CNS Pharmacology Flashcards
1
Q
Idiopathic epilepsy clinical picture
A
- Breed predilection: Golden Retrievers, Beagles, Labradors, GSD, etc.
- 1-5 years of age with onset of first seizure
- No interictal neurologic defects
- Diagnosis made by ruling out structural and metabolic causes
2
Q
Treatment for idiopathic epilepsy
A
- best treatment is to address the underlying cause
- SYmptomatic treatment with anticonvulsants
3
Q
When to treat with anticonvulsants?
A
- More than 1 seizure per month
- Cluster seizures
- Status epilepticus
4
Q
Therapeutic goals for idiopathic epilepsy
A
- Acute: end seizure activity as rapidly and effectively as possible without causing serious side effects
- Maintenance: to DECREASE the frequency and severity of seizures (rarely abolish)
- MUST MANAGE OWNER EXPECTATIONS
5
Q
Important properties for drugs treating acute seizure management
A
- Highly lipid soluble to rapidly reach CNS concentrations
6
Q
Look at the A & B scenario in her slides for which drug has the greatest efficacy
A
- Just do it
7
Q
What is pharmacological effect proportional to?
A
- Concentration of the drug at the site of action
8
Q
What is the concentration of the drug at the site of action proportional to?
A
- Concentration of drug in the blood
- Therapeutic plasma concentrations for anticonvulsants are known (measure concentration of the drug in the plasma or blood)
9
Q
When does a drug reach steady-state?
A
- After five half-lives
10
Q
When do you want to measure if a patient has therapeutic concentrations of a drug?
A
- After five half-lives, when it has reached steady state
11
Q
If you start phenobarbital and the half-life is 48 hours, when do you want to measure to see if you have therapeutic drug concentrations?
A
- 10 days
12
Q
Elimination half-life and therapeutic drug monitoring
A
- If frequency > half-life, you have more fluctuation and less accumulation
- This dog would be prone to having seizures
- If you have an animal with breakthrough seizures, important to do TWO plasma concentrations: one at the peak (4 hours after dosing) and one at the trough (immediately before dosing again)
13
Q
When does the peak for drug dose tend to be?
A
- About 4 hours after dosing
14
Q
When is the trough for drug dosing typically measured?
A
- Immediately before dosing again
15
Q
When do you want to take just a peak sample?
A
- If you think the dog is experiencing toxicity
- If we are worried that the concentration is too high, we will take a peak sample
16
Q
When do you have a trough sample?
A
- If you are worried that your therapy isn’t working
- E.g. for anti-convulsant medications, if you have breakthrough seizures
17
Q
Loading dose
A
- Used to get plasma drug concentrations into the therapeutic range as quickly as possible
18
Q
Who can do therapeutic drug monitoring?
A
ANYONE
19
Q
WIthdrawal of anticonvulsants
A
- Abrupt withdrawal can precipitate status epilepticus
- Client education
- MUST WEAN PATIENT OFF MEDICATION GRADUALLY, even if they haven’t seizured for a year
- Phenobarbital is not a drug that you can run out of over the weekend
20
Q
Maintenance anticonvulsants
A
- Phenobarbital
- Bromide
- Leviteracetam
- Others
21
Q
Phenobarbital drug class
A
- Barbiturate
22
Q
Phenobarbital MOA
A
- Primarily stimulates GABA-gated chloride channel (inhibitory NT)
23
Q
Metabolism of phenobarbital
A
- Cytochrome P450
- If a patient has severe liver problems, you don’t want to use this
24
Q
Phenobarbital elimination half-life
A
- Average of 48 hours but varies
- 10 days to steady state
25
Adverse drug reactions of phenobarbital
- CNS mediated
- PU/PD/PP
- Sedation and ataxia (often seen shortly after initiating therapy, but decreases after a few weeks)
26
Phenobarbital sedation
- Can happen for the first 2 months, and owners don't like it
- 90% of the time it will go away
- If you tell them up front, it may bother them less
27
Hepatic toxicity of phenobarbital
- Dose related (plasma concentrations >30 µg/mL carry higher risk)
- Induce ALP activity
- Mild to moderate increases in ALT
- ALP (5-10x baseline )
- Monitor liver enzymes and liver function
28
What can you do further to investigate if ALP is elevated on phenobarbital?
- Measure bile acids
- Hypoalbuminemia
- Look at cholesterol
29
What is the therapeutic level of phenobarbital that you should never exceed?
- 40 µg/mL
| - Really greater than 30 carries a higher risk
30
Bile acid elevation and phenobarbital
- If bile acids are elevated, do not use phenobarbital
31
Phenobarbital CYP450
- Induces CYP enzymes therefore is perpetrator of drug interactions
- Metabolizes CYP 450 enzymes therefore is "victim" of drug interactions
- Induction has a ceiling
32
Phenobarbital monitoring
- Two weeks after starting PB or after any dose change: get a PB level
- Every 6 months: CBC, serum chemistry, UA, bile acids (pre- and post), PB level
33
What is most important out of 6 month monitoring of phenobarbital levels?
- Phenobarbital level and biochemistry panel
34
Bromides
- Potassium bromide
| - Sodium bromide
35
MOA of bromides
- Traveses chloride channels resulting in hyperpolarization (inhibition) of neurons
36
Metabolization of bromide
- 100% excreted by kidney
- NOT METABOLIZED
- Good choice for a patient that has liver disease
37
Elimination half-life of KBr in dogs
- 25 days in dogs
- Takes 4 months to steady state!
- Loading doses often used to reach therapeutic concentrations faster
- TDM sample collection timing - doesn't matter
38
Elimination half life of KBr in cats
- 10 days
| - Takes 7 weeks to reach steady state in cats
39
Therapeutic level of KBr
- 1-3 mg/mL
- Can exceed therapeutic level as long as the patient is not showing signs of bromide toxicity (severe sedation and ataxia)
40
KBr toxicity
- severe sedation and ataxia
41
KBr formulation
- COMPOUNDING IS OKAY! (FDA says it's fine)
- She promotes compounding this
- Solution might be best
- Tablets and capsules available but they are hypertonic and can cause direct GI irritation and vomiting
- GIVE WITH FOOD***
42
Adverse drug reactions of Bromides
- CNS depression (ataxia, sedation)
- These occur at higher doses, during initial dosing, and DEFINITELY after loading
- PU/PD
- Polyphagia
- GI signs, pancreatitis
- NOT LIVER adverse effects
43
Bromides in cats
- Fatal respiratory distress in 30-50% of cats (AVOID)
| - If that's all you could do, you could try it
44
Drug/diet interactions with bromide
- Basically acts like chloride, so a lot of potential food an drug reactions
- Furosemide enhances excretion of bromide
- Saline (fluid therapy) enhances excretion of bromide
- Increase in dietary salt content increases excretion of bromide
45
Clin path changes with bromide
- Measured as chloride
46
Leviteracetam mechanism
- interferes with presynaptic neurotransmitter release (glutamate side)
47
Metabolism of leviteracetam
- No hepatic metabolism
48
Elimination of leviteracetam
- Primary renal elimination
49
Half-life of leviteracetam
- ~4 hours in dogs
- 5-6 hours in cats
- Ends up being three times a day dosing in dogs and cats; 2x in horses
- Also expensive
50
Which antiepileptic should be first choice?
- Doesn't really matter
- Some neurologists use different ones, which is reasonable
- Often phenobarbital or KBr but leviteracetam, zonisamide also reasonable
51
Potential side effects of leviteracetam
- Tolerance in some dogs
- Minimal side effects - sedation, vomiting, ataxia (rarely)
- Safe for liver
52
Clinical result of leviteracetam in cats
- Tolerable side effects
- Cost less of an issue
- Probably one of the better 2nd line drugs (given that there isn't likely another one)
53
Other maintenance convulsants
- There's a lot
| - Zonisamide is probably next most commonly used
54
What to do with anticonvulsants if seizures continue at unacceptable frequency and/or severity: phenobarbital?
- Increase dose of phenobarbital until either:
1. ) you reach mid 30's µg/mL
2. ) Side effects are unacceptable
55
What to do with anticonvulsants if seizures continue at unacceptable frequency and/or severity: KBr?
- Increase dose of KBr until side effects are unacceptable
56
What can you do if you max out on the first drug?
- Add a second drug
| - Don't typically take them off of the first drug unless they have severe liver toxicity
57
What route of administration is preferred for acute seizure management?
- IV preferred
- Most rapid
- Diazepam (valium)
58
What route should be avoided for acute seizure management?
- Oral route
- Delayed absorption
- Risk of injury
- Possible aspiration
59
What other routes work for acute seizure management with diazepam
- IV preferred
- IM doesn't work great (slow, erratic absorption; painful)
- RECTAL (reaches peak concentrations in systemic circulation in minutes)
- Intranasal (in babies)
60
MOA of Diazepam
- Enhance GABA activity (Inhibitory NT
61
Diazepam pharmacokinetics
1. HIGH lipid solubility
2. SHORT half-life
3. Metabolized by liver
62
High lipid solubility of diazepam
- Fast distribution to CNS
| - Makes diazpeam tx of choice for acute seizures
63
Half-life of diazepam
- Frequent administration so not a good maintenance
- Short half life
- May require CRI
64
Metabolism of diazepam
- Liver
65
Adverse drug reaction of diazepam that is universal to all species
- Sedation
66
Adverse drug reaction of diazepam unique to cats
- Idiosyncratic hepatic necrosis
- Rare but fatal
- Develops early in the course of treatment
- Small fraction of cats will develop it
67
Drug interactions with diazepam
- Not a problem clinically
68
Diazepam practical considerations
- Binding to plastic, light sensitive, precipitates
| - The more flexible the plastic, the more it sticks
69
Status epilepticus with leviteracetam with diazepam
- May help in combination
| - More helpful than placebo
70
What might be your next best bet if pharmacist won't let you give a dog with hx of seizures emergency diazepam?
- Leviteracetam
| - Can be given rectally
71
What is 3rd choice anti-convulsant drug for refractory cases?
- Propofol
- May cause seizures in cats
- Isoflurane
72
Which neurotransmitters do most behavior modifying drugs target?
- Serotonin
- Dopamine
- Norepinephrine
- GABA
73
FDA Approval of Behavior Modifying drugs
- Only 3 are FDA approved FOR DOGS
- Clomipramine
- Fluoxetine
- L-deprenyl; selegiline
74
Buspirone drug class
- Anxiolytic
75
Buspirone mechanism of actinon
- Inhibits serotonin (5-HT) synthesis by binding at presynaptic 5HT1a receptors
- may enhance dopamine activity
76
Adverse drug reactions with buspirone
- No sedative effects
| - Cats may experience increased aggression toward other cats
77
Clinical use of buspirone (we skipped)
- canine aggression
- feline spraying
- Thunderstorm phobias
- Self mutilation
78
Clomipramine and other antidepressant general use
- Treat behaviors that we (humans) find unacceptable
79
MOA of Clomipramine and other antidepressants
- Enhance activity of neurotransmitters (Serotonin 5HT and Norepinephrine NE)
- Block physiologic inactivation by reuptake pumps at the synapse
80
Clomipramine class
- Tricyclic antidepressant
| - Blocking the serotonin and noreinpehrine reuptake inhibitors
81
Therapeutic index of clomipramine
- VERY NARROW
82
Clomipramine side effects (less serious)
- Behavior changes, lethargy, GI
83
Clomipramine side effects (fatal)
- Cardiac arrhythmias
- Hypotension
- CNS depression (coma, death)
84
What type of containers should be used for any drug but especially for tricyclic antidepressants?
- CHILDPROOF CONTAINERS
85
What enzyme metabolizes tricyclic antidepressants like clomipramine?
- CYP450 enzymes
86
Drug interactions with TCAs
- Any p450 inhibitor or inducer
- Inhibitors (toxic effect): Ketoconazole, rifampin, cimetidine, fluoroquinolones
- inducers (subtherapeutic effect): phenobarbital, griseofulvin
87
Other drug interactions that may potentiate NE or 5HT
- MAO inhibitors
88
Clinical use of tricyclic antidepressants (label)
- Labeled for separation anxiety in dogs
89
Clinical use of tricyclic antidepressants (extra-label)
- Dog, cat, and horse behaviors associated with fear, aggression, OCD, self-mutilation
90
How long does it take to see effects with TCAs (e.g. clomipramine)?
-- Several weeks
- Don't give up until you've reached 2+ months
91
SSRIs potential benefit over TCA
- Less likely to cause sedation, which is an advantage in human patients
- Less likely to cause sedation
92
SSRI example
- Fluoxetine
93
SSRI mechanism
- Similar to TCAs but just specific for the serotonin reuptake pump
- Does not impact norepinephrine
94
Adverse drug reactions of SSRI (e.g. fluoxetine)
- Fewer than TCAs
95
Drug interactions with SSRI (e.g. fluoxetine)
- Can inhibit CYP 450 (not super strong)
| - Can cause serotonin syndrome
96
FDA approved use of SSRIs (e.g. fluoxetine)
- Separation anxiety
97
Off-label use of SSRIs (e.g. fluoxetine)
- lick granulomas
- Tail mutilation
- Aggression
- Psychogenic alopecia
- Other behavior disorders
98
What drug is used for canine cognitive dysfunction?
- Selegiline or l-deprenyl (anipryl)
| - Pfizer has a website to help owners diagnose it
99
MOA of selegiline
- MAO inhibitor
| - Essentially inhibits metabolism of norepinephrine, dopamine, and serotonin to their inactive metabolites
100
What is an interesting metabolite of selegiline?
- Methamphetamine
- They appear more active sometimes
- Cannot use in horses
101
Adverse effects of selegiline
- Anorexia
- Restlessness
- Repetitive movements
- Potential for human abuse
102
Drug interactions with selegiline
- Serotonin syndrome
103
Clinical use of selegiline
- Canine cognitive dysfunction
| - In humans, potential benefits in people with Alzheimer's
104
Selegiline and use in performance horses
- Considered as a drug with high abuse potential in performance horses
- Methamphetamine and amphetamine detectable in urine of horses after treatment with selegiline
105
Serotonin syndrome
- Excess serotonin in CNS
106
Risk factors for serotonin syndrome
- Any drug that potentiates serotonin in the brain
- Increases catecholamines and serotonin in the CNS
- Potentially fatal drug reaction
107
Signs associated with serotonin syndrome
- Hypertension
- Seizures
- Tremors
- Hyperesthesia
- Ataxia
- Blindness
- Vomiting/diarrhea
- Abdominal pain
- Hypersalivation
- Hyperthermia
- Death
108
Drugs that can lead to serotonin syndrome
- MAO inhibitors
- Mitoban (mange treatment)
- Amitraz
- St. John's Wort
- Ginseng
- Clomipramine or any TCA
Fluoxetine or any SSRI
- Dextromethorphan
- Selegiline
109
Treating behavioral disorders in general
- Often trial and error
| - Few retrospective studies
110
What level of improvement will you generally see with behavioral medications?
- Often improvement but not 100% improvement
111
Are newer drugs generally better?
- NOPE
| - She likes to wait
112
Are more drugs better medicine?
- Nope
113
Is any drug truly safe?
- NOPE
| - It's about the dose
