Neuropharmacology Flashcards
What is epilepsy characterised by?
Recurrent episodes of paroxysmal brain dysfunction due to a sudden, disorderly, and excessive neuronal discharge.
How can we classify epilesp?
- Idiopathic
- Structural
What are the 3 possible causes of idiopathic epilepsy?
- Proven genetic background
- Suspected genetic background
- Unknown cause and no indication of structural epilepsy
What are the 2 causes of structural epilepsy?
- Epilepsy caused by identified cerebral pathology
- Unknown cause
Name the 3 types of epileptic seizures
- Focal epileptic seizure (partial)
- Generalized epileptic seizures (primary generalized seizure)
- Focal epileptic seizure evolving to become generalized (focal seizure with secondary generalization)
What is causing the seizures in idiopathic seizures?
There is no disease in the brain but the epileptic seizures are caused by a functional problem (chemical unbalance between excitatory and inhibitory messengers of the brain).
What causes the seizures with structural epilepsy?
The epileptic seizures are a sign of a disease in the brain. This disease might be a brain tumour, an inflammation or infection of the brain (encephalitis), a brain malformation, a recent or previous stroke or head trauma. Diagnosis of secondary epilepsy is based on looking for brain disease using MRI or CT-scan of the brain and CSF analysis.
How will a focal epileptic seizure present?
Will present with focal motor, autonomic or behavioural signs alone or in combination.
Fly catching
How were focal seizures once divided?
Simple: partial seizures the dog is usually alert and aware of its surroundings.
Complex: consciousness is altered, fly catching, aggression, running, resonant vocal sounds, crouching or hiding.
What is a Generalized epileptic seizure?
How do they present?
An epileptic seizure with clinical signs indicating activity involving both cerebral hemispheres from the start.
In dogs and cats the seizure presents predominantly as immediate ‘convulsions’ and loss of consciousness. Salivation, urination and/or defecation often also occur during convulsions.
What are the stages of clonic tonic convulsions?
What happens in each stage?
–Prodome : subtle changes in behaviour (often overseen; hours – days)
–(aura) or preictus: anxiety, excitability, barking; seconds - minutes
–ictus or seizure stage : convulsions (clonic – tonic), loss of consciousness, urination, defecation, salivation; seconds – minutes; > 30 minutes = status
–postictus: exhaustion, also aggression or increasing appetite: minutes - days
How many of seizures in dogs are of the generalized tonic clonic type?
80%
Name a breed prediposed to generalized tonic seizures (2)
- Poodle
- Dachsund
What happens when seizures begin in a dog?
The dog stiffens and falls; they then begin jerking movements
They are not in pain during the seizure and cannot control their bladder or bowels.
What is status epilepticus?
Continuous seizure activity lasting >5 minutes
Or
Two or more discrete seizures with incomplete recovery of consciousness between them for 30 minutes
What is a cluster seizure?
Two or more seizures occur in 24 hours, separated by normal interictal periods
Anticonvulsant Therapy:
A) What is the goal?
B) What normally happens?
A) Eradication of all seizure activity
B) Reduction of severity, frequency and duration of seizures
When would we do acute Anticonvulsant Therapy?
- Status epilepticus
- Cluster seizures
- Seziures resulting from toxins
When would we use chronic Anticonvulsant Therapy?
- Epilepsy
- Adjunctive in animal with brain disease
What is selection of Antiepileptic drugs (AED) based on?
- Efficacy
- Pharmacokinetic properties
Adverse effects
Name 3 occasions we start anti-convulsant therapy (4)
- Identifiable structural lesion present or prior history of brain disease or injury;
- Acute repetitive seizures or, status epilepticus (ictal event ≥5 minutes or ≥3 or more;
- Generalized seizures within a 24‐hour period); ≥2 or more seizure events within a 6‐month period;
- Prolonged, severe, or unusual postictal periods
How do drugs of NMDA and GABA A receptors work?
Both receptors are multimeric ligand-gated ion channels. Drugs can act as agonists or antagonists at the neurotransmitter receptor site or at modulatory sites associated with the receptor. They can also act to block the ion channel at one or more distinct sites. In the case of the GABA-A receptor, the mechanism by which ‘channel modulators’ (e.g. ethanol, anesthetic agents) facilitate channel opening is uncertain; they may affect both ligand binding and channel sites. The location of the different binding sites shown in the figure is largely imaginary, although study of mutated receptors is beginning to reveal where they actually reside.
What are the clinical applications of phenobarbital?
Broad-spectrum anticonvulsant in dogs and cats,
effective at subhypnotic doses
What is the mechanism of action of Phenobarbital (Phenobarbitone)?
- increasing the activity of the inhibitory neurotransmitter GABA
- interaction with glutamate receptors to reduce neuronal excitotoxicity?
• inhibition of voltage-gated calcium channels
(= reduced excitation)
What are the pharmacokinetics of phenobarbital?
- high bioavailability (86-96%)
- metabolized by the liver
- 25% excreted unchanged by the kidney
- half-life: 30 – 90 h in dogs, 3 – 83 h in cats,
• in dogs, half-life decreases with chronic
administration (autoinduction of its own hepatic metabolism), not observed in cats
• in dogs, variable metabolism, Beagles metabolize faster
(10% lower when given with food)
Name adverse effects of phenobarbital
•Ataxia, sedation (occasional initial hyperactivity in dogs)
•Polydipsia, polyphagia and weight gain
- Hepatotoxicity in dogs, not in cats
- Haematologic abnormalities (anaemia, thrombocytopenia, neutropenia)
- Pancreatitis in dogs when combined with bromide
- Superficial necrolytic dermatitis
- Hypoalbuminemia
Name the drug interactions of phenobarbital
- Reduced therapeutic efficacy of glucocorticoids, phenylbutazone and some anaesthetic drugs under PB
- Drugs that inhibit hepatic metabolism can induce PB toxicity (e.g. chloramphenicol)
How would you do phenobarbital therapy?
•Dogs and cats: IV administration, may be repeated
•Once seizures are controlled, maintenance
dose
•Oral therapy resumed/initiated q.12 h as soon as the animal can swallow
How should you dose phenobarbitone?
The starting dose is the only time to use weight based
dosage.
All future adjustments should be based on serum drug
concentrations.
Dose adjustment:
Oral daily dose of PB (mg) = (desired concentration/actual
concentration) x total mg PB per day
What are the clinical applications of bromide?
adjunct to PB in refractory epilepsies, recently also
as sole anticonvulsant (dogs with hepatic
dysfunction and mild seizures)
What are the benefits of using bromide?
Sodium bromide seems to be less irritating to the stomach and is often used in dogs that suffer from nausea/vomiting with the potassium salt. Sodium bromide is also preferable in dogs with certain diseases (e.g. primary hypoadrenocorticism) that cannot tolerate excess potassium. Also, some dogs object less to the taste of sodium bromide. Except for the gastrointestinal side effects (which are due to the potassium) the side effects and the effectiveness of these two preparations are identical.
What is the mechanism of action of bromide?
not completely understood, most likely an interaction with GABA-gated chloride channels – bromide competes with chloride ions, crosses the channel easier than chloride and hyperpolarizes the postsynaptic neuronal membrane
What are the pharmacokinetics of bromide?
- No hepatic metabolism
- Half-life in dogs: 24.9 d (steady state after 4-5 months)
- Half-life cats: ~ 12 d
- Distribution volume = extracellular space, but slow elimination (significant renal reabsorption)
Name adverse effects of bromide
- Sedation
- Polyuria
- Polydipsia
- Polyphagia
- Diarrhoea
Less so:
- Gastrointestinal irritation
- Pancreatitis
Why is bromide not recommended in cats?
Fatal asthma
What are the interactions of bromide?
•Dietary factors alter serum drug concentration - High-chloride diet leads to excessive renal secretion. Prescription diets have either high or low chloride content
How does imepitoin work?
potentiates the amplitude of γ -aminobutyric acid (GABA)-evoked currents by acting at the benzodiazepines(BZD) recognition site of the GABA-A receptor
Pexion targets the benzodiazepine binding site of the post-synaptic neuron, which potentiates the GABA mediated inhibitory effect on the neuron.
This causes chloride ions to flood into neuron and suppress the formation of an action potential, thus preventing seizure activity.
What are the clinical applications of Imepitoin?
- Idiopathic epilepsies in dogs (less side effects than PB), not for cluster seizures or status
- half-life (Beagle)
- Rapid onset of action
- No indication that imepitoin alters metabolism of other drugs, no withdrawal
- Well tolerated in healthy and epileptic cats
- Potentially useful to treat anxiety in dogs, but no effect on anxiety in dogs with idiopathic epilepsy
What are the adverse effects of Imepitoin?
•Polyphagia (transient)
- Polyuria
- Polydipsia
- Ataxia
- Apathy
- Diarrhoea
- Decreased sight and sensitivity to sound
- Prolapsed nictitating membrane
How do we go about treating idiopathic epilepsy?
Phenobarbital or Imepitoin
Then
Transition
Then
KBr
Then
Unlisenced
How do we go about treating structural epilepsy?
Phenobarbital
Then
KBr
Then Unlicensed
What is the mechanism of action of Benzodiazepines:
Diazepam / Clonazepam?
- Selective action on GABAA-receptors
- BDZ bind to a regulatory site of the receptor (NOT the GABA binding site)
Increase the affinity of GABA to the receptor and facilitate the opening of GABA-activated chloride channels
What are the adverse effects of Diazepam / Cloanzepam?
- Acute hepatic necrosis (cat), sedation, ataxia
- Tolerance
- Withdrawal seizures
When are Diazepam / Cloanzepam used?
Dogs and cats for status
Discuss the general principles of anti-epileptic therapy
- Start as monotherapy
- Start therapy as early as possible to increase long-term success (no strict rules though)
- Do not start with doses that are too low
- Do not change doses before reaching a steady state
- Avoid fluctuations of plasma concentrations due to big dosing intervals
- Do not stop too early after seizure free intervals
Why would you do serum concentrations of anti-epileptic drugs?
- To determine if a therapeutic value is present at the time where serum concentration is low
- To record that serum concentration fluctuates within the established therapeutic range (during steady state)
- To prevent toxic effects from occurring
To individualize therapy
Which AED do we not need to do serum concentration of?
Imepitoin
