitol

A

-Drug interactions (CYP enzyme induction… NOT INHIBITION)= increase clearance capacity because increase in cytochrome enzymes

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21
Q

Pathology of Phenobarbitol-induced hepatotoxicity

A

-Cirrhosis
-Fibrosis
-nodules

**chronic and dose-dependent hepatotoxicity

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22
Q

Adverse effects of phenobarbitol in cats

A

-sedation/lethargy

-polyphagia (avoid obesity)

-ataxia- dimished over next 10-15 days

-PU/PD

-Allergic reactions (blood dyscrasias= low platelet, WBC counts; and temporary facial swelling)

-blood clotting disorders

-drug interactions (CYP enzyme induction)

**HEPATOTOXICITY IS RARE IN CATS

23
Q

Pharmacokinetics of phenobarbitol

A

Good oral bioavailability, moderate Vd

Dogs:
-Long half life in dogs (half life: 1.5-4days)
-induced cytochrome P450 enzymes (increase enzymes= increase clearance= decreased half life later on)

Cats:
-can become non linear PK

24
Q

Cats non linear PK of phenobarbitol

A

Increased dose may not be proportional to increase in drug exposure

NOTE: minor dosage changes can result in large fluctuations in blood levels
-can make drug ineffective (blood level too low)
OR
-result in excessive sedation (blood level too high)

25
Q

Expected Phenobarb accumulation

A

-dose interval (every 12hrs) is shorter than half life (1.5-4d) so accumulation occurs

-steady state concentrations reached after 5-7half lives (not doses)

26
Q

Actual phenobarb accumulation (due to enzyme induction)

A

Due to hepatic enzyme induction over time, there is an increase in clearance and decrease in concentrations

27
Q

Phenobarbitol in birds

A

-can’t take repeated blood samples in birds
-does work, absorbed, etc.

28
Q

Generic phenobarbitol human drug and switching brands

A

-reported in human epileptics
-probably not an issue for most dogs if its an approved generic drug (not compounded!!!!)
-there is some minor difference in PK and can have significant clinical effect in some dogs

29
Q

Compounded anticonvulsants

A

ex. small dog gets compounded version of phenobarb
-ended up needing increased dosing and were still getting poor effects
-lower plasma concentration of phenobarb present

found out that the solution used was a much lower strength
-Exp date was 3 months… if its a liquid, should only be 2 weeks so possibly lost potency over time

30
Q

Potassium Bromide

A

-very old anti-epileptic drug
-likely hyperpolarizes neural cell membranes
-none approved for vet use in Canada but can get from compounding pharmacies

31
Q

Adverse effects of Potassium Bromide

A

-sedation
-vomiting/diarrhea/constipation
-increased hunger and thirst
-pelvic limb weakness or stiffness (not ataxia)
-pancreatitis
-skin rxns (pruritic)
-occasional behavioural changes (depression, irritation/aggression, attention seeking or aimless pacing)

32
Q

Potassium bromide pharmacokinetics

A

-drug interactions: none but food interactions

-long half life: 24days. Can use loading dose (4x regular dose) for first week to get steady state quicker
> once at steady state then missing single dose not critical

-Elimination: renal BUT reabsorbed with Cl. No hepatic metabolism (so decreased drug interactions)

33
Q

Potassium bromide interactions with salt

A

Salty treats:
-high levels lead to decrease of Br reabsorption from renal tubule=more lost in urine because receptors are pulling in Cl (Cl competition for tubule transporters)
**Common!!

Low salt diets (cardio):
-increase Br resorption from renal tubule, will increase plasma KBr. Decreases clearance resulting in higher levels in the body

34
Q

Treatment of overdose of KBr

A

Use IV 0.9% NaCl = Cl outcompetes and flushes any excess out!

35
Q

Potassium bromide use in cats

A

not used in cats
-show adverse effects= coughing, bronchial asthma due to allergic rxn

36
Q

Diazepam

A

-used to treat status epilepticus in cats and dogs
but not used for seizure prevention
**used in the moment!!

37
Q

Diazepam administration

A
  1. IV- crosses BBB fast

2.Rectal- 50% bioavailability, administer 2x the IV dose
-must be kept in coloured glass vial

  1. Intranasal= 80% bioavailability
  2. Oral= very low bioavailability
38
Q

Metabolism of diazepam

A

Hepatic
-2 active metabolites (nordiazepam and oxazepam which have 10% parent activity)

39
Q

Other uses of Diazepam

A

-behavioural disorders
-appetite stimulant
-pre-anesthetic

40
Q

Diazepam adverse effects

A
  • lethargy, sedation, ataxia
    *seizure will also cause these

-hyperactivity?

-increased appetite= weight gain

-seizures may occur if abruptly stopping chronic diazepam

-fulminant hepatic necrosis in cats

41
Q

Fulminant hepatic necrosis in cats

A

-idiosyncratic
-oral formulation only
-rare; 11 cases documented
-not for chronic admin in cats

42
Q

Newer anticonvulsants

A

-Keppra
-Gabapentin/Pregabalin
-Cannabidol

**not as effective of phenobarbitol or diazepam

43
Q

What are the newer convulsants used for?

A

Usually add ons

-non controlled (no placebo for testing and small sample sizes, not blinded)
-imprecise outcome measures

44
Q

Levetiracetum (Keppra)

A

-used with phenobarbitol or diazepam for seizures
*not as effective alone

-great for cluster seizures
>Keppra with phenobarb or diazepam saw increased response

-can be costly; frequent dosing, compliance may be issue, still need monitoring, and still need to add phenobarbitol or potassium bromide

45
Q

Levetiracetum/Keppra dosing

A

-3x a day dosing
-3-4h half life (difficult for owners)
-high oral bioavailability

-renal excretion: therefore good if worried about hepatic disease, and can just decrease dose in renal impaired patients

46
Q

Safety of Levetiracetum

A

-relatively safe
-no drug interactions
- tolerance may develop= honeymoon period of 4-8mths
-some studies showed link to behaviour changes

47
Q

Keppra use in cats

A

-oral OR Transdermal product- unsure of absorption right now

-leads to increased hypersalivation, some sedation

-SAFE

48
Q

Brivaracetam

A

-newer more potent analogue of levetiracetum
-lots of generic versions in Canada

-Study in cats: longer half life than Keppra, so may be possible for less frequency dosing. Efficacy not known!!

49
Q

Gabapentin

A

-structural analogue of GABA that may blocks or modulates Ca channels

-used in vet med for pain and epileptic;
humans for partial seizures
**probably shouldnt use this instead of big name anti-epileptics

-not many formulations and need frequent dosing

50
Q

Pregabalin (Bonqat)

A

-oral solution now approved as anxiolytic in cats before car transport BUT not approved as anticonvulsant

**older version used as anticonvulsant in humans in the past

51
Q

GABA adverse effects

A

-uncommon
-sedation
-ataxia
-unpredictable efficacy

52
Q

Cannabidiol for epilepsy

A

-decrease in seizure frequency in PB/KBr treated dogs with oral CBD oil

-no difference in overall therapeutic outcome… nothing confirmed!

-often studies are very high doses of cannabidiol and have serious adverse effects

53
Q

Cannabis related issues

A

-neurological adverse events at higher doses= hyperesthesia/ataxia

-uniformity and bioavailability

-cannabis only legal in Canada for humans!

Pharmacology (33 decks)

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