Anti-epileptic drugs

Question 1

What are epileptic seizures?

Answer 1

Disturbance of neuronal environment lowering the threshold for electrical activity- can be caused by tumour, inflammation, etc

Excessive and/or hypersynchronous electrical activity in the cerebral cortex

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

Epilepsy occurs in between 0.5-5.7% of dogs and 0.5-1% of cats.

Epileptic seizures are seen secondary to a variety of underlying causes including forebrain problems, metabolic problems and toxic causes

Question 2

Causes of epileptic seizures

Answer 2

Intracranial: 1) functional/idiopathic (no abnormalities can be detected on investiation) 2) structural (abnormality within the brain i.e. tumor, encephalitis etc)

extracranial: 1) metabolic (e.g. hypoglycemia, hepatic disease, electrolyte distrubance) 2) toxic (e.g. organophosphate, carbamates, lead, ivermectin, strychnine)

Question 3

How do seizures arise?

Answer 3

1) inadequate neuronal inhibition: abnormality of inhibitory neurotransmitters. GABA=major inhibitory NT

primary loss of inhibitory neurons

decreased neuromodulation by serotonin, dopamine, or noradrenaline

2) excessive neuronal excitation: abnormality of excitatory NTs–L-glutamate is major excitatory NT

increased ACh

3) combination of above

Question 4

Normal neuronal cell physiology

Answer 4

Cell membrane is hyperpolarized. membrane potential is determined by influx/efflux of ions through voltage-gated channels.

APs created by reduction in cell membrane potential. Increased permeability of voltage gated chennaleso to sodium results in depolarization (Na+ into cell). At axon terminal, depolarization results in oepning of Ca2+ channels. Calcium enters cell–>release of NTs

Question 5

Termination of seizures

Answer 5

mechanism is unclear but may involve:

input from subcortical areas

development of lactic acidosis- lactic acidosis is thought to inhibit neuronal excitability

in some patients, there might be a failure to terminate seizure activity resulting in 1) cluster seizure activity

2) status epilepticus- continuous seizure

Question 6

Purpose of antiepileptic drugs

Answer 6

prevents excessive or hypersynchronous neuronal activity– dampens focus to avoid spread

avoid spread of seizure activity within the brain

protects brain from excitotoxic effects of seizures and neuronal damage

delay or halt progression of seizures over time

Question 7

Major CNS targets for AEDs

Answer 7

GABA

glutamate

voltage-gated channels: sodium, calcium, chloride

AEDS need to be highly lipid soluble to penetrate CNS

Major effect of AEDs is to hyperpolarize the INSIDE of the cell, as demonstarted by the interaction of major anticonvulsant medications and GABA. Lots of drugs potentiate GABA effects.

Question 8

Major classes of veterinary AEDS

Answer 8

Barbiturates: phenobarbital

Benzodiazepines: dizepam, midazolam, clonazepam, clorazepate

Imepitoin: pexion

bromide: potassium bromide

fatty acidsL sodium valproate

fructose derivatives: topiramate

GABA analogues: gabapentin, pregablin

Hydantoins: phenytoin

Pyrimidinediones: primidone

Pyrrolidines: Levetiracetam

Sulfonamides: zonisamide

Question 9

How do cases with seizures present?

Answer 9

two main groups

1) most present with ocassional brief seizures- by the time they present, usually normal
2) present as emergencies during severe seizures

Clusters of short seizures with minimal to no recovery between seizures (cluster seizures=more than one seizure in 24 hour period)

Status epilepticus: prolonged seizure lasting more than 20-30 minutes

As clusters get closer together, more likely to go into status epilepticus.

Question 10

Management of epileptic seizures

Answer 10

Addressing any underlying cause

Irresepctive of cause, symptomatic control of epileptic seizures with medications

Symptomatic control comprises either 1) chronic ongoing therapy for dogs with occasional brief seizures or 2) immediate, short-term emergency therapy for dogs presenting during status epilepticus or a severe cluster of seizures.

Question 11

Chronic therapy for seizure

Answer 11

TX unlikely to abolish all seizures

Aims of tx: reduce frequency, severity and duration of seizures

delay progression of seizures

minimise side effects i.e. pacing

minimize demands on owner

what medications are most effective: clinical effect is based on maintaining an effective serum concentration, therefore usually use drugs that are eliminated slowly (except imepitoin)

Question 12

Suitable meds for chronic therapy

Answer 12

Phenobarbitol (Pb): Dogs- starting dose at 2-3 mg/kg PO q 12 hours, but dose based on serum concentration

cats: 1.5-2.5mg/kg PO q12 hours

Imepitoin: dogs 10-30mg/kg PO q. 12 hours

KBr: Dogs 20-40 mg/kg PO q. 24 hours but dose based on serum concentration. Contraindicated in cats

Diazepam: in dogs only emergency med; in cats: 0.25-0.5 mg/kg PO q. 12 hours

Levetiracetam, Zonisamide, Gabapentin reserved for refractory cases- from human medicine–add on as adjunctive therapy.

Question 13

Exception to using standard AEDs are some extra-cranial causes

Answer 13

Hepatic encephalopathy

Hypoglycemia

Multiple toxic causes: carbamates, metahldehyde (slug bait), organophosphates, etc

Ion imbalance: hypocalcemia,etc

Question 14

Chronic therapy in dogs

Answer 14

Initial therapy: Pb or pexion

If dogs refractory to Pb, add KBr in addition to Pb

If dogs refractory to this combo therapy, add or change to levetiracetam, zonisamide or gabapentin

Initial therapy in dogs with hepatic impairment: KBr or levetiracetam

Question 15

Chronic therapy in cats

Answer 15

Initial therapy: Pb or diazepam

If cats refractory to a single medication, try the other or try a combo of the two.

If cats refractory to those (or adverse side effects) try adding or changing to levetiracetam

DO NOT USE KBr in CATS- can be fatal

Question 16

When to start maintenance treatment?

Answer 16

ideally as soon as animal develops seizures but definitely if there is more than one seizure per month

or:

if owner objects to their frequency

very severe seizure or cluster seizure (irrespective of frequency)

seizures are increasing in frequency or severity

underlying progressive order ID’ed

objectionable post-ictal signs (i.e. aggression)

Question 17

Daily AED tx

Answer 17

may reduce seizure severity, frequency, or both, but absence of seizure is difficult to achieve.

medication aims at controlling seizures

side effects are common initially- wobbly, etc, eat drink more

side effects may be more severe than seizures i.e. animal is SO sedate

owners must keep a diary of seizure events

withdrawal effects may precipitate seizures–> gradual withdrawal necessary

Question 18

Phenobarbital mechanism of action

Answer 18

Variety of actions, not all of which are fully understood bu major mode of action probably mediated through GABA

in contrast to other barbiturtates, Pb exerts its anticonvulsant effect at subhypnotic doses

enhances activity of GABA, and thereby increases neuronal inhibition

reduces neuronal exciability through interaction with glutamate receptors

inhibits voltage-gated calcium channels

competitive binding of chloride channel picrotoxin site

Question 19

Pharmacokinetics of Pb

Answer 19

Absorption: rapid oral absorption (reduced by 10%if given with food); High bioavailability (86-96%); peak plasma levels at 4-6 hours; plasma binding ~45%

Distribution: widely distributed, but lower lipid solubility than other barbiturates and therefore slower penetration of CNS than other barbiturates. Following IV injection: therapeutic CNS concentrations in 15-20 minutes- this delay has implications for emergency treatment

Metabolism: primarily hepatice. 25% excreted unchanged by kidneys; alkalinization of urine will increase renal excretion of Pb and its metabolites

Elimination half life: ranges from 30-90 hours in dogs and 3-83 hours in cats. In dogs, elimination half life decreases with chronic administration: reduction from 89hours in single dose to 47 hours following 90 days of continuous therapy

Serum concentrations: drug doses should be guided by serum concentration and not oral dose. serum concentrations will decrease with chronic therapy and therefore doses will need to increase. Therapeutic range: 15-45 micrograms/ml or 65 to 170 micromols/liter

Question 20

Concept of serum concentrations

Answer 20

measured serum concentration is most important, not the administered oral dose

TR= serum concentration providing optimal seizure control while minimizing side effects

Steady serum state= 5 elimination half lives

-7 days to 2 weeks in Pb

3 months (up to 6 months) in KBr

Question 21

Loading doses

Answer 21

use to increase serum concentration to steady state faster

requires admin of 5x maintenance dose

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

because of these side effects, loading doses are restricted to emergency use.

Question 22

How do we monitor serum Pb concentrations?

Answer 22

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 the same time relative to time of drug admin

less hepatic induction in cats: timing probably less important

serum separation tubes may falsely reduce the serum Pb concentration.

nb: 60% of dogs started at manufacturer’s recommended dose will be sub-therapeutic at time of first monitoring

Question 23

Adverse effects of Pb: initial

Answer 23

Polyuria, polydipsia, polyphagia

transient sedation or less commonly, hyperexcitability

transient ataxia

less commonly: blood dyscrasias (including neutropenia, anemia and thrombocytopenia), usually as an idiosyncratic or allergic response that resolves with cessation of therapy.

Question 24

Adverse effect of Pb associated with chronic therapy

Answer 24

hepatic toxicity: reduced by maintaing serum concentrations within TR, by avoiding combinations of hepatotoxic therapies and by monitoring serum biochemistry every 6 months

Induction of hepatic enzymes, in particular ALP and ALT (no hepatic enzyme induction in cats)

Mild reduction in serum albumin

Increased metabolism of thyroid hormones and suppression of TSH

Induction of hepatic microsomal P450 enzyme systems (helps eliminate drugs).

Question 25

Pb half life and chronic therapy

Answer 25

In dogs, Pb half life declines with time

Hepatic enzymes induction–> decreased half life

Question 26

Monitoring hepatic function with Pb

Answer 26

because of induction of hepatic enzymes, theres are a poor guide to hepatic impairment

Bile acid assay is 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 particularly ALT: greater than would be expected with enzyme induction should raise concern

dramatic or sustained hypoalbuminemia.

Question 27

Pb treatment failure

Answer 27

“control” epileptic seizures

Minimize side effects- dogs will still seizure despite therapy

Low serum concentration: dose too low (TR), poor owner compliance, interference with absorption

Drug interaction

incorrect diagnosis

a second disease causing seizures

refractory epilepsy: 25-40% of dogs with primary epilepsy. –if refractory to Pb, add KBr or pexion

Question 28

Potassium bromide mechanism of action

Answer 28

not fully understood but involves bromide interaction with chloride channels

Chloride channels are modulated by GABA and function to hyperpolarize the neuronal cell membrane, making it more stable

Bromide crosses the chloride channels in preference of chloride as it has a smaller hydrated diameter. Bromide therefore faciliates the effect of NTs acting on GABA channel by hyperpolarizing cell membrane.

bromide may act synergisticaly with Pb.

Question 29

Pharmacokinetics of KBr

Answer 29

Absorption: from SI, peak absorption after 1.5 hours, not protein-bound

Distribution: distributed to the extracellular space. eliminated slowly due to marked renal absorption- however, increased dietary salt will increase elimination.

Metabolism: NO hepatic metabolism: this combined with the absence of protein binding makes it useful in dogs with hepatic disease

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

Serum concentrations: drug doses should be guided by serum concentration and not oral dose

TR: 0.8-2.4mg/ml or 0.8-3.0mg/ml if used as sole anticonvulsant.

Question 30

Adverse effects of KBr

Answer 30

initially: vomiting and anorexia: these will often resolve if a different formulation is used or if medication is mixed with food

Adverse effects depend on therapy duration and dose:

ataxia and sedation

asthma in over 50% of cats: may be fatal, therefore use is contraindicated

Pancreatitis

Pruritis

Question 31

Use of KBr in dogs

Answer 31

sole anticonvulsant if Pb is contraindicated (i.e. pre-existing severe hepatic insufficiency)

with Pb in refractory epilepsy: 50% of cases controlled; preferably only when Pb is at top end of TR.

Question 32

Pexion (Imepitoin)- mechanism of action

Answer 32

Partial agonist at benzodiazepine recognition site of GABA receptor

Potentiates GABA receptor-mediated inhibitory effects on neurons

Also has a weak calcium channel blocking effect.

Question 33

Pharmacokinetics of Pexion

Answer 33

Absorption: >92% absorbed. Peak absorption around 2 hours. Bioavailability varies with food, so relation with feeding should be consistent

Distribution: wide, rapidly crosses BBB; not protein-bound; no accumulation once steady state reached

Metabolism: metabolised prior to elimination. Metabolites in urine and feces

Elimination half life of 1.5-2 hours

Serum concentrations aren’t measured

Recommended initial dose is 10mg/kg BID

Dose can be increased by 50-100% increments to a max of 30mg/kg BID

Question 34

Pexion adverse effects

Answer 34

not fully known yet but polyphagia, hyperactivity, polyuria, polydipsia, somnolence, hypersalivation, vomiting, ataxia, apathy, diarrhea, decreased sight and sound sensitivity have all been reported at the beginning of treatment

when compared when Pb, fewer adverse events were noted.

Question 35

Use of pexion

Answer 35

reducing frequency of generalized seizures due to idiopathic epilepsy in dogs (licensed)

Efficacy as an add-on therapy hasn’t been demonstrated

After 20 weeks, tx considered as effective as Pb

No loss of anticonvulsant activity

No increase in liver enzymes- don’t have to up the dose–> no tolerance seen.

Question 36

Emergency management of seizures

Answer 36

Status epilepticus: 1 epileptic seizure lasting more than 30 minutes or 2 or more seizures without a break lasting more than 30 minutes in total

Cluster seizures: 2 or more generalized epileptic seizures in 24 hours.

Question 37

Aims of emergency tx

Answer 37

totally abolish acute seizure episode

emergency tx only for the duration of the episode

if there’s an ongoing underlying cause, then the animal may also demonstrate chronic seizures that may require control with chronic therapy.

Use short-acting medication and therefore don’t achieve maintained serum concentration

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

These drugs are NOT suitable for maintenance (except diazepam in cats)

Question 38

Pharmacokinetics of Diazepam and Midazolam

Answer 38

specific to seizure control

Diazepam: effective as maintenance in cats (longer duration of effect). only used as emergency med in dogs.

wide margin of safety

anticonvulsant effect of diazepam following IV admin is 2-3 minutes but despite half life of over 3 hours, CNS concentrations decline rapidly and anticonvulsant effect only lasts around 20 minutes in dog. tx will need to be repeated

Midazolam: wide margin of safety and broad therapeutic index; rapid elimination (half life= 53-77 minutes)

Question 39

Cluster seizures

Answer 39

2 or more generalized seizures in 24 hours

in severe clusters: in addition to maintenance therapy, can use pulse therapy with:

levetiracetam (Keppra)***

long acting BZP

rectal diazepam

gabapentin

slow release phenytoin formulations

Aim is to reduce number of seizures in a cluster. Keppra at 20-30mg/kg TID to QID for the duration of the cluster only. At the end of the cluster, stop the additional drug. All the time, the dog remains on it’s normal maintenance therapy. Most clusters typically last between 24-72 hours.

Question 40

Management of Status Epilepticus

Answer 40

Aims: stop seizures using short-acting convulsant drugs; supportive care; follow-up maintenance anticonvulsant therapy; obtain diagnostic samples

Short acting anticonvulsant therapy:

Diazepam: 0.5-1.0mg/kg IV: 2-3 minutes to clinical effect, repeat up to 3 times

Can give rectally at 0.5-2.0mg/kg

Remember: half life of diazepam is longer in cat; dose carefully.

Question 41

Status epilepticus in Pb-naive animals

Answer 41

initial loading dose of 12mg/kg IV

blood concentration of 65-100 micromol/liter

Clinical effect in 20 minutes

if animal too sedated: further boluses at 3mg/kg to take total dose to 18-24mg/kg

Question 42

Status epilepticus in animals currently on Pb

Answer 42

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); KBr loading dose

Question 43

Bromide loading regime

Answer 43

Dogs going into status epilepticus in the presence of therapeutic levels of Pb

oral or rectal loading dose:

rectal loading may cause severe diarrhea

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

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

Monitor level post-load and one month later

Question 44

If seizures continue

Answer 44

may need to sedate or GA for 12-36 hours

Constant diazepam infusion: 0.5-2mg/kg/hour

Constant midazolam infusion: 0.3mg/kg/hour

Levetiracetam infusion

Propofol coma

barbiturate coma

Maintain normal body temp, patent airway

turn patient every 2-4 hours

monitor vitals

broad spectrum ABX due to lying in hospitalized state.