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NEU2 > Neuropharmacology > Flashcards

Neuropharmacology Flashcards

1
Q

Compare the use of antiepileptic drugs in dogs and cats

A
  • Phenobarbital better in cats than dogs
  • Imepitoin better for dogs
  • Bromides have shorter half life in cats than dogs, not recommended in cats due to risk of fatal asthma
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2
Q

What are the main sites of anti-epileptic drug action?

A
  • Glutamate/NMDA (excitatory) and GABA (inhibitory) receptors
  • Can agonise, antagonise or block
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3
Q

What is the effect of increasing the duration of chloride channel opening on neurones?

A

Chloride hyperpolarises membrane and therefore inhibitory to impulses, longer opening means more time for chloride to get in and hyperpolarise

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4
Q

Which anticonvulsatn drugs act on the GABA-a receptor?

A
  • Imepitoin
  • Barbiturates
  • Bromide
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5
Q

Outline the mechanisms of action of phenobarbital

A
  • Increases activity of GABA
  • Interaction with glutamate receptors to reduce neuronal excitotoxicity (experimental finding)
  • Inhibition of voltage-gated calcium channels which reduces excitation
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6
Q

Outline the pharmacokinetics of phenobarbital anticonvulsants

A
  • High bioavailability, lower when given with food
  • Metabolised by the liver
  • 25% exreteed unchanged by kidney
  • Half life: 30-90h in dgos, 3-83 h in cats
  • Half life decreases with chronic administation in the dog due to autoinfuction of own hepatic metabolism
  • Variable metabolism in dog breeds, beagles metabolise faster
  • Functional tolerance due to receptor desensitisation
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7
Q

Describe the adverse effects of phenobarbital anticonvulsants

A
  • Ataxia, sedation, occasional initial hyperactivity in dogs
  • PD, polyphagia, weight gain
  • Hepatotoxicity in dogs only
  • Haematological abnromalities: anaemia, thrombocytopaenia, neutropaenia
  • Pancreatitis in dogs when combined with bromide
  • Superficial necrolytic dermatitis
  • Hypoalbuminaemia
  • Generally transient other than hepatotoxicity
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8
Q

Outline the drug interactions of phenobarbital anticonvulsants

A
  • P450 induction in dogs only
  • May lead to interactions with drugs metabolised by the liver e.g. reduced therapeutic efficacy of glucocorticoids, phenulbutazone and some anaestehtic drugs
  • Some drugs increase toxicity of phenobarb e.g. chloramphenicol, by inhibiting hepatic metabolism
  • Withdrawal seizures over time due to increased enzyme induction and increased enzyme metabolism
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9
Q

Discuss the use of phenobarbital in the therapy for status epilepticus

A
  • Not first choice
  • Dogs and cats: IV admin, may be repeated
  • Once seizures controlled, use maintenance dose
  • Oral therapy resumed/initiated q12h as soon as animal can swallow
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10
Q

Outline the use of phenobarbital for the long term treatment of epilepsy in dogs and cats

A
  • Starting dose based on weight
  • All future adjustments based on serum drug concentrations due to pharmacokinetic properties
  • MOnitor drug serum levels for trough value every 14 days
  • If controlled, no change to treatment
  • If not controlled, adjust dose and recheck after 14 days
  • If plasma PB concentration >35ug/ml risk of liver dysfunction, recheck PB and bile acid levels in 3-6 months
  • Monitor at 45, 90, 180 and 360 days thereafter, adjust dose as needed
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11
Q

What action is indicated if the serum phenobarbital levels are >30ug/ml and are having .1 seizure/3 months?

A

Startpotassium bromide

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12
Q

What are the clinical appplications of potassium bromide in the treatment of epilepsy?

A
  • Adjunct to phenobarbital in refractory epilepsies
  • Sole anti-convulsant in dogs with hepatic dysfunction and mild seizures
  • Mostly superseded by imepitoin and phenobarbital
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13
Q

Discuss the use of sodium bromide in the treatment of epilepsy in dogs

A
  • LEss irritating to stomach vs KBr, good in dogs with nausea/vomiting
  • Preferable in dogs with hypoadrenocorticism, other conditions where cannot tolerate excess potassium
  • Some dogs object less to the taste
  • Otherwise is identical to KBr
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14
Q

Describe the mechanism of action of bromide as an anti-convulsant

A
  • Not completely understood
  • Most likely interaction with GABA-gated chloride channels
  • may be that Br competes with Cl ions, crosses cahnnels easer than Cl adn hyperpolariss post-synaptic neuronal membrane
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15
Q

Describe the pharmacokinetics of bromides for anti-convulsant therapy

A
  • No hepatic metabolism- Half life in dogs 24.9 days, steady state after 4-5 months
  • Half life in cats ~12 days
  • Distribution volume = extracellular space, but slow elimination due to significant renal reabsorption
  • Therapeutic plasma concentration = 1.502mg/mg as monotherapy
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16
Q

Describe the adverse effects of bromides as anti-convulsant therapy

A
  • Sedation
  • PU, PD, polyphagia
  • Diarrhoea
  • GI irritation
  • Pancreatitis
  • Caution in animals with renal insufficiency
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17
Q

Describe the interactions of bromide anticonvulsants with diet

A
  • Diet alters serum drug concentration
  • High chloride leads to excessive renal excretion
  • Prescription diets often have either low or high chloride content
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18
Q

Describe the mechanism of action of benzodiazepines as anticonvulsants

A
  • Selective action on GABAa receptors
  • BZD bind to regulatory site of receptor
  • Increase affinity of GABA to the receptor, facilitate opening of GABA activated chloride channels
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19
Q

Describe the pharmacokinetics of diazepines

A
  • Diazepam half life: 15-20h in cats

- Clanzepam half life unknown

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20
Q

Describe the adverse effects of benzodiazepines in the treatment of seizures

A
  • Acute hepatic necrosis in cats, sedation, ataxia
  • Tolerance develops so cannot be used long term
  • Withdrawal seizures
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21
Q

What is the main use of benzodiazepines with regards to epilepsy?

A

Used for status, not long term management

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22
Q

Describe the mechanism of action of imepitoin

A
  • Potentiates amplitude pf GABA evoked currents by acting at the BZD recognition site of GABAa receptor
  • Low affinity partial agonist with low intrinsic activity
  • Potentiates GABA mediated inhibitory effect of neuron by causing Cl ions to flood into neuron and suppress formation of action potential, preventing seizure activity
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23
Q

Describe the clinical applications of imepitoin

A
  • Licensed for idiopathic epilepsy in dogs, not for cluster seizures or status
  • LEss side effects than PB
  • Half life in beagles ~1.47h fasted, 195h fed
  • Rapid onset of action
  • Potentially for cats refractory to PB
24
Q

What property allows imepitoin to act as an anti-epileptic drug in spite of its short half life?

A

Slow drug absorption

25
Q

What are the main advantages of imepitoin?

A
  • No indicaton fo altering metabolism of other drugs, so can combine
  • No withdrawal seizures
  • Well tolerated in healthy and epileptic cats
  • Potentially useful to treat anxiety in normal dogs
  • Does not require plasma monitoring which saves cost
26
Q

Describe the adverse effects of imepitoin

A
  • Transient polyphagia
  • PUPD
  • Ataxia
  • Apathy
  • Diarrhoea
  • Decreased sight and sensitivity to sound
  • Prolapse nictitating membrane
  • Same as for any other antiepileptic drug acting on GABA receptor
27
Q

What is epilepsy?

A

A group of neurological disorders all of which develop periodic seizures, characterised by recurrent episodes of paroxysmal brain dysfunction due to a sudden ,disorderly and excessive neuronal discharge

28
Q

Describe idiopathic epilepsy

A
  • Genetic cause in some, others may have no known cause and no indication of structural epilepsy
  • Functional problem: chemical imbalance between excitatory and inhibitory messengers of brain
29
Q

Describe structural epilepsy (cause, diagnosis)

A
  • Epilepsy caused by identified cerebral pathology
  • Seizures are signs of disease in the brain e.g. inflammation or infection, brain tumour, brain malformation, recent or previous stroke or head trauma
  • Diagnosis based on looking for disease: MRI/CT, CSF analysis
30
Q

Name the different types of epileptic seizures

A
  • Focal
  • Generalised
  • Focal epileptic evolving to become generalised
31
Q

Define a focal epileptic seizure

A

Localised abnormal discharges of nervous system, mainly in the forebrain

32
Q

Describe the appearance of focal epileptic seizures

A
  • Epileptic seizures showing signs inficating activity which starts in a localised area in the brain
  • Will present with focal motor, autonomic or behavioural signs alone or in combination
  • May only affect one side of body
  • Behavioural changes common but vague
33
Q

Give examples of behavioural signs of focal epileptic seizures

A
  • Aggression
  • Anxiety
  • barking
  • Fly catching
34
Q

Compare simple and complex focal epileptic seizures

A
  • NB historical division
  • Simple: partial seizure, but alert and aware of surroundings
  • Complex: altered consciousness, fly catching, aggression, running, resonant vocal sounds, crouching, hiding
  • Impaired consciousness cannot be objectively investigated in animals
35
Q

What are generalised epileptic seizures

A
  • Aka primary generalised

- Affect both hemispheres and large areas of the forebrain

36
Q

Describe the clinical signs of generalised epileptic seizures

A
  • Signs due to involvement of both cererbal hemispheres from the start
  • Mainly immediate convulsions and loss of consciousness
  • Autonomic signs e.g. salivation, urination/defaecation
  • Clonic tonic convulsions
  • Prodome -> aura/preictus -> ictus -> post ictus
37
Q

Describe the prodome stage of generalised epileptic seizures

A

Subtle changes in behaviour, often overlooked, can last hours to days

38
Q

Describe the aura/preictus stage of generalised epileptic seizures

A

Anxiety, excitability, barking, lasts seconds to minutes

39
Q

Describe the ictus stage of generalised epileptic seizures

A
  • Convulsions
  • Loss of consciousness
  • Urination
  • Defaecation
  • Salivation
  • Can last seconds to minutes
40
Q

Describe the postictus stage of generalised epileptic seizures

A
  • Exhaustion
  • Aggression or increasing appetite possible
  • Minutes to days
41
Q

Describe the breed predispositions for epilepsy

A
  • Poodle
  • Dachshund
  • GSD
  • Some retrievers
  • Idiopathic more common in pure than cross
42
Q

What are status seizures?

A
  • Continuous seizure >5mins

- Or 2 or more discrete seizures within incomplete recovery of consciousness between them for 30 mins

43
Q

What is the ideal and realistic goal of anticonvulsant therapy?

A
  • Ideal: Eradication of all seizure activity

- Reality: reduction of severity, frequency and duration of seizures

44
Q

What are the indications for acute anticonvulsant therapy?

A
  • Status epilepticus
  • Cluster seizures
  • Seizures resulting from toxins (non-epileptic seizures)
45
Q

What are the indications for chronic anticonvulsant therapy?

A
  • Epilepsy

- Adjuntive in animal with brain disease

46
Q

What are the main limitations of antiepileptic drugs in veterinary?

A
  • Toxicity
  • Tolerance
  • Inappropriate pharmacokinetics due to species differences
  • Expense (drug and monitoring)
47
Q

List the indications for starting therapywith antiepileptic drugs

A

1: Identifiable structural lesion present, or prior history of brain disease/injury
2: Acute repetitive seizures or status epilepticus (ictal event >5mins)
3: >3 generalised seizures within a 24 hour period, 2 or more events in a 6 month period
4: prolonged, severe or unusual post-ictal periods

48
Q

Outline the general principles of antiepileptic therapy

A
  • Start as monotherapy
  • Start as early as possible to increase long term success
  • Do not start with doses that are too low
  • Do not change dose before reaching steady state
  • Avoid fluctuations of plasma conc due to too big dosing intervals
  • Do not stop early after seizure free intevals
  • Measure serum concentrations of any AED other than imepitoin
49
Q

What is the main life threatening effect of status epilepticus?

A

Second phase is the deep compensatory phase with reduced blood flow to the brain and oedema, causing significant damage

50
Q

Outline gabapentin as an antiepileptic drug (mech of action, adverse effects, clinical use)

A
  • Mech: voltage dependent Ca channel blockaged, enhanced GABAergic effects
  • Adverse: sedation, ataxia (less severe)
  • Clinical: refractory epilepsies, s2nd line, high therapeutic index so no serum moniioring
51
Q

Outline levetiracetam as an antiepileptic drug (mech of action, adverse effects, clinical use)

A
  • Mech: enhanced GABA effects, Ca channel blockade, reduced glutamatergic activity suggeste, SV2A receptor binding
  • Adverse: sedation, ataxia, decreased appetite, vomiting, behavioural changes
  • Clinical: refractory epilepsiies, second line, serum monitoring required
52
Q

Outline topiramate as an antiepileptic drug (mech of action, adverse effects, clinical use)

A
  • Mech: Na channel activation, enhanced GABAergic effects, reduce glutamatergic effects
  • Adverse: sedation, ataxia, weight loss
  • Clinical: refractory epielpsies, 3rd line, high therapeutic index no serum monitoring
53
Q

Outline zonisamide as an antiepileptic drug (mech of action, adverse effects, clinical use)

A
  • Mech: Na channel inactivation, CA channel blockade, GABA enhancing
  • Adverse: sedation, ataxia, decreased appetite
  • Clinical: refractor y epilepsies, 3rd line, high therapeutic index, no serum monitoring
54
Q

Outline felbamate as an antiepileptic drug (mech of action, adverse effects, clinical use)

A
  • Mech: Na channel inactivation, enhanced GABAergic effects, reduced glutamatergic activity, NMDA receptor antagonism
  • Adverse: no sedation, but liver disease in humans
  • Clinical: US can be imported through Special Treatment Authorisation
55
Q

List the main line antiepileptic drugs used in veterinary

A
  • Phenobarbital
  • K/NaBR
  • Benzodiazepines
  • Imepitoin
56
Q

List the additional (2nd and 3rd line) antiepileptic drugs that can be used in veterinary

A
  • Gabapentin
  • Levetiracetam
  • Topiramate
  • Zonisamide
  • Felbamate

NEU2 (23 decks)

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