Chapter 9 Nervous System (Anticonvulsants & Behavior Modifying Drugs) Flashcards
Seizures
Periods of excessive brain electrical activity - can appear outwardly as a variety of signs depending on what area of the brain is affected
Focal Seizures
May appear as a muscle movement of one limb or area of the body - animal does not typically lose consciousness
Generalized Seizures
Involve all of the body and often are associated with loss of consciousness
Convulsions
Seizures that manifest themselves as spastic muscle movement caused by stimulation of motor nerves in the brain of spinal cord and are characterized into 3 categories (tonic, clonic and tonic-clonic seizures)
Tonic Seizures
Characterized by increased muscle tone and stiffening of the limbs
Clonic Seizures
Rare and are characterized by rapid contraction and relaxation of the muscles
Tonic-Clonic Seizures
(Grand Mal Seizures) Characterized by rapid alternation between tonic and clonic seizures
Epilepsy
Recurrent seizures originating from the brain - characterized by sudden loss of motor control, unconsciousness, and tonic-clonic seizures of relatively short duration (2-3 minutes)
Idiopathic Epilepsy
Has no known cause (even after diagnostic workup)
Genetic Epilepsy
Associated with familial genetic or breed predisposition
Structural Epilepsy
Occurs because of the presence of brain lesions
Prodrome/Prodromal Phase
Signs that occur prior to the onset of a seizure
Status Epilepticus
Refers to the state of being in the seizure - also used to describe the condition of animals with prolonged seizure activity
Ictus
Actual seizure itself
List at least 3 secondary pathologic conditions that can cause seizure activity
Hypoxia Hypocalcemia Hypoglycemia Toxicity (strychnine, lead, xylitol) Canine Distemper Brain migration of parasites Brain tumors Hypocephalus
Postictal Phase
Post-seizure period of confusion, anxiety, exhaustion and even blindness depending on nature and location of the seizure activity within the CNS - can last for seconds or hours
Epilepsy of Unknown Origin
When the cause of epilepsy has not been identified
Anticonvulsants
Drugs used to control seizures
Hyperthermia
Elevated body temperature
Hypoxia
Low blood oxygen level
Severe acidosis
pH of blood becomes more acidic
Phenobarbital
Barbiturate - Decreases likelihood of spontaneous depolarization in brain cells and reduces the spread of electrical activity throughout the brain from this seizure focus by enhancing the action of the GABA neurotransmitter
Mixed Function Oxidases (MFOs)
Family of enzymes primarily found in the liver
Cytochrome P-450 (CYP)
The MFO enzyme involved in phenobarbital metabolism (and also many other drugs as well)
Half life of Phenobarbital in dogs
30-90 hours
Therapeutic Monitoring
Evaluating the adequacy of a dosage regimen by checking blood concentrations of a drug
Refractory
Unable to be controlled
Why do animals started on Phenobarbital often exhibit signs of sedation and ataxia shortly after beginning the drug?
Initial high concentration of phenobarbital being achieved in the blood and body tissues - this initial effect usually diminishes in 2-3 weeks after therapy has been started (if symptoms persist serum levels should be checked for potential overdose)
List 2-4 other clinical signs of Phenobarbital therapy
Polyphagia Polydipsia Polyuria Inhibitory effect on the release of the antidiuretic hormone (which causes pu/pd) Increase ALT and ALP serum levels
Phenobarbital-Induced Hepatotoxicity
Liver disease cause by a drug and is an idiosyncratic adverse reaction - can be fatal if not recognized and treated early enough
Idiosyncratic Adverse Reaction
Reaction that cannot be predicted
What is the infrequent side effect of Phenobarbital that is sometimes exhibited in dogs?
Hyperactive / more excitable instead of lethargic or sedated - idiosyncratic - often animals need to be switched to a different anticonvulsant
Approximately how many mg’s are in 1 grain
Approximately 60mg (64.8mg exactly)
True or False
Seizure conditions in horses and livestock are very easily and successfully medically managed
FALSE.
Seizure conditions in these animals often leads to humane euthanasia due to the danger of animals that large harming themselves, handlers or other animals near them when seizures occur
Induced Metabolism
Results in the concentrations of active drug in the blood decreasing as the body becomes more efficient at metabolizing the drug
What is ADH?
Anti-diuretic hormone is the hormone that usually helps the body conserve water by reducing water loss through the kidneys as urine
What does a decrease in ADH typically cause?
Polyuria and Polydipsia (compensating)
Benzodiazepine Tranquilizers for seizure control work by what method?
Controls seizures by rapidly penetrating the blood-brain barrier and enhancing the inhibitory effect of the CNS neurotransmitter GABA
GABA helps counter the effect of stimulation neurotransmitters in the brain (Acetylcholine and Norepinephrine) enhancing the GABA effect quiets the activity and excitability of the CNS
Diazepam (Valium)
Older bezodiazepine - Drug of choice for animals in status epilepticus - Not used for long term seizure control (develops tolerance very quickly)
Approximately how much Diazepam reaches systemic circulation when administered PO?
2-5% due to significant liver metabolism from the first-pass-effect - making it relatively ineffective
Why do Benzos cause ataxia and weakness?
Benzos are muscle relaxants
What effects do Benzos have on learned behaviors?
The reduce the effects of training or learned behaviors, potentially allowing for more aggressive or territorial behaviors exhibited prior to training to be exhibited again
True or False
Animals can just discontinue the use of benzos with no significant side effects
FALSE. This drug needs to be tapered!
Abrupt cessation of these drugs can lead to withdrawal signs: listlessness, decreased appetite, weight loss, fever and even recumbency
What is Distat?
Gel formulation of Diazepam available in the US for rectal administration
Midazolam
Benzodiazepine similar to Diazepam that can be used as a substitute for control of active seizures - similar significant first pass effect
Clonazepam
Adjunct drug given PO to help control seizures on a long term basis
Significant first-pass-effect
Must be administered multiple times a day to maintain therapeutic concentrations
Most animals develop a significant tolerance to these drugs within a relatively short period of time (limiting their use long-term)
Clorazepate
Adjunct drug given PO to help control seizures on a long term basis
Significant first-pass-effect
Must be administered multiple times a day to maintain therapeutic concentrations
Most animals develop a significant tolerance to these drugs within a relatively short period of time (limiting their use long term)
How do Bromides control seizures?
Mechanism of Bromides is not clearly defined, but it may act like Chloride ions to change the resting membrane potential or neurons, making them more difficult to depolarize OR may enhance the activity of GABA neurotransmitters
What is the net effect of Bromides?
A nervous system that is less likely to spontaneously discharge and produce a seizure
How are Potassium and Sodium Bromide used in seizure control?
Adjunct therapies for dogs whose seizures are not well controlled by Phenobarbital alone
It takes Potassium Bromide ___-___ months to reach a steady-state concentration
3-5 months
Steady State concentration equation
Steady State = 5 x half life
True or False
Potassium bromide has a long half life
TRUE.
Potassium bromides half life is 21-24 days in the dog
What is the most common side effect of Potassium bromide?
Vomiting - it is thought that the potassium/sodium salts directly irritate the gastric lining
True or False
Bromides are not used in cats
TRUE
Bromides can produce a respiratory syndrome that resembles Bronchial Asthma and it occurs commonly enough in cats on bromides to warrant avoiding the use of bromides for seizure control in cats
Zonisamide
Unique anticonvulsant because it belongs to the sulfa-antibiotic drug class Mechanism is unknown Used in dogs that are refractory to other anticonvulsants
Levetiracetam (Keppra)
Adjunct anticonvulsant
Mechanism not completely understood and not similar to any of the other anticonvulsants discussed
(may interfere with the release of neurotransmitters from neurons, decreasing the ability of neurons to communicate with each other across synapses)
Keppra is often advocated as
First-line drug for mild seizures in fairly low frequency due to its safety and availability
How often does Keppra need to be administered?
Every 8 hours
Can Keppra be used in both dogs and cats safely as an adjunct drug?
Yes
Gabapentin’s use as an adjunct drug for seizure control
Used in the 1990’s and early 2000’s - has fallen out of use since it is NOT as effective as Leviteracitam or Zonisamide in helping control refractory seizures in dogs and has mixed reviews on its effectiveness
Neuropathic Pain
Pain that originates not from a nociceptor but from the pain neurons themselves depolarizing and sending pain signals that confuse the brain into thinking there is a trauma or injury to the part if the body supplied by that particular pain sensory nerve
Personality, emotions and fears are the result of what?
Complex, integrated balance (or imbalance) of a wide variety of chemical neurotransmitters. Demonstrating how readily normal brain function can be altered by even minor changes in concentrations of various neurotransmitters
What are some side effects of neurotransmitter imbalances?
Clinical depression Behavior changes Old-age memory changes Self-destructive activities Anxiety/fear
Primidone
Approved drug for use as anticonvulsant for dogs - Alone it has some anticonvulsant activity but its efficacy mostly attributed to primidones metabolism of phenobarbital
Behavior modifying drugs
Change the concentrations of selected neurotransmitters in the brain with the intent of decreasing or enhancing a specific mental activity and work by one of six mechanisms
Enhancing the release of either inhibitory or excitatory neurotransmitters
One of the mechanisms of how behavior modifying drugs work
Enhancing binding (affinity) or neurotransmitters to their receptors
One of the mechanisms of how behavior modifying drugs work
Imitating the natural neurotransmitter and combining with the neurotransmitter’s receptor to stimulate the receptor (agonist effect)
One of the mechanisms of how behavior modifying drugs work
Imitating the natural neurotransmitter and combining with the neurotransmitters receptor to reduce or prevent stimulation of the receptor (antagonist effect)
One of the mechanisms of how behavior modifying drugs work
Prolonging the action of the neurotransmitter by decreasing the breakdown or slowing the rate of termination of the neurotransmitter itself
One of the mechanisms of how behavior modifying drugs work
Shortening the action of the neurotransmitter and its activity in specific regions of the brain
One of the mechanisms of how behavior modifying drugs work
Antipsychotic Drugs
Major tranquilizers and include Phenothiazine tranquilizers
Not commonly used in vet med (limited anxiolytic properties, abundant side effects and spontaneous muscle movement caused by blocking dopamine receptors in the brain)
Limbic System
Parts of the brain involved with emotion
What are antipsychotics most commonly used for in vet med?
To control learned fear responses associated with thunderstorms, fireworks and other stimuli (Acepromazine)
Increased dopamine and stimulation of receptors in the limbic system have been shown to result in what?
Abnormal behaviors
Blocking dopamine receptors in this area of the brain allows other neurotransmitters to dominate and decreases the incidence of the abnormal behaviors related to emotions
One major drawback Phenothiazine tranquilizers is…
Decreases LEARNED responses but NOT instinctual responses so treatment can sometimes uncover underlying inappropriate behaviors
Antidepressant Drugs
Mood elevating drugs used in human therapy that consist of 3 classes used in vet med
What are the 3 classes of antidepressants used in vet med?
TCA’s (Tricyclic Antidepressants), SSRI’s (Selective Serotonin Reuptake Inhibitors), and MAOI’s (Monoamine Oxidase Inhibitors)
Describe TCA’s (Tricyclic Antidepressants) Mechanism
Works by decreasing the reuptake of serotonin and norepinephrine from the synaptic cleft, which allows the neurotransmitter to accumulate and prolongs its stimulatory activity
SSRI’s (Selective Serotonin Reuptake Inhibitors Mechanism
Antidepressants derived from TCA drugs - they share the same mechanism but SSRI’s are more selective for blocking only serotonin reuptake instead of both serotonin and norepinephrine like TCA’s
MAOI’s (Monoamine Oxidase Inhibitors) Mechanism
Inhibits the enzyme monoamine oxidase (whose purpose is to catabolize serotonin, dopamine, and norepinephrine) allowing for additional accumulation of these neurotransmitters, stimulating the CNS in general
Synaptic Cleft
Space in the synapse between two communicating neurons
List 2-5 TCA drugs commonly used in vet med
- Clomipramine (Clomicalm)
- Amitriptyline
- Doxepin
- Imipramine
- Desipramine
- Nortriptyline
Reconcile
FDA approved version of Fluoxetine for use in dogs to treat separation anxiety
What are TCAs used to treat in vet med?
Generalized anxiety
Separation anxiety behaviors in dogs and cats
Reduce excessive feather plucking in birds
True of False
Evaluation of treatment with TCAs can be immediately observed within a few days of starting administration
FALSE
- TCA drugs MUST be administered every day to work appropriately
- Changes will not be observed right away because the brain biochemistry takes time to adjust to the drugs effects
- 2-4 weeks minimum for effects to be evaluated
True or False
Serotonin is a neurotransmitter identified as playing a significant role in determining mood and behavior
TRUE
What behaviors are SSRIs used to treat in vet med?
- OCD
- Anxiety
- Aggression
- Fear of people
What drug class should never be administered with SSRIs?
MAOIs - because they inhibit the breakdown of precursors for several catecholamine compounds, including serotonin
Serotonin Syndrome
- Caused by combination of excessive production and release of serotonin by MAOIs and inhibition of serotonin and removal from the synapse by SSRIs
- Potentially fatal
What symptoms are observed in a patient experiencing serotonin syndrome?
Hypertension Hyperthermia Tremors Seizures Altered mental status
What are 2 SSRI drugs used in vet med to treat separation anxiety and fear of people (specifically)
Fluoxetine
Sertraline
What is the only MAOI used to any extent in vet med?
Selegiline (Deprenyl) or Anipryl
What is Selegiline used to treat in animals?
Cushings disease
Canine Cognitive Dysfunction (old dog senility)
Anxiolytic Drugs
Drugs the lyse anxiety or decrease fear responses
Benzodiazipines work by:
Facilitating stimulation of the Gamma (y)-aminobutyric acid A (GABAA) receptors by the inhibitory neurotransmitter GABA, depressing the neurons of the CNS
What are anxiolytic drugs used to treat in vet med?
- Generalized anxiety
- Compulsive licking
- Aggression
- Canine cognitive dysfunction syndrome in geriatric dogs
Cannabidiol (CBD)
Clinical studies in humans using CBD (non-psychoactive cannabinoid derived from cannabis) for the treatment of seizures
Veterinarians cannot currently legally prescribe CBD
What are the 3 most important things that are absolutely REQUIRED when it comes to behavior modification in pets?
1) TRAINING TECHNIQUES
2) Persistence on the part of the pet owner
3) Possibility of medication to assist with the behavior modifying process
* * There is NO MAGIC BULLET drug that exists for behavior therapy ***
