Neuropharmacology Flashcards
Compare the use of antiepileptic drugs in dogs and cats
- 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
What are the main sites of anti-epileptic drug action?
- Glutamate/NMDA (excitatory) and GABA (inhibitory) receptors
- Can agonise, antagonise or block
What is the effect of increasing the duration of chloride channel opening on neurones?
Chloride hyperpolarises membrane and therefore inhibitory to impulses, longer opening means more time for chloride to get in and hyperpolarise
Which anticonvulsatn drugs act on the GABA-a receptor?
- Imepitoin
- Barbiturates
- Bromide
Outline the mechanisms of action of phenobarbital
- Increases activity of GABA
- Interaction with glutamate receptors to reduce neuronal excitotoxicity (experimental finding)
- Inhibition of voltage-gated calcium channels which reduces excitation
Outline the pharmacokinetics of phenobarbital anticonvulsants
- 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
Describe the adverse effects of phenobarbital anticonvulsants
- 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
Outline the drug interactions of phenobarbital anticonvulsants
- 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
Discuss the use of phenobarbital in the therapy for status epilepticus
- 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
Outline the use of phenobarbital for the long term treatment of epilepsy in dogs and cats
- 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
What action is indicated if the serum phenobarbital levels are >30ug/ml and are having .1 seizure/3 months?
Startpotassium bromide
What are the clinical appplications of potassium bromide in the treatment of epilepsy?
- Adjunct to phenobarbital in refractory epilepsies
- Sole anti-convulsant in dogs with hepatic dysfunction and mild seizures
- Mostly superseded by imepitoin and phenobarbital
Discuss the use of sodium bromide in the treatment of epilepsy in dogs
- 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
Describe the mechanism of action of bromide as an anti-convulsant
- 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
Describe the pharmacokinetics of bromides for anti-convulsant therapy
- 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
Describe the adverse effects of bromides as anti-convulsant therapy
- Sedation
- PU, PD, polyphagia
- Diarrhoea
- GI irritation
- Pancreatitis
- Caution in animals with renal insufficiency
Describe the interactions of bromide anticonvulsants with diet
- Diet alters serum drug concentration
- High chloride leads to excessive renal excretion
- Prescription diets often have either low or high chloride content
Describe the mechanism of action of benzodiazepines as anticonvulsants
- 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
Describe the pharmacokinetics of diazepines
- Diazepam half life: 15-20h in cats
- Clanzepam half life unknown
Describe the adverse effects of benzodiazepines in the treatment of seizures
- Acute hepatic necrosis in cats, sedation, ataxia
- Tolerance develops so cannot be used long term
- Withdrawal seizures
What is the main use of benzodiazepines with regards to epilepsy?
Used for status, not long term management
Describe the mechanism of action of imepitoin
- 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
Describe the clinical applications of imepitoin
- 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
What property allows imepitoin to act as an anti-epileptic drug in spite of its short half life?
Slow drug absorption
What are the main advantages of imepitoin?
- 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
Describe the adverse effects of imepitoin
- 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
What is epilepsy?
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
Describe idiopathic epilepsy
- 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
Describe structural epilepsy (cause, diagnosis)
- 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
Name the different types of epileptic seizures
- Focal
- Generalised
- Focal epileptic evolving to become generalised
Define a focal epileptic seizure
Localised abnormal discharges of nervous system, mainly in the forebrain
Describe the appearance of focal epileptic seizures
- 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
Give examples of behavioural signs of focal epileptic seizures
- Aggression
- Anxiety
- barking
- Fly catching
Compare simple and complex focal epileptic seizures
- 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
What are generalised epileptic seizures
- Aka primary generalised
- Affect both hemispheres and large areas of the forebrain
Describe the clinical signs of generalised epileptic seizures
- 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
Describe the prodome stage of generalised epileptic seizures
Subtle changes in behaviour, often overlooked, can last hours to days
Describe the aura/preictus stage of generalised epileptic seizures
Anxiety, excitability, barking, lasts seconds to minutes
Describe the ictus stage of generalised epileptic seizures
- Convulsions
- Loss of consciousness
- Urination
- Defaecation
- Salivation
- Can last seconds to minutes
Describe the postictus stage of generalised epileptic seizures
- Exhaustion
- Aggression or increasing appetite possible
- Minutes to days
Describe the breed predispositions for epilepsy
- Poodle
- Dachshund
- GSD
- Some retrievers
- Idiopathic more common in pure than cross
What are status seizures?
- Continuous seizure >5mins
- Or 2 or more discrete seizures within incomplete recovery of consciousness between them for 30 mins
What is the ideal and realistic goal of anticonvulsant therapy?
- Ideal: Eradication of all seizure activity
- Reality: reduction of severity, frequency and duration of seizures
What are the indications for acute anticonvulsant therapy?
- Status epilepticus
- Cluster seizures
- Seizures resulting from toxins (non-epileptic seizures)
What are the indications for chronic anticonvulsant therapy?
- Epilepsy
- Adjuntive in animal with brain disease
What are the main limitations of antiepileptic drugs in veterinary?
- Toxicity
- Tolerance
- Inappropriate pharmacokinetics due to species differences
- Expense (drug and monitoring)
List the indications for starting therapywith antiepileptic drugs
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
Outline the general principles of antiepileptic therapy
- 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
What is the main life threatening effect of status epilepticus?
Second phase is the deep compensatory phase with reduced blood flow to the brain and oedema, causing significant damage
Outline gabapentin as an antiepileptic drug (mech of action, adverse effects, clinical use)
- 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
Outline levetiracetam as an antiepileptic drug (mech of action, adverse effects, clinical use)
- 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
Outline topiramate as an antiepileptic drug (mech of action, adverse effects, clinical use)
- 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
Outline zonisamide as an antiepileptic drug (mech of action, adverse effects, clinical use)
- 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
Outline felbamate as an antiepileptic drug (mech of action, adverse effects, clinical use)
- 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
List the main line antiepileptic drugs used in veterinary
- Phenobarbital
- K/NaBR
- Benzodiazepines
- Imepitoin
List the additional (2nd and 3rd line) antiepileptic drugs that can be used in veterinary
- Gabapentin
- Levetiracetam
- Topiramate
- Zonisamide
- Felbamate
